Chromosomal illegitimate recombination in mammalian cells is associated with intrinsically bent DNA elements.

Illegitimate recombination is the most frequent mechanism for chromosomal rearrangements in mammalian cells, yet little is known about this process. Most of the studies to date have looked at the sequences present at illegitimate junctions. These revealed the presence of recurrent DNA motifs, none of which was consistently found. We have undertaken to determine if intrinsic DNA structures such as bent DNA elements could be a major determinant in chromosomal illegitimate recombination. Using a two dimensional electrophoretic assay we found that eight out of eight junctions, resulting from various types of chromosomal rearrangements, had migration behaviour characteristic of DNA containing intrinsically bent DNA elements. In all cases, these occurred within one kilobase of the junctions, and in most cases could be found in both participating DNA segments. We also found that these bent DNA elements were present before the recombination event. When we analysed the frequency of intrinsically bent DNA elements in random chromosomal fragments, we found it to be about one per 11 kilobases. Thus these results suggest that bent DNA is associated with chromosomal illegitimate recombination.


A coiled-coil related protein specific for synapsed regions of meiotic prophase chromosomes.

Synaptonemal complexes (SCs) are structures that are formed between homologous chromosomes during meiotic prophase. They are probably involved in chromosome pairing and recombination. Using a monoclonal anti-SC antibody we isolated cDNAs encoding a major component of SCs which is localized specifically in synapsed segments of meiotic prophase chromosomes. The protein predicted from the nucleotide sequence of a full-length cDNA, named SCP1, consists of 946 amino acid residues and has a molecular weight of 111 kDa. It shares several features with nuclear lamins and some recently identified nuclear matrix proteins. The major part of SCP1 consists of long stretches capable of forming amphipathic alpha-helices. This region shows amino acid sequence similarity to the coiled-coil region of myosin heavy chain. A leucine zipper is included in this region. The carboxy-terminus has two small basic domains and several S/T-P-X-X motifs, which are characteristic of DNA-binding proteins. One of these motifs is a potential target site for p34cdc2 protein kinase. The amino-terminus is acidic and relatively proline-rich, but does not contain the S/T-P-X-X motif. The transcription of the gene encoding SCP1 is restricted to zygotene-diplotene spermatocytes. A polyclonal antiserum raised against the fusion protein of one of the cDNA clones recognizes a single protein on Western blots of isolated SCs, with an electrophoretic mobility identical to that of the antigen recognized by the original monoclonal antibody (mAb), IX5B2. From a detailed comparison of the immunogold labelling of rat SCs by mAb IX5B2 and the polyclonal anti-fusion protein antiserum respectively, we tentatively infer that the carboxy-terminus of SCP1 is orientated towards the lateral elements and that the other domains of the protein extend towards the central region between the lateral elements. We conclude that SCP1 is the major component of the transverse filaments of SCs, and speculate that it has evolved by specialization of a nuclear matrix protein.


E.coli MukB protein involved in chromosome partition forms a homodimer with a rod-and-hinge structure having DNA binding and ATP/GTP binding activities.

mukB mutants of Escherichia coli are defective in the correct partitioning of replicated chromosomes. This results in the appearance of normal-sized anucleate (chromosome-less) cells during cell proliferation. Based on the nucleotide sequence of the mukB gene, the MukB protein of 177 kDa was predicted to be a filamentous protein with globular domains at the ends, and also having DNA binding and nucleotide binding abilities. Here we present evidence that the purified MukB protein possesses these characteristics. MukB forms a homodimer with a rod-and-hinge structure having a pair of large, C-terminal globular domains at one end and a pair of small, N-terminal globular domains at the opposite end; it tends to bend at a middle hinge site of the rod section. Chromatography in a DNA-cellulose column and the gel retardation assay revealed that MukB possesses DNA binding activity. Photoaffinity cross-linking experiments showed that MukB binds to ATP and GTP in the presence of Zn2+. Throughout the purification steps, acyl carrier protein was co-purified with MukB.


Virulence in bacteriophage Mu: a case of trans-dominant proteolysis by the Escherichia coli Clp serine protease.

The importance of proteases in gene regulation is well documented in both prokaryotic and eukaryotic systems. Here we describe the first example of genetic regulation controlled by the Escherichia coli Clp ATP-dependent serine protease. Virulent mutants of bacteriophage Mu, which carry a particular mutation in their repressor gene (vir mutation), successfully infect Mu lysogens and induce the resident Mu prophage. We show that the mutated repressors have an abnormally short half-life due to an increased susceptibility to Clp-dependent degradation. This susceptibility is communicated to the wild type repressor present in the same cell, which provides the Muvir phages with their trans-dominant phenotype. To our knowledge this is the first case where the instability of a mutant protein is shown to trigger the degradation of its wild type parent.


Exercise dependent complete left bundle branch block.

Eleven patients with an exercise dependent complete left bundle branch block (CLBBB) were followed-up over a period of 2-13 years (mean 6.5 +/- 3.8). Their ages ranged from 19 to 62 years (mean 48). Four patients complained of chest pain on effort and one of palpitations. All patients underwent a clinical examination, 12 lead ECG, routine blood tests, chest X-ray, a multistage exercise test, echo Doppler, radionuclide ventriculography with TC99 and 48-h Holter monitoring. Ten were submitted to a coronary angiography with left ventriculography. The ECG at rest displayed a normal ECG in seven patients and an incomplete left bundle branch block (ILBBB) in four patients. The onset heart rate (HR) of CLBBB ranged from 95-146 beats.min-1 (mean 123) and the offset HR75-135 (mean 102 beats.min-1). Coronary angiography showed three-vessel disease in two patients and an obstruction of the left anterior descending coronary artery (LAD) in the third. In the other seven patients all the investigations (including coronary angiography) were normal. During the follow-up period the HR at onset of CLBBB decreased from 145 beats.min-1 to 100 beats.min-1 in four patients but no coronary artery disease (CAD) could be proven at coronary angiography. In our series chest pain did not always signify the presence of CAD. We conclude, that in patients with exercise-dependent CLBBB the prognosis is good if no underlying heart disease can be detected. It appears from our limited experience that an exercise-dependent CLBBB at heart rate below 125 beats.min-1 does not by itself constitute a sign of CAD.


Heart involvement in AIDS: a prospective study during various stages of the disease.

The goal of our study was to evaluate the incidence of heart involvement in AIDS patients during various stages of the disease. Between January 1988 to September 1991, we conducted a prospective study in 114 anti-HIV positive patients. The patients, whose mean age (+/- SD) was 34.6 +/- 5.4 years (range 20 to 54), were divided into three groups: anti-HIV positive asymptomatic (n = 31; 27%), AIDS related complex (ARC) group IV-A (n = 11; 10%), and AIDS subgroups IV-C1 (n = 62; 54%) and IV-D (n = 10; 9%). Overall, 84 patients (74%) were i.v. drug abusers, 24 (21%) were homosexuals, and six (5%) were partners at risk. Zidovudine (AZT) was administered to 94 patients (82%). Opportunistic infections and/or secondary malignancies were detected in 72 patients (63%). Electrocardiographic changes were of little clinical relevance. Of 72 AIDS patients, 47 (65.2%) presented a cardiac involvement: 12 subjects (16.6%) were affected by a dilated cardiomyopathy, 13 (18%) by pericardial effusion, three (4.1%) by mitral valve prolapse, four (5.5%) by myocarditis, five (6.9%) by valvular bacterial endocarditis, and 10 (13.8%) by alterations of left ventricle regional contractility. During a mean follow-up period of 44 months, 29 AIDS patients (40.2%) died. Death was attributed to a cardiac event in four patients; autopsy could be performed in 24 of the 29 patients who died. Our results demonstrate that heart involvement is present in 45.6% of HIV-infected patients, but only in the end-stage of the disease (AIDS) and it is presumably due to opportunistic infections and/or secondary malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)


Food in chronic heart failure: improvement in central haemodynamics but deleterious effects on exercise tolerance.

Food has been known to have significant central haemodynamic effects for over half a century; it causes an increase in cardiac output and a fall in systemic vascular resistance. These changes are potentially desirable in patients with chronic heart failure but how they relate to exercise tolerance is unknown. This study was designed to examine the haemodynamic effects of food with changes in exercise capability in a group of patients with chronic heart failure. Fifteen patients with chronic heart failure and 10 normal control subjects were studied. They underwent treadmill exercise testing whilst fasting and after a standardized meal. Measurements were made of symptom-limited exercise tolerance, cardiac output, limb blood flow and respiratory gases. Superior mesenteric artery blood flow was measured fasting and postprandially only. Despite an increase in cardiac output, at rest and during exercise, which was not, however, as great as that in the control subjects, the symptom-limited exercise tolerance of the patients fell by 37 s postprandially (P < 0.05). Superior mesenteric artery blood flow increased postprandially by a mean of 133 ml.min-1 (P < 0.05) in the patients and 424 ml.min-1 (P < 0.01) in the control subjects. Calf blood flow increased in both groups during exercise, but there was no change in limb blood flow when comparisons were made between the fasting and postprandial states. The normal postprandial increase in oxygen consumption did not occur in the patients although their minute ventilation was higher than the control subjects (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Prognostic importance of predischarge exercise capacity for long-term mortality and non-fatal myocardial infarction in patients admitted for suspected acute myocardial infarction and treated with metoprolol.

To evaluate the influence of acute beta-blockade on the ability of predischarge exercise test data to predict long-term prognosis in patients admitted for suspected acute myocardial infarction, patients randomized at hospital admission to intravenous metoprolol or placebo were studied. Among 190 patients discharged alive, total 4-year mortality was 20.5% (n = 39); (33 cardiac deaths, 6 non-cardiac deaths). Non-fatal infarction rate was 6.8% (n = 13). Multiple logistic regression analysis revealed that total mortality and non-fatal infarctions were independently predicted by (a) inability to perform predischarge stress testing (event-free survival for patients exercise tested 79.5% vs 56.9% for patients not eligible for testing; relative risk (RR) 1.40, 95% confidence interval (CI) 1.10-1.78; P = 0.01), and (b) low predischarge exercise capacity (RR 1.44, CI 1.08-1.93; P = 0.034). ST segment shift > or = 1 mm did not predict mortality or reinfarction. Administration of metoprolol in the acute phase did not influence the predictive value of these parametres. It is concluded that assessment of exercise capacity at early exercise testing yields independent information for later death and myocardial infarctions, and that beta-blockade with metoprolol does not influence the predictive value of early exercise testing.


Plasma calcitonin gene-related peptide decreases in chronic congestive heart failure.

