Type IIb Patients Research Articles

Reorganization of Parvalbumin Immunopositive Perisomatic Innervation of Principal Cells in Focal Cortical Dysplasia Type IIB in Human Epileptic Patients.

Focal cortical dysplasia (FCD) is one of the most common causes of drug-resistant epilepsy. As several studies have revealed, the abnormal functioning of the perisomatic inhibitory system may play a role in the onset of seizures. Therefore, we wanted to investigate whether changes of perisomatic inhibitory inputs are present in FCD. Thus, the input properties of abnormal giant- and control-like principal cells were examined in FCD type IIB patients. Surgical samples were compared to controls from the same cortical regions with short postmortem intervals. For the study, six subjects were selected/each group. The perisomatic inhibitory terminals were quantified in parvalbumin and neuronal nuclei double immunostained sections using a confocal fluorescent microscope. The perisomatic input of giant neurons was extremely abundant, whereas control-like cells of the same samples had sparse inputs. A comparison of pooled data shows that the number of parvalbumin-immunopositive perisomatic terminals contacting principal cells was significantly larger in epileptic cases. The analysis showed some heterogeneity among epileptic samples. However, five out of six cases had significantly increased perisomatic input. Parameters of the control cells were homogenous. The reorganization of the perisomatic inhibitory system may increase the probability of seizure activity and might be a general mechanism of abnormal network activity.

Long-term outcome of spontaneous isolated superior mesenteric artery dissection in different angiographic types.

This study aimed to compare the follow-up and outcomes of spontaneous isolated superior mesenteric artery dissection (SISMAD) in different angiographic types and to determine the optimal therapeutic options for SISMAD patients. This is a retrospective study of 61 SISMAD patients between December 2010 and January 2019 in a single center. Data analysis consisted of demographics, clinical data, radiology review, treatment, follow-up, and outcomes. A total of 61 SISMAD patients were reviewed in this study. Median age was 53 (quartile, 47.5-63.0), 90.2% were males with hypertension (50.8%), dyslipidaemia (54.1%), and smoking history (60.7%). Among all, 43 patients underwent periodic follow-up of computed tomography (CT) angiography for follow-up analysis. 11 (25.6%) patients showed "No Change" during follow-up, including 6 type I patients. 23 patients (53.5%) were "Partially Remodelled" and 18 of them were type II patients. 7 "Completely Remodelled" patients (16.3%) were all in type II group. Two type III patients (4.6%) died after the emergent surgical intervention within 30days. Different SISMAD angiographic types present with variant progression. Type I SISMAD may be inclined to remain "unchanged." Type II SISMAD shows a clear trend to remodeling, especially type IIb patients. The progression of type III SISMAD varies in the extent of collateral bypasses.

Comparison of the efficacy of the tension band wiring with eyelet wire versus anatomical locking plate fixation for the treatment of displaced olecranon fractures.

This retrospective study was conducted to assess the clinical outcome and complications between tension band wiring (TBW) with eyelet wire and locking plate fixation used for the treatment of displaced olecranon fractures. A total of 58 patients (36 males and 22 females; mean age: 63years) were reviewed between April 2014 and September 2020. TBW with Ring Pin (RP group) was applied in 24 patients, including 15 Mayo type ⅡA and 9 Mayo type ⅡB patients. Anatomical locking plate (ALP group) was used in 34 patients, including 22 Mayo type ⅡA and 12 Mayo type ⅡB patients. Clinical outcome was evaluated using the Mayo Elbow Performance Score (MEPS), and active range of motion of the elbow and forearm and postoperative complications were reviewed. General characteristic of the patients and the fracture type were similar in the two groups. The mean MEPS values were 96.5 ± 7.3 in the RP group and 94.9 ± 9.4 in the ALP group. The mean elbow flexion arc was 127°±11 in the RP group. The mean elbow flexion arc was 122°±18 in the ALP group. No significant differences in clinical outcomes were observed between the two groups. Complication rates were significantly higher in the ALP group (19/34: 56%) than in the RP group (6/24: 25%). Although there were no statistically significant differences in clinical outcomes between the two groups, the ALP group had a higher proportion of any complication than the RP group.

