Modulation of glutamate release from hippocampal mossy fiber nerve endings by arachidonic acid and eicosanoids.

Arachidonic acid has been implicated in normal synaptic transmission processes, including those related to the development of hippocampal long-term synaptic potentiation. Hippocampal mossy fiber (MF) synaptosomes were used to investigate the role of arachidonate in the evoked accumulation of presynaptic Ca2+ and the release of endogenous glutamate, since these nerve terminals express long-term potentiation and selectively release glutamate as the excitatory transmitter. It was demonstrated that membrane depolarization evoked the accumulation of Ca2+, the release of glutamate, and the production of unesterified arachidonic acid. These events may be functionally related, since exogenous arachidonate and phospholipase A2 activation mimicked the effects of depolarization on Ca2+ availability and glutamate release, while secretion processes were attenuated in the presence of phospholipase A2 inhibitors. In addition, pretreatment of the nerve terminals with arachidonate or melittin allowed for the facilitated release of glutamate in response to a subsequent depolarizing stimulus. Inhibition of cyclooxygenase or lipoxygenase activities also potentiated presynaptic responses to membrane depolarization. In contrast, 12-lipoxygenase products attenuated the depolarization-evoked accumulation of intraterminal free Ca2+ and glutamate release. It is suggested that arachidonic acid acts as a positive modulator of mossy fiber secretion processes, including those involved in the increased glutamate release required for the induction of long-term potentiation, while 12-lipoxygenase metabolites provide negative feedback signals designed to limit neurotransmitter secretion.


Reciprocal regulation of fatty acid release in the brain by GABA and glutamate.

Several model systems have been used to test the hypothesis that the release of FFA in the brain is regulated by depolarization of neurons. This FFA release is likely the result of the activation of phospholipase A2. The increased neuronal activity that occurs due to synchronous depolarization during seizures causes activation of phospholipase A2. Decreasing neuronal activity by administering the anxiolytic, diazepam, appears to decrease the activity of phospholipase A2. The GABA antagonist, bicuculline, which causes depolarization by negating the hyperpolarizing tone imposed on neurons by GABA, causes FFA release in synaptosomes and in neurons in tissue culture. Likewise, the glutamate agonist, kainic acid, which depolarizes neurons by opening sodium channels, increases the activity of phospholipase A2. PC-specific phospholipase C, another enzyme important in the generation of the second messenger, DG, is also activated by depolarization. Several important questions remain to be answered. The site of FFA release, in terms of the pre-vs. postsynaptic membrane, is not clear, although the experiments with synaptosomes support the hypothesis that activation of phospholipase A2 may be an important regulator of presynaptic events. This idea has also been suggested by studies on the phenomenon of long-term potentiation, where free 20:4 or its metabolites may be involved in presynaptic facilitation of neurotransmitter release (Freeman et al., 1990; Massicotte et al., 1990; Williams et al., 1989; also see Dorman, this volume). The activation of the PI cycle and subsequent stimulation of protein kinase C may be a postsynaptic event important in the integration of inputs at the dendrite and soma or a presynaptic event involved in the modulation of neurotransmitter release (Taniyama et al., 1990; El-Fakahany et al., 1990; also see Nishizuka, this volume). Therefore the stimulation of a PC-specific phospholipase C, which is capable of generating large amounts of DG over a prolonged period of time (Exton, 1990; Martinson et al., 1990; Diaz-Laviada et al., 1990), could occur at either site. Another important question is the role of FFA and DG in affecting cell-cell signaling events, particularly with regard to ion fluxes. Modulation of an acetylcholine-linked K+ channel in the heart by FFA and their oxygenation products has been reported (Kim and Clapham, 1989). The cardiac muscarinic receptor is linked to a hyperpolarizing K+ channel via a G protein.(ABSTRACT TRUNCATED AT 400 WORDS)


[Pulmonary embolism caused by liver tissue].

Embolism of hepatic tissue to the lung in coincidence with severe injury to the liver is a rare complication. We report on a case of a 22-year old motor-cyclist who was involved in a traffic accident and incured a blunt abdominal trauma. The autopsy revealed a crushed right hepatic lobe. Careful microscopically investigations of the lungs showed multiple small emboli composed primarily of hepatic tissue in pulmonary arterial branches.


[Fat embolism and fracture, a review of the literature].

The reasons of fat embolism as well as the following fat embolism syndrome are most likely long bone fractures, especially if the femur is participated. On the other hand there are cases, where a severe concussion of the entire body caused fat embolism. But it is also supposed, that intramedullary reaming as well as the insertion of knee- and hip-prostheses could be a releasing factor, because the applicated pressure on the medullary canal can cause a fat release in the systemic blood system. The morbidity depends on age and fracture, which is on fractures between 0.9 and 2%. The most affected group are people between 18 and 28 years of age. The fat embolism is manifesting at 46-60% of the patients in the first 24 hours and over 90% of the patients are affected in the first three days. If you look at the metabolic changes, you will find shortly after the fracturing process a rapid increase of free fatty acids (FFA), as well as an increase of the plasmatic enzyme levels (lipase, GPT, GOT, GLDH, LDH, etc.), catecholamines and glucocorticoids. In order to discuss the pathogenesis in a fairly complete way, you have to take different theories into consideration, because several parallel running processes--which are influencing each other--are leading to the syndrome. Infloating theory: Proceeding on the assumption that contents of the bone marrow are floating out of the fracture gap into the venous system and are leading to fat embolism in the lungs. Lipase theory: You can diagnose in 50-70% of the fracture patients an increase of the lipase level, which is correlating with the manifestation of the fat embolism. The lipase releases fat from the body depositories in addition to the fat, who is coming out of the fracture gap. Shock and coagulation theory: During shock the microcirculation is decelerated, the blood viscosity is increased and the suspension stability of the cellular blood components is decreased, which is leading to the sludging phenomenon. So the capillaries of the lungs and the brain are a kind of sludge filter of the blood, that is changed in its suspensions stability. Free fatty acids theory: Primary existing capillary defects are reasonable caused by free fatty acids (FFA). They are hydrolyzed of the neutral fats and are histotoxic for the walls of the blood vessels.(ABSTRACT TRUNCATED AT 400 WORDS)


[Thromboembolism complications in orthopedics and traumatology. A prospective study of 598 operated patients].

From 1.10.-31.12. 1989, 598 patients who underwent orthopaedic surgery in the Staatliche Orthopädische Klinik were examined by a pre-, intra- and postoperative questionnaire up to 3 months from the date of operation. All patients were separated into 4 groups corresponding to the calculated risk and duration of the operation. 46 patients in Group I, who underwent minor surgery, received 3 x 5000 I.E. Heparin subcutaneously. 243 patients in Group II received besides 3 x 5000 I.E. Heparin, 500 ml HAES 6% preoperatively. They underwent operations of greater intensity and duration at the upper and lower extremities. 302 patients of Group III were given 3 x 5000 I.E. heparin and 500 ml 6% dextrane 60 preoperatively because of severe operations (pelvis, hip). 7 high-risk patients received apart from 3 x 5000 I.E. Heparin subcutaneously 500 ml 6% dextrane 60 preoperatively and 250ml 10% dextrane 40 postoperatively for 5 days. In Group I we had 2.2% thromboembolic complications, whereas in Group II 1.7% and in Group III 3.3% complications with thrombosis and pulmonary embolism occurred. This was proved by pulmonary scintigraphy and phlebography. No such complications were seen in Group IV. The total incidence of deep vein thrombosis was 2.0% and of pulmonary embolism 0.5%. These results show the importance of preoperative risk check and individual prophylaxis of thromboembolic complications in orthopaedic and traumatologic surgery.


[Importance of the Segond avulsion fracture as a sign of complex ligamentous knee injury].

The Segond fracture is a small bony avulsion of the lateral tibial condyle. A study of 11 patients, treated between 1986 and 1990, points out the importance of this injury. In our series all patients showed an additional major ligamentous damage. 10 patients had an injury of the anterior cruciate ligament. This harmless "lateral capsular sign" on the standard x-ray of the knee-joint should give reason for further diagnostic measures, mainly the arthroscopic examination.


[Importance of measuring stability and function in knee ligament surgery].

To compare results in knee ligament surgery between different surgeons and between different centers, too, is difficult. We investigated if an improvement can be achieved by using easy to handle methods of measurement. The long-term results of 180 patients who underwent ACL surgery between 1983 and 1986 (n = 191) were evaluated. For international comparing of our results we used the scoring of the OAK (Orthopädische Arbeitsgemeinschaft Knie). In addition stability was measured by use of the KT-1000 arthrometer and function by "one leg hop for distance". Together with different usual functional tests those two methods were investigated for being comparable, practicable, and relevant. We found that both measurements came up to these conditions. We succeeded in rating the patients' result by measuring KT-1000 and one leg hop for distance. Examination after knee ligament surgery has to contain these two parameters for international comparison.


[Expert assessment of so-called post-thrombotic syndrome in compulsory accident insurance].

Expertising a late damage after thrombosis requires most careful investigation of the findings, a detailed description of the damage, and a definition of the impairment of functions. This is imperative for arriving at an administrative decision to implement the conclusions arrived at by the expert without committing a legal error by such implementation. Estimation and determination of the damage and of awarding a reasonable compensation requires a detailed consideration of the circumstances of each case and observance of the legal principle of equal rights.


[A simple method for repositioning metatarsal fractures].

Because of small direct contact to the fracture fragments reduction of metatarsal fractures can be achieved only indirectly by applying traction to the toes. In this article a method for simple direct manipulation of the distal main fragment of metatarsal fractures is described: A K-wire is drilled in dorsi plantar direction across the head of the fractured metatarsal and mounted on a traction bow. In this manner the distal fracture fragment can be moved in all directions and placed exactly onto the proximal fragment. All 8 patients with multiple metatarsal fractures could be treated by closed reduction and percutaneous pinning. The described method allows simple and precise reduction of metatarsal fractures, reduced x-ray exposure of the surgeon's hand by short operation times, and manipulation for fracture reduction outside the x-ray beam.


[Accidents with bicycles and motorcycles. The injury pattern, costs, and possibilities for prevention].

