Daniel Yeshurun

Relationship between plasma lipid concentrations and coronary artery disease in 496 patients.

The relationship between fasting plasma cholesterol and triglyceride concentrations and the frequency and extensiveness of coronary artery disease (CAD) was studied in 496 subjects evaluated for chest pain by coronary arteriography at The Methodist Hospital. One hundred six of the patients had no CAD while 390 had 25% or greater stenosis of one or more major vessels. Ninety-one percent had 75% or greater stenosis of at least one major vessel. Mean age for the group with CAD was 55.7 ± 8.7 and without disease 49.4 ± 11.6 (P < 0.01). Both cholesterol and triglyceride concen- trations were higher (P < 0.001) in the group with CAD. Mean cholesterol concentration in males increased from 195 ± 36 mg/dl in the group without CAD to 219 ± 41 in the group with three vessel disease and in females from 207 ± 40 to 252 ± 42. A progressive increase in triglyceride values was also detected but was less consistent. At the level of 25% and greater obstruction, the partial correlation coefficients between the number of vessels involved and the cholesterol and triglyceride concentrations, respectively, were + 0.201 and + 0.181.

Control of 3-Hydroxy-3-Methylglutaryl-CoA Reductase Activity in Cultured Human Fibroblasts by Very Low Density Lipoproteins of Subjects with Hypertriglyceridemia

Very low density lipoproteins (VLDL) and low density lipoproteins (LDL) from human normolipemic plasma, and the VLDL, the intermediate density lipoprotein (IDL), and LDL from patients with Type III hyperlipoproteinemic plasma were tested for their abilities to suppress the activity of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase in cultured human fibroblasts from normal subjects and a Type III patient. Regulation of cholesterol synthesis in the fibroblasts of a patient with Type III hyperlipoproteinemia appears to be normal. VLDL from normal subjects, isolated by angle head ultracentrifugation (d < 1.006) or by gel filtration on BioGel A-5m, were about 5 times less effective than LDL in suppressing HMG-CoA reductase activity, based on protein content, in agreement with previous reports with normal fibroblasts. Zonal centrifugation of normal VLDL isolated by both methods showed that the VLDL contained IDL. Normal VLDL from the angle head rotor, refractionated by the zonal method, had little, if any, ability to suppress the HMG-CoA reductase activity in either normal or Type III fibroblasts. VLDL, IDL, and LDL fractionated by zonal ultracentrifugation from Type III plasma gave half-maximum inhibition at 0.2-0.5 mug of protein/ml, indistinguishable from the suppression caused by normal LDL. Type III VLDL did not suppress HMG-CoA reductase in mutant LDL receptor-negative fibroblasts. Zonally isolated VLDL obtained from one Type IV and one Type V patient gave half-maximal suppression at 5 and 0.5 mug of protein/ml, respectively. Molecular diameters and apoprotein compositions of the zonally isolated normal and Type III VLDL were similar; the major difference in composition was that Type III VLDL contained more cholesteryl esters and less triglyceride than did normal VLDL. The compositions and diameters of the Type IV and Type V VLDL were similar to normal VLDL. These findings show that the basic defect in Type III hyperlipoproteinemia is qualitatively different from the cellular defect found in familial hypercholesterolemia, since the regulation of HMG-CoA reductase activity is normal in Type III fibroblasts. The metabolic defect in hypertriglyceridemia is related to the triglyceriderich lipoproteins which, free of other lipoproteins, have an enhanced ability to interact with cultured fibroblasts to regulate HMG-CoA reductase activity. These studies suggest that, in hypertriglyceridemia, there is a mechanism for direct cellular catabolism of VLDL which is not functional for normal VLDL.

bcl-2 and immunoglobulin gene rearrangement in patients with hepatitis C virus infection