Management of Extracranial Carotid Artery Aneurysms: A 6-Year Case Series.

BackgroundWe discuss the presentation and management of extracranial carotid artery aneurysms (ECAAs) and to develop a new type of classification.Material/MethodsA retrospective review of 35 ECAAs patients who were admitted in our institution from January 2010 to June 2016 was conducted. The mean follow-up period was 25.58±22.13 months.ResultsDuring the study period, 35 aneurysms were diagnosed and treated (mean age, 50.8±15.6 years; 15 men). There were 28 true aneurysms, 5 false aneurysms, and 2 dissecting aneurysms. A total of 16 patients with true aneurysms underwent open surgical treatment (group 1), whereas 15 received endovascular management, including all false and dissecting aneurysms (group 2). The remaining 4 true aneurysms were treated with hybrid operation (group 3). The patency rates of groups 1, 2, and 3 were 100%, 93.3%, and 100%, respectively. According to the Peking Union Medical College Hospital (PUMCH) Classification, all 24 cases of type Ia aneurysms were treated by either open surgery and/or endovascular treatment, whereas all 3 type Ib cases were treated solely by open surgery. All 5 type IIa patients were treated by endovascular treatment, with the exception of 1 failure that was transferred to hybrid operation. All 3 type IIb patients were treated by hybrid operation.ConclusionsOpen surgery was more frequently feasible in true aneurysms, and endovascular surgery was the first choice for false and dissecting aneurysms. Hybrid operation was available for complicated cases. The PUMCH classification may be helpful for selection of management strategies for ECAAs.

COMPLEX ASSESSMENT OF EFFICACY OF STATINS PRESCRIBED AT MOST BY CLINICIANS

Aim. To evaluate a complex clinical efficacy, tolerability and safety of statin drugs — simvastatin, atorvastatin, rosuvastatin in patients with hyperlipidemia (HL).Material and methods. The assessment of clinical efficacy was done in 90 patients with HL and arterial hypertension of the grades 1 and 2, age 40-75 y.o.; some of them had coronary heart disease.Results. In 90 patients with cardiac pathology and HL, selected to 3 groups by 30 persons, the clinical efficacy of the listed statins was assessed. A significant hypolipidemic effect was noted as a decline of atherogenicity of the blood, with slight more prominent effect of rosuvastatin.Conclusion. The data makes it to conclude the simvastatin, atorvastatin and rosuvastatin are equally effective hypolipidemic drugs in HL type IIA and IIB patients. The time frame, type and grade of positive changes in lipid profile are almost the same, and in rosuvastatin just slightly more prominent.

Laparoscopic Sigmoidectomy for Diverticulitis: a Prospective Study

Surgical treatment of complicated colonic diverticular disease is still debatable. The aim of this prospective study was to evaluate the outcome of laparoscopic sigmoid colectomy in patients with diverticulitis. Patients offered laparoscopic surgery presented with acute complicated diverticulitis (Hinchey type I, II, III), chronically recurrent diverticulitis, bleeding, or sigmoid stenosis caused by chronic diverticulitis. All patients who underwent laparoscopic colectomy within a 12-year period were prospectively entered into a database registry. One-stage laparoscopic resection and primary anastomosis constituted the planned procedure. A 4-trocar approach with suprapubic minilaparotomy was performed. Main data recorded were age, sex, postoperative pain, return of bowel function, operation time, duration of hospital stay, and early and late complications. During the study period, 260 sigmoid colectomies were performed for diverticulitis. The cohort included 104 male and 156 female patients; M to F ratio was 4:6. Postoperative pain was controlled by NSAIDs or weak opioid analgesia. Fifteen patients (5.7%) required conversion from laparoscopic to open colectomy. The most common reasons for conversion were directly related to the inflammatory process, abscess, and peritonitis. Mean operative time was 130±54. Average postoperative hospital stay was 10±3 days. A longer hospital stay was recorded for Hinchey type IIb patients. Complications were recorded in 30 patients (11.5%). The most common complications that required reoperation were hemorrhage in 2 patients (0.76) and anastomotic leak in 5 patients (only 3 of them required reoperation). The mortality among them was 2 patients (0.76%). Laparoscopic surgery for diverticular disease is safe, feasible, and effective. Therefore, laparoscopic colectomy has replaced open resection as standard surgery for recurrent and complicated diverticulitis at our institution.