This review comprises all 641 patients subjected to inpatient treatment in 1976, 1980 and 1984 at the Basel district hospital after accidents involving bicycles or motorcycles. A study of the case histories--supplemented by phone conversations--yielded the following results: Accidents involving bicycles or motor-driven bicycles were seen in all age groups, but motorcycle accidents occurred exclusively among the younger generation. Whereas motorcycle accidents mostly happened during joyrides, accidents with bicycles or mobikes mainly occurred on the way to work. The incidence rate was highest during summertime and in the rush hours at noon or in the evening. Motorcycle accidents resulted in more severe injuries, longer hospitalisation, longer periods of disability and higher costs than bicycle or mobike accidents the latter being mainly characterised by mostly slight head injuries and the former by injuries of the legs and arms.


[Gunshot injuries--their incidence and surgical problems].

Since the time when firearms became readily available, surgeons have had to deal with the gunshot wounds which have presented for treatment. In middle europe, in peace time, gunshot wounds account for only a small percentage of the total number of trauma cases seen. This is reflected in our patient census in which a mere 0.065% of cases were associated with such injuries. It would seem that a relevant knowledge of the technical and physical attributes of firearms is important. With this understanding, the formulation of an according treatment plan is made easier. Gunshot wounds are frequently not confined to the extremities. The trauma surgeon, who largely deals with limb injuries, is now confronted with an increasing number of chest and trunk wounds and their particular therapeutic consequences.


Selective dopamine-1 receptor agonist augments regional myocardial blood flow: comparison of fenoldopam and dopamine.

A new class of vasodilators exhibiting selective dopamine-1 receptor agonist activity is being introduced into clinical practice. Inasmuch as various vasodilators either augment or decrease myocardial blood flow ("coronary steal") depending on their pharmacologic action, the goal of this study was to assess the effects of fenoldopam (selective dopamine-1 receptor agonist) and dopamine (nonselective dopamine-1 receptor agonist) on regional myocardial blood flow in the presence of coronary occlusion. Accordingly, in 16 dogs anesthetized with pentobarbital, the left anterior descending coronary artery was occluded. Cardiovascular and renal hemodynamic effects were measured before and after intravenous infusion of renal equipotent doses of either fenoldopam (n = 9, 0.1 micrograms/kg/min) or dopamine (n = 7, 1 micrograms/kg/min). Both fenoldopam and dopamine caused a significant and comparable increase in renal blood flow. Fenoldopam but not dopamine significantly decreased the calculated peripheral vascular resistance and subsequently increased cardiac output. Dopamine had no effect on regional myocardial blood flow. In contrast, fenoldopam augmented transmural myocardial blood flow in normal (from 114 +/- 10 to 188 +/- 27 ml/100 gm/min, p less than 0.02) and ischemic border myocardium (from 45 +/- 5 to 68 +/- 11 ml/100 gm/min, p less than 0.03 and p less than 0.02 vs dopamine). There was a significant increase in blood flow to both the endocardial and epicardial layers of normal and ischemic border myocardium. These changes were accompanied by a significant reduction in coronary vascular resistance in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)


CD4 status and P24 antigenemia. Are they useful predictors of survival in HIV-infected children receiving antiretroviral therapy?

To determine the relationship between CD4 status and the P24 antigen level and survival in children infected with the human immunodeficiency virus. Cohort, case-control. Clinical Center at the National Institutes of Health, Bethesda, Md. One hundred forty-seven children infected with the human immunodeficiency virus enrolled in antiretroviral therapy protocols at the National Cancer Institute were reviewed and the relationships between CD4 counts, P24 antigenemia, and death were analyzed. None. The presence of a very low CD count, less than 21% of the lower limit of normal values for age (equivalent to 0.05 x 10(9)/L in an adult), was associated with a significantly increased risk of death within 2 years. Although the risk of death was highest for children with CD4 counts below this level and who had detectable P24 antigen levels, P24 antigenemia by itself contributed little to the prognostic value of the CD4 count alone. However, it was also notable that a group of children with low CD4 counts also experienced prolonged survival. The association between low CD4 counts and death suggests that the age-adjusted CD4 count should be used as a marker to guide therapeutic intervention. At the same time, the presence of a very low CD4 count alone should not be considered a reason for therapeutic nihilism.


Adrenergic and nonadrenergic cotransmitters inhibit insulin secretion during sympathetic stimulation in dogs.

Vascular and biochemical responses to pancreatic sympathetic nerve stimulation were investigated in the blood-perfused pancreas of anesthetized dogs. During sympathetic nerve stimulation, pancreatic perfusion pressure and norepinephrine release increased, whereas insulin secretion decreased. The latter effect did not occur after pretreatment with the alpha 2-adrenoceptor antagonist idazoxan. However, after beta-adrenoceptor blockade with propranolol, neither single administration of idazoxan nor the alpha 1-adrenoceptor antagonist prazosin or glibenclamide, a blocker of ATP-modulated K+ channels, affected the decrease in insulin secretion induced by sympathetic nerve stimulation. In contrast, the combination of glibenclamide with idazoxan markedly antagonised the decrease in insulin release evoked by the latter procedure. After depletion of catecholamines with syrosingopine, the stimulation-induced inhibition of insulin secretion remained unchanged even though no increases in pancreas perfusion pressure or norepinephrine release were observed. In this preparation, glibenclamide inhibited the decrease in insulin release by 50%. In animals pretreated with the neuronal blocking agent bretylium, all of the responses to sympathetic nerve stimulation were abolished. These results indicate that the inhibitory effects exerted by the sympathetic nervous system on insulin secretion are mediated not only by the classical neurotransmitter norepinephrine acting on alpha 2-adrenoceptors but also by a nonadrenergic cotransmitter that can maintain transmission under conditions of catecholamine deficiency. The postulated nonadrenergic cotransmitter(s) acts, at least partly, via the opening of ATP-modulated K+ channels blockable by glibenclamide, and its release can be prevented by the neuronal blocking agent bretylium.


Effects of erythromycin in the dog upper gastrointestinal tract.

The effects of erythromycin on motor and electrical behavior of the antrum, pylorus, and duodenum were determined in chronically instrumented, awake dogs. Erythromycin infusion resulted in an abrupt, powerful increase in motility. The motility index increased 18-fold in the antrum, 15-fold in the pylorus, and 8-fold in the duodenum. Bradyarrhythmia with a 30% decrease in slow-wave frequency occurred in all animals. Retrograde giant contractions in association with retching and vomiting occurred in 88% of the dogs. Neostigmine was less potent than erythromycin in increasing motility. Hexamethonium given intra-arterially during erythromycin infusion abolished motility for 7.2 +/- 2.9 min and intra-arterial atropine did so for 51 +/- 25 min. Hexamethonium or atropine restored the electrical slow-wave frequency. The results provide evidence that erythromycin action involves cholinergic pathways including ganglionic transmission.


Guanylate cyclase inhibitors: effect on inhibitory junction potentials in esophageal smooth muscle.

Electrical field stimulation (EFS) of nerves intrinsic to the opossum lower esophageal sphincter (LES) produces LES relaxation, an increase in its guanosine 3',5'-cyclic monophosphate (cGMP) content, and hyperpolarization of its circular muscle membrane potential difference. Activation of esophageal nerves produces an analogous hyperpolarization of the circular esophageal smooth muscle. These studies test the hypothesis that cGMP is an intracellular mediator of this hyperpolarization. The transmembrane potential difference of circular smooth muscle cells was recorded with glass microelectrodes. Nerve-mediated smooth muscle hyperpolarization was evoked by EFS (1 ms, 50 V pulses). Forskolin, an activator of adenylate cyclase, and sodium nitroprusside, an activator of guanylate cyclase, produced hyperpolarization. Cystamine and methylene blue, inhibitors of guanylate cyclase, blocked the hyperpolarization elicited by sodium nitroprusside, but not that by forskolin. Both also reversibly abolished the hyperpolarization evoked by EFS. Membrane-permeable derivatives of cGMP produced a concentration-dependent hyperpolarization. These data support the hypothesis that cGMP is an intracellular mediator of nerve-induced esophageal smooth muscle hyperpolarization.


Guanylate cyclase inhibitors: effect on tone, relaxation, and cGMP content of lower esophageal sphincter.

Relaxation of the lower esophageal sphincter (LES) results from activation of its intrinsic innervation. This relaxation is associated temporally with an increase in the guanosine 3',5'-cyclic monophosphate (cGMP) content of the muscle. This study tests the hypothesis that variations in the production of cGMP mediate resting LES tone and nerve-induced relaxation. We examined the effects of guanylate cyclase inhibitors, such as cystamine and methylene blue (MB), on the resting tone, resting membrane potential, electrical field stimulation (EFS)-induced relaxation, and cGMP content of circular smooth muscle from the LES of the opossum. Strips of sphincter muscle were placed in a tissue bath and stretched to 125% resting length. Both cystamine and MB increased the resting tone of LES muscle in a concentration-dependent manner (EC50 = 1.1 +/- 0.2, n = 12, and 1.6 +/- 0.4 mM, n = 10, respectively). The increase in tone by cystamine was not blocked by tetrodotoxin, atropine, or propranolol. Cystamine (1 mM) did not alter the resting membrane potential of circular muscle cells of the LES. The removal of extracellular Ca2+ by the addition of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA, 4 mM) and nifedipine (1 microM) shortened the duration but not the amplitude of the response to cystamine. Pretreatment with caffeine (5 mM) in the presence of EGTA and nifedipine to deplete intracellular Ca2+ stores blocked the increase in tone by cystamine. Cystamine (1 mM) failed to inhibit LES relaxation induced by EFS. Carbachol, at a concentration that induced a similar increase in base-line tone, attenuated the nerve-mediated relaxation. Cystamine did not alter basal cGMP levels, but inhibited the rise in cGMP induced by EFS. The data indicate that cystamine increases LES tone but does not inhibit EFS-induced relaxation, even though it inhibits EFS-induced increases in cGMP content. The increase in tone is dependent on the presence of intracellular Ca2+ stores.


Pulmonary arterial hypoxic contraction: signal transduction.

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)


Selective induction of intercellular adhesion molecule-1 by interferon-gamma in human airway epithelial cells.

