Lipoproteins as a specific circulatory transport system

In accordance with the systemic approach, each circulatory transport system is highly specific and transports an elementary substance from cell to cell in the hydrated medium. In the author's opinion, the lipoprotein system has also a functional specificity and carries the elementary substance fatty acid in the blood stream. A great variety of fatty acids, the individuality of their physicochemical properties, great stereochemic differences of saturated and polyenic fatty acids make their transport virtually impossible. The steric individuality of fatty acids can be reduced if the acids are covalently bonded by a matrix as complex lipids. For formation of complex lipids, nature prefers esterification of fatty acids with alcohols which have a varying hydrophoby, such as glycerol, sphingosine, cholesterol, cetyl alcohol. The steric differences of saturated and polyenic fatty acids form a basis for their being structurized in different lipids. Triacyl glycerides are a transport form of saturated, monounsaturated fatty acids and their transforms and give rise to a crystalline phase. Phospholipids and cholesterol esters are a transport form of mainly polyunsaturated fatty acids in the polar phase in the former case and in the crystalline phase in the latter one. The individual apolipoproteins structure complex lipids into individual lipoprotein particles and transport them in the hydrated medium of blood flow. Saturated fatty acids chiefly transport lipoprotein particles formed by apoB-48- and apoB-100-isoproteins. Polyenic acids transport mainly high-density apoA-1-lipoprotein particles, which makes up a main physiological function of the latter. Cholesterol is nothing more than a matrix; it reesterifies polyenic fatty acids from the polar transport form of phospholipids into the unpolar transport form of cholesterol esters. Cholesterol esterification of polyenic fatty acids may structure complex lipid in the unpolar phase and transport it to the cells via apoB-100-ligand-receptor interaction, which is considered to be a key stage in the multistage process of active transport to the cells of polyenic fatty acids. However, the significant differences of active and inactive transport of polyenic fatty acids in the blood stream await a separate consideration.     

Lipoproteins and atherogenesis

Like many complex disease processes, atherogenesis represents the interaction of an array of genetic and environmental factors. From nonhuman animal models to the investigation of epidemiologic factors in man, no single, overriding cause for the development of this indolent vascular disease has been identified. However, the cholesterol-enriched lipoprotein particles are closely tied to the development of the disease. The genetic and environmental influences on the concentrations of specific lipoprotein subspecies provide a context for identifying patients at risk as well as for developing effective therapeutic strategies to influence and prevent the sequelae of atherogenesis.     

Activation of the haemostatic system in children with juvenile rheumatoid arthritis correlates with disease activity

Twenty-four children with juvenile rheumatoid arthritis (JRA) and 10 children with postinfectious arthropathies were investigated for markers of blood coagulation and fibrinolytic activity: Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), and D-Dimer were measured using solid phase enzyme linked immunosorbent assays (ELISA). Results were compared with clinical and conventional laboratory signs of disease activity. F1+2, TAT, D-Dimer, and fibrinogen were significantly elevated in children with JRA as compared with healthy children and children with postinfectious arthropathies. F1+2, TAT, and D-Dimer correlated significantly with disease activity, assessed by determination of the joint index score and C-reactive protein (CRP). The study demonstrates a subclinical activation of the haemostatic system in children with JRA correlating with disease activity, which might be caused by the action of several immunomediators on cells (monocytes, endothelial cells) playing a role in the regulation of blood coagulation activity.     

Markers of platelet activation and oxidant stress in atherothrombotic disease

Several new approaches to the study of platelet activation have been developed. Logically, these should be combined with novel indices of coagulant function (60,61) to select rational targets for antithrombotic drugs. They may also be invaluable in dose-finding, which has been a particular weakness in this area of drug development (62,63). While activation of platelets and the coagulation cascade are virtually simultaneous events, markers of the atherosclerosis are also artificially segregated from those of the complicating thrombotic process. Oxidant stress has been implicated in both platelet activation (64) and atherogenesis (65), yet our ability to study this system has been so constrained that we are unsure of appropriate doses of antioxidant vitamins. Novel approaches to this problem promise the ability to study oxidative modification of proteins (46,66,67), lipids (57) and DNA (45,68) in clinical studies.     

