Combination of nicotinamide and steroid versus nicotinamide in recent-onset IDDM. The IMDIAB II Study.

OBJECTIVE: The aim of this study was to compare the effect of nicotinamide (NCT) alone or in combination with a cortisone-like substance, deflazacort (DFL), on the integrated parameters of metabolic control in patients with the recent-onset of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: Thirty-six patients who were diagnosed with diabetes between 5 and 35 years of age entered a randomized, double-blind, 1-year prospective study. Group A (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus DFL for 3 months (0.6 mg.kg-1.day-1 in the first month, 0.3 mg.kg-1.day-1 in the other 2 months). Group B (n = 18) received NCT for 1 year (25 mg.kg-1.day-1) plus placebo for the first 3 months. All patients were treated with intensified insulin therapy. RESULTS: At 3 months after diagnosis, the insulin dose was significantly higher in group A compared with group B (P < 0.03) with similar HbA1 levels. Basal and stimulated C-peptide levels in group A of both adults and children were significantly higher compared with patients of group B (P < 0.05 and P < 0.03, respectively). At the end of a 1-year follow-up, basal C-peptide did not differ between the two groups, although stimulated C-peptide was still significantly higher in patients of group A compared with group B (P < 0.05). Finally, insulin requirement did not differ between the two groups. CONCLUSIONS: A short-term course of DFL therapy at diagnosis in addition to NCT slightly increases glucagon-stimulated but not basal beta-cell function after 1 year.

Human cytomegalovirus product UL44 downregulates the transactivation of HIV-1 long terminal repeat.

OBJECTIVE: Human cytomegalovirus (HCMV) is often isolated from HIV-1-infected patients and the two viruses can infect the same cell type giving rise to direct bidirectional interactions. Whereas the long terminal repeat (LTR) transactivation ability of HCMV immediate early gene (IE1/IE2) is well documented, no information is available on the possible role of other HCMV proteins. In this study, the activity of ppUL44, an early DNA-binding protein, on HIV LTR transactivation was investigated. METHODS: HIV LTR transactivation by ppUL44 in presence or absence of HIV-1 Tat and HCMV IE1/IE2 was determined in J-Jhan and U973 cells through transient transfection experiments with a series of different expression vectors. Some experiments were also performed on U373-MG astrocytoma cells permanently transfected with UL44 or with another HCMV gene used as a control (UL55). RESULTS: The basal transactivation activity of the HIV LTR was not influenced by the presence of ppUL44. On the contrary, the transactivation observed in the presence of Tat, IE1/IE2 or both factors in synergy was strongly downregulated by ppUL44 in a dose-dependent manner. Deletion constructs of ppUL44 demonstrated that the region of the molecule responsible for the inhibition of the LTR is located within the last 114 amino acids at the carboxyl-terminal region. CONCLUSIONS: The results obtained indicate that within the last 114 amino acids of ppUL44 there is a domain that has a negative effect on the ability of HIV-1 LTR to be activated by both its autologous transactivator Tat and the heterologous transactivator HCMV IE1/IE2 functioning individually or synergistically.

Prokaryotic expression of a large fragment of the most antigenic cytomegalovirus DNA-binding protein (ppUL44) and its reactivity with human antibodies.

We isolated and characterized from a lambda gt11 expression library clones expressing portions of human cytomegalovirus (HCMV)-p52. This nonstructural viral protein is encoded by UL44 and is known to be one of the best IgM reactive antigens. The reactivity of these clones was studied with human antibody and the gene fragment coding for the most immune-reactive portion of p52 (aa 202-434) was cloned in a prokaryotic expression vector, pROS, which overexpresses the antigen as a fusion protein to a truncated molecule of beta-galactosidase.

Disruption of iris adrenergic transmission as an index of poor endorphin modulation in headache.

Pupillometry was used to evaluate the effect of oral or topically applied adrenomimetic drugs and of local morphine on pupillary size in headache patients and controls. In headache sufferers, a disruption of adrenergic transmission is suggested since the iris adrenergic nerve terminal is apparently poor in NE; this neuron also exhibits a reduced capacity of neurotransmitter synthesis and an adrenoceptor hypersensitivity. The spontaneous reduction of pupillary size detected in headache sufferers also suggests a decreased sympathetic input. The miosis, registered after conjunctival instillation of morphine, demonstrates that iris is a possible example of an opioid-dependent adrenergic neuron in man. A poor modulation of the iris adrenergic transmission induces, in headache sufferers, a neuronal incontinence and therefore a chronic intrasynaptic leakage of NE, resulting in an exhausted empty neuron on the one hand and a compensatory hyperactivity of the effector muscular cell on the other. Since indirect evidence suggests a morphine modulation of the iris adrenergic neuron, a deficiency of endorphin modulation could be the mechanism of disruption of iris adrenergic transmission. Apart from the theoretical aspects, the exploration of iris neuroeffector junction represents a noninvasive an simple diagnostic tool in headache.