To evaluate the factors controlling migration of leukocytes into pulmonary airway epithelium, we determined the biochemical mechanisms responsible for the regulation of intercellular adhesion molecule-1 (ICAM-1) expression on cultured monolayers of human tracheal epithelial cells (HTECs) or SV40 virus-transformed human bronchial epithelial cells (BEAS-2B). Validation experiments with human umbilical vein endothelial cells (HUVECs) demonstrated little detectable ICAM-1 expression on unstimulated cells or on cells incubated with interferon-gamma (IFN-gamma), but HUVEC monolayers responded to interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) with significant increases in ICAM-1 and ICAM-1-dependent adherence of polymorphonuclear leukocytes (PMNs). HTEC monolayers also exhibited no significant basal ICAM-1 expression but, in contrast to HUVEC monolayers, had marked increases in ICAM-1 expression and ICAM-1-dependent PMN adherence only after incubation with IFN-gamma (and not after IL-1 beta or TNF-alpha) treatment. BEAS-2B cells also exhibited relatively selective IFN-gamma stimulation of ICAM-1 expression and ICAM-1-dependent PMN adherence but (like late passage HTEC) showed significant basal ICAM-1 expression. Differences in IFN-gamma effect on ICAM-1 levels between HUVEC and HTEC monolayers were not due to differences in number or responsiveness of IFN-gamma receptors, because both cell types exhibited a similar number of receptors and other IFN-gamma-dependent responses of HUVECs remained active. In all analyses, ICAM-1 mRNA levels correlated closely with detection of ICAM-1 on the cell surface.(ABSTRACT TRUNCATED AT 250 WORDS)


Renal receptors for atrial and C-type natriuretic peptides in the rat.

Receptors for alpha-atrial natriuretic peptide (alpha-ANP) and C-type natriuretic peptide [CNP-(1-22)] were quantified in kidneys from adult Wistar rats by in vitro autoradiography. 125I-labeled alpha-ANP (100 pM) bound reversibly to glomeruli, outer medullary vasa recta, and inner medulla with an apparent dissociation constant (Kd) of 3-6 nM. The presence of 10 microM des-[Gln18,Ser19,Gly20,Leu21,Gly22]ANP-(4- 23) (C-ANP), a specific ligand of the ANPR-C subtype of alpha-ANP receptor, inhibited approximately 50% of the glomerular binding of 125I-alpha-ANP, and this moiety of glomerular binding was also inhibited by CNP-(1-22) with an apparent inhibitory constant (Ki) of 10.47 +/- 7.59 nM. C-ANP and CNP-(1-22) showed little affinity for the medullary binding sites of alpha-ANP. 125I-[Tyr0]CNP-(1-22) (110 pM) bound solely to glomeruli and was competitively displaced by increasing concentrations of [Tyr0]CNP-(1-22) with an apparent Kd of 1.42 +/- 0.48 nM. Binding of increasing concentrations (25 pM to 1 nM) of 125I-[Tyr0]CNP-(1-22) in the presence or absence of 1 microM [Tyr0]CNP-(1-22) also demonstrated a high affinity (Kd of 0.41 +/- 0.07 nM) for the glomerular binding of 125I-[Tyr0]CNP-(1-22). Bound 125I-[Tyr0]CNP-(1-22) could be displaced by excess alpha-ANP and excess CNP-(1-22), both with high affinities. The glomerular binding of 125I-[Tyr0]CNP-(1-22) was also prevented by 10 microM C-ANP. Guanosine 3',5'-cyclic monophosphate produced by isolated glomeruli was measured by radioimmunoassay.(ABSTRACT TRUNCATED AT 250 WORDS)


Dynorphin, naloxone, and overflow of norepinephrine during cardiac nerve stimulation in dogs.

The effects of dynorphin-(1-9) and naloxone on norepinephrine (NE) overflow and myocardial contractility were determined during left cardiac nerve stimulation in the anesthetized dog. Stimulation-induced increases in NE overflow from the left ventricle were monitored during control conditions, during infusion of dynorphin-(1-9), during dynorphin plus naloxone, and after naloxone alone. Four electrical stimulations were applied for 1 min at 20-min intervals. Repeated left cardiac nerve stimulations (control group) reduced stimulated NE overflow 50-60% by 1 h. If stimulations were only conducted at 0 and 1 h, the decline in NE overflow was not observed. Intracoronary dynorphin (2 nmol.min-1.kg-1, 20 min) lowered the stimulation-induced increase in NE overflow further and reduced first time derivative of left ventricular pressure (dP/dt) and myocardial O2 consumption responses. Naloxone (100 micrograms/kg) prevented all of the dynorphin-mediated effects. When given alone, naloxone increased both NE overflow and left ventricular dP/dt during stimulation and prevented or significantly delayed the gradual decline in overflow observed in stimulated controls. A postjunctional effect of dynorphin was evaluated by comparing contractile responses to the intracoronary infusion of NE before and during dynorphin. Dynorphin did not alter contractile function at rest or during NE infusion. In summary, dynorphin-(1-9) depresses nerve stimulation-induced, cardiac NE overflow, and myocardial contractility in a naloxone-reversible fashion. Alone, naloxone appears to regulate stimulated NE overflow through a qualitatively different mechanism. Endogenous opioids may normally moderate myocardial function during cardiac nerve stimulation by regulating junctional NE concentrations through a combination of effects on NE release and/or its subsequent reuptake.


Lower brain stem controls cardiac ANF secretion.

The purpose of these studies was to investigate whether the central nervous system (CNS) can modulate the plasma level of atrial natriuretic factor (ANF). In anesthetized, spontaneously breathing rats, electrical stimulation was stereotaxically applied bilaterally to four medullary nuclei: 1) the rostral nucleus of the solitary tract (rNTS), 2) the intermediate portion of the NTS (iNTS), 3) the ventrolateral nucleus ambiguus (NA) 0.3 mm rostral to obex, and 4) the rostral ventrolateral medulla (RVL). Electrical stimulation of the rNTS and RVL caused a 55 +/- 18% (P less than 0.025, n = 6) and 187 +/- 80% (P less than 0.001, n = 5) increase in plasma ANF, respectively, compared with baseline (56-88 pg/ml), whereas sham stimulations had no effect on plasma ANF release. In contrast, electrical stimulation of the iNTS and the NA elicited a 35 +/- 6 (P less than 0.01, n = 7) and 31 +/- 6% (P less than 0.05, n = 5) decrease in plasma ANF, respectively. In artificially ventilated rats, unilateral electrical stimulation of the RVL induced a 94 +/- 39 (left RVL, n = 6, P less than 0.01) and 186 +/- 68% (right RVL, P less than 0.01, n = 5) increase in plasma ANF over baseline. Unilateral microinjection of L-glutamate into RVL also resulted in a 81 +/- 23% (n = 9, P less than 0.01) increase in plasma ANF compared with baseline and vehicle control injections. These results suggest that activation of the central sympathetic system potently stimulates the secretion of cardiac ANF.


Pituitary-adrenal responses to head-up tilt in humans: effect of H1- and H2-receptor blockade.

Effects of the histamine H1- or H2-receptor antagonists mepyramine (Mep) and cimetidine (Cim) on neuroendocrine and cardiovascular responses to 50 degrees head-up tilt were evaluated in seven human males. Central hypovolemia was characterized by two phases. The first is a normotensive phase with increases in heart rate (HR), total peripheral resistance (TPR), and decrease in cardiac output. Plasma adrenocorticotropic hormone, beta-endorphin, cortisol, catecholamines, and renin activity increased moderately. Normotension lasted 39 +/- 7 min during infusion of saline but was reduced by Mep [18 +/- 3 min, F(2,12) = 9.60, P less than 0.01] and was unaffected by Cim (44 +/- 4 min). The second is a hypotensive phase associated with presyncopal symptoms (hypovolemic shock) and decreases in HR and TPR and a further increase in pituitary-adrenal and sympathoadrenal activity. Decreases in mean arterial pressure and TPR were augmented by Mep, which inhibited release of norepinephrine. Cim inhibited epinephrine release without affecting the development of hypovolemic shock. It is concluded that histaminergic mechanisms are involved in activation of the sympathoadrenal system but not in the pituitary-adrenal axis during central hypovolemia in humans.


Adrenergic regulation of neonatal brown fat adenylyl cyclase and Gs alpha activity.

Norepinephrine (NE)-stimulated adenylyl cyclase (AC) activity increases during the perinatal period in rat brown adipose tissue (BAT), and this increase is associated with changes in the activities of both the catalytic subunit (C) and Gs alpha, the GTP-binding protein that mediates activation of C. The present study examined the role of the sympathetic nervous system in the postnatal sensitization of AC. The sympathetic innervation of BAT increased 7- to 13-fold after birth, and this increase was temporally correlated with the postnatal enhancement of AC responsiveness. 6-hydroxydopamine (6-HDA) treatment of neonates reduced tyrosine hydroxylase levels by greater than 90%. This treatment greatly reduced the perinatal increase in NE- and NaF-stimulated AC and completely abolished the increase in forskolin-Mn(2+)-stimulated activity. However, sympathectomy did not alter the postnatal increase in Gs alpha-specific activity and did not prevent the postnatal reduction in Gs alpha levels. These results demonstrate that the sympathetic innervation of BAT develops fully after birth and is essential for the postnatal increase in the activity of C but not of Gs alpha.


Possible mediation by luminal somatostatin of bombesin-induced satiety in the cat.

Intravenous bombesin produced a dose-related stimulation of luminal gastric somatostatin output and a concomitant dose-dependent inhibition of food intake in the gastric fistula cat. Maximal food intake inhibition was observed at 1,280 pmol.kg-1.h-1 and corresponded to 65 +/- 7% (P less than 0.01). These effects of bombesin were dose dependently abolished by the specific bombesin-receptor antagonist, [Leu13-psi(CH2NH)-Leu14]bombesin. Furthermore, intragastric administration of somatostatin-14, at doses corresponding to those found in the gastric lumen in response to intravenously administered bombesin, significantly inhibited the first 30 min of food intake. This administration had however no effect on total (daily) food intake. We therefore suggest that luminal gastric somatostatin could at least account for bombesin-induced short-term satiety.


Bright light treatment of behavioral and sleep disturbances in patients with Alzheimer's disease.