To investigate the role of calcitonin gene-related peptide (CGRP) in cardiac failure, a sensitive and specific radioimmunoassay was developed to study plasma levels of CGRP in 37 normal subjects and 41 patients with heart failure (HF). The mean plasma levels of CGRP were 294.3 pg.ml-1 (SEM: 41.4) in normal subjects and 121.2 pg.ml-1 (SEM: 21.2) in HF patients. The significant decrease observed in HF patients suggests that CGRP is involved in the pathogenesis of heart failure via a direct effect or via modulation of sympathetic nervous activity.


Transoesophageal stress echocardiography for pre-operative detection of patients at risk of intra-operative myocardial ischaemia.

Patients with coronary artery disease have an increased risk of developing intra-operative myocardial ischaemia and peri-operative myocardial infarction. Pre-operative identification of patients at risk of developing peri-operative myocardial ischaemia is often difficult or even impossible due to the inability of the patient to perform an exercise test. For those unable to perform physical exercise a system has recently been described combining transoesophageal echocardiography with simultaneous transoesophageal atrial pacing via the same probe to detect pacing-induced wall motion abnormalities, a sign of coronary artery disease. In a prospective study, 20 patients with clinically suspected coronary artery disease undergoing hip replacement were examined pre-operatively by transoesophageal stress echocardiography. During the subsequent operation the incidence of intra-operative ischaemia was evaluated again in all 20 patients by transoesophageal echocardiography. In eight of the 20 patients (40%) wall motion abnormalities could be induced by transoesophageal stress echocardiography pre-operatively. Intra-operative wall motion abnormalities occurred in six of these eight patients. In two patients with wall motion abnormalities induced by transoesophageal stress echocardiography no abnormalities occurred during surgery. However, in those in whom wall motion abnormalities did occur during operation they occurred in the same left ventricular segment as those initiated by stress echocardiography. None of the patients without pre-operatively inducible wall motion abnormality developed them during surgery. No patient developed a myocardial infarction intra- or post-operatively. Thus, preoperative transoesophageal stress echocardiography is a valuable technique for the detection of patients who may develop ischaemic wall motion abnormalities during surgery.(ABSTRACT TRUNCATED AT 250 WORDS)


Improved diastolic function with the calcium antagonist nisoldipine (coat-core) in patients post myocardial infarction: results of the DEFIANT study. Doppler Flow and Echocardiography in Functional cardiac Insufficiency: Assessment of Nisoldipine Therapy.

A multicentre, randomized, double-blind, placebo-controlled, parallel-group trial was undertaken in 135 patients to determine whether 4 weeks of treatment with long-acting nisoldipine coat-core (20 mg once a day) could alter diastolic function in patients with a recent myocardial infarction and with mild left ventricular dysfunction as indicated by a left ventricular ejection fraction < or = 50%. The primary endpoint was the change in diastolic filling parameters assessed by Doppler and two-dimensional echocardiography. The mean time of admission to the study was 20 days (range 7-35) after myocardial infarction. Mean left ventricular ejection fraction was 41%. The drug increased early diastolic peak velocity at the tips of the mitral leaflet by 0.06 m.s-1 (95% confidence intervals (CI): 0.01, 0.11). The time velocity integral was increased by 1.2 cm (95% CI: 0.16, 2.27). These findings are indicative of increased early diastolic flow across the mitral valve. An important determinant appeared to be a reduced isovolumic relaxation time (by 14.7 ms, 95% CI: -22.5, -6.9). As there was no change in heart rate, systolic and diastolic blood pressure or cardiac output, afterload reduction appeared unlikely as an explanation. Peak workload on exercise was 12 watts higher in the group on nisoldipine (95% CI: 0.8, 23.3). Thus, nisoldipine was shown to improve indices of diastolic ventricular function, as well as exercise capacity, in this group of patients. The observed effects of nisoldipine may reflect an anti-ischaemic effect or be due to improved relaxation of the myocardium.


Prevalence and mechanism of streptokinase-induced platelet stimulation. Effect of acetylsalicylic acid.

It was recently shown that streptokinase may induce clot formation in vivo by immunoglobulin G mediated platelet stimulation. We evaluated the in vitro effect of streptokinase on platelet function in 103 subjects, of whom 52 were < or = 30 years and 51 were > or = 50 years old. Although streptokinase inhibited platelet aggregation in the majority of cases, in nine the threshold concentration of ADP required to induce irreversible aggregation decreased with streptokinase (1 million Units. l-1) by 30% or more. This observation was confirmed in five of the nine by repeated measurements indicating reproducible streptokinase-induced platelet stimulation. Among the five, two were < or = 30, and three were > or = 50 years old. In none of the five subjects did the radio allergo sorbent test detect type E immunoglobulins directed against streptokinase in the serum. In contrast, in four of the five subjects, streptokinase-induced platelet hyperaggregability was suppressed by addition of goat antibodies against human immunoglobulin G, or F(ab')2-fragments of such antibodies. Acetylsalicylic acid did not prevent streptokinase-induced platelet stimulation, but in three of five cases, led to an increase in the control threshold concentration for ADP, so that after the decrease induced by streptokinase the threshold concentration for ADP was in the same range as before acetylsalicylic acid and streptokinase administration. Thus, streptokinase led to an inhibition of platelet aggregation in the majority of subjects evaluated. In a minority of five out of 103, however, streptokinase reproducibly caused platelet stimulation, presumably mediated by immunoglobulin G.(ABSTRACT TRUNCATED AT 250 WORDS)


Practical issues when initiating captopril therapy in chronic heart failure. What is the appropriate dose and how long should patients be observed?

To assess the feasibility of introducing captopril in patients with chronic heart failure on an outpatient rather than an inpatient basis a double-blind placebo-controlled study was carried out to compare either 6.25 mg or 25.0 mg of captopril as a starting dose; followed by either incremental doses of 6.25, 12.5, and 25.0 mg (low dose group), or 25.0 mg 8 hourly (high dose group) respectively. Forty-one patients in a general medical ward within a large teaching hospital with moderate to severe, stable, diuretic-controlled chronic heart failure, who were not hyponatraemic, hypokalaemic or on a dose of diuretic greater than 120 mg of frusemide took part. No patient experienced symptomatic hypotension. Both doses of captopril produced a significant drop in blood pressure (BP), the magnitude of which was similar in both groups. The first dose-induced fall correlated significantly with subsequent dose-related reductions in BP. Therefore if a patient did not have a hypotensive response to the first dose of captopril he/she would be unlikely to have one with subsequent doses. In the group as a whole, the magnitude of the fall in BP after the first dose correlated significantly with starting plasma levels of angiotensin II, atrial natriuretic peptide (ANP), aldosterone, and renin. However, on an individual basis, the two patients with the greatest fall in blood pressure did not have the most activated renin-angiotensin-aldosterone (RAA) system. This serves to emphasise the unpredictability of this response and the need to initiate therapy under clinical observation.(ABSTRACT TRUNCATED AT 250 WORDS)


Ubiquinone (coenzyme Q10) in the long-term treatment of idiopathic dilated cardiomyopathy.

Using a placebo-controlled, double-blind cross-over study the potential therapeutic effect of ubiquinone (coenzyme Q10) was investigated in 25 patients suffering from idiopathic dilated cardiomyopathy (New York Heart Association functional classification I, II and III). Over an initial period of 4 months, 15 patients were administered verum (3 x 33.3 mg coenzyme Q10 x day-1 p.o.) and subsequently given a placebo during the ensuing 4 months (V/P). The sequence of treatment was reversed within the remaining 10 patients (P/V). Therapeutic efficacy was assessed by means of echocardiogram, chest X-ray, radionuclide ventriculography in combination with exercise test and impedance cardiography. Control values for left ventricular function parameters were similar in both groups; left ventricular ejection fraction: 39.5 +/- 11.5% (P/V), 37.6 +/- 17.0% (V/P); left ventricular end-diastolic diameter: 65 +/- 9 mm (P/V), 67 +/- 8 mm (P/V); and cardiac output: 5.1 +/- 1.41 x min-1 (P/V), 5.1 +/- 1.11 x min-1 (V/P). Chronic treatment with ubiquinone had no influence on haemodynamic parameters, electrocardiogram, incidence of ventricular arrhythmias or on exercise tolerance. It was therefore impossible to demonstrate any therapeutic effect of ubiquinone in patients suffering from idiopathic dilated cardiomyopathy.


Usefulness of intracoronary isosorbide dinitrate in alleviating myocardial ischaemia during coronary balloon angioplasty.

The effect of intracoronary isosorbide dinitrate on provoked myocardial ischaemia during percutaneous transluminal coronary angioplasty (PTCA) was studied in 60 patients who had at least 1 mm electrocardiographic (ECG) ST segment deviation during a 70 s control balloon inflation period. Isosorbide dinitrate (dose 1 mg, 2 mg or 3 mg) or placebo (saline) was administered by slow intracoronary injection, and the ST segment changes recorded again during an identical dilatation period 2-4 min later. Following injection of isosorbide dinitrate, the severity of ST segment deviation decreased (1 mg -31 +/- 30%, P = 0.03; 2 mg -51 +/- 35%, P = 0.0001; 3 mg -36 +/- 32%, P = 0.002) during coronary balloon inflation, and the time until onset of 1 mm ST deviation was prolonged (1 mg +79 +/- 137%, P = 0.06; 2 mg +85 +/- 87%, P = 0.02; 3 mg +78 +/- 109%, P = 0.02). With the 3 mg dose, the time to maximum ECG change increased (+37 +/- 87%, P = 0.02). In the placebo group, there was a small decrease in the severity of ST segment deviation in patients receiving placebo (-23 +/- 32%, P = 0.03), but no change in the time to its onset or in the time to maximum ST deviation. Isosorbide dinitrate did not alter heart rate, systolic arterial pressure or the rate-pressure product at maximum ST segment change, implying that when isosorbide was administered by direct intracoronary injection, a direct cardiac effect was responsible for the major anti-ischaemic effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of dobutamine on pulmonary gas exchange in patients with severe heart failure.

Twenty patients (two female, 18 male, mean age 57 +/- 11 years) with severe heart failure NYHA IV (7 coronary artery disease, 13 congestive cardiomyopathy) were treated with 8.8 +/- 1.7 micrograms.kg-1 x min-1 of dobutamine. Pulmonary gas exchange was analysed by withdrawal of blood samples from a central venous catheter and a radial artery cannula. Dobutamine increased SvO2 from 58.7 +/- 11.2% to 72.2 +/- 6.3% (P = 0.0001) and decreased avDO2 from 7.7 +/- 2.45 Vol% to 4.97 +/- 1.34 Vol% (P = 0.0001). PaO2 and PaCO2 were not changed. Qs/Qt increased slightly from 9.1 +/- 8.3% to 11.3 +/- 6.4% (P = 0.035). Cardiac index increased by 51% (P = 0.0001), pulmonary capillary wedge pressure decreased by 28% (P = 0.0001). In patients with severe heart failure, dobutamine improved haemodynamics without detrimental effects on arterial oxygen concentration.