A new nonvascular interpretation of syncopal migraine.

Migraine suffers who experience spontaneous syncopes (syncopal migraine) during attacks exhibit a dramatic intolerance to bromocriptine, a dopamine agonist. An oral dose of this drug renders these patients unable to stand, even for some hours, because of precipitously falling of arterial blood pressure. Treatment with domperidone, a specific dopamine receptor antagonist, abolishes the syncopal effect of bromocriptine. This evidence is compatible with a supersensitivity of those dopamine receptors, which exert an inhibiting activity and are located on blood pressure regulating centers as well as on cardiovascular sympathergic neurons.

Early dysfunction of iris sensory fibres in diabetic patients.

BACKGROUND: The present study was designed to propose transcutaneous electrical nerve stimulation (TENS) of the infratrochlear nerve as a noninvasive test useful in the detection of early iris small nerve fibre dysfunction in patients with diabetes mellitus. METHODS: A total of 32 diabetic patients with no symptoms or signs of diabetic neuropathy were enrolled from a clinical practice. Sixteen of them, 6 women and 10 men, ranging in age from 19 to 53 years, had been affected by IDDM for 13 +/- 2 years. The remainder, 6 women and 10 men, age range 32 to 58 years, were suffering from NIDDM (duration of manifestation 5 +/- 1 years). Twenty-six healthy individuals, 11 women and 15 men, ranging in age from 21 to 47 years, served as controls. Pupil area changes induced by TENS of the infratrochlear nerve were investigated. The electrical stimulus was not painful and consisted of a single square wave pulse of 40 mA intensity and 0.8 ms duration. Measurements were carried out by means of a TV monocular electronic pupillometer. RESULTS: A clear-cut miosis was provoked in controls (p < 0.01 versus basal values 100 sec to 220 sec from stimulation). NIDDM patients also showed a miotic response, but it was slower in onset (p < 0.05 versus basal values 140 sec after stimulation) and shorter (p < 0.01 at 180 sec from stimulation) in duration. No pupillary changes were registered in IDDM patients. CONCLUSIONS: An abnormality of iris sensory nerve fibres in inducing pupillary constriction was detected in both diabetic groups. The differences in the severity of the dysfunction could be related to the differences in duration of the disease among the diabetic patients in the two groups. In conclusion, TENS of the infratrochlear nerve could represent an original noninvasive method in detecting early iris sensory alterations in diabetic patients.

Asymmetric mydriatic response to topical tyramine in cluster headache relatives.

A pupillometric study was performed to evaluate the mydriatic response to tyramine, a noradrenaline releaser. There were three groups of subjects: (a) 10 cluster headache patients, in an asymptomatic period; (b) 20 of their close relatives, exempt from this disease; (c) 10 healthy controls. The tyramine was instilled into both eyes of each subject. The controls displayed an isocoric tyramine-induced mydriasis but the cluster headache sufferers and their relatives showed an anisocoric mydriasis. This anisocoric mydriasis was caused by a deficient mydriatic response on one side, which in the cluster patients corresponded to the symptomatic side. The sympathetic abnormality of the iris may be the expression of a functional asymmetry in the hypothalamus. Central sympathetic asymmetry could thus represent a dysgenetic family predisposition to lateralized headache attacks.

Construction of a polyepitope fusion antigen of human cytomegalovirus ppUL32 and detection of specific antibodies by ELISA.

We have previously shown that single linear epitopes of the major human cytomegalovirus (HCMV) antigens, expressed as fusion proteins or synthesized as oligopeptides can be valuable diagnostic material in the serology of HCMV infection (5, 6, 13). In this work we fused sequences expressing two different epitopes (aa 1005-1048 and aa 595-614) contained in the basic phosphoprotein of 150 KD coded by UL32 (1, 2), (ppUL32), which has repeatedly been shown to be the strongest immunogen present in the viral particle. The fusion protein was tested by ELISA with HCMV-positive human sera in comparison with other fusion proteins of ppUL32. We found that the double epitope fusion protein was recognised by IgM present in a larger number of sera and with more intense reactions than all the other ppUL32 fusion proteins. The double epitope reacted positively with 81.3% and, when denatured, with 94.7% of IgM-positive sera respectively. IgG reactivity was also high, reaching a percentage of 90.7.

Peripheral small vessel involvement in chronic nephritides.

Small cutaneous vessels, obtained by ear lobe biopsies, were studied in 14 patients with various chronic nephritides and in 10 normal controls. The capillaries in the group of patients with nephritis were found to undergo two main changes: thickening of the adventitia reticularis and perivascular cellular infiltration in an inverse ratio. This infiltration was seen to be made up of mononuclear cells and an increased number of mast cells in various stages of degranulation. Changes in the basement membrane as seen by electron microscopy are not constant. All of the above changes were absent in the controls and are similar to what has been described in previous studies in both experimental and spontaneous pathologic conditions, such as experimental hypertension, diabetes mellitus, scleroderma, rheumatoid arthritis, etc. Small vessel involvement in chronic nephritides could be part of a process of diffuse microvascular damage that includes the kidneys or it may be related to hypertension or to the biochemical changes which follow uremic and pre-uremic states.