The authors tested the hypothesis that evening bright light pulses would improve sleep-wake patterns and reduce agitation in patients with Alzheimer's disease who have severe sundowning (a syndrome of recurring confusion and increased agitation in the late afternoon or early evening) and sleep disorders. Ten inpatients with Alzheimer's disease on a research ward of a veterans' hospital were studied in an open clinical trial. All patients had sundowning behavior and sleep disturbances. After a week of baseline measurements, patients received 2 hours/day of exposure to bright light between 7:00 p.m. and 9:00 p.m. for 1 week. During the baseline week, the treatment week, and a posttreatment week, patients were rated by nurses for agitation, sleep-wake patterns, use of restraints, and use of prescribed-as-needed medication. On the last 2 days of each week, patients wore activity monitors. Activity counts were analyzed for circadian rhythmicity. Clinical ratings of sleep-wakefulness on the evening nursing shift improved with light treatment in eight of the 10 patients. The proportion of total daily activity occurring during the nighttime decreased during the light-treatment week. The relative amplitude of the circadian locomotor activity rhythm, a measure of its stability, increased during the light-treatment week. More severe sundowning at baseline predicted greater clinical improvement. Evening bright light pulses may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease. This effect may be mediated through a chronobiological mechanism.


Toward a brain map of auditory hallucinations.

This study asks whether auditory hallucinations are reflected in a distinctive metabolic map of the brain. Regional brain metabolism was measured by positron emission tomography with [18F]-fluorodeoxyglucose in 12 DSM-III schizophrenic patients who experienced auditory hallucinations during glucose uptake and 10 who did not. All patients were free of neuroleptics and 19 had never been treated with neuroleptics. Nine patients were reexamined after 1 year to assess effects of neuroleptic treatment. Compared with the patients who did not experience hallucinations, the patients who did experience hallucinations had significantly lower relative metabolism in auditory and Wernicke's regions and a trend toward higher metabolism in the right hemisphere homologue of Broca's region. Hallucination scores correlated positively and significantly with relative metabolism in the striatum and anterior cingulate regions. Neuroleptic treatment resulted in a significant increase in striatal metabolism and a reduced frontal-parietal ratio, which was significantly correlated with a decrease in hallucination scores. Auditory hallucinations involve language regions of the cortex in a pattern similar to that seen in normal subjects listening to their own voices but different in that left prefrontal regions are not activated. The striatum plays a critical role in auditory hallucinations.


Painful sensory symptoms in neuroleptic-induced extrapyramidal syndromes.

The authors tested the hypothesis that neuroleptic-induced extrapyramidal syndromes are associated with painful sensations objectively conforming to the characteristics of primary sensory symptoms as reported in idiopathic and postencephalitic parkinsonism. The frequency of subjective painful sensory symptoms and their relation to neuroleptic-induced extrapyramidal syndromes were examined in a consecutive series of 107 psychiatric patients newly admitted to acute care units at a teaching hospital. Patients without illnesses or conditions likely to be associated with pain were included in the study if they had a diagnosis other than organic mental syndromes and were receiving psychotropic medications as prescribed by their treating physicians. Structured interviews with a modified version of the McGill Pain Questionnaire to assess sensory complaints and neurological examinations for neuroleptic-induced extrapyramidal syndromes (parkinsonism and akathisia) were conducted independently by two raters blind to each other's findings and patients' medication status. Fourteen (23%) of 60 patients receiving neuroleptics reported experiences of spontaneous pain subjectively attributed to pharmacological treatment, compared with only one (2%) of 47 patients receiving psychotropic medications other than neuroleptics. There was no difference between these two groups in subjective complaints of paresthesia (8% versus 9%). Twelve (55%) of the 22 patients with neuroleptic-induced extrapyramidal syndromes reported pain, compared with only two (5%) of the 38 patients who received neuroleptics but did not experience extrapyramidal syndromes. Although consonant with the study hypothesis, these results should be regarded as preliminary and interpreted conservatively in the light of the methodological limitations of the study.


Prevalence of tardive dyskinesia, tardive dystonia, and respiratory dyskinesia among Chinese psychiatric patients in Hong Kong.

Only scanty information on the prevalence of tardive dyskinesia in Chinese patients has been available. This study was undertaken to examine the prevalence of tardive dyskinesia, tardive dystonia, and respiratory dyskinesia in Chinese psychiatric patients in Hong Kong. All inpatients of a mental hospital in Hong Kong, except those in the admission and children's wards, were surveyed with the Abnormal Involuntary Movement Scale, and standard research criteria were used to establish the diagnosis of tardive dyskinesia. In addition, patients were screened for tardive dystonia, according to published criteria, and for respiratory dyskinesia by physical examination and laboratory tests. Among the 917 patients surveyed, the prevalence rates were 9.3% for tardive dyskinesia, 0.4% for tardive dystonia, and 1.2% for respiratory dyskinesia. With multivariate analysis, greater age and a lower current dose of antipsychotic, but not the presence of mood disorder, were factors found to be significantly associated with tardive dyskinesia. The prevalence rates were much lower than those found in Western studies. This may indicate that there is an ethnic difference in the prevalence of these conditions. Prospective cross-cultural studies are necessary to explore this possibility.


CSF beta-endorphin and dynorphin in bulimia nervosa.

Preclinical and clinical evidence suggests that central opioid dysfunction may play a role in the pathophysiology of the eating disorders. In particular, endogenous opioids are known to regulate feeding behavior, mood, perception, and neuroendocrine function, all of which are disturbed in patients with eating disorders. Although low concentrations of CSF beta-endorphin have been reported in low-weight patients with anorexia nervosa, central opioid activity in normal-weight patients with bulimia nervosa has not been reported. The authors therefore measured CSF concentrations of beta-endorphin and dynorphin in drug-free female patients with DSM-III-R-defined bulimia nervosa and normal comparison subjects. After 4 days of a low monoamine diet and overnight bed rest, CSF was obtained (12-26 cc) from 11 women with bulimia and 17 normal comparison subjects (eight women and nine men). The women with bulimia had significantly lower CSF concentrations of beta-endorphin than did the female comparison subjects. However, CSF concentrations of dynorphin were not significantly different in patients and female or male comparison subjects. beta-Endorphin concentrations were inversely correlated with Beck Depression Inventory scores and the depression subscale of the Eating Disorders Inventory. These data support a role for central opiates in the mediation of the pathophysiology of the signs and symptoms of bulimia nervosa, although it is impossible to rule out the effects of depression on the results.


Psychodynamic psychiatry in the "decade of the brain".

To illustrate the continued relevance of psychodynamic thinking in the practice of contemporary psychiatry, the author reviews a number of studies that demonstrate the intimate connection between psychosocial and neurophysiological factors in the etiology and pathogenesis of psychiatric disorders. A survey of three specific anxiety disorders illustrates the complex interaction between mind and brain in these disorders. Research on both primates and humans suggests that psychological influences result in permanent alterations of a neurobiological nature. Similarly, psychological interventions in a treatment context may have a profound impact on neurophysiology. Clinical case examples demonstrate that "biologically based" disorders may be rich in unconscious meaning. Clinical understanding of the meaning of symptoms may be instrumental in ensuring patients' compliance with pharmacotherapy regimens and in the removal of other resistances to treatment. In contemporary psychiatry, a psychodynamic perspective must be preserved. Without it, meaning will be lost, and both diagnostic understanding and informed treatment planning will suffer as a result.


Transduction of psychosocial stress into the neurobiology of recurrent affective disorder.

Early clinical observations and recent systematic studies overwhelmingly document a greater role for psychosocial stressors in association with the first episode of major affective disorder than with subsequent episodes. The author postulates that both sensitization to stressors and episode sensitization occur and become encoded at the level of gene expression. In particular, stressors and the biochemical concomitants of the episodes themselves can induce the protooncogene c-fos and related transcription factors, which then affect the expression of transmitters, receptors, and neuropeptides that alter responsivity in a long-lasting fashion. Thus, both stressors and episodes may leave residual traces and vulnerabilities to further occurrences of affective illness. These data and concepts suggest that the biochemical and anatomical substrates underlying the affective disorders evolve over time as a function of recurrences, as does pharmacological responsivity. This formulation highlights the critical importance of early intervention in the illness in order to prevent malignant transformation to rapid cycling, spontaneous episodes, and refractoriness to drug treatment.


Pancreaticoduodenectomy.

Few major abdominal operations have undergone the extent of dramatic change as that associated with pancreaticoduodenectomy in the last 20 years. The precipitous drop in the mortality rate most likely has a multifaceted explanation. Possibilities include the concentration of the operations at specialized centers, the improvement in the quality of critical care and anesthesia, and the improvement in the skill and experience of surgeons performing the procedure. Concomitant with the drop in the morality rate has been an increase in the resectability rate, along with the early encouraging evidence of improved long-term survival. However, many aspects of the technical portion of the procedure, particularly the pancreaticojejunostomy, need to be evaluated in prospective trials. The changes in the mortality and resectability rates make the operation more widely available to a larger number of patients, and the effectiveness of pancreaticoduodenectomy even for palliation is now well established.


[The SPECT demonstration of an improvement in cerebral perfusion in a female patient with Takayasu's disease following carotid revascularization].

Computed tomography and magnetic resonance imaging play an important role in the diagnosis of cerebrovascular disease, but only in the morphological aspect. To assess changes in cerebral perfusion are necessary functional images techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). By these methods we can evaluate the cerebral hemodynamics to better understand the significance of chronic ischemia as a stroke risk factor for patients with carotid stenosis. A case of improvement of cerebral blood flow demonstrated by SPECT after carotid revascularization in a young woman with Takayasu's disease is described.


Midbrain dopaminergic cell loss in Parkinson's disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells.

Computer imaging and immunohistochemical staining techniques were used to determine which midbrain dopaminergic (DA) cells are spared in Parkinson's disease (PD), and in animals treated with the DA neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and whether the spared cells contain the calcium-binding protein, calbindin-D28k (CaBP). The PD patients had more than 55% fewer midbrain DA neurons than age-matched normal subjects. The cell loss occurred within the combined substantia nigra and retrorubral area (greater than 61%; DA nuclei A9 and A8, respectively), and the ventral tegmental area (greater than 42%; DA nucleus A10). The cell loss was greatest within the ventral portion of the nucleus A9. A similar pattern of DA cell loss was observed in MPTP-treated Macaca fascicularis monkeys. The CaBP-containing cells were located specifically in the cell regions spared by PD and by MPTP-treatment in both monkeys and C57BL/6 mice. These data suggest that PD and MPTP both destroy the same population of midbrain DA neurons within nuclei A8, A9, and A10, and that perhaps CaBP protects the DA neurons from cell death caused by both PD and MPTP.