Preservation of myocardial function by mechanical circulatory support during prolonged ischaemia.

The effect of mechanical circulatory support on left ventricular (LV) function was evaluated during prolonged myocardial ischaemia. Regional wall thickening of a normal and an ischaemic LV region were determined in eight calves (mean body weight 76 kg) using pairs of ultrasonic crystals. LV end-diastolic (mmHg) and peak systolic (mmHg) pressure as well as maximum dP/dt (mmHg s-1) were calculated from LV high-fidelity pressure tracings. The left circumflex coronary artery was ligated proximally for 6 h and reperfused for 18 h. Circulatory support by the assist device was performed from the beginning of ischaemia to the end of the experiment. After a mean time of 4 h all animals showed ventricular fibrillation, which was converted successfully in six animals after a mean time interval of 5 h. Five animals survived after 24 h. The non-surviving animals had larger infarcts, greater creatine kinase release and a larger drop in cardiac output during ischaemia. Haemodynamic measurements were carried out after turning off the assist device. Inotropic stimulation with 0.68 mg.min-1 dopamine i.v. was performed at the end of the study. LV regional function showed systolic bulging during myocardial ischaemia. After 18 h of reperfusion, the ischaemic wall recovered and showed normal systolic wall thickening in the presence of an increased LV preload. LV relaxation was prolonged after reperfusion, suggesting diastolic dysfunction. It is concluded that mechanical circulatory support is effective in protecting myocardial function during prolonged ischaemia in approximately two-thirds of the animals, despite severe ischaemic ventricular dysfunction and intermittent ventricular fibrillation.


The potential role of endothelin as a vasoconstrictor substance in congestive heart failure.

A rapidly growing body of data supports the concept of in situ regulation of vascular tone: the ability of vasoactive substances to regulate vascular tone at their site of production within the wall of the vasculature. Sufficient data exist to suggest that ineffective production or response to endothelium-dependent vasodilator substances, or excessive production or responsiveness to endothelium-dependent vasoconstrictor substances may play an important role in cardiovascular disorders such as hypertension, coronary artery spasm, restenosis following coronary angioplasty, and congestive heart failure. The present review summarizes data which support the concept that endothelin, a potent vasoconstrictor produced by the endothelium, may play a role in the excessive vasoconstriction of heart failure. Increased circulating plasma endothelin may be particularly relevant to the range of pulmonary vasoconstriction encountered in congestive heart failure, with a correlation revealing that the greatest increase of plasma endothelin occurs in patients with marked pulmonary hypertension within the congestive heart failure patients studied.


Enhanced A-V nodal conduction (Lown-Ganong-Levine syndrome) by congenitally hypoplastic A-V node.

The basic anatomical substrate of enhanced A-V nodal conduction, manifesting or not as Lown-Ganong-Levine syndrome, is still a controversial issue. We describe the case of a 34-year-old man who presented episodes of ventricular fibrillation. Electrophysiological studies showed that the AH interval was 55 ms, and increased by only 20 ms at paced cycle lengths of 300 ms; atrial pacing induced atrial fibrillation, with a shortest RR interval of 240 ms. Despite verapamil therapy, this patient died suddenly at home. Histological study disclosed a severe A-V node hypoplasia that was evidently congenital in nature; the rest of the conduction system was normal, and no accessory A-V pathways were present. We suggest that enhanced A-V nodal conduction in this patient was due to the developmental defect in the A-V node; this abnormality caused a loss of specific impulse-delaying function, and thus allowed rapid, unfiltered atrial impulses to reach the lower A-V junction and ventricles.


Bilocular atrial malignant mesenchymoma causing mitral and localized pulmonary vein flow obstruction: diagnosis by transoesophageal echocardiography.

Cardiac malignant mesenchymoma is an extremely rare malignancy with poor prognosis. We report a patient presenting with a history and clinical findings typical of mitral stenosis. Transthoracic echocardiography showed a mass on the thickened posterior mitral leaflet. Transoesophageal echocardiography revealed two tumoural masses: one on the atrial side of the posterior mitral leaflet causing mitral obstruction, the other arising in the region of the right lower pulmonary vein orifice and obstructing inflow through this vein.


Endocarditis on a left atrial myxoma.

A 55-year-old woman presented with fever and malaise. Three blood cultures were positive for Streptococcus sanguis. A diagnosis of endocarditis was made and the patient was treated with intravenous penicillin and gentamicin. Endocardiography revealed a large left atrial tumour. At operation a myxoma covered by deposits of fibrin was excised. Microscopy revealed massive infiltrates of neutrophils and remnants of bacteria, indicating that this myxoma was a nest for infection.


Correlative imaging study in the diagnosis of ovarian cancer recurrences. The INSERM Research Network (Nantes, Rennes, Reims, Villejuif, Saclay), France.

A correlative imaging study was carried out in 61 female patients previously treated for ovarian carcinoma. Upon suspicion of recurrence, abdominopelvic immunoscintigraphy (IS) using F(ab')2 fragments of indium-111-labelled OC 125 monoclonal antibody was performed in all patients, Ultrasonography (US) and computed tomography (CT) were performed 53 and 37 times, respectively. The diagnostic accuracy of the different imaging techniques was studied per site (abdomen and pelvis) and per patient. The diagnostic accuracy of planar scintigraphy (PS) was slightly lower than that of emission computed tomography (ECT): 66% vs 73% for abdomen, 65% vs 72% for pelvis, and 78% vs 84% in analysis per patient. The accuracy of IS (PS and ECT combined) was markedly better than that of US and CT for abdomen (IS = 73%; US = 30%; CT = 47%), pelvis (IS = 73%; US = 37%; CT = 52%) and analysis per patient (IS = 85%; US = 43%; CT = 59%). The results of IS and morphological imaging techniques (MIT: US and/or CT) were correlatively analysed with the frequency of recurrence. When IS and MIT were both negative, the frequency of non-recurrence was 14/23 for abdomen, 7/12 for pelvis and 8/13 in analysis per patient. On the other hand, when both IS and MIT were positive, the frequency of recurrence was high (9/9 for abdomen, 17/21 for pelvis and 24/26 for analysis per patient). It was also found that a positive IS associated with a negative MIT was still highly suggestive of recurrence (17/21 for abdomen, 16/22 for pelvis and 17/19 for analysis per patient).(ABSTRACT TRUNCATED AT 250 WORDS)


Immunoscintigraphy in the detection of tuberculosis with radiolabelled antibody fragment against Mycobacterium bovis bacillus Calmette-Guérin: a preliminary study in a rabbit model.

Immunoscintigraphy with radiolabelled monoclonal antibodies is widely used to detect solid tumours, but only a few trials have been carried out concerning the specific in vivo localization of an inflammatory process. The purpose of this study was to investigate the detectability of tuberculous foci utilizing this method with radiolabelled bacillus Calmette-Guérin (BCG)-specific F(ab')2 in rabbits. All of the tuberculous lesions (n = 8) were clearly visualized on serial scintigraphy for up to 48 h after injection of the antibody. Immunohistochemical and Ziel-Neelson staining of the tuberculous lesions confirmed the presence of the tuberculous antigens and bacilli. It failed to demonstrate any sustained retention of the BCG-specific antibody fragment in the control group with syphilitic orchitis (n = 2). Therefore, the specific in vivo localization of tuberculosis is feasible by immunoscintigraphy.


Blood platelet kinetics in normal subjects modelled by compartmental analysis.

The purpose of this study was to describe the function of platelets throughout their life span by expressing their in vivo distribution and kinetic behaviour in mathematical terms by using multicompartmental analysis. The distribution of indium-111 labelled platelets in five normal subjects was imaged and quantified with a scintillation camera image processing system. Serial blood samples were also obtained. The data were modelled using the SAAM (Simulation Analysis and Modelling) compartmental computer program. Five models were entertained to evaluate the role of platelets that were either functional or injured during collection and their interaction with the liver, spleen and vascular endothelium. Models were evaluated by comparing F values calculated from the least squares estimate obtained from each model. The Dornhorst function was used to describe the sequestration of platelets in the compartmental model. Results indicated that the data could not be satisfactorily simulated when compartments were included that simulated only functional and sequestered platelets (model 1). It was necessary to include compartments that simulated the kinetics of collection-injured platelets in the liver (model 2) and spleen (model 3). The model that simulated the interaction with the vascular endothelium (model 5) showed a visual but not significant improvement in the fitting of the observed data compared to model 3. The mean organ uptake and range indicated in parentheses were calculated at equilibrium. There were 20% (15%-27%) of the injected platelets in the spleen, 10% (8%-11%) in the liver and 70% (64%-75%) in the circulation.(ABSTRACT TRUNCATED AT 250 WORDS)


Automatic detection of the left ventricular myocardium long axis and center in thallium-201 single photon emission computed tomography.

A new method for centering and reorienting automatically the left ventricle in thallium-201 myocardial single photon emission computed tomography (SPET) is proposed. The processing involves the following steps: (a) the transverse sections of the left ventricle are segmented, (b) the three-dimensional skeleton of the left ventricle is extracted using tools of mathematical morphology, (c) the skeleton is fitted to a quadratic surface by the least-squares method, (d) the left ventricle is reoriented and centered using the long axis and the coordinates of the centre of the quadratic surface. A series of 30 consecutive exercise and redistribution 201Tl SPET studies were centered and reoriented by two operators twice with this method, and twice manually. There was no significant difference in the mean realignment performed by the automatic and the manual methods while centering differed moderately in some instances. In all cases and for all parameters, the reproducibility of the automatic method was 1.00, while it ranged between 0.74 and 0.98 with the manual centering and reorientation. This automatic approach provides a fast and highly reproducible method for the reconstruction of short- and long-axis sections of the left ventricle in 201Tl SPET.


Assessment of changes in regional cerebral blood flow in patients with major depression using the 99mTc-HMPAO single photon emission tomography method.

Regional cerebral blood flow was investigated in 14 patients with major depression diagnosed according to the DSM-III-R criteria (six patients with single and eight patients with recurrent episodes) and in ten healthy volunteers. The mean ages of the patients and the controls were 33.5 +/- 2.7 and 31.6 +/- 2.6 years, respectively. The severity of the depression was assessed using the 17-item Hamilton Depression Scale (mean: 23.2 +/- 1.5). None of the patients was under medication. After administration of 500 MBq technetium-99m hexamethylpropylene amine oxime, a single photon emission tomography study was performed and then transaxial, sagittal and coronal slices were obtained. For the semiquantitative analysis of the data, the ratios of the mean counts/pixel to the whole slice were calculated for 24 regions on three consecutive transaxial slices in the orbitomeatal plane. Additionally, left/right and frontal/occipital ratios were calculated. Both sides of the temporal region had a significantly decreased cerebral blood flow (CBF) when compared to the controls. The left/right ratio of the prefrontal region was also significantly lower in the patients than in the controls. The Hamilton score had a negative correlation with blood flow in the anterofrontal and left prefrontal regions. According to our results, regional CBF seems to be decreased in the left prefrontal and in both temporal regions in major depression. The severity of depression is correlated with the reduction in CBF in the regions of the anterofrontal and left prefrontal cortex.


