Tyrosine hydroxylase deficiency presenting with a biphasic clinical course.

Tyrosine hydroxylase deficiency, a cause of the autosomal recessive form of L-DOPA responsive dystonia, has been associated with a broad spectrum of movement disorders and clinical courses. We describe a new patient presenting with an early onset spastic paraplegia who later developed a progressive generalized dystonic-dyskinetic syndrome. He markedly improved with a very low dosage of L-DOPA/carbidopa, while higher dosages were not tolerated. Two novel mutations (p.G414R/p.L510Q) were detected in the TH gene.

The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency.

A fall in blood phenylalanine (Phe) after tetrahydrobiopterin (BH(4)) administration is a common trait in phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (McKusick 261600). To explore the extent and biological correlates of this phenomenon we studied: (a) the spectrum of BH(4) response in patients with PAH deficiency; (b) the variability of BH(4) response according to the severity of the biochemical phenotype; and (c) the variability of the response to BH(4) in subjects with the same genotype. Fifty PAH-deficient subjects (age 1 month-35 years) were enrolled for the study (5 with mild hyperphenylalaninaemia (MHPHE), 15 with mild phenylketonuria (MPKU) and 30 with classic phenylketonuria (CPKU) and underwent an identical schedule of blood samplings 24 h before and after oral BH(4) challenge (6(R)-BH4, 20 mg/kg per day), leaving Phe intake unchanged. The effect of BH(4) on blood Phe concentration was evaluated according to the percent decrease of Phe during the 24 h following the challenge (criterion a), and as variation exceeding the individual variability of blood Phe (criterion b). The number of BH(4)-responders according to criterion b was 31 (including all the 14 detected by criterion a): 17 out of 30 CPKU (57%), 9 out of 15 MPKU (60%), and all the MHPHE subjects (chi(2) = 3.45, df = 2, p = 0.178). The effect of BH(4) showed a large interindividual variability unrelated to diagnostic classification, basal value of blood Phe, maximum percentage of Phe reduction, Phe intake, and genotype. Some inconsistencies were found in patients with identical genotype. The first responsive case homozygous for the severe R408W mutation was found. Two new mutations, Y387X and G352C, were identified (the former was BH(4)-responsive), and the responsiveness of three already reported mutations (R261Q, D338Y, T92I) was substantiated.

ET-1 levels in cardioischemic patients undergoing atrial pacing.

Atrial pacing (AP) procedure was carried out in 11 cardioischemic patients to reproduce tachycardia-induced myocardial ischemia. Six control subjects underwent the same procedure until the maximum pacing rate was reached. During the procedure, endothelin-1 (ET-1) and plasma lactate levels were measured in the coronary sinus and in the aortic root. In all the patients, atrial pacing provoked electrocardiographic signs and metabolic evidence of myocardial ischemia and a significant decrease (p<0.001) in left ventricular ejection fraction. At AP-induced ischemia, coronary sinus (17.31 +/- 4.20 pg/mL) and arterial (9.60 +/- 3.31 pg/mL) ET-1 plasma levels were significantly different (p<0.001) in the patients. On the contrary, at maximum pacing rate, no significant difference (p=0.186) emerged between coronary sinus (9.72 +/- 1.09 pg/mL) and arterial (8.95 +/- 0.75 pg/mL) plasma ET-1 levels in the control group. These results suggest that, in cardioischemic patients, tachycardia can induce the coronary endothelium to release significant amounts of ET-1.

Met-enkephalin levels during PTCA-induced myocardial ischemia.

Met-enkephalin (Met-enk) has been demonstrated to modulate myocardial-ischemia mechanisms via the opioid receptors, but no studies are now available on Met-enk levels in the coronary circulation. In this experience Met-enk levels were evaluated in aortic root and in coronary sinus at baseline (T0), during PTCA induced transient ischemia (T1) and during reperfusion (T2). No significant differences were found at any time. Thus, it appears that there is no Met-enk extraction from the coronary circulation during provoked myocardial ischemia and no Met-enk release from the ischemic heart.