Late-onset metachromatic leukodystrophy: molecular pathology in two siblings.

We report on a new allele at the arylsulfatase A (ARSA) locus causing late-onset metachromatic leukodystrophy (MLD). In that allele arginine84, a residue that is highly conserved in the arylsulfatase gene family, is replaced by glutamine. In contrast to alleles that cause early-onset MLD, the arginine84 to glutamine substitution is associated with some residual ARSA activity. A comparison of genotypes, ARSA activities, and clinical data on 4 individuals carrying the allele of 81 patients with MLD examined, further validates the concept that different degrees of residual ARSA activity are the basis of phenotypical variation in MLD.


Creutzfeldt-Jakob disease cosegregates with the codon 178Asn PRNP mutation in families of European origin.

We recently discovered an amino acid-altering heterozygous mutation in codon 178 of the PRNP amyloid precursor gene in patients with familial Creutzfeldt-Jakob disease. This mutation is now shown to be associated with the occurrence of disease in 7 unrelated families of Western European origin, among which a total of 65 members are known to have died from Creutzfeldt-Jakob disease. The mutation was detected in each of 17 tested patients, including at least 1 affected member of each family, and in 16 of 36 of their first-degree relatives, but not in affected families with other mutations, patients with the nonfamilial form of the disease, or 83 healthy control individuals. Linkage analysis in two informative families yielded a lod score of 5.30, which, because no recombinants were found, strongly suggests that codon 178Asn is the actual disease mutation.


Phenotypic characteristics of familial Creutzfeldt-Jakob disease associated with the codon 178Asn PRNP mutation.

A group of 43 patients from seven families affected by Creutzfeldt-Jakob disease (CJD) with the codon 178Asn mutation of the PRNP amyloid precursor gene is compared to a group of 211 patients with the sporadic form of the disease. As a group, the patients with the codon 178Asn mutation had an earlier age at onset of illness (almost always presenting as an insidious loss of memory), a longer duration of illness, and an absence of periodic electroencephalographic activity. Transmission of disease to primates was accomplished using brain tissue homogenates from 6 of 10 patients, resulting in significantly shorter incubation periods than those due to sporadic CJD inocula. These findings are interpreted and discussed in terms of possible differences in the temporospatial evolution of damage to the brain, and of accelerated induction of polymerized amyloid protein by its mutationally altered template precursor.


GM1 gangliosidosis in adults: clinical and molecular analysis of 16 Japanese patients.

Clinical findings were compared with the results of molecular analysis in 16 Japanese patients from 10 unrelated families with the adult/chronic form of GM1 gangliosidosis. Age of onset ranged from 3 to 30 years. Major clinical manifestations were gait and speech disturbances caused by persistent muscle hypertonia. Dystonic postures and movements, facial grimacing, and parkinsonian manifestations were commonly seen. Cerebellar signs, myoclonus, severe intellectual impairment, dysmorphism, or visceromegaly were not observed. A common single-base substitution, 51Ile(ATC)----Thr(ACC), reported in a previous study of ours, was confirmed in 14 patients by the Bsu36I restriction site analysis; one was a compound heterozygote with another mutation (457Arg[CGA]----Gln[CAA]) and the others were homozygotes of this mutation. Clinically, the compound-heterozygous patient showed more severe neurological manifestations and a more rapid clinical course than those of homozygotes. The homozygotes showed considerable variations in the age of onset and subsequent clinical course. The 51Ile----Thr mutant allele expressed a significant amount of beta-galactosidase activity, whereas the 457Arg----Gln mutant allele expressed extremely low activity in human GM1 gangliosidosis fibroblasts. We conclude that these gene mutations causing different residual enzyme activities are related to the severity of clinical manifestations, but some other genetic or environmental factors contribute to clinical heterogeneity. The Bsu36I restriction site analysis was performed in 7 families and provided clear results for the diagnosis of heterozygotes as well as homozygotes of this specific clinical form of GM1 gangliosidosis. The technique is applicable to prenatal diagnosis and genetic counseling.


Assessment of genetic diversity and population structure of Xanthomonas oryzae pv. oryzae with a repetitive DNA element.

A repetitive DNA element cloned from Xanthomonas oryzae pv. oryzae was used to assess the population structure and genetic diversity of 98 strains of X. oryzae pv. oryzae collected between 1972 and 1988 from the Philippine Islands. Genomic DNA from X. oryzae pv. oryzae was digested with EcoRI and analyzed for restriction fragment length polymorphisms (RFLPs) with repetitive DNA element as a probe. Twenty-seven RFLP types were identified; there was no overlap of RFLP types among the six races from the Philippines. Most variability (20 RFLP types) was found in strains of races 1, 2, and 3, which were isolated from tropical lowland areas. Four RFLP types (all race 5) were found among strains isolated from cultivars grown in the temperate highlands. The genetic diversity of the total population of X. oryzae pv. oryzae was 0.93, of which 42% was due to genetic differentiation between races. The genetic diversities of strains collected in 1972 to 1976, 1977 to 1981, and 1982 to 1986, were 0.89, 0.90, and 0.92, respectively, suggesting a consistently high level of variability in the pathogen population over the past 15 years. Cluster analysis based on RFLP banding patterns showed five groupings at 85% similarity. The majority of strains from a given race were contained within one cluster, except for race 3 strains, which were distributed in three of the five clusters.


Surgical reconstruction of an ascending aortic dissection in Takayasu's arteritis.

A 45-year-old Japanese woman with Stanford type A dissecting aortic aneurysm underwent a reconstructive operation on the ascending aorta. Histopathological diagnosis was Takayasu's arteritis in the chronic and inactive phase. It is very rare that a dissecting aortic aneurysm results from Takayasu's arteritis. Long-standing hypertension and fragility of the aortic media due to disruption of elastic fibers were suspected to cause dissection in the entire aorta in this case.


Periodontal bone loss in mice induced by different periodontopathic organisms.

Periodontal bone loss in mice orally inoculated with Peptostreptococcus anaerobius, Pept. magnus and Actinobacillus actinomycetemcomitans was compared to that in sham-inoculated mice. Six-to-8-week-old BALB/c mice were inoculated with 1 x 10(5), 1 x 10(7) or 1 x 10(9) colony-forming units (c.f.u.) of bacteria in 50 microliters of medium. Ten mice received each concentration of bacteria and 10 sham-inoculated mice acted as controls. Five mice from each of the groups were killed 6 weeks after inoculation and the remaining five mice at 12 weeks. Right hemimandibles were defleshed, stained and bone loss was measured using an image analyser. All the organisms tested were associated with bone loss. Animals that had received Pept. anaerobius and Pept. magnus had up to 18% more bone loss than those sham inoculated. In contrast, mice inoculated with A. actinomycetemcomitans had up to 38% more bone loss than the sham-inoculated animals, this amount of loss occurring at the lowest inoculation of 1 x 10(5) c.f.u. These data demonstrate a differential ability of micro-organisms to cause periodontal bone loss in mice.


Growth-hormone-prolactin interactions in the regulation of mammary and adipose-tissue acetyl-CoA carboxylase activity and gene expression in lactating rats.

The factors and mechanisms responsible for the reciprocal changes in lipogenesis in rat mammary gland and adipose tissue during the lactation cycle have been investigated. Lactation decreased the activation status and mRNA concentration of acetyl-CoA carboxylase in adipose tissue. Litter removal decreased the mRNA concentration of acetyl-CoA carboxylase in the mammary gland and increased the enzyme's mRNA concentration and activation status in adipose tissue. Lowering serum prolactin concentration in lactating rats decreased the amount of mammary acetyl-CoA carboxylase mRNA and increased that of adipose tissue, and increased the activation status of the enzyme in adipose tissue. Decreasing serum growth hormone (GH) alone had little effect on acetyl-CoA carboxylase in lactating rats, although it did lower pup growth rate and serum concentration of insulin-like growth factor-I. Lowering serum GH concentration exacerbated the effects of decreasing serum prolactin on mammary-gland (but not adipose-tissue) acetyl-CoA carboxylase mRNA and further increased the rise in activation status of the adipose-tissue enzyme induced by decreasing serum prolactin. Changes in acetyl-CoA carboxylase mRNA in both mammary and adipose tissue were paralleled by changes in total enzyme activity except after litter removal, when there was a disproportionately large decrease in total enzyme activity of the mammary gland. Thus prolactin has a major and GH a minor role in the regulation of acetyl-CoA carboxylase activity during lactation. Changes in mammary activity in response to prolactin and GH are primarily due to alterations in gene transcription, whereas adaptation in adipose tissue involves both changes in gene transcription and activation status.


[Current ideas on hay fever and its treatment].

Etiological treatment of atopic dermatitis cannot be considered without taking account of all the data of the syndrome: Search for the etiological; mechanism; Treatment of the cause and skin changes; Preventative treatment of infection; Above all, treatment of pruritus that determines the final state of the skin by the consequent scratching and the future psychological condition from the implicated prolonged suffering. Even though it may be difficult, responsible allergens must be detected and the entire range of allergy treatments tried. The local treatments to give a good skin condition must be understood. Finally, it is essential to educate the parents for the best possible family effort.


Hemodynamic responses and activity tolerance to stair climbing during the second week post-myocardial infarction.

The purpose of this study was to evaluate the hemodynamic responses and activity tolerance to stair climbing of second week post-myocardial infarction (MI) patients. Forty MI patients were stratified into beta-blocker medication users and non-users and randomly assigned to the experimental or control conditions. The 21 experimental subjects performed a walk/stair climb, and the 19 control subjects, a walk/stand activity protocol. Changes in heart rate and blood pressure from before, to immediately after both the walk/stair and walk/stand activity protocols were clinically small. No significant differences existed in the distribution of hemodynamic signs among the experimental and control subjects. However, proportionately more experimental than control subjects had symptoms of activity intolerance (7/21 vs 1/19; p less than 0.05). No correlation existed between activity (in) tolerance and either days post-MI or time required for stair climbing. Based upon these preliminary findings, assessment of tolerance to stair climbing activities is warranted during the second week post-MI.


The role of growth factors in embryonic induction in Xenopus laevis.