Lipoproteins and hydrolysis of organophosphorus compounds

Paraoxonase of human and animal sera was shown to be a structural part of high density lipoproteins (HDL) by immunoprecipitation, heparin- or polyethyleneglycol fractionation, ultracentrifugation and gel chromatography. Frequency distribution of paraoxonase activity in human sera is trimodal. Human individuals, with respect to paraoxon detoxication, can be distinguished into low and high detoxicators using ratios of phenylacetate and paraoxon hydrolysis as well as activation with ethanolamine and sodium chloride. With conversion of alpha-lipoprotein subtype HDL3 to HDL2, specific activities of paraoxonase and arylesterase are increasing about 3.5-fold in low detoxicator individuals and 1.9-fold in high detoxicators, indicating that more than 90% of HDL2 particle-bound paraoxonase and arylesterase activity are incorporated during the HDL conversion process. HDL cholesterol concentrations in individual sera were shown to be positively correlated to both serum paraoxonase and arylesterase activities.     

Lipoproteins in clinical laboratory medicine]

The characteristics and metabolism of lipoproteins were reviewed. Apolipoproteins has been studied in the fields of neurological diseases as well as hyperlipidemia. A highly significant association between apolipoprotein E (ApoE) epsilone 4 allele and late-onset familial and sporadic Alzheimer's disease (AD) was reported. The recent studies also described the following: (1) late-onset familial AD linked to the proximal long arm of chromosome 19; (2) the presence in the CSF of several proteins, one of which was ApoE, what bound to immobilized amyloid beta-peptide (beta A4) with high avidity; and (3) staining by antisera to ApoE of senile plaques, neurofibrillary tangles, and cerebral vessel amyloid deposits in AD brains. Furthermore, (4) both purified ApoE isomers, ApoE3 and ApoE4, bound to beta A4 synthetic peptide, forming a complex that resisted dissociation by boiling in sodium dodecyl sulfate, but the isomers showed different kinetics in doing so: binding by ApoE4 was observed in minutes, while binding by ApoE3 required hours; and (5) ApoE4 did not bind to beta A4 peptide at pH less than 6.6, while ApoE3 bound to beta A4 peptide from pH7.6 to 4.6. We studied ApoE phenotype expression and the corresponding allele frequencies (epsilon 2, epsilon 3 and epsilon 4) in Japanese patients with late-onset sporadic AD. The frequency of the ApoE epsilon 4 allele was obviously high in AD patients compared with the controls, but it was not different between vascular dementia patients and the controls. These results suggest that ApoE isoforms may play a functional role in the pathophysiology of late-onset familial and sporadic AD and that the isoform-specific difference in beta A4 binding may be involved in forming the AD lesion.     

The role of rheological and haemostatic factors in hypertension

Research into the pathogenesis of hypertension has, in the past, tended to concentrate on changes in vascular geometry, cardiac output and blood volume. However, patients with hypertension are known to be at an increased risk of both coronary heart disease and cerebrovascular disease; complications which are thrombotic in origin. Since rheological and haemostatic factors are known to be involved in thrombogenesis, their potential role in the pathogenesis of patients with hypertension has received increasing attention. The purposes of this review are to update previous reviews and to summarise the relationship between hypertension, its complications and treatment and a range of haemorheological factors.     

Symptoms of the stomatognathic system in temporomandibular and cervical spine disorders

This study was performed to assess the prevalence of signs and symptoms of temporomandibular disorders (TMD) in patients with cervical spine disorders (CSD) and to compare patients with CSD and subgroups of patients with TMD with regard to the results of orthopaedic tests of the stomatognathic system. A group of 103 consecutive patients with signs and symptoms of CSD and a group of 111 consecutive patients with TMD were examined. All subgroups of TMD patients showed a significantly smaller range of motion than the CSD patients. Patients with TMD had limited mouth opening (< 40 mm) on active and passive mouth opening more often than CSD patients. TMD patients with myogenous problems reported oral habits more often than CSD patients, although no objective differences between CSD and TMD patients were found. Subgroups of TMD patients reported joint sounds, and pain on palpation and joint play tests of the temporomandibular joint (TMJ) more frequently than CSD patients. Joint sounds on active movements, pain on palpation of the TMJ, and pain on joint play tests correctly classified 82% of the patients with TMD and 72% of the patients with CSD. In spite of the biomechanical and anatomical relationship between the neck and the stomatognathic system, the results of the study show that CSD patients have signs and symptoms of TMD comparable with those of the adult Dutch population. It was concluded that the function of the masticatory system should be evaluated in patients with neck complaints in order to rule out a possible involvement of the masticatory system.     