The role of met-enkephalin in silent myocardial ischemia in diabetic patients.

Met-enkephalin plasma levels were evaluated in 20 cardioischemic diabetic patients. All the patients had ECG ischemic signs. Ten patients with diabetic autonomic neuropathy, experienced no pain during myocarial ischemia. Met-enkephalin levels in the diabetic patients with silent myiocardial ischemia were significantly lower compared to those in the symptomatic patients. This demonstrates that the absence of myocardial ischemic pain in neuropathic diabetic patients is not accounted for by met-enkephalin action.

Mitral prolapse. A heart anomaly in a clinical neuroendocrine context.

Mitral valve prolapse was identified as a separate nosological entity by Barlow in 1963. A characteristic of this cardiac anomaly is blood reflux into the left atrium during the systole owing to the lack of adhesion between valve flaps. The presence of symptoms linked to neuroendocrine dysfunctions or to the autonomic nervous system lead to the onset of the pathology known as mitral valve prolapse syndrome (MVPs). It is usually diagnosed by chance in asymptomatic patients during routine tests. MVPs includes complex alterations to the neurovegetative system and a high clinical incidence of neuropsychiatric symptoms, like anxiety and panic attacks. A neuroendocrine mechanism thought to underlie panic attacks was recently proposed based on a biological model. In general, the cardiovascular anomaly manifested by patients with MVPs could be defined in neuroendocrine-constitutional terms.

A case of chronic adrenocortical insufficiency with iatrogenic anasarca.

The decrease in active hormones that characterizes chronic adrenal insufficiency results in hypovolemia. In some patients, residual adrenal function, mineralocorticoid therapy, and concomitant heart or liver failure, or both, can paradoxically provoke edema. The case report that follows describes a patient with iatrogenically induced anasarca resulting from the unhappy confluence of usually appropriate therapy and coexisting medical conditions.

Are elevated levels of soluble ICAM-1 a marker of chronic graft disease in heart transplant recipients?

Positivity for circulating intercellular adhesion molecule-1 (ICAM-1) in heart transplant recipients has been claimed to predict the development of coronary artery disease and risk of graft failure. Soluble ICAM-1 were evaluated in 32 heart transplant recipients. Five of these patients, who had undergone transplantation several years before, were positive for soluble ICAM-1 but did not present any clinical sign of graft rejection. Furthermore, although heart graft coronary disease was diagnosed in 15 of the 32 patients, they did not show significantly higher titres of soluble ICAM-1 compared to the remaining patients. These findings suggest that major caution is necessary when considering ICAM-1 positivity as a marker of graft disease.

Clinical importance of thrombomodulin serum levels.

Thrombomodulin is a glycoprotein that can bind to thrombin and activate protein C, thus mitigating the effects of cytokines produced by inflammatory and immunological processes. The molecule exerts a protective function on endothelial cells. Thrombomodulin is cleaved to its soluble form by neutrophil elastase and by other substances produced during acute and chronic inflammatory responses, immunologic reactions and complement activation. ELISA technique yields normal serum levels of 3.1 +/- 1.3 ng/ml; in males these levels are higher; TM levels also rise during menopause. Other circumstances associated with an increase of serum TM levels are smoking, disseminated intravascular coagulation (DIC), cardiac surgery, atherosclerosis, ARDS, liver cirrhosis, diabetes mellitus, cerebral and myocardial infarction, and multiple sclerosis. Serum levels of TM represent an useful prognostic index, because they are associated with an increase in mortality rate, or however a progression of the underlying pathological condition.

The relationship between glycated hemoglobin and polymorphonuclear leukocyte leukotriene B4 release in people with diabetes mellitus.

