Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells.

BACKGROUND: Targeting exclusive antigens in atherosclerotic plaques with antibodies may provide a noninvasive means to detect rapidly proliferative atherosclerotic lesions. 111In-labeled negative charge-modified Z2D3 F(ab')2 (Z2D3) specific for an antigen expressed exclusively by proliferating smooth muscle cells has been shown to accumulate in rabbit atherosclerotic plaques. METHODS: The safety, biodistribution, accumulation, and elimination of Z2D3 were assessed in 11 patients who were candidates for carotid endarterectomy. The presence of atheromas in these patients was confirmed by angiography and Doppler ultrasound. Z2D3 (250 microg) labeled with 5 mCi of 111In was administered by slow intravenous injection. Planar and single photon emission computed tomography (SPECT) images were obtained 4, 24, 48, and 72 hours later. Carotid endarterectomy was performed and the surgical specimens were imaged, weighed, gamma-counted, and analyzed by immunostaining. RESULTS: Uptake of Z2D3 at the site of the carotid plaques was observed in the planar and SPECT views at 4 hours in all subjects. In addition, antibody uptake was noted in the contralateral vessel in 5 subjects. SPECT images identified the atherosclerotic plaques with focal uptake. The antibody uptake corresponded with the angiographic location of the disease. Immunohistochemical studies of the endarterectomy specimens confirmed the localization of Z2D3 into the plaque areas containing smooth muscle cells. Adverse drug reactions were not observed. CONCLUSION: This study demonstrates the feasibility of targeting atherosclerotic lesions with negative charge-modified antibody. It also proposes the possibility of selective identification of various components of atherosclerotic plaque, which may contribute to determining strategies of intervention in future.

Taste sensitivity to PTC and thyroid function (FT4 and TSH) in high- and low-altitude Kirghiz populations in the Pamir.

PTC taste sensitivity distribution, determined using the Harris and Kalmus method, and analysis of thyroid activity using FT4 and TSH hormone assays were studied in a sample of 108 high-altitude subjects (3200 m) and in 90 lowlanders (900 m) from two different regions of Kirghizstan (Central Asia). All subjects were healthy Kirghiz males. In agreement with other available data on Kirghiz populations, a higher nontaster frequency was found in the high-altitude subjects. Furthermore, the results of our study indicate no association between thyroid function, PTC sensitivity, and age in both samples. No difference in thyroid function indicators was noted between highlanders and lowlanders.

[Evaluation of the safety and efficacy of the lisinopril + hydrochlorothiazide and captopril + hydrochlorothiazide combinations in the treatment of essential arterial hypertension]. / Valutazione della sicurezza e dell'efficacia delle associazioni lisinopril + idroclorotiazide e captopril + idroclorotiazide nel trattamento dell'ipertensione arteriosa essenziale.

The aim of this study was to assess the efficacy and tolerability of the combinations of lisinopril (LIS) 20 mg + hydrochlorothiazide (HCTZ) 12.5 mg and captopril (CAP) 50 mg + HCTZ 25 mg in moderately hypertensive patients not adequately controlled by LIS or CAP alone. The study was multicentre (11 centres), open, random and carried out in parallel groups. After two weeks' placebo run in patients were randomly assigned to LIS 10-20 mg/o.d. or CAP 25-50 mg/b.i.d. treatment for 6 weeks. After this, patients with supine diastolic blood pressure (SDBP) greater than 90 mmHg were treated with the combinations LIS 20 mg + HCTZ 12.5 mg/o.d. or CAP 50 mg + HCTZ 25 mg/o.d. for 4 weeks; this dose was doubled if DBP was found to be greater than 90 mmHg after 2 weeks' combined therapy. A total of 175 patients were enrolled (92 females and 83 males) of which 153 completed the study. The LIS + HCTZ association caused a significant reduction of DBP in comparison to the other combined treatment (88.1 +/- 0.7 vs 90.3 +/- 0.7; p = 0.026). The statistical analysis of mean SBP values showed no significant difference between the two groups (144.0 +/- 1.3 vs 146.8 +/- 1.3; p = 0.15). At the end of the study 79.5% of patients treated with LIS + HCTZ presented normal results (DBP less than or equal to 90 mmHg), whereas the percentage of similar results in the comparison group was 72%. The percentage of "responder" patients to therapy (DBP reduced by 10 mmHg or more in relation to basal values) was 96.3% in the LIS + HCTZ group and 86.7% in the CAP + HCTZ group. In the CAP + HCTZ group 0.6% of patients reported adverse reactions, while only 0.3% were observed in the LIS + HCTZ group.

[Autoimmune neuropathy in monoclonal gammopathy]. / Neuropatie disimmuni in corso di gammopatie monoclonali.

The relationship between polyneuropathies and monoclonal gammopathies is well known even though the pathogenetic hypotheses are controversial. The role of autoantibodies against neural antigens has been recently underlined. 45 patients (29 M and 16 F), affected by multiple myeloma (MM) non-Hodgkin lymphoma (NHL) with paraproteinemia and monoclonal gammopathies of undetermined significance (MGUS)4, underwent an EMG study including SCV, MCV and late responses of several nerves, and a search for serum antibodies against neural antigens by immunoblotting assay. 19 out of 45 pts. tested positive to EMG and 15 out of 45 (10 MM and 5 NHL) showed a serological positivity. Among them 11 were positive to EMG too. The results confirm the hypothesis of a possible pathogenetic role of high-titer autoantibodies against neural antigens in cases of polyneuropathy.