Establishment of the body pattern in all animals, and especially in vertebrate embryos, depends on cell interactions. During the cleavage and blastula stages in amphibians, signal(s) from the vegetal region induce the equatorial region to become mesoderm. Two types of peptide growth factors have been shown by explant culture experiments to be active in mesoderm induction. First, there are several isoforms of fibroblast growth factor (FGF), including aFGF, bFGF, and hst/kFGF. FGF induces ventral, but not the most dorsal, levels of mesodermal tissue; bFGF and its mRNA, and an FGF receptor and its mRNA, are present in the embryo. Thus, FGF probably has a role in mesoderm induction, but is unlikely to be the sole inducing agent in vivo. Second, members of the transforming growth factor-beta (TGF-beta) family. TGF-beta 2 and TGF-beta 3 are active in induction, but the most powerful inducing factors are the distant relatives of TGF-beta named activin A and activin B, which are capable of inducing all types of mesoderm. An important question relates to the establishment of polarity during the induction of mesoderm. While all regions of the animal hemisphere of frog embryos are competent to respond to activins by mesoderm differentiation, only explants that include cells close to the equator form structures with some organization along dorsoventral and anteroposterior axes. These observations suggest that cells in the blastula animal hemisphere are already polarized to some extent, although inducers are required to make this polarity explicit.(ABSTRACT TRUNCATED AT 250 WORDS)


TGF-beta family factors in Drosophila morphogenesis.

Many Drosophila genes have now been identified with substantial sequence similarity to vertebrate protooncogenes and growth factors. Some of these have been isolated directly by cross-hybridization with vertebrate probes and some have been recognized in the sequences of genes cloned because of their intiguing mutant phenotypes. An example of a gene isolated for its interesting development functions but with homology to a vertebrate growth factor is the Drosophila decapentaplegic gene (dpp). An example of a Drosophila gene isolated by virtue of its sequence conservation is the vgr/60A gene. Both dpp and vgr/60A are members of the transforming growth factor-beta family and are most similar to the human bone morphogenetic proteins. The regulation of the dpp gene by several different groups of pattern formation genes including the dorsal/ventral group, the terminal group, the segment polarity genes, and the homeotic genes indicates that many events in embryogenesis require the cell to cell communication mediated by the secreted dpp protein. The temporal and spatial pattern of vgr/60A expression differs from that of dpp indicating that it may be regulated by different pattern information genes. The experimental advantages of the Drosophila system should permit a better understanding of the importance of growth factor homologs in specific developmental events, aid in establishing the functional interactions between these regulatory molecules, and identify new genes that are important for the biological functions of growth factors. It is likely that some of the newly identified genes will have vertebrate homologs and the analysis of these may be helpful in studies on vertebrate development and tumor biology.


Chronic ethanol treatment of rats and the myocardial beta-adrenoceptors.

We examined the effect of chronic treatment with ethanol on the dynamics of beta-adrenoceptor binding in left ventricular myocardium of rats. After treatment with BAAM (20 mg/kg i.p.), an irreversible inhibitor of beta-adrenoceptors, the inhibition of beta-adrenoceptor binding was less, and the recovery of receptor binding was faster in chronically ethanol-treated rats compared to the control animals given equicaloric dextrin maltose treatment. When intracellular beta-adrenoceptor recycling was inhibited with colchicine, cytoplasmic left ventricular beta-adrenoceptor binding was greater in ethanol-treated compared to dextrin maltose-treated animals. We conclude that the previously reported decreased functional activity of the beta-adrenoceptor-mediated system probably reflects the contribution of ethanol-mediated effects not entirely restricted to the receptor-binding mechanisms.


["Telescopic" pancreatico-jejunal anastomosis after duodenocephalopancreatectomy for cancer].

The Authors report their experience and a review of the literature on the "telescopic" pancreatojejunostomy following pancreatoduodenectomy. The alternative modalities proposed for the management of the pancreatic stump and their results are also described. Although no technique seems free from complications, the relatively low rate of anastomotic leaking (7.9%) encountered convinced the Authors to adopt this technique on routine basis.


[Duodenocephalopancreatectomy with preservation of the pylorus in ampullary cancer].

The Authors report their experience in the surgical management of ampullary cancer using the Longmire-Traverso technique of pancreatoduodenectomy with pylorus preservation. They consider this operation as the most functional in restoring digestive continuity.


["Telescopic" terminoterminal pancreatico-jejunal anastomosis after duodenocephalopancreatectomy].

Pancreaticojejunostomy represents the most important step of the reconstructive process following pancreaticoduodenectomy. Anastomotic dehiscence at this level accounts for two thirds of total postoperative mortality. In order to reduce the incidence of anastomotic complications, we have recently adopted a new technique of "telescopic" end-to-end-pancreaticojejunostomy where, differently from our previous technique, we are not any longer invaginating the small bowel over the pancreatic stump. Our preliminary results obtained in 5 consecutive patients appear to be promising.


[Personal trends concerning pancreatic head or periampullary neoplasms].

On the basis of his recent experience with twelve consecutive cases of periampullary or pancreatic head carcinoma, the Author reports on some technical aspects of reconstruction following pancreaticoduodenectomy. Preference is expressed for the end-to-end jejunopancreatic anastomosis of the residual stump as this act never caused significant complications.


[Jejunal mucosectomy as a preliminary technique of pancreatico-jejunal anastomosis].

The Authors describe mucosectomy as a preliminary technique to pancreatico-jejunal anastomosis. The removal of the last few centimeters of the jejunal mucosa enhances the perfect adhesion of the loop to the pancreatic parenchyma. Results seem to confirm theory: in our experience, "telescopic" technique associated with mucosectomy and somatostatin administration prevented so far anastomotic leakages.


Cell proliferation of transitional cell bladder tumours determined by PCNA/cyclin immunostaining and its prognostic value.

Cell proliferation of transitional cell bladder cancer (TCC) was determined by PCNA (proliferating cell nuclear antigen)/cyclin immunostaining in 178 TCCs and the results were related to established prognostic factors, progression and survival during a mean follow-up period of 10 years. The fraction of PCNA/cyclin positive nuclei was related to T-category (P = 0.008), papillary status, WHO grade, DNA ploidy, S phase fraction, M/V index (volume corrected mitotic index) and AgNORs (silver stained nucleolar organiser regions) (for all P less than 0.001). TCCs presenting with pelvic lymph node metastasis at diagnosis had a significantly higher growth fraction than the tumours confined to the bladder wall (P less than 0.001). The fraction of PCNA/cyclin positive nuclei predicted progression in T-, N- and M-categories (P less than 0.001). In Ta-T1 tumours high fraction of PCNA/cyclin positive nuclei predicted metastasis (P = 0.019). In survival analysis the fraction of PCNA/cyclin positive nuclei predicted survival in the entire cohort (P less than 0.001) and in Ta-T1 tumours (P = 0.0005). In a multivariate survival analysis the fraction of PCNA/cyclin positive nuclei showed independent predictive value in the entire cohort (P = 0.046), in papillary tumours (P = 0.006) and in Ta-T1 tumours (P = 0.015). The results show that the growth fraction as determined by PCNA/cyclin immunostaining is a significant prognostic variable in TCC.


Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia.

Bucindolol is a new beta blocker with marked vasodilatory properties and intrinsic sympathomimetic activity. We tested its potential effect against ventricular fibrillation (VF), in a pig model of acute myocardial ischemia. Bucindolol 6 mg/kg IV was administered in two equally divided doses, the first 30 minutes prior to, and the second 10 minutes after, ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Bucindolol decreased the incidence of VF to 1/11 versus 14/16 in the control group (p less than 0.005). Bucindolol also decreased the duration of ventricular tachycardia, 15 +/- 8 seconds versus 104 +/- 32 seconds in the control group (p less than 0.01). Bucindolol maintained LVmaxdP/dt at predrug and pre-CAL values, whereas LVmaxdP/dt was decreased by CAL in the control group. Bucindolol decreased arterial pressure and heart rate. Bucindolol increased blood flow in the peripheral ischemic zone (24.6 +/- 1.8% versus 16.2 +/- 1.7% (percent of pre-CAL value) in controls, p less than 0.002), as well as in the nonischemic zones (periischemic zone: 126.4 +/- 6.1% versus 96.7 +/- 4.8% in the control group, p less than 0.0005; remote nonischemic zone: 126.6 +/- 7.1% versus 87.1 +/- 4.3% of pre-CAL value in the control group, p less than 0.0001). Bucindolol had marked antiarrhythmic effects that were associated with beneficial effects on the mechanical function of the left ventricle and on blood flow to the ischemic myocardium.


Large-scale culture system of human CD4+ helper/killer T cells for the application to adoptive tumour immunotherapy.

A simple method for the rapid expansion of human CD4+ T cells with both helper and killer functions was established. CD4+ T cells separated from peripheral blood mononuclear cells using immunomagnetic beads were stimulated with immobilised OKT-3 monoclonal antibody (mAb) plus recombinant interleukin 2 (rIL-2) in 96 well culture plates. After 6 day-culture, the CD4+ T cells were restimulated by immobilised OKT-3 mAb for an additional 24 h, then inoculated into concentrated rotary-tissue culture bag and cultured for further 9 days. This procedure yielded a 3000-fold increase in cell number (about 3-5 x 10(9) per bag). Most of the cells (over 96%) continued to express CD4+ antigen and retained their capacity to produce IL-2. The activated CD4+ T cells showed marked cytotoxicity against Fc receptor positive tumour cells in the presence of OKT-3 mAb. Moreover, we succeeded in a specific targeting of the expanded CD4+ helper/killer T cells to c-erb B-2 positive tumour cells by means of anti-CD3 x anti-c-erb B-2 bispecific antibody. These results suggested that our established simple system will be available for the expansion of large number of CD4+ helper/killer T cells which may provide an efficient strategy for adoptive tumour immunotherapy.


Exercise tolerance with nebivolol and atenolol.