Inhibition of CETP by Torcetrapib Attenuates the Atherogenicity of Postprandial TG-Rich Lipoproteins in Type IIB Hyperlipidemia

The purpose of this study was to evaluate the impact of torcetrapib on atherogenic TG-rich lipoprotein subfractions in the postprandial phase in Type IIB hyperlipidemia. The quantitative and qualitative features of the postprandial profile of TG-rich lipoproteins were determined at baseline, after treatment for 6 weeks with 10 mg/d atorvastatin, and subsequently with an atorvastatin/torcetrapib combination (10/60 mg/d) in Type IIB patients (n=18). After ingestion of a standardized mixed meal, TG-rich lipoprotein subfractions were evaluated over 8 hours after each experimental period. On a background of atorvastatin, torcetrapib significantly attenuated the incremental postprandial area under the curve (iAUC 0 to 8 hours) for VLDL-1 (-40%), and the AUC 0 to 8 hours for VLDL-2 (-53%), with minor effect on chylomicron iAUC (-24%); concomitantly, the CE/TG ratio in both VLDL-1 and VLDL-2 was significantly reduced (-27% to -42%). Such reduction was attributable to torcetrapib-mediated attenuation of postprandial CE transfer to Chylomicrons (-17%) and VLDL-1 (-33%). Marked reduction in postprandial VLDL-1 levels was associated with apoE enrichment. On a background of atorvastatin, torcetrapib attenuated the quantitative and qualitative features of the atherogenic postprandial profile of chylomicrons, VLDL-1 and VLDL-2. Such changes reflect the sum of torcetrapib-mediated effects on TG-rich lipoprotein production, intravascular remodeling, and catabolism.

Type IIB von Willebrand Disease: Role of Qualitative Defects in Atherosclerosis and Endothelial Dysfunction

To verify whether a hereditary bleeding tendency, such as von Willebrand disease (vWD) type IIB, protects against the onset of atherosclerosis. Twenty-four patients with vWD type IIB and 24 healthy controls, matched for common atherosclerotic risk factors. All patients were evaluated by color Doppler ultrasound of the common carotid, carotid bifurcation, common femoral artery, brachial artery, and abdominal aorta, investigating intima-media thickness (IMT) and presence of plaques in each arterial district. Flow mediated dilation (FMD) of the brachial artery was used to test endothelial function. vWD type IIB patients presented no significant difference in IMT in any arterial district. FMD showed no differences between the 2 groups. The quantitative clotting defect characteristic of vWD type IIB does not seem to protect against atherosclerosis.

Effect of atorvastatin on the concentration, relative distribution, and chemical composition of lipoprotein subfractions in patients with dyslipidemias of type IIA and IIB.

The authors investigated the effect of atorvastatin (40 mg qd) on low-density lipoprotein (LDL) particle distribution in patients with dyslipidemias of type IIA (n = 55) and IIB (n = 21). Atorvastatin therapy induced a significant decrease in total and LDL cholesterol in both patient groups. A significant reduction in triglyceride values, which was more profound in type IIB patients, was also observed. In type IIA patients, LDL-3 was the predominant subfraction. Atorvastatin therapy induced a significant reduction in total LDL mass in this group of patients that was mainly due to the reduction in large and intermediate subspecies (LDL-1 to LDL-3), whereas the mass of dense LDL particles (LDL-4 and LDL-5) remained unchanged. As a consequence, the percentage contribution of dense subfractions to the total LDL mass increased significantly after atorvastatin therapy. The dense LDL-4 subfraction was the predominant one in type IIB patients. In this group, atorvastatin therapy resulted in a significant reduction in the total LDL mass, which was due to the reduction in all LDL subfractions. Thus, the percentage mass distribution of LDL particles remained unaffected. These results suggest that the effect of atorvastatin on LDL subfractions is affected by the underlying genetic defect.