The significance of a dipyridamole induced 99mTc-MIBI perfusion abnormality on single photon emission tomography: a quantitative validation with labelled water and positron emission tomography.

To relate technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI) uptake to regional myocardial blood flow (rMBF), 99mTc-MIBI single photon emission tomography (SPET) and H2(15)O positron emission tomography (PET) scans were obtained at rest and after dipyridamole infusion in six patients with single vessel coronary artery disease. 99mTc-MIBI and H2(15)O data sets were created for each segment perfused by the stenotic vessel and for a normal reference area, assigning regions on the SPET tomograms to comparable regions on the PET by similar transaxial image reconstructions. All patients demonstrated post-dipyridamole 99mTc-MIBI perfusion defects in the territories supplied by the stenotic arteries. Resting rMBF in these regions was slightly lower than that in the normal areas (0.82 +/- 0.05 vs 0.90 +/- 0.09 ml/g/min, P = NS). A 43% +/- 14% reduction in 99mTc-MIBI activity in the area at risk was coupled with on average a 60% +/- 9% reduction in post-dipyridamole rMBF compared with control regions (0.98 +/- 0.08 vs 2.52 +/- 0.51 ml/g/min, P < 0.001). Thus, SPET assessment of 99mTc-MIBI uptake tends to underestimate the perfusion contrast between areas with normal and areas with low coronary vasodilatory reserve when compared to PET. However, these findings may still not affect the clinical usefulness of 99mTc-MIBI and more extensive studies are required to confirm these results in the clinical environment.


A role for gamma scintigraphy in cancer immunology and immunotherapy.

Facilities for radiolabelling and gamma scintigraphy are largely restricted to nuclear medicine departments or specialised research institutions and are therefore not widely available to workers in cancer research. Despite this, there is growing interest in gamma scintigraphy, which can provide information relevant to the entire field of cancer immunology. This review discusses the present and future roles of gamma scintigraphy in respect of antibody-targeted, cell-mediated and cytokine therapy. The authors aim to show that gamma scintigraphy is an investigative tool of great potential.


Atrial fibrillation after intravenous dipyridamole for thallium imaging.

Dipyridamole 0.56 mg/kg was administered intravenously for thallium tomography after myocardial infarction. Fast atrial fibrillation developed which failed to resolve with aminophylline. Sinus rhythm returned within 3 days. Myocardial tomography revealed apical infarction without reversible ischaemia. Atrial fibrillation after dipyridamole is rare and may be caused by direct electrophysiological effects on the atrial myocardium.


Porcine platelets in vitro and in vivo studies: relevance to human thrombosis research.

This review summarizes present knowledge on porcine platelets in vitro and recent studies on in vivo activation of platelets in the pig. There are certain differences compared to human platelets: Platelet aggregation and secretion cannot be achieved by epinephrine, and the arachidonate pathway seems poorly developed in porcine platelets. Genetic models for von Willebrand disease (vWD) and storage pool deficiency (SPD) have been developed in the pig. Several models for the study of in vivo platelet deposition and early thrombus formation have been developed. Platelet radio-labeling techniques (with 111In) have been used extensively. We conclude that the pig seems to be a good choice for the investigation of in vivo platelet activation and deposition based on present knowledge of porcine platelets and on already established animal models.


Human neutrophil gelatinase: a marker for circulating blood neutrophils. Purification and quantitation by enzyme linked immunosorbent assay.

Human neutrophil gelatinase was purified to apparent homogeneity. The N-terminal amino-acid sequence of the purified enzyme could be aligned to an internal part of the cDNA-derived amino-acid sequence of 92-kDa type IV collagenase from SV 40-transfected human lung fibroblasts and from a TPA differentiated monocytic cell line, U937. Total amino-acid composition of U937 and neutrophil gelatinases was identical. Gelatinase was susceptible to treatment with o- and n-glycanase, indicating that posttranslational addition of oligosaccharide side chains occurs. An enzyme-linked immunosorbent assay for gelatinase was developed using specific polyclonal rabbit antibodies. The assay was specific, sensitive, accurate, and reproducible. Ninety percent range for plasma gelatinase from normal subjects was 17.3 to 102.9 ng/ml. In patients treated with cytostatic agents for non-Hodgkin's lymphoma, there was a parallel drop in plasma gelatinase and peripheral granulocyte count. This indicates that plasma gelatinase is a marker for circulating neutrophils. Plasma gelatinase does not seem to reflect bone marrow cellularity.


Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption.

We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption--as judged by the eroded surface--increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.


Antenatal diagnosis of haemophilia B by amplification and electrophoresis of an exon fragment with a short deletion.

Carrier identification and antenatal diagnosis were performed in 2 sisters by electrophoretic separation of the normal and abnormal bands obtained after amplification of a fragment of exon h in the factor IX gene. The mutation in the family had been characterised as an 8-base pair (bp) deletion in exon h. By amplification of a 326 bp fragment containing the site of deletion, the shorter 318 bp band of the haemophilia B gene could be separated by electrophoresis of the fragments. The comprehensive data collection at the Haemophilia Centre is of vital importance in the genetic counselling of haemophilia families, and was a crucial step for the successful diagnoses in these sisters.


Mechanisms of excitotoxicity in neurologic diseases.

Excitotoxicity refers to neuronal cell death caused by activation of excitatory amino acid receptors. A substantial body of evidence has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurologic diseases. A major recent advance has been the successful cloning and expression of the N-methyl-D-aspartate (NMDA), non-NMDA, and metabotropic glutamate receptors. The cellular mechanisms responsible for cell death after activation of these receptors are still being clarified. In acute neurologic diseases such as stroke and head trauma, excitotoxicity may be related to excessive glutamate release. In chronic neurodegenerative diseases, however, a slow excitotoxic process is more likely to occur as a consequence of either a receptor abnormality or an impairment of energy metabolism. Recent therapeutic studies have demonstrated the efficacy of non-NMDA receptor antagonists in experimental studies of global ischemia.


New insights into chromatin function in transcriptional control.

Transcription requires the recognition of numerous DNA sequences by diverse transcription factors, which together assemble large nucleoprotein complexes that tether RNA polymerase and facilitate the initiation of RNA synthesis. In vivo the assembly of these transcription complexes occurs in a nuclear environment where the template DNA is compacted more than 10(5)-fold through the assembly of chromatin. Our current knowledge of chromatin structure raises the major issues of the accessibility of DNA to both transcription factors and RNA polymerase and of the progression of RNA polymerase along the chromatin fiber. Novel genetic and biochemical approaches have established that specific chromatin structures have a major impact on the transcription process. Precise alterations in histone sequence, nucleosome structure, and folding of the chromatin fiber influence both the activation and repression of genes. These results offer substantial insight into the role of modulations in chromosome structure during vertebrate development. Transcription factors, histones, and the organization of DNA within the chromosome are intimately linked, and only when the correct framework is assembled can they function together to achieve correct genetic regulation.


Complexity of FGF receptors: genetic basis for structural diversity and functional specificity.

Since 1989, the receptors for fibroblast growth factors (FGFs) were cloned and characterized as a subgroup of the family of receptor tyrosine kinases. Four FGF receptor genes were identified, all of which encode membrane-bound glycoproteins containing three immunoglobulin (Ig) -like domains at the extracellular region, where only two of these domains are involved in ligand binding. Three unique features characterize the FGF receptors: 1) overlapping recognition and redundant specificity, where one receptor may bind with a similar affinity several of the seven known FGFs and one FGF may bind similarly to several distinct receptors. 2) The binding of FGFs to their receptors is dependent on the interaction of FGF with cell surface heparan sulfate proteoglycans. 3) A multitude of isoforms of cell-bound or secreted receptors are produced by the same gene. The gene structure of these receptors revealed two major mechanisms that are responsible for the formation of the diverse forms: alternative mRNA splicing, resulting in deletions or alternate exons usage, and internal polyadenylation, resulting in truncated products. These are reminiscent of mechanisms that also operate in the immunoglobulin family to generate diversity and to produce either secreted or cell-bound molecules. Tissue-specific alternative splicing in FGF receptors allows for the generation of two distinct receptors from a single gene because alternative exons determine the sequence of the COOH-terminal half of the third Ig-like domain involved in ligand binding. This represents a novel genetic mechanism to generate receptor diversity and specificity and to increase receptor repertoire.


Endowing T cells with antibody specificity using chimeric T cell receptors.

T cells recognize antigen in the form of a peptide associated with a cell surface molecule encoded by the major histocompatibility gene complex (MHC). The elaborate requirements for the T cell receptor (TCR)-antigen interaction stand in contrast to the simple and defined nature of the antigenic determinants recognized by antibodies. The similarity in the molecular structure and gene organization between antibodies and the TCR has prompted attempts to interchange the antigen-binding, variable regions of these molecules. To this end, chimeric TCR (cTCR) genes, composed of the variable domains of antibodies linked to TCR constant regions, have been used to confer antibody-type specificity on T cells. cTCR-expressing T cells respond to stimulator cells as well as to immobilized antigen in an MHC unrestricted and independent manner. The antibody-like specificity of the resulting T cells has been exploited, using defined ligands, to elucidate the physicochemical parameters that govern TCR-mediated signaling, and to provide a useful experimental system to study the role of MHC and cell-adhesion/accessory molecules in T cell activation. The successful expression of such cTCR in transgenic mice opens new avenues to explore the role of the MHC in T cell development and maturation. Eventually, chimeric receptors specific to tumor or viral antigens might be used for in vivo targeting of T cells in the framework of immuno- and gene therapy.


Carnitine function and requirements during the life cycle.

L-Carnitine has been described as a "conditionally essential" nutrient for humans. Segments of the human population suggested as having a requirement for carnitine include infants (premature and full-term), patients on long-term parenteral nutrition, and perhaps children. The evidence to support these claims includes 1) low circulating carnitine concentrations; 2) abnormal (or at least different) circulating metabolite concentrations (free fatty acids, triglycerides, ketone bodies), and 3) very limited and inconsistent growth data. A number of subjective observations and anecdotal case reports have been offered in support of a requirement for carnitine. Exogenous carnitine is required to maintain "normal" (in the epidemiologic sense) plasma or serum carnitine concentrations in humans of all ages. But "functional carnitine deficiency," defined by abnormal clinical presentation correctable by carnitine administration, has not been demonstrated in an otherwise normal (nonpathologic) population. On the other hand, nutritional or pharmacological intervention with carnitine or its esters may be beneficial for very premature infants, infants and children with various clinical conditions associated with low circulating carnitine concentrations, and in some chronic diseases associated with the aging process.