Patients treated with beta-blocking agents often complain of fatigue during exercise. Exercise capacity is decreased under this condition. Nebivolol is a new beta 1-adrenoceptor antagonist with a particular hemodynamic profile, which might be due to an ancillary property. Five milligrams once daily seems the optimal dose for antihypertensive treatment. In a double-blind, placebo-controlled crossover study, the effects of nebivolol on maximal and endurance exercise capacity are compared with those of atenolol in healthy volunteers. The hemodynamic and metabolic effects during exercise are also studied. Nebivolol 5 mg once daily and atenolol 100 mg once daily decrease blood pressure at rest similarly. At these dosages nebivolol shows a smaller decrease in heart rate than atenolol. During exercise, the rise in systolic blood pressure and heart rate is less depressed with nebivolol than with atenolol. In contrast to atenolol, nebivolol does not decrease maximal and endurance exercise capacity, and does not increase perceived exertion significantly. Changes in hemodynamics influence maximal exercise capacity. Since nebivolol has less effect on exercise hemodynamics than atenolol, this might explain why maximal work capacity is not changed during nebivolol. During endurance exercise metabolic effects are thought to be more important. Under nebivolol glycerol and NEFA production is less depressed during exercise and might explain the preserved endurance capacity. These data suggest less beta blockade during nebivolol than during atenolol at the dosages used in this study. In conclusion, at a dose known to be antihypertensive, nebivolol does not alter exercise capacity significantly in healthy volunteers.


Comparison of bisoprolol and diazepam in the treatment of cardiac neurosis.

In order to compare the beta blockers bisoprolol and diazepam in the treatment of cardiac neurosis, 40 patients (16 males and 24 females, mean age: 39 +/- 11 years) were examined in a double-blind, crossover study. Following a 4-week placebo period, patients were randomized to receive either bisoprolol 10 mg daily or diazepam 5 mg twice daily for 4 weeks. After a second 4-week washout period on placebo, patients were switched to the alternative regimen for a further 4 weeks. At the end of the placebo periods and during each phase of treatment, the following parameters were evaluated: somatic symptoms by self-assessment questionnaire, anxiety state by Hamilton rating scale, reaction time to both acoustic and visual stimuli, blood pressure, and heart rate. Both treatments were effective in reducing somatic symptoms of cardiac neurosis, but bisoprolol was significantly more effective than diazepam (p less than 0.01). On the contrary, diazepam was superior to bisoprolol in improving the Hamilton scale related to psychic symptoms. Only diazepam prolonged reaction times. Both treatments were well tolerated; however, 12 patients complained of drowsiness and nine of sedation under diazepam. In conclusion, bisoprolol appeared to be as effective as diazepam in the treatment of cardiac neurosis, but with better effects on somatic symptoms and without affecting patients' psychomotor performance.


50 kD prolactin binding protein in schizophrenics on neuroleptic medication.

Serum samples from 15 age-matched normal male subjects and 15 male schizophrenic patients on neuroleptic medication were subjected to immunoprecipitation with anti-human prolactin (PRL) and analysis of the immunoprecipitate by two-dimensional gel electrophoresis. We report the unexpected immunoprecipitation of large amounts of an approximately 50 kD protein in 12/15 of the schizophrenic patients. Preliminary analyses suggest that this 50 kD protein may be an IgG heavy chain. Since total levels of IgG and each of the IgG subclasses are the same in the normal and schizophrenic group, the increased amount of the 50 kD protein in the schizophrenics is clearly specific to anti PRL precipitation. Since the anti-PRL does not directly recognize either the 50 kD protein or any immunoglobulin light chains in the precipitate, we suggest that the 50 kD protein is precipitated because it is bound to PRL. Perhaps immunoglobulin binding of PRL is a mechanism used to compensate for chronically elevated PRL levels during neuroleptic treatment.


Solution structure of the Lewis x oligosaccharide determined by NMR spectroscopy and molecular dynamics simulations.

The Lewis x (Lex) determinant is a trisaccharide fragment that has been implicated as a specific differentiation antigen, as a tumor antigen, and as a key component of the ligand for the endothelial leukocyte adhesion molecule, ELAM-1. High-resolution nuclear magnetic resonance spectroscopy shows it to have a relatively rigid structure. Only a small range of glycosidic dihedral angles in the trisaccharide produce simulated nuclear Overhauser effect spectra agreeing with data measured for the human milk pentasaccharide, lacto-N-fucopentaose-3, which contains the Lex determinant. Independently, the same average structure for the Lex determinant arises from in vacuo molecular dynamics simulations. The proposed conformation of the Lex trisaccharide is very similar to that recently determined for the closely related Lea trisaccharide. In agreement with the recent finding that both sialylated Lea and Lex react with ELAM-1, the results presented here show that the Lea and Lex determinants contain very similar carbohydrate domains.


The relationship of structural brain imaging parameters to antipsychotic treatment response: a review.

Over the last decade, a number of studies have attempted to relate brain morphology to treatment response to neuroleptics. This approach has scientific potential to define subtypes of schizophrenia as well as potential clinical utility. In the present report, a review of 33 studies, including a meta-analysis, is provided. Although the overall test of the effect was not significant, the analysis revealed marked heterogeneity in the results of the various studies. The following factors were significant predictors of effect size: age, illness duration and age of onset of the patient cohort, the percentage of patients with marked structural abnormality included in the study overall, the duration of treatment and the degree of symptom improvement in the study overall. The following factors were unrelated to study effect size: date of study, gender, and the presence of a washout period. In future studies, attention to the parameters utilized in the meta-analysis should help to clarify the strength and generality of the relationship between brain morphology and treatment response.


Lipophilic beta-blockers inhibit monocyte and endothelial cell-mediated modification of low density lipoproteins.

The effects of propranolol, pindolol and metoprolol on the modification of low density lipoprotein (LDL) by U937 monocyte-like cells, endothelial cells and copper ions were studied by determination of the lipid peroxidation product content and measurement of the relative electrophoretic mobility of the particle. Propranolol and pindolol inhibited LDL oxidation by U937 cells in a dose-dependent manner from 10 to 100 microM, whereas metoprolol had no effect. In the case of LDL modification by endothelial cells, all the three beta-blockers were efficient within the same range of concentrations, and the order of potency was propranolol greater than pindolol greater than metoprolol. In vitro oxidation of LDL in the presence of copper ions was also inhibited by propranolol; pindolol and metoprolol had no significant protective effect in this system. These results concerning the inhibitory action of beta-blockers were confirmed by testing the degradation of modified LDL by J774 macrophages. Although the concentrations of the drugs utilized in this study are relatively high, in long-term treatment beta-blockers might accumulate in target tissues, and the protective effect of propranolol against LDL oxidation might be involved in its inhibitory action on atherosclerosis previously reported in animal models.


4-Methoxytranylcypromine, a monoamine oxidase inhibitor: effects on biogenic amines in rat brain following chronic administration.

4-Methoxytranylcypromine (MeOTCP), a ring-substituted analogue of the monoamine oxidase (MAO)-inhibiting antidepressant tranylcypromine (TCP), was investigated in the rat after chronic (28-day) administration and the results compared with those observed with TCP using equimolar doses of both drugs. At the dose tested, MeOTCP produced a greater inhibition of type A MAO in brain, liver, and heart than did TCP. Both drugs caused a reduction in the specific binding to beta-adrenergic and tryptamine receptors in cortex from brain. MeOTCP produced a marked increase in 5-hydroxytryptamine levels in pons-medulla, hypothalamus, and hippocampus relative to values in vehicle-treated rats and also produced a significant increase in these levels over those observed in the TCP-treated rats.


Antidepressant-like effects of dopamine agonists in an animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synpases. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, intermittent administration of DA agonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three to four twice-weekly injections of quinpirole (100-200 micrograms/kg) or bromocriptine (2.5 mg/kg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raclopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.


Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia.

The chromosomal translocation t(15;17)(q22:21) of acute promyelocytic leukemia (APL) fuses PML, a novel gene, with RAR alpha, a retinoic acid receptor gene. PML-RAR hybrid transcripts were studied in 18 cases of APL using RNA-PCR. Two forms were noted: one designated 5', producing a 439-bp chimeric fragment, and a 3' form, producing a pair of fragments of 765 bp and 909 bp. 5' forms were found in 7 of the 18 cases while the other 11 patients expressed the 3' forms. The chromosome 15 specific probes K3 and K2 were used to study genomic breakpoints in 12 APL patients. Comparison of these results with RNA PCR in 11 patients for whom both were available yielded a rearrangement pattern predictive of whether the hybrid transcript was 5' or 3'. In this way, an additional three patients in whom DNA but not RNA was available were identified as having 3' (downstream) breakpoints and, therefore, 3' hybrid forms. Thus, 21 cases categorized as having 5' or 3' PML-RAR transcripts were analyzed for various phenotypic differences. Surface phenotyping of leukemic promyelocytes demonstrated expression of the CD2 antigen in all cases with the 5' splice variant. Only 1 of 11 cases with the 3' form showed CD2 expression. This difference is significant at P = .001.


2-Chlorodeoxyadenosine: an active agent in the treatment of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphomas are disfiguring malignant lymphoproliferative disorders for which standard therapy has been principally palliative. 2-Chlorodeoxyadenosine (2-CdA), a new purine analogue resistant to degradation by adenosine deaminase that has substantial activity against lymphoid neoplasms, was administered to 16 patients with cutaneous involvement by T-cell lymphoma. All patients had failed topical treatment modalities and/or systemic therapies. Fifteen patients were evaluable; one patient was not evaluable due to incomplete therapy and follow-up. The overall response rate was 47%. Three of 15 patients (20%) achieved complete responses and four of 15 patients (27%) achieved partial responses. The median duration of response was 5 months. One patient remains in unmaintained complete remission at 52+ months. Therapy was well tolerated. Myelosuppression was the principal toxicity encountered, occurring in 8 of 15 (53%) patients. 2-CdA is an effective new agent for the treatment of cutaneous T-cell lymphoma and warrants further study both as a single agent and in combination regimens.


Morphometric evaluation of populations of neuronal profiles (cell bodies, dendrites, and nerve terminals) in the central nervous system.

Morphometric techniques have been developed to quantitatively characterize groups of transmitter-identified neuronal profiles, such as cell groups, dendrite and nerve terminal fields. These morphometric techniques will be illustrated by introducing some general tools for image analysis which can be considered as a background for the present specific applications. The following methods have been included: (1) methods to identify and quantitatively characterize, from both numerical and geometrical standpoints, groups of profiles in a two- and three-dimensional frame; (2) methods to evaluate the evenness of a certain distribution of profiles in the plane; (3) methods to identify subgroups of profiles based on their different spatial or optical density; and (4) methods to compare the distributions of two or more groups of profiles. The applications of these general tools to some neuroanatomical problems, such as cell group definition and description, have been illustrated. Practical examples performed on immunocytochemical preparations of neuronal profile populations are also given. Finally, the potentiality of numerical classification to classify and compare morphometric data has been shown. As an example, numerical classification methods have been applied to the morphometric and microdensitometric analysis of adrenaline/neuropeptide Y costoring neuronal systems of the brainstem in adult and aged rats.