Comparison of Micronized Fenofibrate and Pravastatin in Patients With Primary Hyperlipidemia

Micronized fenofibrate lowers total cholesterol and low-density lipoprotein cholesterol to a similar extent as statins but raises high-density lipoprotein cholesterol and lowers triglycerides to a greater extent. The comparative lipid-modifying efficacy of micronized fenofibrate and pravastatin has not been evaluated in dyslipidemic patients. This prospective, multicenter, randomized trial compared the efficacy of 3 months' treatment with micronized fenofibrate (200 mg once daily) or pravastatin (20 mg once daily) in hypercholesterolemic type IIa and mixed dyslipidemic type IIb patients. Two hundred sixty-five male and female patients (18-75 years) were recruited from 28 European centers, and 151 were analyzed. Micronized fenofibrate was at least as effective as pravastatin in reducing levels of low-density lipoprotein cholesterol and total cholesterol in primary dyslipidemia but was significantly more effective than pravastatin in raising high-density lipoprotein cholesterol (respectively, 13.2% vs. 5.6%; p = 0.0084) and lowering triglycerides (-38.7% vs. -11.8%; p = 0.0001). In type IIa dyslipidemia, micronized fenofibrate was as effective as pravastatin in raising high-density lipoprotein cholesterol (+8.6% vs. +8.0%) but was fivefold more effective in lowering triglycerides (-34.3% vs. -7.2%; p = 0.0001). In type IIb dyslipidemic patients with low baseline high-density lipoprotein cholesterol levels, micronized fenofibrate was 10-fold and nearly 3-fold superior to pravastatin in raising high-density lipoprotein cholesterol and lowering triglycerides, respectively. Micronized fenofibrate may be considered an effective first-line therapy for patients with primary hyperlipidemia, particularly those with type IIb mixed dyslipidemia or type 2 diabetes.

Preferential reduction of very low density lipoprotein-1 particle number by fenofibrate in type IIB hyperlipidemia: consequences for lipid accumulation in human monocyte-derived macrophages

The combined (mixed) type IIB phenotype is typically associated with premature atherosclerosis and characterised by concomitant elevation of plasma levels of atherogenic triglyceride-rich lipoproteins, consisting of very low density lipoprotein (VLDL)-1 (Sf 60–400), VLDL-2 (Sf 20–60), and intermediate density lipoprotein (IDL) (Sf 12–20), as well as small dense LDL. After dietary stabilisation, type IIB patients received micronised fenofibrate (267 mg/day) for up to 12 months. At baseline ( T0), patients ( n=11) displayed fasting triglyceride, cholesterol and apoB levels of 308±13, 350±17 and 187±9 mg/dl, respectively. Micronised fenofibrate (M-fenofibrate) induced marked reductions in plasma triglyceride (TG) (−61%, P<0.0001), total cholesterol (−32%, P=0.0005) and apolipoprotein (apo) B (−33%, P<0.001) at 12 months ( T12); similar effects were seen after 3 months ( T3) of treatment. These changes resulted from significant reductions in VLDL-1 (−75%, P=0.00001), VLDL-2 (−46%, P=0.002) and LDL (−33%, P<0.0003); IDL concentrations were unchanged. At baseline, VLDL-1 constituted the major TG-rich lipoprotein (TRL) fraction (50% of total mass), but only 25% at T12. These drug effects were accompanied by marked increase in HDL-C (+20%, P=0.018). Quantitative changes in triglyceride-rich lipoproteins were accompanied by significant qualitative modifications in particle size and chemical composition (VLDL-1: TG, −10.7%, P<0.001; FC, +59%, P=0.0002; PL, +19%, P=0.033; VLDL-2: FC, +11%, P=0.027; IDL: FC, +14%, P=0.0004; PL, +12%, P=0.002). Reduction in the TG content of VLDL-1 was reflected in a shift of particle size distribution to smaller diameters (mean 45.4 and 42.3 nm, respectively, at T0 and T12). We evaluated the relative atherogenicity of TRL subfractions by determining their capacity, when normalised to equal particle numbers (as apoB 100 content), to induce lipid accumulation in human monocyte-derived macrophages. Among TRL subfractions, VLDL-1 (100 μg apoB/ml) possessed the highest capacity to induce macrophage lipid loading (up to sevenfold increase in TG content, P<0.001; free cholesterol, up to 1.7-fold; P<0.05). At 100 μg apoB/ml, cellular TG loading from VLDL-1 was twofold greater than that for VLDL-2 ( P<0.01), and fivefold greater than for IDL ( P<0.01). Despite drug-induced changes in the qualitative properties of TRL subfractions, the activity of VLDL-1, VLDL-2 and IDL as ligands which lead to induction of macrophage lipid accumulation, at equivalent particle numbers, was not detectably altered. By contrast, the fibrate-mediated reduction in the number of circulating VLDL-1 and VLDL-2 particles (four and twofold, respectively) resulted in marked decrease in cellular lipid loading. Considered together, these findings suggest that fenofibrate may act at systemic and arterial levels to reduce the cardiovascular risk associated with VLDL subfractions in patients with a combined hyperlipidemic (type IIB) phenotype. Indeed, we speculate that reductions in circulating levels of VLDL-1 and VLDL-2 may diminish intimal penetration of these particles and thus their propensity to enhance arterial macrophage lipid accumulation and foam cell formation. Finally, fenofibrate further attenuated the atherogenic lipid profile in these patients by inducing marked reduction in LDL and elevation in cardioprotective HDL.