Forces involved in the assembly and stabilization of membrane proteins.

Hydrophobic organization: Determination of the structure of the bacterial photosynthetic reaction center, bacterial porins, and bacteriorhodopsin allows a comparison of the basic structural features of integral membrane proteins. Structure parameters of membrane- and water-soluble proteins are surprisingly similar, given the different dielectric environments, except for the polarity of residues on the protein surface. Hydrophobic and electrostatic forces: 1) Intramembrane helix-helix interactions that are sensitive to small structure changes can dictate assembly of membrane proteins, as indicated by reconstitution of bacteriorhodopsin from proteolytic fragments and specific dimer formation of the human erythrocyte sialoglycoprotein glycophorin A. 2) Electrostatic interactions have an important role in determining the trans-membrane orientation of integral membrane proteins of the bacterial inner membrane, as expressed by the "positive-inside" rule for the distribution of basic residues on the cis relative to the trans side of the membrane-spanning alpha-helices. The use of this charge asymmetry rule, in conjunction with a hydrophobicity algorithm for prediction of membrane-spanning domains, allows accurate prediction of the folding patterns of such polypeptides across the membrane. A role of electrostatic interactions in assembly and maintenance of the structure of oligomeric integral membrane protein complexes is also implied by the separation and extrusion from the membrane, at high pH, of the major hydrophobic subunits of the cytochrome b6f complex from the chloroplast thylakoid membrane. It is inferred that the hydrophobic helix-helix interactions between the subunits of this complex, whose function is electron transfer and proton translocation, are relatively weak compared to those in bacteriorhodopsin.


Structural and evolutionary relationships among the immunophilins: two ubiquitous families of peptidyl-prolyl cis-trans isomerases.

The immunophilins, protein receptors for the immunosuppressing drugs cyclosporin A and FK506 and related proteins from plants, fungi, and bacteria, have been analyzed structurally and evolutionarily. The cyclosporin A binding proteins (cyclophilins) represent one ubiquitous family of homologous proteins, and the FK506- and rapamycin-binding proteins (FKBPs) constitute a second, unrelated family. Multiple sequence alignments of members of each of these two protein families define the highly conserved residues that are likely to play important structural and functional roles, and mutations in representative members of these two families that abolish or alter function have been evaluated. FKBPs have undergone greater evolutionary divergence than the cyclophilins. Evolutionary trees were constructed using two distinct programs, and these trees establish the structural relationships that allow division of each of these families into subgroups. The results lead to the suggestion that several genes encoding isozymic forms of the FKBPs and possibly also of the cyclophilins existed in prokaryotes before the emergence of eukaryotes on earth and that representatives of these genes were transmitted to both kingdoms to give rise to current subfamilies of these proteins. By contrast, compartmentalization of both classes of immunophilins appears to have arisen independently in prokaryotes and eukaryotes, late in evolutionary history.


[Anemia in Jerusalem children aged 3-6 years].

Anemia in Israel is prevalent in nursing infants but there are few data on its prevalence in children aged 3-6 years. In 436 children in this age group in 18 family practice clinics in the Jerusalem area a hemoglobin level of less than 11.0 g% was found in only 17 (3.9%). Age, sex, and suburban versus urban residence were not related to the incidence of anemia. In 74 children (17%) the average mean red cell volume (MCV) was less than 74 fl but it was not associated with low hemoglobin. This finding might indicate the presence of thalassemia or a predisposition to the development of iron deficiency. This group of children is at risk of developing iron deficiency anemia and therefore requires follow-up. Results of blood tests at ages 9-12 months were available in 198 of the children but the results were not of high predictive value for the development of iron deficiency at 3-6 years of age. Iron supplementation administered to them when nursing did not affect the incidence of anemia in the children studied.


[Inappropriate antidiuretic hormone secretion in T-cell non-Hodgkin's lymphoma].

A 45-year-old woman was hospitalized for an acute confusional state which was preceded by behavioral changes of a few weeks duration. The diagnosis of the syndrome of inappropriate antidiuretic hormone secretion as a presenting symptom of non-Hodgkin's T-cell lymphoma (needle biopsy) was made. In spite of intensive chemotherapy, and although hyponatremia did not recur, the clinical course was stormy, her condition deteriorated rapidly, and she died 3 months later.


[Multimodal management of bone sarcomas in children].

Osteogenic sarcoma and Ewing's sarcoma are the most common malignant bone tumors in childhood and adolescence. Marked improvement in prognosis and long-term survival have been achieved using combined modality protocols. We present a retrospective analysis of our experience with combined therapy of malignant bone tumors in children. Among 20 (ranging in age from 6-16, mean 11.4 years) with Ewing's sarcoma, 14 (70%) had complete remission by the end of treatment, 5 (25%) had partial response and 1 did not respond. The overall 10-year actuarial survival was 64%. Of the 10 with osteogenic sarcoma, 5 (50%) fully responded and are alive, 4 (40%) died after a partial or no response and 1 is receiving second-line therapy after partial response to primary treatment. The 10-year actuarial survival was 37.5% and the efficacy of combined modality therapy was demonstrated. However, further efforts are needed to arrive at optimal treatment for improved outcome.


[Thiamin deficiency is common in Israel].

Diseases due to vitamin B1 (thiamin) deficiency are considered to be uncommon in Israel. We present 13 patients admitted during the course of a year who were found to have thiamin deficiency. 5 had classic syndromes such as beri-beri, Wernicke's encephalopathy and cerebellar degeneration. In another 8 the thiamin deficiency was found during workup for less specific neurological abnormalities. Only a minority were alcoholics. Mainly at risk for developing nutritional deficiency were the solitary elderly of low socio-economic status with poor nutrition. Other reasons for thiamin deficiency were drug abuse and hyperemesis gravidarum. Thiamin levels should be determined not only in alcoholics and those with classic B1 deficiency syndromes, but in the routine workup of patients with sensory-motor neuropathy, dementia, gait disorders, cerebellar syndromes and confusional states. It is advised to give vitamins prophylactically to asymptomatic high risk patients.


[Anesthesia for cesarean section].

Of 684 parturients who underwent cesarean section between July 1985-August 1990, 371 (54.2%) were given epidural anesthesia; 50 (7.3%) required general anesthesia after a failed attempt at epidural anesthesia; and 5 (0.7%) underwent inadvertent spinal anesthesia because of dural penetration by the epidural needle. In 258 (37.7%) general anesthesia was decided on before operation. The intentional avoidance of spinal anesthesia for cesarean section in this university hospital is criticized.


[Infantile neuroaxonal dystrophy].

Infantile neuroaxonal dystrophy is a degenerative disease, mostly of nerve endings in the central and peripheral nervous system, with typical pathological findings. We describe a 3-year-old boy who had suffered from nystagmus, progressive muscle weakness and dementia since the age of 10 months. Biochemical work-up, MRI of the brain, and electrophysiological studies were within normal limits. Only skin biopsy, and sural nerve biopsy at a later stage, were diagnostic. We stress the importance of performing tissue biopsy even when intensive investigation is negative.


[Percutaneous drainage of pancreatic pseudocyst in children].

Pancreatic pseudocysts in children are usually the consequence of blunt abdominal trauma. Spontaneous resolution can be expected in up to 50%, while surgical drainage is required in the others. Percutaneous drainage of these pseudocysts has recently been reported to give good results. We present a 7-year-old boy treated successfully with percutaneous drainage of a traumatic pseudocyst of the pancreas.


[Combined cholestatic jaundice due to cholelithiasis and primary biliary cirrhosis].

An 82-year-old man was admitted because of painless jaundice and pruritus. Multiple small gallstones were seen on ultrasonography. Hepatic needle biopsy revealed bile stasis, intrahepatic bile ducts proliferation and inflammatory infiltration of the portal spaces. As the jaundice deepened, cholecystectomy was performed and a gallbladder full of small calculi was removed. Wedge biopsy of the liver led to the diagnosis of primary biliary cirrhosis (PBC). Colchicine was started and since then his condition has improved and become stable. PBC in an old man is very uncommon. The combination with gallbladder stones imposed special diagnostic and therapeutic problems. Although gallbladder stones are more common in PBC than in the general population, the combination of the 2 clinical entities is not sufficiently emphasized in the literature.


[Retrorectal cystic hamartoma].

The pathogenesis of retrorectal cystic hamartomas in the presacrococcygeal space, while known to be related to embryological remnants of the caudal region, is controversial. These lesions are rarely found in children; in the early stages of their development they may be symptomless. Diagnosis is usually made when the tumor is large enough to cause pain or intestinal obstruction, or when it becomes infected. A 2-month-old girl with a retrorectal cystic hamartoma initially treated as a perianal abscess is presented.


[Effects of analgesic-antipyretics on the spinal reflex potentials in cats: an analysis of the excitatory action of aminopyrine].

The effects of some analgesic-antipyretics on the spinal reflex potentials were studied in spinal cats. Aminopyrine at 25-100 mg/kg, i.v. produced a marked increase in mono- and poly-synaptic reflex potentials (MSR and PSR), and a decrease in dorsal root reflex potentials (DRR) in a dose-dependent manner. The amplitude of DRR decreased by aminopyrine was reversed by diazepam at 0.2 mg/kg, i.v.; however, the increased amplitudes of MSR and PSR were not affected by diazepam. Pretreatment of semicarbazide at 200 mg/kg, i.v. did not influence the increasing effect of aminopyrine on MSR and PSR. DL-5-Hydroxytryptophan produced facilitation of the MSR and PSR. In DL-5-hydroxytryptophan-treated cats, the amplitude of MSR was further increased by aminopyrine. Methysergide at 1 mg/kg, i.v. antagonized this increasing effect of aminopyrine on MSR and PSR. These observations suggest that the excitatory action of aminopyrine may be partly related to 5-hydroxytryptamine and not connected to the GABAergic mechanism. Other pyrazolone derivatives were also studied. Isopropylantipyrine at 50 mg/kg, i.v. produced increases in MSR and PSR. Intravenous sulpyrine at 500 mg/kg, antipyrine at 50 mg/kg or 4-aminoantipyrine at 50 mg/kg did not affect the reflex potentials. The non-pyrazolones, acetaminophen and indomethacin, did not increase the MSR and PSR. These results suggest that the N-dimethyl or isopropyl residue at the 4 position of the pyrazolone structure plays an important role in the excitatory action of analgesic-antipyretics in cat spinal cord.