[The blood rheological and microcirculatory changes in the hypertensive patient]. / Modificazioni emoreologiche e microcircolatorie nell'iperteso.

The authors examined the microcirculatory system alterations which are present in case of arterial hypertension. These alterations consist of an increase in capillary peripheral resistances and in total blood viscosity, of a reduction in red cell deformability and of a vasomotion alteration. The authors evaluated the opportunities of a therapeutic intervention with hypotensive treatments also affecting the microcirculatory system in hypertensive patients with or without associated diabetes mellitus.

[Subclinical neuropathies and paraproteinemias]. / Neuropatie subcliniche e paraproteinemie.

The relationship between monoclonal gammapathies and peripheral nerve involvement is well known. The pathogenesis of neuropathy has been ascribed to infiltrative, compressive, ischemic or haemorrhagic phenomena, to an amyloid storage or to antibody autoaggression toward neural antigens. Forty-five patients suffering from monoclonal gammapathy of uncertain significance (MGUS), multiple myeloma (MM), MG IgM, were submitted to a neurophysiological examination. 10 pts. were excluded because of neurotoxic drugs, diabetes or alcohol abuse. The investigation included SCV of median, ulnar, and sural n., MCV and F wave of peroneal n., H reflex, and computerized analysis of recruitment pattern. A subclinical neuropathy was found in 11 of 35 pts. (30%) without any neurological symptom. A CTS was found in 4 patients. The high rate of subclinical neuropathy in asymptomatic pts. is underlined by the Authors, while the presence of subclinical neuropathy in cases of MGUS needs further studies.

[Capillaroscopy and diabetic microangiopathies]. / Capillaroscopie et microangiopathie diabétique.

Using conjunctival capillaroscopy, the authors studied 40 diabetic patients during glycemic decompensation. The capillaroscopic test, after all metabolic control tests, was repeated 1 and 3 months later and demonstrated improved microcirculation in 10 patients, and proved that therapeutic control is possible during the progression of diabetic microangiopathy.

The effect of treatment with coenzyme Q10 on the mitochondrial function and superoxide radical formation in cardiac muscle hypertrophied by mild aortic stenosis.

A 40% reduction of the diameter of the ascending aorta maintained for 60 days induced the formation of a compensate cardiac hypertrophy in rabbits without changing the value of the azide insensitive Ca2+-ATPase activity in comparison to control hearts. The cardiac mitochondria isolated from constricted animals assayed in presence of glutamate and succinate did not show a change in the R.C.I. and ADP/O values in comparison to the controls, whilst the QO2 value enhanced or decreased respectively when determined with glutamate or succinate. The intramuscular injections of CoQ10 (12 mg/kg body weight/48 h) enhanced the mitochondrial CoQ10 concentrations both in the control and in the constricted animals and further increased the QO2 value determined in both groups of animals when glutamate was used as the substrate. The production of O2.- radicals by the level of the complexes I and III of the respiratory chain, did not change in the constricted animals, nor in the animals administered with CoQ10 in comparison to the control. CoQ10 augmented the rate of oxygen consumption by the submitochondrial particles only in the constricted animals. Moreover, the treatment with the coenzyme or the constriction of the aorta, did not modify the cardiac superoxide dismutase activity, but increased the glutathione peroxidase activity only in the banded animals. In addition, in the CoQ10 treated animals there was a reduction of NADH-diaphorase activity both in the control and constricted animals, while the malondialdehyde, generated during the thiobarbituric acid test, and the cardiac content of lipofuscin were decreased.

Osmotic fragility of erythrocytes, cell deformability and secondary hyperparathyroidism in uremic patients on maintenance hemodialysis.

The possible relationship between erythrocyte (RBC) function and secondary hyperparathyroidism (HPT) was examined in 35 uremic patients on maintenance hemodialysis. Mechanical tests (i.e., osmotic fragility and deformability) were used to assess RBC function. Secondary HPT was evaluated by means of serum biochemistry (parathyroid hormone, calcium, phosphorus, and alkaline phosphatase) and radiographic examinations (X-ray films of the hand skeleton). Sixteen sex and age-matched normal volunteers acted as controls. This study shows that the mechanical properties of RBC were indeed markedly altered in hemodialysis patients when compared with controls. No significant correlations between either the osmotic fragility or the deformability of RBC and the hematochemical changes associated with secondary HPT were found. No differences in RBC function tests were found as far as the activity (alkaline phosphatase) or the severity (X-ray findings) of secondary HPT are concerned. Effective treatment of secondary HPT by either pharmacological means (1,25-dihydroxycholecalciferol) or surgical removal was not associated with consequent improvement in RBC function. These findings clearly speak against secondary HPT as a major cause of RBC dysfunction in uremic patients on maintenance hemodialysis.