Remnant-like particle cholesterol and triglyceride levels of hypertriglyceridemic patients in the fed and fasted state

Potentially atherogenic triglyceride-rich lipoprotein (TRL) remnants can be isolated and quantitated as remnant-like particles (RLP), using an immunoaffinity gel containing specific anti-human apolipoprotein A-I (apoA-I) and apoB-100 monoclonal antibodies. The aim of the present study was to determine the relationship between postprandial changes in RLP levels and changes in total serum triglyceride (TG) in patients with different forms of hypertriglyceridemia (HTG). Three groups of patients were selected, having similarly elevated serum TG levels: a) HTG with TRL remnant accumulation (i.e., type III patients, n = 15, TG: 3.8 +/- 0.2 mm), b) HTG with increased LDL (i.e., type IIb patients, n = 15, TG: 3.7 +/- 0.2 mm), and c) HTG without evidence of remnant or LDL accumulation (i.e., type IV patients, n = 15, TG: 3.9 +/- 0.3 mm). Ingestion of a 45-g fat meal caused a significant increase in serum TG (30;-50%) in all patients. Mean serum TG levels of the three groups were not significantly different at 4 or 6 h after the meal. RLP cholesterol (C) and TG levels increased after the meal in all patients, but these postprandial increases were also not significantly different among groups. Type III patients had significantly higher (P < 0.01) levels of RLP-C and RLP-apoE in the fasted and fed state, and also had significantly higher RLP-C-to-serum TG ratios (P < 0.001) compared with the other groups. These results indicate that 1) RLP-C and RLP-TG levels are significantly increased in the fed versus fasted state in patients with elevated fasting TG levels; 2) patients with different forms of HTG, but similar TG levels, have similar postprandial increases in RLP-C and RLP-TG; and 3) type III patients have significantly elevated levels of RLP-C and RLP-apoE in both the fed and fasted state.

HDL steady state levels are not affected, but HDL apoA-I turnover is enhanced by Lifibrol in patients with hypercholesterolemia and mixed hyperlipidemia

Lifibrol (4-(4′-tert-butylphenyl)-1-(4′carboxyphenoxy)-2-butanol) is a new hypocholesterolemic drug effectively reducing total cholesterol, LDL cholesterol, and apolipoprotein (apo) B in experimental animals and in humans. In contrast to fibrates and HMG-CoA reductase inhibitors the cholesterol and triglyceride lowering effect of Lifibrol is not accompanied by increases in HDL cholesterol and apoA-I levels. We examined the impact of Lifibrol on the metabolism of HDL apoA-I in patients with hyperlipoproteinemia, using endogenous labeling with stable isotopes. Kinetic studies were performed in five male hypercholesterolemic individuals (type IIa), before and on treatment with 450 mg of Lifibrol daily for 4 weeks and in five male individuals suffering from mixed hyperlipidemia (type IIb), before and on therapy, for 12 weeks. Lifibrol reduced total cholesterol by 14% ( P=0.02) and LDL cholesterol by 16% ( P=0.014) in all patients, and decreased triglycerides by 34% in type IIb patients. During Lifibrol therapy, HDL cholesterol and ApoA-I concentrations did not change. Tracer kinetics revealed that the fractional catabolic rate (FCR) of HDL apoA-I increased by 22% ( P=0.013). This increase in the apoA-I FCR was accompanied by a 23% increase in HDL apoA-I production rate ( P=0.006). We conclude that Lifibrol, although not changing HDL steady state concentrations, enhances the turnover of apoA-I containing HDL particles.