[Effects of green tea extract on galactosamine-induced hepatic injury in rats].

The present study examined the preventive effects of green tea extract on D-galactosamine (GalN)-induced hepatic injury in rats, an animal model of viral hepatitis. A single i.p.-injection of GalN (700 mg/kg) to male Wistar rats caused fulminant hepatitis by 48 hr as assessed by marked increases in the serum aspartate aminotransferase (GOT), alanine aminotransferase (GPT) and alkaline phosphatase (ALP) activities; decreases in the serum protein and cholesterol levels and the amount of liver microsome P-450; and marked changes in organ weights. The lecithin: cholesterol acyltransferase (LCAT) activity markedly increased at 8 hr and markedly decreased at 24 hr after the GalN injection. In the experiment, animals were orally administered green tea extract at doses of 50, 100 or 200 mg/kg five times each before and after the GalN injection. Treatment with green tea extract significantly prevented the increases in the GOT, GPT and ALP activities in a dose-related manner. It also significantly prevented the decreases in serum albumin and total cholesterol, although not in a dose-related manner. A tendency to prevent the increase in LCAT activity and the decrease in liver microsome P-450 was also noted. Little effect was found on the other abnormal changes in the serum lipids and proteins and the organ weights. These results suggest that green tea may have an ameliorating effect on hepatic dysfunction.


[Effects of vanadyl sulfate on osteopenia in streptozotocin-induced diabetic (STZD) rats. Comparison with those of insulin].

The insulin mimetic effects of vanadium salts on glucose metabolism have been well-documented in STZD rats. In this study, the long-term effects of vanadyl sulfate (vanadium) on osteopenia in STZD rats were examined and compared with those of insulin. From 2 days after an intravenous injection of streptozotocin (30 mg/kg), the rats with hyperglycemia (> 300 mg/dl) received either vanadium (0, 0.02, 0.1 or 0.5 mg/ml) in drinking water or daily subcutaneous injections of insulin (0, 0.4 or 4.0 U/day) for 54 days. Their tibiae and femurs were examined by chemical analyses, by contact microradiography and by the method of double tetracycline labeling. Decreases in bone mass, bone density and in the rate of bone formation were observed in STZD rats. Development of these symptoms in the STZD rats with osteopenia was prevented by the administration of either vanadium or insulin in a dose-dependent fashion. The effects of vanadium at a dose of 0.5 mg/ml for preventing bone loss in STZD rats were similar to those of insulin at a dose of 4.0 U/day. These results indicate that vanadium has insulin mimetic effects on osteopenia in STZD rats.


[Hypoglycemic effects of Siamese Momordica charantia and Phyllanthus urinaria extracts in streptozotocin-induced diabetic rats (the 1st report)].

Hypoglycemic effects of the extracts of two Siamese plants, Momordica charantia (M.c.) and Phyllanthus urinaria (P.u.), were examined in streptozotocin-induced diabetic rats. Oral administration of a 50% methanol extract (30 mg/kg) of M.c. and P.u. decreased the blood glucose levels (BGL) by 25% and 24%, respectively, at 3 hr after administration. Among other fractions such as the ethyl ether or water soluble fractions, the 10 and 30 mg/kg n-butanol soluble fraction from M.c. extract was most effective in lowering BGL by 26% and 34%, respectively. Similarly with M.c., the n-butanol fraction from P.u. extract decreased BGL by 23% and 39% at the doses of 10 and 30 mg/kg, respectively. In the oral glucose tolerance test, n-butanol fractions from M.c. and P.u. (30 mg/kg, p.o.) both inhibited the initial increase in BGL to the same degree. In the intraperitoneal glucose tolerance test the n-butanol fraction of M.c. inhibited the increase of BGL prominently, but the n-butanol fraction of P.u. did not. These plants generally contain moderately non-polar hypoglycemic compound(s) soluble in n-butanol; and specifically, with regards to the hypoglycemic mechanism, the M.c. extract seems to act like insulin or via insulin secretion from the pancreas, like the action of sulfonyl ureas, and the P.u. extract may act via facilitation of glucose metabolism and/or the inhibition of glucose absorption in the gut like the action of biguanides.


[Pharmacological studies of nutritive and tonic crude drugs on fatigue in mice].

The aim of the present study was to clarify acute anti-fatiguing effects of three crude liquid drug preparations (S1-S3), containing almost the same amounts of Ginseng Radix, Epimedii Herba and Agkistrodon Japonicae, with each differentially containing an additional 11, 13 or 15 crude drugs. After preloading forced swimming or tetrabenazine (TBZ: 50, 100 mg/kg, i.p.), each of the S1-S3 preparations applied orally (0.1 ml/10 g) significantly increased the duration times of swimming together with decreased total duration times of immobility during swimming. These effects peaked 60 min postinjection with the following decreasing order of effectiveness: S3 > S2 > S1. The same order of efficacy was also found for increased locomotor activity and decreased durations of swimming immobility after TBZ. After pretreatment with 200 mg/kg TBZ preparations S1-S3 also increased the numbers of jumping on a hot plate with greatly reduced latency. Without preloading the forced swimming, S1-S3 did not have any effect on jumping and its latency, but both S2 and S3 significantly, but more weakly, as compared to those after its preloading, decreased the immobility times. These results indicate that these crude preparations may cause tonic effects and so far tested, these effects seem to be more effective on subjects fatigued with physical and/or mental works than an normal subjects.


[An injury of the liver caused by ischemia-reperfusion in rat liver. Report 2: Relationship between the damage of the liver and during the period of reperfusion].

Liver injury by 30-min ischemia following reperfusion was examined biochemically and histopathologically. A greater increase in the level of LDH was observed after 1-hr reperfusion. However, the level of LDH decreased in proportion to the period of reperfusion, while the levels of GOT and GPT were also increased rapidly and reached its peak at 12 hr following reperfusion and were almost restored to the control level by 48 hr. A similar increase was obtained in the lipid peroxides of the liver. In addition, cyt. P-450 content and NADPH cyt. c reductase activity decreased in proportion to the period of reperfusion up to 12 hr and then recovered by 96 hr. On the other hand, heme oxygenase activity was significantly increased by ischemia-reperfusion. The ischemia-reperfused liver resulted in various morphological changes with the period of reperfusion. The destruction of Disse's space, vacuolization of the cytoplasm and nonviable hepatocytes were observed after 12-hr reperfusion. These results indicate the greatest damages of the liver induced by 30-min ischemia following reperfusion is observed after 12-hr or 24-hr reperfusion. The liver injury by ischemia-reperfusion could be a useful experimental model to develop for future studies.


[Antihypertensive effect of felodipine, a new calcium antagonist].

The antihypertensive effect of felodipine was examined in various hypertensive animal models. In spontaneously hypertensive rats, felodipine administered singly at 0.1-1.0 mg/kg (p.o.) had a dose-dependent antihypertensive effect. Nifedipine was effective at 1 mg/kg. In the repeated oral administration experiment, both the maximum decrease in blood pressure and duration of the effect increased gradually and reached steady levels at 3 weeks of administration, which were maintained thereafter. Similar results were noted with nifedipine, but felodipine was longer-acting (4-6 hr) in the steady state than nifedipine (1-2 hr). No development of tolerance was observed during the administration period. In DOCA-salt and renal hypertensive (2K1C) rats, felodipine at 0.1-0.5 mg/kg (p.o.) was superior to nifedipine in the maximum decrease in blood pressure and duration of the effect. Felodipine up to 1 mg/kg (p.o.) caused no significant heart rate increase in any rat model. In renal hypertensive (2K2C) dogs given felodipine at 0.2-0.5 mg/kg (p.o.), the effect lasted for 2 hr after injection. This felodipine effect was stronger and longer lasting than the nifedipine one. At 0.5 mg/kg of felodipine, the heart rate was transiently increased. The present results show that felodipine has a stronger and long-lasting antihypertensive effect than nifedipine in the hypertension models.


[Investigation of the incidence of aberration in various indication for prenatal cytogenetic analysis].

In order to evaluate the role of prenatal cytogenetic analysis for the management of pregnant women, we studied the incidence of chromosomal aberration in 1,258 cases. In 502 cases with advanced maternal age (at least 35 years older), 12 (2.4%) cases of chromosome aberration were detected. The incidence of chromosomal aberration in the cases with women who had a previous child with chromosome aberration, women who had given birth to a congenital malformation child, and women who had ultrasonographic abnormalities were 3.0% (8/271), 0% (0/103) and 11.7% (36/307), respectively. Of cases with advanced maternal age, the incidence of chromosome aberration is 0% (0/21) at age 35, 0% (0/22) at age 36, 19% (1/52) at age 37, 2.2% (2/92) at age 38, 10% (1/102) at age 39, 1.3% (1/75) at age 40, 5.3% (3/56) at age 41, 6.9% (3/43) at age 42, 4.4% (1/23) at age 43 and 6.7% (1/15) at age 44. These results indicate that the incidence of chromosome aberration increases with maternal age. On the basis of these data, we recommend medical practice to offer prenatal diagnosis to all women who will be 37 or older. In the cases of fetal anomaly, they were diagnosed by ultrasonographic examination, the high incidence of chromosome aberration was detected in comparison with another group. Therefore, the prenatal cytogenetical analysis may also be performed in these cases.


Ca(2+)-and Sr(2+)-sensitivity of Akazara scallop troponin.

Ca(2+)-and Sr(2+)-sensitivity of desensitized myosin B-tropomyosin was investigated in the presence of troponin prepared from Akazara scallop, rabbit fast skeletal or bovine cardiac muscles. The Sr2+/Ca2+ concentration ratio at 50% activation in the presence of Akazara troponin was in the same range as the ratio in the presence of rabbit fast skeletal troponin, but higher than the ratio in the presence of bovine cardiac troponin.


[Comparative study of brain tumors treated at China Medical University, China and Kyushu University, Japan].

We have re-examined histopathological specimens of brain tumors extirpated at China Medical University from May, 1990 to June, 1992. During the last 2 years, about 400 cases of brain tumors were operated and 349 cases were histopathologically diagnosed and classified by one of the authors (T. I). The most common tumor was meningioma, 97 cases, followed by gliomas, 87 case and neurinoma, 71 cases. The sex and age distributions of these three tumor types were compared to those of Kyushu University Hospital, Japan. The most striking difference was age of meningioma and neurinoma patients, and Chinese patients were 10 years younger than Japanese patients. The incidence of 30th age group of meningioma was 25% in China and 10% in Japan. Thirty percent of neurinoma patients were operated at 30th and 40th age in China and Japan, respectively. The sex and ages of astrocytoma patients were almost the same frequencies in China and Japan. Among 22 cases of congenital tumors, 11 cases of epidermoid tumor in cerebello-pontine cistern was included. Cerebral tuberculoma, although rarely encountered in Japan, was 2 cases in China.