Hemodialysis-associated platelet loss: study of the relative contribution of dialyzer membrane composition and geometry.

To evaluate the relative contribution that dialyzer membrane composition and geometry make to hemodialysis-associated platelet loss, the effect of a single dialysis with three different types of dialyzers on platelet count was examined on a cross-over basis in 19 uremic patients on maintenance hemodialysis. Also, the plasma levels of antithrombin-iii before and after dialysis were measured, but no significant variations were found regardless of which dialyzer was in use. Our patients suffered significant platelet loss during cuprophan dialysis, but not polyacrylonitrile dialysis. More than 99% of initial circulating platelets were recovered at the end of polyacrylonitrile dialysis, whereas cuprophan dialysis did leave a significantly lower percentage of circulating platelets (p less than 0.05). The internal comparison of results obtained with the two cuprophan dialyzers used shows no difference as to the dialyzer geometry (flat plate or hollow fiber). This indicates that the membrane composition is the major factor influencing hemodialysis-associated platelet loss. We suggest that patients with low platelet count and/or with risk of bleeding may benefit from polyacrylonitrile dialysis.

Red blood cell deformability and secondary hyperparathyroidism in uremic patients on maintenance hemodialysis.

The possible relationship between red blood cell (RBC) deformability and secondary hyperparathyroidism (HPT) in 23 patients on maintenance hemodialysis was examined. Secondary HPT was evaluated by means of serum biochemistry (parathyroid hormone, calcium, phosphorus, and alkaline phosphatase) and radiographic examinations. This study showed that RBC deformability is markedly reduced in hemodialyzed patients when compared with normal controls. No significant correlation between RBC deformability and the hematochemical changes associated with secondary HPT was found. No difference in RBC deformability was observed as far as the activity (alkaline phosphatase) and the severity (radiographic findings) of secondary HPT are concerned. Effective treatment of secondary HPT by either pharmacological means (1 alpha, 25-dihydroxycholecalciferol therapy) or surgical removal was not associated with consequent improvement in RBC deformability. It is concluded that secondary HPT is probably not a major factor influencing RBC deformability in uremic patients on maintenance hemodialysis.

[Blood filterability in cerebral vascular disease]. / La filtrabilita' ematica nelle vasculopatie cerebrali.

The aim of this paper is to test whether an alteration of blood flow in microcirculation and in particular of red cell deformability is present in cerebrovascular insufficiency. To this end we determined by the method proposed by Reid and Dormandy (J. Clin. Pharmacol. 1976, 29, 855) whole-blood filterability in 31 patients with cerebrovascular disease, in 15 clinically healthy subjects and in 99 subjects without clinical evidence of ischemic pathology displaying one or more vascular risk factors. Blood filterability turned out to be significantly lower in cases of cerebrovascular disease than in the controls (p less than 0,001), while data about presence of risk factors in cerebrovascular insufficiency and in controls are almost overlapping. Reduction of blood filterability in cerebrovascular disease may therefore be attributed directly to the risk factors associated to the disease, which can significantly reduce red cell deformability. Further we didn't find any significant correlation between blood filterability and levels of fibrinogen, platelets, triglycerides and cholesterol in blood.

[Blood filterability in peripheral obstructive arterial disease]. / La filtrabilita' ematica nelle arteriopatie ostruttive periferiche.

The aim of this paper is to test whether an alteration of blood flow in microcirculation and in particular of red cell deformability is present in chronic arterial occlusive disease. To this end we determined by the method proposed by Reid and Dormandy (J. Clin. Pharmacol. 1976, 29, 855) whole-blood filterability in 18 patients with peripheral vascular disease, in 15 clinically healthy subjects and in 99 subjects without clinical evidence of ischemic pathology displaying one or more vascular risk factors. Blood filterability turned out to be significantly lower in cases of arterial disease that in the controls (p less than 0,001), and we found a constant reduction of blood filterability with the increase of number of risk factors. Comparison of the results obtained in arteriopatics and in controls displaying risk factors shows that though risk factors have an important impact on blood filterability, their presence alone is not enough to explain the reduction of blood filterability which, risk factors being equal, in vascular disease is always significantly lower than in controls. We also found a significant correlation between levels of fibrinogen and reduction of blood filterability.

[Blood filterability in ischemic heart disease]. / La filtrabilita' ematica nella cardiopatia ischemica.

The aim of this paper is to test whether an alteration of blood flow in microcirculation and in particular of red cell deformability is present in myocardial ischaemia. To this end we determined by the method proposed by Reid and Dormandy (J. Clin. Pharmacol. 1976, 29, 855) whole-blood filterability in 23 patients with myocardial ischaemia, in 15 clinically healthy subjects and in 99 subjects without clinical evidence of ischemic pathology displaying one or more vascular risk factors. Blood filterability turned out to be significantly lower in cases of coronary diseases than in controls (p less than 0,001), while it was lower but not significantly so, than in subjects displaying risk factors. We conclude therefore that the presence of risk factors is enough important to be considered one of the fundamental elements (though non the only one) in causing the reduction of blood-filterability encountered in ischemic cardiopathology.