Geographic origin of the Y chromosomes in "old" inbred strains of mice.

Six distinct Y Chromosomes (Chr) were identified among 39 standard inbred strains of mice with five probes that identified Y Chr-specific restriction fragments on Southern blots. Three Y Chr types, distributed among 31 strains, were of Asian Mus musculus origin. The remaining three Y Chr types, distributed among eight strains, were of M. domesticus origin. The Asian source of the M. musculus Y Chr was confirmed by determining the DNA sequence of 221 bp from an open reading frame within the Sry (sex determining region Y) gene (Gubbay et al., Nature 346: 245-250, 1990) in three inbred strains (C57BL/6J, AKR/J, and SWR/J) and comparing the sequence to the homologous sequences derived from wild caught European and Asian M. musculus males. These data indicate that a minimum of six male mice contributed to the formation of the old inbred strains.


The gene for proliferating cell nuclear antigen (Pcna) maps to mouse chromosome 2.

The structural gene for proliferating cell nuclear antigen (Pcna) has been mapped to mouse Chromosome (Chr) 2 by use of a PCR-based assay. With somatic cell hybrids, Pcna was mapped between the T(2;4)13H and T(2;4)1Sn breakpoints. An interspecific backcross was employed to map Pcna 1.9 +/- 1.3 cM distal to Il-lb. This was confirmed by mapping Pcna in the BXH recombinant inbred (RI) strains; no recombinants were seen between Il-la and Pcna. In addition, a PCNA-related sequence (Pcna-rsl) was mapped to Chr 19 in the BXH RI strains.


The vasodilating effect of spinal dorsal column stimulation is mediated by sympathetic nerves.

Spinal dorsal column stimulation has been used in the treatment of a patient with a painful vasospastic condition in the right arm following surgical sympathectomy on the left side. After sympathectomy the left arm became constantly dry and warm and consistently lacked skin vasomotor (laser Doppler flowmetry) responses to arousing stimuli, indicating a complete loss of sympathetic vasomotor innervation. The return of minimal sudomotor (skin resistance) responses to mental stress 2 years after sympathectomy indicated a partial reinnervation of sweat glands. Immediately after sympathectomy, the contralateral right arm became increasingly cold and cyanotic and the patient complained of chronic painful coldness and severe cold-intolerance in the right arm. Attempts to pharmacologically vasodilate the arm with felodipine did not affect the local vasoconstriction and pain. Dorsal column stimulation (associated with symmetrical paraesthesia in both arms) induced an immediate and marked (ten-fold) increase in skin blood flow in the right arm (and in the leg), whereas skin blood flow in the left arm remained unaffected. The lack of vasomotor response in the left arm was not due to maximal vasodilatation at rest, since skin blood flow in the left arm showed a normal capacity for axon reflex vasodilatation following antidromic activation of sensory afferents. The results suggest that the marked vasodilatation induced by dorsal column stimulation is mediated by sympathetic vasomotor fibres, via modulation of central neuronal circuits involved in the regulation of skin sympathetic discharge.


A study of the alpha-1 adrenoceptor blocker prazosin in the prophylactic management of autonomic dysreflexia in high spinal cord injury patients.

The ability of the alpha-1 adrenoceptor antagonist, prazosin, to reduce the severity and duration of episodes of autonomic dysreflexia was studied in cervical and high thoracic spinal cord injury patients with documented episodes of autonomic dysreflexia. Sixteen patients participated in a double blind parallel group study comparing prazosin 3 mg b.d. with placebo given for 2 weeks. Both groups were matched for age, sex and baseline severity of autonomic dysreflexia episodes. Prazosin was well tolerated and did not produce a significant lowering of resting blood pressure. Compared to baseline measurements, patients allocated to prazosin therapy were found to have fewer severe episodes of autonomic dysreflexia and during these episodes to have significant reductions in average rise in systolic and diastolic blood pressure, symptom duration and requirement for acute antihypertensive medication. The severity of headache during individual autonomic dysreflexia episodes was also diminished with prazosin therapy. No symptom parameter was significantly altered by placebo therapy. It is concluded that prazosin is superior to placebo in the prophylactic management of autonomic dysreflexia and that these findings are consistent with suggestions that alpha-1 adrenoceptors play an important role in the pathogenesis of this syndrome.


Early clinical results with the neuroleptic roxindole (EMD 49,980) in the treatment of schizophrenia--an open study.

The neuroleptic effect and tolerability of roxindole (EMD 49,980), an agonist of the dopamine-D2 autoreceptor, was studied during a 4 week treatment period in 7 patients with paranoid-hallucinatory schizophrenia (ICD-9: 295.3). In patients with a daily dosage of up to 4.5 mg/day, there was no improvement as measured with the total score of the BPRS scale. In contrast, patients with a daily dosage of up to 30 mg/day showed a slight improvement, especially in items associated with negative symptoms. In 3 patients there were slight adverse events (dizziness, hypersalivation, hypotonia, nausea/vomiting, miction disturbance) which were probably connected with the intake of roxindole.


Thrombospondin: a new attachment protein in preretinal traction membranes.

Thrombospondin (TSP), an adhesive integrin-binding protein of plasma and platelets, was detected in preretinal traction membranes from patients with idiopathic (8/8) and traumatic (7/8) proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR) (6/8). TSP immunoreactivity was compared to the pattern of von Willebrand factor, plasma transglutaminase (blood coagulation factor XIII), fibronectin, and mononuclear phagocytes, using double-label immunofluorescence microscopy. TSP was partially colocalised with the endothelial cell marker, von Willebrand factor, in PDR. The codistribution of catalytic factor XIII and two cross-linking substrates, fibronectin and TSP, suggests a functional role of the enzyme in the extracellular matrix build-up in PVR and PDR. No significant TSP synthesis by mononuclear phagocytes was observed. Western blotting indicated a plasmin-mediated intravitreal breakdown of presumably plasmatic TSP in PVR and PDR.


Neurotransmitter release: facilitation and three-dimensional diffusion of intracellular calcium.

In order to account for the time courses of both evoked release and facilitation, in the framework of the Ca2+ hypothesis, Fogelson and Zucker (1985, Biophys. J. 48, 1003-1017) suggested treating diffusion of Ca2+, once it enters through the Ca2+ channels, as a three-dimensional process (three-dimensional diffusion model). This model is examined here as a refined version of the "Ca(2+)-theory" for neurotransmitter release. The three-dimensional model was suggested to account for both the time course of release and that of facilitation. As such, it has been examined here as to its ability to predict the dependence of the amplitude and time course of facilitation under various experimental conditions. It is demonstrated that the three-dimensional diffusion model predicts the time course of facilitation to be insensitive to temperature. It also predicts the amplitude and time course of facilitation to be independent of extracellular Ca2+ concentration. Moreover, it predicts that inhibition of the [Na+]o in equilibrium with [Ca2+]i exchange does not alter facilitation. These predictions are not upheld by the experimental results. Facilitation is prolonged upon reduction in temperature. The amplitude of facilitation declines and its duration is prolonged upon increase in extracellular Ca2+ concentration. Finally, inhibition of the [Na+]o in equilibrium with [Ca2+]i exchange prolongs facilitation but does not alter the time course of evoked release after an impulse.


Ten-year review of treatment of the undescended testis in the west of Ireland.

Advances continue to be made in the treatment of the undescended testis, and treatment recommendations are continually changing. We reviewed 543 patients admitted for treatment of undescended testes in the 10-year period 1977 to 1986. The side and position of the testis were recorded, the patient's age at operation and the procedure carried out. The presence of an associated inguinal hernia was noted. The necessity for reoperation was recorded and predisposing factors sought. We found the mean age at operation to be 9.5 years and this decreased significantly over the study period. Dartos pouch orchiopexy was the commonest operation (69%). No significant link was found between the procedure performed or the presence of a hernia and the need for further procedures; 2.7% of patients required such further procedures. A coherent classification of position is lacking for abnormally descended testes. We report a classification which we used to tackle this situation.


Surgical outcome of orchiopexy. I. Previously unoperated testes.

A total of 1209 undescended testes in 961 boys who had no previous surgery for this problem have been reviewed with particular regard to the outcome of surgery in relation to the pre-operative and intra-operative assessment of the position of the testis. A third of impalpable testes were found at operation in the abdomen, a third in the inguinal canal and a quarter in the superficial inguinal pouch; 1% of all testes and 7% of impalpable testes were absent; 96% of all testes reached the scrotum at operation and this figure included 69% of abdominal and 94% of canalicular testes. In all 24 testes were excised--7 of which were abdominal, 8 canalicular and 9 were in the superficial inguinal pouch. The generalisation that the higher the undescended testis before operation the poorer the result, does not always hold true.


Neural changes in acute arthritis in monkeys. II. Increased glutamate immunoreactivity in the medial articular nerve.

Glutamate and other excitatory amino acids have been shown to play a key role in nociception and the hyperalgesia associated with the acute inflammatory response. In an effort to understand more fully the role of Glu in this process, we determined that there is Glu in a percentage of axons in the medial articular nerve (MAN) of monkeys, a source of preterminal afferent fibers innervating the knee joint. After induction of the experimental knee joint inflammation with a kaolin/carrageenan mixture, comparison was made of the percentage of Glu positive axons in the MAN on the side of the inflammation versus the contralateral MAN using post-embedding immunogold electron microscopic methods. A doubling in the percentage of Glu-containing axons was observed on the side of the experimental arthritis as compared to the MAN of the other side or of uninjected controls. Glu positive axons were unmyelinated or were included in the small, thinly myelinated group in control nerves. Following induction of the inflammation, axonal diameter measurements revealed an increase in Glu content primarily in the small, thinly myelinated axons, which correspond to the group III afferent fibers. These increases were observed in the anesthetized preparation only when injection of kaolin/carrageenan was combined with joint flexion and mechanical stimulation. The dramatic increase in percentages of fibers stainable for Glu in the MAN following the induction of inflammation suggests that Glu content is greatly increased in the afferent fibers and may be a major contributor to the enhanced responses of sensory neurons in inflammatory states such as arthritis.