Glucogenolytic and hyperglycemic effect of 33-49 C-terminal fragment of pancreastatin in the rat in vivo.

The effects of the 33-49 C-terminal fragment of pancreastatin on glycogen content, glycemia, insulinemia and glucagonemia were studied in the rat in vivo. It was found that after intramesenteric vein injection of the peptide, the glycogen content of liver decreased compared with control group injected with saline-1 < % BSA. Blood glucose levels were increased by the C-terminal fragment of pancreastatin. This study shows that the 33-49 C-terminal fragment of pancreatasin could play a role in glucose metabolism not mediated by insulin or glucagon.


Comparison of the insulinotropic activity of glucagon-superfamily peptides in rat pancreas perfusion.

Previous studies have demonstrated that glucagon-superfamily peptides stimulate insulin release from the pancreatic islets in a glucose dependent manner. In this study we have carried out a structure-activity study of their insulinotropic activity using a rat pancreas perfusion with 5.5 mM glucose concentration. The following peptides were examined: glucagon-like peptide-1(7-36)amide (tGLP-1), glucagon, gastric inhibitory peptide (GIP), peptide having an amino-terminal histidine and carboxy-terminal isoleucine amide (PHI), vasoactive intestinal polypeptide (VIP), growth hormone releasing factor(1-29)amide (GRF), GRF(1-27)amide and synthetic hybrid-peptides of PHI-GRF, PHI(1-11)-GRF(12-27) and PHI(1-20)-GRF(21-27). Their potencies were evaluated as: tGLP-1 = GIP > glucagon > PHI = VIP > PHI(1-20)-GRF(21-27) > PHI(1-11)-GRF(12-27) >> GRF(1-29) = GRF(1-27). It is clear that 0.1 nM tGLP-1 stimulated insulin release, whereas 1 microM GRF(1-29) did not. These results indicate that 1) in addition to N-terminal amino acid (histidine or tyrosine), position 4 (glycine), position 9 (aspartic acid) and position 11 (serine) in the amino acid sequence are important for their insulinotropic activity, 2) not only the N-terminal portion but also the C-terminal portion of these peptides contribute to their insulinotropic activity.


Thyroidectomy blocks stress-induced prolactin rise in rats: role of the central serotonergic system.

Thyroidectomized (TX) adult Wistar male rats and their sham-operated controls were submitted to immobilization stress during forty minutes. Thyroidectomy partially blocks stress-induced prolactin (PRL) secretion. Previous administration of MK 212, a serotonin agonist, reverts this picture. The effect of MK 212 is specifically due to its interaction with 5HT2 receptors, since the injection of LY 53857, a selective blocker of these receptors, 30 min before MK 212, prevents the effect of this serotonin agonist. LY 53857, injected alone, yields a partial blockade of PRL secretion during stress in sham-operated rats. TX rats receiving LY 53857 or saline have comparable low values of plasma PRL during stress. It is suggested that thyroidectomy disrupts the functional integrity of the central serotonergic pathways involved in the stress-induced PRL rise.


Comparative effects of thyroxine and/or retinoic acid treatment in vivo on growth hormone synthesis and release by pituitaries from thyroidectomized rats.

Thyroid hormones and retinoic acid (RA) coregulate growth hormone (GH) synthesis and release from cultured pituitary tumor cells by interacting with nuclear receptors that activate GH gene transcription. Whether these two compounds share overlapping GH regulatory activities in vivo is unclear. Therefore we compared the effects of in vivo replacement therapy with thyroxine (T4) and/or retinoic acid (RA) on GH synthesis and release in pituitaries from hypothyroid rats. Three weeks after thyroidectomy, male rats (100-150 grams, body weight) received 7 days of intraperitoneal T4 (20 ug/kg/day) and/or RA (500 ug/kg/day) or vehicle. Isolated pituitary fragments were incubated for 3 h with [14C]leucine followed by 2 h with [3H]leucine and 3 nM rat growth hormone-releasing hormone (GHRH). Basal synthesis, GHRH-induced release of stored [14C]GH, and GHRH-stimulated release of newly synthesized [3H]GH were assessed by specific immunopercipitation of media and tissue homogenates. T4 increased the synthesis of GH in the absence and presence of GHRH. T4, but not RA, increased the absolute amount of stored and newly synthesized GH released by GHRH. Neither T4 nor RA altered the percent of stored GH released by GHRH, however, both independently or additively decreased the percent of newly synthesized GH released by GHRH. In summary, treatment of hypothyroidism with T4 increased GH synthesis and absolute release. Interestingly the fractional release of GH was unchanged or decreased by T4 treatment. RA treatment had no effect on GH synthesis or absolute release, but like T4 it decreased the fractional release of newly synthesized GH. Thus T4 and RA did not share similar regulatory effects on GH synthesis and stored GH release but did have similar effects on the fractional release of newly synthesized GH in pituitaries from thyroidectomized male rats.


Pre- and postnatal protein undernutrition increases hepatic carnitine palmitoyltransferase I activity and decreases enzyme sensitivity to inhibitors in the suckling rat.

Rats were pair-fed isocaloric diets containing either 25% (control diet) or 6% protein (low-protein diet) during the 5 weeks prior to conception and through the gestation and lactation periods; then, carnitine palmitoyltransferase I (CPT-I) activity was determined in liver and skeletal muscle mitochondria isolated from the corresponding pups. Maternal protein undernutrition increased the activity of hepatic CPT-I all along the suckling period, whereas the activity of the skeletal muscle enzyme was unaffected. Moreover, the sensitivity of hepatic CPT-I to inhibition by both malonyl-CoA and 4-hydroxyphenylglyoxylate was decreased in the low-protein group. These alterations in the properties of hepatic CPT-I may be involved in the appearance of hyperketonemia in the rat pup upon maternal administration of low-protein diets.


Dynamics of circulating osteocalcin in rats during growth and under experimental conditions.

Osteocalcin is the most abundant non-collagenous protein produced in the process of bone formation. A specific radioimmunoassay has been developed using a rabbit antiserum raised against osteocalcin extracted from rat bone. The sensitivity of the assay was tested in male and female rats under different experimental conditions: ovariectomy led to a mild increase in circulating osteocalcin (70.6 +/- 6.9 vs 51.6 +/- 6.3 ng/ml; p < 0.05) and deprivation of dietary calcium elevated plasma levels further (119 +/- 6.3 ng/ml; p < 0.01). As expected, pharmacological enhancement of bone turnover with calcitriol produced a significant increase in plasma osteocalcin (296 +/- 24.1 vs 89.5 +/- 5.1 ng/ml; p < 0.01), whereas prednisolone, a steroidal compound known to inhibit osteoid mineralization, significantly reduced circulating concentrations of this protein (70 +/- 7.4 vs 100 +/- 6.3 ng/ml; p < 0.05). Plasma kinetics recorded in female rats between birth and the 100th week revealed a highly significant (p < 0.001) elevation peaking at the third week (231 +/- 70.6 ng/ml) and slowly declining to reach values measured at birth (41.3 +/- 9.2 ng/ml) at the 16th week (47 +/- 4.6 ng/ml). Subsequently, a small but significant (p < 0.05) decline towards senescence was recorded. The osteocalcin surge preceded the period of rapid growth (weeks 3 to 11) estimated by vertebral length progression, showing a tendency to stabilize as growth spurt slowed down. A moderate but significant (p < 0.01) increment was observed after mating (87.8 +/- 5.1 vs 69.5 +/- 4.0 ng/ml). Although plasma osteocalcin remained stable during lactation, average levels were elevated in comparison with age-matched non-pregnant controls.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of insulin treatment on HbA1c, body weight and lipids in type 2 diabetic patients with secondary-failure to sulfonylureas. A five year follow-up study.

No conclusive data are available about the long-term effect of insulin treatment in type 2 diabetic patients failing to maximal doses of sulfonylureas and caloric restriction. In total 160 non-obese type 2 diabetic patients with secondary failure were substituted with insulin using a diabetic teaching and care program. From these 160 patients 40 died within the observation period of five years; 102 patients had a complete five year follow-up, whereas the remaining 18 patients did not come to regular follow-up visits. Metabolic control parameters improved significantly in the 102 patients with the complete five year follow-up. Postprandial plasma glucose (16.0 mM vs 10.9 mM; p < 0.0001) and HbA1c values (8.7% vs 7.1%, p < 0.0001) decreased significantly from the state before to five years after insulin substitution. In addition, plasma lipid levels could be significantly lowered under insulin therapy (cholesterol 6.2 +/- 1.5 mM vs 5.4 +/- 3.6 mM, p < 0.0002; triglycerides 2.8 +/- 1.6 mM vs 2.4 +/- 2.1 mM, p < 0.01). However, we observed a significant weight gain (mean: 10.6 kg) associated with insulin application during the five year follow-up. Thus, the body-mass-index decreased from 28.9 at onset of type 2 diabetes to 24.5 (p < 0.0001) at time of secondary failure and increased again to 28.5 (p < 0.0001) at five years after onset of insulin treatment. Furthermore, small increases of plasma creatinine from 88.4 microM to 115 microM, as well as systolic (19.3 kPa to 20.7 kPa) and diastolic (10.7 kPa to 11.3 kPa) blood pressures were observed.(ABSTRACT TRUNCATED AT 250 WORDS)


Refractoriness at peripheral and pituitary receptors in general and pituitary types of thyroid hormone resistance.

Patients with the general type (patient #1 and #2) and the selective pituitary type (#3) of thyroid hormone refractoriness (TR) were studied to clarify defects at peripheral and pituitary receptors. Products of T3 and TSH (n = 63) were calculated when T3 was above the normal limit (T3 > 1.8 ng/ml, 2.8 nmol/l) as one of the indices of pituitary resistance. Means of T3 (ng/ml) x TSH (mU/l) of patient #1 (mean; 40.8), #2 (15.0) and #3 (8.6) were significantly greater than patients with Graves' disease (2.1), suggesting pituitary refractoriness in the 3 patients. The products of patient #1 and #2 were also significantly larger than patient #3, demonstrating that the pituitary insensitivity in the latter (#3) was less than the former patients. Means of serum cholesterol in patients #1 and #2 were higher than patient #3 and patients with Graves' disease. Products of T3 (ng/ml) and cholesterol (mg/ml) (n = 28) in the patient #1 (541.9) and #2 (461.0) were significantly greater than the patient #3 (292.8) and the patients with Graves' disease (275.3). The results demonstrate generalized refractoriness in the patient #1 and #2 and selective pituitary resistance in the patient #3. It is suggested that our patient with the pituitary type (#3) had less severely affected receptors at the pituitary than our two patients with the general type. These results are consistent with the previous hypothesis that the pituitary type of TR is a partial form of this disease.