[Indices of treatment needs in orthodontics: the applicability of the DAI (Dental Aesthetic Index)]. / Indici di necessità di trattamento in ortodonzia: l'applicabilità del DAI (Dental Aesthetic Index).

The objective assessment of esthetic impairment and relative psychosocial handicap for unacceptable dental aspect (useful for characterizing the need of treatment), could be satisfied by an index that measures each individual's occlusal trait and the psychological impact of the same. An index with these characteristics was suggested by Cons and Jenny, already since 1985. This is an index (DAI: Dental Aesthetic Index) designed specifically to measure dental esthetics, based on esthetic standards socially defined and focused through an extensive and finalized search. Therefore this index assesses the social acceptability of the dental appearance based on the public perception of dental esthetics. The authors, in this work, indicate as measuring the objective traits of occlusion and arriving to final score trough simple calculation. This score provides severity levels of esthetic, psychologic and functional impairment relative to dental aspect in examination.

The pressor hyperresponsiveness to phenylephrine unmasks sympathetic hypofunction in migraine.

The pressor responsiveness to phenylephrine, an almost pure agonist of peripheral alpha-1-adrenoceptors, was studied in 32 migraine patients in headache-free intervals. Eighteen healthy volunteers served as a control group. Fourteen patients and 14 controls also underwent the tilt test. The following observations were made: (1) the pressor response to phenylephrine was significantly greater and longer lasting in patients than in controls; (2) the reflex decrease of heart rate did not differ in the two groups; (3) a normal orthostatic increase of blood pressure and heart rate occurred in migraineurs with hyperresponsiveness to phenylephrine. These findings suggest a supersensitivity of vascular adrenoceptors which is compatible with a chronic adrenergic deficiency in migraineurs. Since patients did not show an orthostatic hypotension in attack-free periods, the compensatory character of receptoral supersensitivity and the possible mechanisms of cardiovascular dysautonomia, which may occur during migraineous attack, were discussed.

Does lithium balance the neuronal bilateral asymmetries in cluster headache?

Pupil size was measured using a pupillograph, and an asymmetric responsiveness to tyramine, instilled bilaterally, was observed in asymptomatic cluster headache patients. Relatives of cluster headache patients showed an anisocoric mydriasis to tyramine, too. This asymmetry was caused by a less marked mydriatic response of one side which, in the cluster headache sufferers, corresponds to the symptomatic side. After three months of treatment with lithium carbonate (900 mg/die), a bilateral decrease of pupil size was noted, possibly due to a reduced sympathergic tone. After six months of continued treatment an unknown mechanism, likely adaptive in nature, attenuated the effect of lithium on pupil size. Lithium also induced a symmetric response to tyramine by increasing tyramine mydriasis on the symptomatic pupil while reducing it on the asymptomatic pupil. It is postulated that lithium improves cluster headache by correcting abnormal bilateral asymmetries in central neuronal systems which regulate autonomic function and pain sensitivity of the structures involved in the cluster attack.

Morphine eye-drops reduce homatropine induced mydriasis in man.

In 7 healthy volunteers 4% morphine eye-drops, when administered to one eye, caused a miosis limited to that eye. In 7 other healthy volunteers morphine was administered into one eye after bilateral instillation of 0.5% homatropine ophthalmic drops; the eye treated with morphine and homatropine showed a mydriasis less intense than the other eye treated only with homatropine. It is suggested that topical morphine locally affects sympathetic function by inhibiting noradrenaline release into the iris neuromuscular junction.

Coexistence of pupillary and heart sympathergic asymmetries in cluster headache.

Ten cluster headache patients and 10 healthy controls were subjected to electrocardiographic and pupillometric procedures in a search for cardiac and pupillary sympathergic asymmetry. Sympathergic stimulation was provoked by hyperventilation and by instilling tyramine into both eyes. In the control group, hyperventilation changed neither the T-wave form and polarity nor the QTc. Tyramine provoked an equal mydriasis on the two sides. In cluster headache sufferers, hyperventilation produced changes in the T-wave form and polarity as well as an increase of the QTc due to a disproportionate shortening of the R-R and Q-T intervals. An unequal mydriasis was noted after tyramine instillation due to less marked response on the symptomatic side. The observed electrocardiographic abnormalities are considered an expression of an asynchronous repolarization attributed to a sympathergic asymmetry. It is postulated that both the cardiac and pupillary sympathetic imbalance associated with cluster headache are central in origin.