In order to evaluate polymorphonuclear leukocyte (PMN) activity in diabetes mellitus, leukotriene B4 (LTB4) levels were measured in sixty patients, 31 affected with Type 1 diabetes mellitus and 29 affected with Type 2 diabetes mellitus. The LTB4 levels (12.1+/-0.2 pg/100 microl) in diabetic patients were higher compared to those of the control group (7.9+/-0.1 pg/100 microl) (P < 0.001), and remained significantly higher (P < 0.001) (12.8+/-0.2 pg/100 microl) than in the control group (11.0+/-0.2 pg/100 microl) after stimulation with calcium ionophore. A significant and positive correlation between glycated hemoglobin and LTB4 was demonstrated (P < 0.001, r = 0.80). This study demonstrates that in diabetic patients there is a PMN activation and that this activation is correlated to glycated hemoglobin level.

Anti-neutrophil cell antibodies in newly diagnosed patients with type-1-diabetes.

Both anti neutrophil cell antibodies and anti endothelial cell antibodies were found in 7 out of 30 newly-diagnosed type-1 diabetic patients. This confirms the abnormal activation of the immunological system in the early stage of type-1 diabetes mellitus.

Adrenomedullin assay and its clinical significance.

Adrenomedullin (Am) is a recently discovered peptide, first purified from pheochromocytoma specimens, with a chemical structure similar to that of CGRP and amylin. Adrenomedullin is present in numerous human body tissues and its powerful vasodilatatory activity is thought to play an essential role in cardiovascular and renal homeostasis.

CGRP and ET-1 plasma levels in normal subjects.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) is a 37 amino acid peptide displaying about 50% homology with amylin which is secreted from the pancreatic islets of Langerhans. The main form, the beta-CGRP, is produced by the enteric nervous system and perivascular nerves of the vasa-vasorum. It represents one of the most powerful vasodilator yet discovered but its role is not yet completely clarified. High levels of this peptide have been shown in patients affected with thyroid medullary carcinoma, phaemocromocytoma and lung carcinoma. Recently circulating levels of CGRP have been found in normal subjects. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, isolated from porcine endothelial cells, is an important regulator of the vascular tone acting in physiological antagonism with atrial natriuretic hormone (ANH). With this study we intended to investigate the presence of any correlation between CGRP and ET-1 in normal subjects. PATIENTS: For the study we considered 20 normal subjects (11 males and 9 females) aged 23 to 50. MEASURES: Plasma levels of CGRP and ET-1 were measured by radioimmunological Kit. RESULTS: A positive and significant correlation between calcitonin gene-related peptide and endothelin-1 was found. CONCLUSIONS: Our results confirms that CGRP and ET-1 have opposing actions on vessels and that they can act together in haemodinamic regulation.

Coronary sinus plasma beta endorphin levels in cardioischemic patients undergoing PTCA.

Plasma beta-endorphin levels were studied in the coronary sinus of 8 patients undergoing percutaneous transluminal coronary angioplasty (PTCA). All the patients had ECG ischemic signs and pain during the inflation of the balloon. No significant changes in plasma beta-endorphin levels were observed during PTCA-induced ischemia. Baseline coronary sinus plasma beta-endorphin levels were found to be elevated when compared with peripheral ones which would suggest an accumulation of beta-endorphin in the ischemic heart.

Simultaneous isothermal determination of diphenylhydantoin and phenobarbital serum levels by gas-liquid chromatography following flash-heater hexylation.

A rapid, accurate, precise, and sensitive procedure for the simultaneous determination of diphenylhydantoin and phenobarbital under isothermal conditions involves on-column hexylation of the compounds. After extraction of serum samples, the evaporated residues are dissolved in tetrahexylammonium hydroxide. An aliquot of the resulting solution is introduced directly into a gas chromatograph where conversion to hexyl derivatives and subsequent separation takes place. The hexylated derivatives are identified by their retention times relative to appropriate internal standards. Concentrations are obtained from standard curves plotting relative peak height versus concentration of drug.

Gas chromatographic studies of phenobarbital and diphenylhydantoin after flash-heater alkylation.

The functionally excellent flash-heater methylation, ethylation and butylation techniques have been extended to include the higher alkyl homologs. Phenobarbital and diphenylhydantoin have been alkylated using the tetraalkylammonium hydroxides in which the alkyl group ranges from methyl to hexyl. The gas chromatographic properties of the resulting alkyl derivatives have been investigated.