Are adrenal and testicular androgen levels correlated?

To investigate the reported correlation between adrenal and testicular serum androgen levels, testosterone, DHEAS and androstenedione were measured in the serum of 92 healthy young males. Testosterone and androstenedione were found to have a weak but statistically significant correlation, while no correlation existed between testosterone and DHEAS, or DHEAS and androstenedione. These results indicate that although common steroidogenic pathways lead to androgen synthesis in both adrenals and testes, the regulation of steroid production in these glands is influenced by different factors. The correlation of testosterone with androstenedione can be attributed to their peripheral interconversion as well as to the fact that half of androstenedione is of testicular origin. Various other aspects of the androgen regulation mechanism such as ACTH stimulation and the role of aging, are presented and discussed.


Combination of microdialysis and glucosensor permits continuous (on line) SC glucose monitoring in a patient operated device. II. Evaluation in animals.

The microdialysis technique was used for following the glucose content of the extracellular subcutaneous (SC) fluid under varying blood glucose levels in rats. The glucose content in the microdialysis perfusion fluid was continuously analyzed by means of the measuring flow chamber of an ex vivo glucose monitor. In six ChBB rats blood glucose levels were varied between 40 mg/dl and 575 mg/dl by intravenous (IV) infusion of glucose and by SC injections of insulin, respectively. After a running-in period of about half an hour, the glucose content in the perfusion fluid was closely related to the blood glucose concentration (r > 0.92) up to a time period of 6 hrs. The "relative recovery" rate of glucose by the microdialysis probe in the SC tissue varied within the 6 experimental sessions. The relative recovery rate could be shown to be not dependent on the absolute blood glucose levels in the individual rat within the glucose concentration range tested.


Effect of SH reagents on rod photoresponse of isolated frog retina.

Several SH reagents, N-ethylmaleimide (NEM), p-chloromercuribenzoic acid (PCMB), p-chloromercuribenzene sulphonate (PCMBS) and monoiodoacetic acid (MIAA) changed the wave form and the peak of the amplitude of the photoresponse remarkably. The effects of amino group modifying reagents, ethyl acetimidate (EA) and isethinyl acetimidate (ITA) on photoresponse were very slight. The possibility of a SH protein as cGMP-sensitive cation channel protein is discussed.


Cyclic vertical squint.

A rare case of cyclic vertical squint which developed after surgery on medial rectus muscle and its subsequent management by the Faden operation is described.


Bilateral proptosis due to metastatic Ewing's sarcoma of the orbit: fine needle aspiration cytology (FNAC) and histopathology of a case.

Bilateral proptosis due to metastatic Ewing's sarcoma is an extremely rare presentation and thus merits reporting. The role of fine needle aspiration cytology in the diagnosis is highlighted.


Unusual Marcus Gunn phenomenon in adults.

Two unusual cases of Marcus Gunn phenomenon in adults are presented. The first case was characterised by a bilateral jaw-winking phenomenon along with an asymmetric bilateral congenital ptosis, whereas the second case had bizarre spontaneous movements of the affected lid, deficient abduction and pseudoptosis in association with jaw-winking. The pathogenesis of Marcus Gunn phenomenon is discussed.


Characterization of specific binding sites for [3H]-1,3-di-o-tolyl-guanidine (DTG) in the rat glioma cell line C6-BU-1.

The aim of the present study was to find out if a cell line of glial origin possesses sigma and/or phencyclidine (PCP) binding sites. Binding of [3H]1,3-di-o-tolyl-guanidine (DTG), a highly selective ligand for sigma binding sites, and of [3H]N-[1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP), a radioligand specific for PCP receptors, to C6-BU-1 glioma cells was investigated. Binding of [3H]DTG to C6-BU-1 cell membranes was reversible, saturable (Bmax = 10.5 pmol/mg protein), and of high affinity (KD = 26 nM). C6-BU-1 cells do not possess PCP receptors as indicated by negligible specific binding of [3H]TCP to C6-BU-1 cell membranes. Specific binding of [3H]DTG was reduced in the presence of Ca2+ and to a lesser extent by Mg2+. The rank order of potency of various PCP and sigma ligands was DTG > (+)3-[(3-hydroxy-phenyl)-N-n-propyl-piperidine] [(+)3-PPP] > haloperidol > pentazocine > (-)3-PPP > PCP > metaphit > dextromethorphan > (-)butaclamol > (+)butaclamol > (-)N-allylnormetazocine [(-)SKF 10,047] > MK801 > (+)SKF 10,047 > ketamine. The drug specificity, confirmed by a reversed stereoselectivity for the benzomorphan opiate SKF 10,047, indicated that these sites correspond to a subtype of sigma binding sites, the so-called sigma 2 binding site. Thus, the C6-BU-1 cell line is the first glial cell line demonstrated to have sigma 2 binding sites.


Use of beta radiation to control I.O.P.

The use of ophthalmic applicator containing Strontium-90 beta ray was used to bring about a change in I.O.P. by its effect on the ciliary body. The change in I.O.P. depends on the degree of damage done to the ciliary body. The study showed that the change in I.O.P. was directly proportional to the intensity of beta rays application - higher the dose of beta radiation more was the damage and more the reduction in I.O.P.


Effect of insulin on glucose and glycogen metabolism and leucine incorporation into protein in cultured mouse astrocytes.

Insulin, following binding to its receptor, produces a dose- and time-dependent stimulation of entry of 2-deoxy-D-[U-14C] glucose and glycogen synthesis from D-[U-14C] glucose in cultured mouse astrocytes following differentiation. Maximal stimulation of both glucose entry (217% above basal) and of glycogen synthesis (209% above basal) was observed at an insulin concentration of 1.7 x 10(-8) M. Insulin also stimulates the incorporation of leucine into astrocytic proteins with maximal stimulation (156% above basal) at an insulin concentration of 1.7 x 10(-7) M, but no effect on leucine uptake was observed at an insulin concentration of 1.7 x 10(-6) M. These results, together with a previous demonstration that insulin and certain insulin analogues stimulate pyrimidine nucleoside incorporation into nucleic acid, indicate that insulin has diverse actions on biomacromolecular metabolism in cultured mouse astrocytes.


Involvement of the eye and orbit in neurofibromatosis type 1.

11 individuals were diagnosed to have neurofibromatosis type 1 and were examined for evidence of any ophthalmic lesions. Lisch nodules were the commonest manifestation of the disease and were present in 73% of all the patients (88% of those aged 16 years or more). 55% of the cases showed presence of neurofibroma on the lids. Other findings were optic glioma, unilateral sphenoid dysplasia with enlarged orbit, medullated nerve fibers and prominent corneal nerves with an incidence of 9% each.


Norries disease.

A 2-month-old male infant was found to have Norrie's disease. The clinical presentation and detailed histological features diagnostic of the disease are discussed. This is the first authentic, histologically proven case of Norrie's disease from India. The absence of hearing loss and mental retardation at the time of presentation at the early stage of infancy and the fact that the case was sporadic do not detract from the diagnosis. However the child at the age of one year developed hearing loss.


Differential proliferative response of human and mouse astrocytes to gamma-interferon.

We have previously shown that gamma-interferon promoted the proliferation of adult human astrocytes isolated from brain biopsy specimens. In contrast, in the present study, astrocytes derived from neonatal mouse brains and treated with recombinant murine gamma-interferon responded by a decrease (average of 50% at 100 U/ml) in proliferation. The basal rate of proliferation as assessed by bromodeoxyuridine incorporation was markedly increased in neonatal mouse astrocytes when compared to the adult human cells, suggesting that age, and the corresponding metabolic activity of cells, could be important determinants in the mitogenic response of astrocytes to cytokines. However, subsequent examinations of fetal human and adult mouse astrocytes, with comparable basal rate of proliferation to neonatal mouse and adult human cells respectively, showed gamma-interferon to promote DNA synthesis in fetal human astrocytes while inhibiting that of adult mouse astrocytes. The results suggest species differences in the proliferative response of human and mouse astrocytes to the cytokine gamma-interferon.


Immunotherapy in allergic conjunctivitis.

Eighty patients with allergic conjunctivitis were treated with immunotherapy employing specific allergens. Sixty-two percent of these showed beneficial response. In cases of vernal conjunctivitis needing topical steroid preparations frequently for control of symptoms, immunotherapy is worth attempting to cause remission of symptoms.


Migration of Schwann cells from the distal stump of the sciatic nerve 1 week after transection: the effects of insulin and cytosine arabinoside.

We have examined the migratory capacity of Schwann cells from the distal stump of a 1-week transected sciatic nerve of adult rat for a distance of 10 mm. The distal stump was introduced into the open end of a silicone chamber packed with artificial fibrin sponge (Gelaspon) soaked in phosphate-buffered saline (control chambers), cytosine arabinoside (Ara-C) (0.05 mM), or insulin (40 U/ml). Migrating Schwann cells were distinguished from fibroblasts by the presence of non-specific cholinesterase (nChE) activity and glial fibrillary acidic protein (GFAP). The cells of distal stumps including Schwann cells accepted Gelaspon as a suitable adhesive substratum. In the chambers filled with Gelaspon soaked in phosphate-buffered saline alone Schwann cells were outnumbered by fibroblasts. The addition of Ara-C resulted in greater numbers of Schwann cells, which migrate longer distances into the chambers. The application of insulin enhanced Schwann cell migration as well. These morphologic observations were further supported by biochemical measurements of nChE activity. The results suggest an influence on Schwann cell migration by fibroblasts of connective tissue sheaths and a stimulation of Schwann cell migration by insulin.


Ultrasonic study to see the effect of topical pilocarpine and homatropine on anterior chamber depth in phakic cases.

Pilocarpine and Homatropine are the drugs having known effect on the depth of anterior chamber. The purpose of this study was to demonstrate the time of onset, peak effect and its duration of action as well as shallowing/deepening of the anterior chamber, after single instillation of pilocarpine 2% or homatropine bromide 2%, topically in one eye. Also we tried to see if there is any effect on the contralateral eye, due to systemic absorption of pilocarpine, homatropine after topical instillation of the drug in one eye. Pilocarpine causes a measurable shallowing of the anterior chamber with onset of effect with in 20 minutes and a peak in 60 minutes, the average narrowing being 0.26 mm. (range 0.20-0.29 mm.). Homatropine has a measurable deepening effect on the anterior chamber, due to axial flattening of the lens because of cycloplegia, with a range of 0.33 to 0.36 mm. In 70% of the cases the effect passes away with in 24 hours., but in 30% it comes to normal in 48 hours.