The intestinal immune system in children and their disorders

The specificities of arrangement and normal function of the intestinal immunological system are presented, and non-immunological and immunological gastrointestinal defense mechanisms are described. Of immunological defense mechanisms, cellular and humoral mechanisms are described separately, and their characteristics in childhood are highlighted. After a general survey of the intestinal immunological system disorders and their role in various diseases, three most frequent such diseases are described in detail: food intolerance, gluten enteropathy and chronic inflammatory bowel disease.     

Heart and autonomic nervous system in connective tissue disorders

Heart rate variability (HRV) is a suitable diagnostic tool in identifying patients with autonomic nervous system (ANS) disorders even in pre-clinical stage. We have enrolled in this study all patients with large variety of connective tissue disorders, given the possibility of an involvement of ANS in these diseases. The study population consisted in eighty-five patients (68 females and 17 males), 35 of whom affected by systemic lupus erythematosus, 16 by rheumatoid arthritis, 14 by Sj?gren syndrome, 12 by progressive systemic sclerosis, 3 by Beh?et syndrome and 5 by antiphospholipid antibodies syndrome. The mean age ranged between 33.7 of patients with lupus erythematosus and 51.8 of those with Sj?gren syndrome. As control, we enrolled healthy subjects of different age, divided into two groups, to rule out the aging as potential source of considered parameters alteration. The autonomic function has been evaluated by 24 hours ambulatory monitoring, using a Zymed 1210 Scanner with Zymed 3.74-PC 1990 software. We have considered: in the time domain, the standard deviation of the RR intervals average (SDNN) and the percentage of RR adjacent intervals differing each other more than 50 msec (pNN50); in the frequency domain, the low (LF) and high (HF) frequencies, the LF/HF ratio, and the total power (RT). The HRV parameters resulted abnormal in every type of the connective tissue diseases considered: particularly SDNN, pNN50, LF, HF and RT (p < or = 0.01). In conclusion: the results of our study suggest that autonomic neuropathy may be present in any kind of connective tissue disorders even in preclinical stage.     

Interstitial cells of the medulla and the renin-angiotensin system in disorders of water-salt homeostasis

Electron microscopic studies of the intersticial cells of the renal medullar layer and the count of lipid granules in them were conducted in two experimental states accompanied by a reduction of the circulating blood volume--72 hours of water-free diet and intravenous administration of Lazyx that possesses a potent natriuretic and diuretic effect. The concentration of renin and angiotensin was determined in the plasma of the same animals, using the radioimmunoassay technique, and the juxtaglomerular apparatus of the kidneys was examined. The study has demonstrated that the reduction of the circulating blood volume is accompanied, on the one hand, by a significant elevation of the plasma concentration of renin and angiotensin, and, on the other hand, by a reduction of the number of lipid granules in the intersticial cells that is interpreted by the authors as an index of an increased synthesis of renal prostaglandins. It has been concluded that a close functional interrelashionship exists between the two hormonal systems of the kidneys that regulate the water-electrolyte homeostasis, i.e. the renin-angiotensin system and the prostaglandins system.     