RELATIONSHIP BETWEEN PLASMA FENOFIBRIC ACID LEVELS AND THE EFFECT OF MICRONIZED FENOFIBRATE ON CHOLESTEROL, LOW DENSITY LIPOPROTEIN CHOLESTEROL AND APOLIPOPROTEIN B IN PATIENTS WITH PRIMARY HYPERCHOLESTEROLEMIA.

Objective: We examined the relationship between plasma levels of fenofibric acid, the active metabolite of fenofibrate, and differences in concentrations of plasma lipids, in subjects with primary type IIA or IIB hyperlipoproteinemia (HLP). Subjects and methods: Twenty-nine patients (13 with type IIA and 16 with type IIB HLP) were treated with a single daily 200-mg dose of micronized fenofibrate for 3 months, after which the plasma levels of fenofibric acid were determined by HPLC after an overnight fast. Results: In the type IIA HLP phenotype, statistically significant correlations were found between fenofibric acid levels and changes in total cholesterol, LDL-C and apo-B at all three control visits, with the highest correlation coefficients at V3 visit (total cholesterol r = 0.85, LDL-C r = 0.68, apo-B r = 0.85). In type IIB HLP, statistical significance was confirmed only when performing an analysis of pooled values for total cholesterol and LDL-C (r = 0.42, r = 0.34, respectively). The high correlation between plasma fenofibric acid levels and its effect on betalipoprotein changes might reflect the effect of fenofibrate on the catabolism of plasma LDL by the LDL receptor, since that type of relationship is typical of drugs which directly influence the target compartment without an effect on intermediary steps of metabolism. An explanation for the different levels of correlations in type IIA and IIB patients might be found in their different metabolic defects. The fact that fenofibrate's impact on VLDLs is such an important part of its effect on lipoprotein metabolism supports the concept that the effect of circulating fenofibric acid is less pronounced on the LDL receptor in type IIB HLP.

Lifibrol enhances the low density lipoprotein apolipoprotein B-100 turnover in patients with hypercholesterolemia and mixed hyperlipidemia

Lifibrol (4-(4′-tert-butylphenyl)-1-(4′carboxyphenoxy)-2-butanol), a new hypocholesterolemic drug, effectively reduces total cholesterol (CH), low density lipoprotein (LDL)-CH, and apolipoprotein (apo) B in experimental animals and in humans. The impact of Lifibrol on the metabolism of apoB-100 containing lipoproteins in patients with hyperlipoproteinemia using endogenous labeling with stable isotopes is examined. Kinetic studies were performed in four male hypercholesterolemic individuals (type IIa) before and on treatment with 450 mg of Lifibrol daily for 4 weeks, and in five male individuals suffering from mixed hyperlipidemia (type IIb) before and on therapy for 12 weeks. Kinetic parameters were estimated by multicompartmental modeling. Lifibrol therapy reduced total CH by 16% ( P=0.012) in all patients, increased triglycerides (TG) by 11% (not significant) in type IIa patients and decreased TG by 34% ( P=0.059) in type IIb patients. During Lifibrol therapy, LDL apoB-100 concentrations decreased by 19% ( P=0.011) in all patients. The decrease in LDL apoB concentrations with Lifibrol therapy was due to an overall increase (75%, P=0.006) of the fractional catabolic rates (FCR) of LDL apoB. This increase was partially attenuated by a 33% increase in LDL apoB production rate (PR) ( P=0.041). The overall production of apoB increased only slightly. Our data suggest that the major mechanism by which Lifibrol lowers LDL-CH is an increase in receptor-mediated catabolism of LDL rather than a decrease in hepatic apoB production.

Mass concentration of plasma phospholipid transfer protein in normolipidemic, type IIa hyperlipidemic, type IIb hyperlipidemic, and non-insulin-dependent diabetic subjects as measured by a specific ELISA.

Mean plasma phospholipid transfer protein (PLTP) concentrations were measured for the first time by using a competitive enzyme-linked immunosorbent assay. PLTP mass levels and phospholipid transfer activity values, which were significantly correlated among normolipidemic plasma samples (r=0.787, P<0.0001), did not differ between normolipidemic subjects (3.95+/-1.04 mg/L and 575+/-81 nmol. mL-1. h-1, respectively; n=30), type IIa hyperlipidemic patients (4. 06+/-0.84 mg/L and 571+/-43 nmol. mL-1. h-1, respectively; n=36), and type IIb hyperlipidemic patients (3.90+/-0.79 mg/L and 575+/-48 nmol. mL-1. h-1, respectively; n=33). No significant correlations with plasma lipid parameters were observed among the various study groups. In contrast, plasma concentrations of the related cholesteryl ester transfer protein (CETP) were higher in type IIa and type IIb patients than in normolipidemic controls, and significant, positive correlations with total and low density lipoprotein cholesterol levels were noted. Interestingly, plasma PLTP mass concentration and plasma phospholipid transfer activity were significantly higher in patients with non-insulin-dependent diabetes mellitus (n=50) than in normolipidemic controls (6.76+/-1. 93 versus 3.95+/-1.04 mg/L, P<0.0001; and 685+/-75 versus 575+/-81 nmol. mL-1. h-1, P<0.0001, respectively). In contrast, CETP levels did not differ significantly between the 2 groups. Among non-insulin-dependent diabetes mellitus patients, PLTP levels were positively correlated with fasting glycemia and glycohemoglobin levels (r=0.341, P=0.0220; and r=0.382, P=0.0097, respectively) but not with plasma lipid parameters. It is proposed that plasma PLTP mass levels are related to glucose metabolism rather than to lipid metabolism.

Platelet Activity In Vivo in Hyperlipoproteinemia – Importance of Combined Hyperlipidemia

Platelet hyperactivity in vitro is found in patients with isolated hypercholesterolemia. It is, however, less well established if platelet activity in vivo is enhanced, and if there are differences between various types of hyperlipoproteinemia. Platelet function in vivo was studied at rest and during mental stress in men with isolated hypercholesterolemia (phenotype IIa; n = 21) or combined hyperlipidemia (phenotype IIb; n = 29), and age-matched normolipidemic controls (n = 41). The urinary excretion of 11-dehydrothromboxane B2 was elevated in patients compared to controls (IIa, p <0.05; IIb, p <0.001), and higher in type IIb than in IIa patients (p <0.05). Platelet secretion, assessed as plasma beta-thromboglobulin levels, was higher in type IIb patients compared to controls (p <0.01) and type IIa patients (p <0.05) during mental stress. The urinary excretion of beta-thromboglobulin was also elevated in type IIb patients compared to controls (p <0.05). Platelet aggregability at rest, as measured by filtragometry ex vivo was, however, reduced in both patient groups compared to controls (p <0.05). No correlations were found between plasma lipoprotein levels and markers of platelet function in vivo. Type IIb patients had higher plasma fibrinogen levels and higher leukocyte counts than controls (p <0.05 and p <0.001) and type IIa patients (p <0.05 and p = 0.06). Thromboxane excretion was positively related to fibrinogen levels and leukocyte counts (p <0.01 for both). Preliminary data regarding serum TNF-alpha also indicated an elevation of this inflammatory cytokine in type IIb patients (p <0.05 vs controls). In conclusion, thromboxane generation and platelet secretion in vivo are enhanced in patients with hypercholesterolemia, and particularly so among patients with concomitant elevation of plasma triglycerides. The mechanism is unknown, but inflammatory mediators may be involved. The present findings are of interest in relation to the role of triglycerides in coronary artery disease.