REM sleep behavior disorders in multiple system atrophy

We report the results of clinical and polysomnographic investigations on 39 consecutive multiple system atrophy (MSA) patients. Twenty-seven patients (69%) reported nocturnal motor paroxysmal episodes related to dreams, suggesting the clinical diagnosis of REM sleep behavior disorder (RBD). In 12 of them (44%), RBD preceded the clinical onset of the disease by more than 1 year. In seven (26%), the RBD onset was concomitant with and in eight (30%) was at least 2 years after the appearance of motor or autonomic symptoms. On polysomnographic recordings, 35 of 39 MSA patients (90%) had RBD. Other polysomnographic findings included nonclinical obstructive sleep apnea in 6 patients, laryngeal stridor in 8 patients, and periodic limb movements during sleep in 10 patients. Our data show that RBD represents the most common clinical sleep manifestation and polysomnographic finding in patients with MSA. RBD can frequently herald the appearance of other MSA symptoms by years. Extended polysomnographic montages are recommended in MSA sleep studies.     

An epidemiological study of the haemostatic and other effects of oral contraceptives

Factors V, VII and VIII (each determined by biological assay), fibrinogen, platelet count and adhesiveness, and fibrinolytic activity were measured in 234 white pre-menopausal women, of whom 57 (24%) were on oral contraceptives and 177 (76%) were not. Cholesterol, triglyceride and blood pressure levels were also recorded. In 20 of the women on oral contraceptives, and in an age-matched group of 20 who were not, prothrombin, factor X, antithrombin III and alpha 2-macroglobulin levels were determined, and factors VII and VIII were also measured immunologically. For the majority of the variables studied, the differences between those using and not using oral contraceptives were greater in younger than older women; in the case of factor VII (biological assay) and fibrinogen, the differences between the regression slopes on age were statistically significant, and mean values were substantially higher in those on oral contraceptives. There was also a significant difference between regression slopes on age for cholesterol. Mean levels of prothrombin, factors VII (immunological assay) and X, triglycerides and blood pressure were significantly higher, and mean levels of antithrombin III significantly lower, in those on oral contraceptives compared with those not. Overall, fibrinolytic activity was significantly higher in the women on oral contraceptives; this difference was, however, almost entirely due to the greatly increased fibrinolytic activity of the non-smokers on oral contraceptives, activity in the smokers on oral contraceptives being similar to that of the women not on these preparations. There were no significant differences in mean platelet count or adhesiveness, or in haemoglobin, packed cell volume, uric acid and blood sugar levels. Among the women on oral contraceptives, there was a significant negative correlation between factor VIII and fibrinolytic activity; this was largely due to five women all of blood groups A and B, in whom, besides high factor-VIII levels and poor fibrinolytic activity, other variables (e.g. fibrinogen) were raised in a direction that might be expected to favour thrombogenesis. It is possible that it is those women whose fibrinolytic activity does not increase in order to compensate for the effects of oral contraceptives on clotting factors, lipids and blood pressure, who are at special risk of thromboembolic episodes. The differential effects of oral contraceptives by age must be borne in mind in evaluating the effects of these preparations on the haemostatic and lipid systems.     

Neuroimaging in children with congenital disorders of the peripheral visual system

The study investigates the neurological substrate in children with congenital disorders of the peripheral visual system (CDPVS), i.e. disorders of the anterior visual pathways and the globe. The design is retrospective; brain MRI and/or CT scans were traced and reviewed for 79 of 254 children with CDPVS on our database. The neuroradiological findings were considered in the context of degree of visual impairment (profound [PVI] and severe [SVI]), developmental outcome (setback and non-setback), and mode of imaging (MRI and CT). Scans were abnormal in 40 of 79 (51%) children; 23 of 40 (58%) had more than one lesion; and in some children lesions not previously reported were found. The number of abnormalities per child was significantly higher in the PVI than the SVI group (P<0.05); the level of significance varied according to the method of scanning (MRI, P<0.001; CT, ns). Seven children were known to have had developmental setback; significantly more brain abnormalities per child were found in the group with setbacks than in the group without (P<0.001). Eighty-six percent (24 of 28) of MRI compared with 38% (22 of 58) of CT scans were abnormal. MRI detected more lesions per child than CT (P< 0.001). Thus, a significant amount of brain pathology occurs in children with CDPVS. The number of lesions varies directly with degree of visual impairment and both correlate with developmental outcome. As brain pathology will be only one of many factors influencing developmental progress in visually impaired children, prospective multifactorial studies of the CDPVS population, which include MRI studies of the neurological substrate, will be required to clarify the latter.