FLUVASTATIN AND TISSUE FACTOR PATHWAY INHIBITOR IN TYPE IIA AND IIB HYPERLIPIDEMIA AND IN ACUTE MYOCARDIAL INFARCTION

Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor that regulates tissue factor-induced blood coagulation. In an open-label 8-week study, 20 hypercholesterolemic patients (10 type IIa and 10 type IIb) were enrolled and given fluvastatin 40 mg once daily at bedtime. At baseline (after a 4-week controlled diet) and at week 8, total cholesterol, total triglycerides and lipoprotein subfractions were assessed. TFPI antigen levels were measured at the same time by ELISA. We also measured TFPI concentrations in 10 control subjects and in 10 patients at the time of and ten days after acute myocardial infarction. In type IIa patients fluvastatin reduced total cholesterol levels by 26% and LDL-cholesterol by 30% ( P<0.001); in type IIb, fluvastatin significantly reduced total cholesterol levels by 24% ( P<0.001). In both dyslipidemic groups the baseline total TFPI levels were significantly higher than in the control group ( P<0.002). The therapeutic lipid-lowering effect was paralleled by a significantly reduction of total TFPI antigen concentrations: from 132 ± 23 to 71 ± 37 ng/mL ( P<0.001) in type IIa and from 120 ± 30 to 91 ± 29 ng/mL ( P<0.05) in type IIb patients; in control subjects total TFPI levels were 81 ± 22 ng/mL; however the lipoprotein-bound TFPI antigen subfractions did not differ significantly in the treated and control groups. In patients with recent myocardial infarction there was a significant reduction from day 0 to day 10 in total TFPI antigen levels, from 120 ± 48 ng/mL to 80 ± 16 ng/mL ( P<0.05). The reported reduction of TFPI antigen levels after fluvastatin treatment could be a sign of normalization of an up-regulated clotting system rather than an unfavourable reduction of a natural anticoagulant. © 1997 Elsevier Science Ltd

A Type 2b von Willebrand Disease Mutation (lle546→Val) Associated with an Unusual Phenotype

Type 2B von Willebrand disease (vWD) is typically characterized by enhanced ristocetin-induced platelet aggregation (RIPA) caused by increased von Willebrand factor (vWF) affinity for platelets. Furthermore, absence of larger vWF multimers in plasma is characteristic of the originally described type IIB patients, now considered a subgroup of type 2B. We describe here three affected members of a family presenting with prolonged bleeding time, thrombocytopenia, markedly enhanced RIPA and spontaneous platelet aggregation, but normal plasma vWF antigen and ristocetin cofactor activity. Larger plasma vWF multimers, albeit decreased, were present in relatively greater proportion than in other type IIB patients. Genetic studies performed in two of these patients resulted in the identification of a previously unreported A-->G transition at nucleotide 4175 in the sequence of the pre-pro-vWF cDNA, corresponding to the substitution Ile546-->Val in the mature vWF subunit. This mutation appears to be responsible for an unusual type 2B phenotype, with greater enhancement of the vWF-platelet interaction than in typical cases but partial preservation of the larger vWF multimers in plasma.

Evaluation of the Abnormal Platelet Function in von Willebrand Disease by the Blood Filtration Test

We have evaluated platelet function in different subtypes of von Willebrand disease (vWD) by pushing blood through the capillary-sized channels of a glass filter. Patients, including those with type IIB vWD, showed lower than normal platelet retention and increased cumulative number of blood drops passing through the filter as a function of time. In contrast, shear-induced platelet aggregation, measured in the cone-and-plate viscometer, was paradoxically increased in type IIB patients. Treatment with 1-desamino-8-D-arginine vasopressin (DDAVP) tended to normalize the filter test in patients with type I-platelet normal and type I-platelet low vWD, but infusion of a factor VIII/von Willebrand factor (vWF) concentrate lacking the largest vWF multimers was without effect in type 3 patients. Experiments with specific monoclonal antibodies demonstrated that the A1 and A3 domains of vWF, as well as the glycoproteins Ib alpha and IIb-IIIa on platelets, are required for platelet retention in the filter. Thus, the test may reflect vWF function with regard to both platelet adhesion and aggregation under high shear stress, and provide relevant information on mechanisms involved in primary hemostasis.