An association between chronic hepatitis C virus (HCV) infection and clonal proliferation of B cells, including B cell lymphoma, has recently been demonstrated. However, the mechanism of malignant transformation is still unknown. It has been shown that B cells from patients with type II mixed cryoglobulinaemia (MC), strongly express the antiapoptotic bcl‐2 oncogene product. Therefore, we investigated a possible mechanism of lymphomagenesis, the occurrence of bcl‐2 and immunoglobulin gene rearrangement (IgH) in HCV‐infected patients. Three groups of patients were studied: (1) 44 patients with HCV and MC (anti‐HCV and HCV RNA positive); (2) 59 patients with chronic HCV infection without MC; (3) 50 patients with chronic liver disease (CLD) not related to HCV infection. The t(14;18) translocation (MBR bcl‐2–JH) and IgH rearrangement (FR3/JH) were detected by polymerase chain reaction (PCR) in peripheral mononuclear cells. bcl‐2 translocation was detected in 17/44 (39%), 7/59 (12%) and in none of the patients of groups 1, 2 and 3 respectively (Pu2003<u20030·01). Monoclonal IgH rearrangement was detected in 15/44 (34%), 5/59 (8·5%) and 2/50 (4%) patients of groups 1, 2 and 3 respectively (Pu2003<u20030·05). HCV‐infected patients had a higher prevalence of monoclonal IgH rearrangement and bcl‐2 translocation than patients with CLD of other aetiologies. These data suggest that HCV may play a role in the multistep mechanism of lymphomagenesis by inducing clonal proliferation of B cells and inhibition of apoptosis.

Drug treatment of hyperlipidemia

The most frequent indication for treatment of hyperlipidemia is for prevention of arteriosclerosis, a suspected but unproved benefit. The cornerstone of treatment of primary hyperlipidemia is diet; drugs may be added to, but do not replace, diet. When a drug is used with any patient, its potential benefits and hazards must be carefully weighed for the given subject. The subjects should be carefully followed and observed for side effects. Plasma lipids should be monitored during the course of treatment. Five drugs have been approved by the U.S. Food and Drug Administration for the treatment of hyperlipidemia: cholestyramine, clofibrate, nicotinic acid, sodium dextrothyroxine and beta-sitosterol. The use, the actions and the side effects of each and of several nonapproved agents are discussed.

The fasciitis panniculitis syndromes. clinical and pathologic features

The authors propose to encompass under the designation of fasciitis-panniculitis syndromes (FPS) a group of disorders characterized by induration of the skin due to chronic inflammation and fibrosis of the subcutaneous septa and muscular fascia. The prototype of the FPS is eosinophilic fasciitis. Thirty-two consecutive patients with FPS were cared for at the authors hospital during a 10-year period. The association of the FPS with other diseases, clinical presentations, histologic features, and response to treatment were analyzed. Idiopathic FPS, that is, eosinophilic fasciitis, was diagnosed in 14 patients. In the remaining 18 cases, the FPS were ascribed to vascular disorders (n = 6), infections (n = 6), and neoplastic disorders (n = 3), while trauma, insect bites, and Sweet syndrome antedated the FPS in 1 patient each. The lesions had a sleeve-like distribution in 20 patients, plaque-like distribution in 7, and a combined pattern in 5. Skin biopsies revealed lesions in the deep subcutaneous layers with the pathologic triad of septal and fascial fibrosis, chronic inflammatory infiltration, and small-vessel vasculopathy. Spontaneous improvement occurred in 4 cases. Following cimetidine monotherapy, complete remission was achieved in an additional 3 of 5 patients. The concept of the FPS serves to advance our understanding on several fronts: emphasizing the clinical and etiologic diversity; recognizing a stereotypic tissue reaction pattern; highlighting the panniculitis in addition to the fasciitic component; and describing a similar response to drug therapy in different clinical settings. Based on the results of the present series, cimetidine may be recommended as first-line treatment.

Management of Hepatitis C Virus-Related Arthritis

Hepatitis C virus (HCV) infection is often associated with extrahepatic manifestations among which arthropathy is common, affecting up to 20% of HCV-infected individuals. This arthropathy is to be distinguished from the more superficially prominent myalgias and fatigue. HCV-related arthritis is commonly presented as rheumatoid-like, symmetrical inflammatory polyarthritis involving mainly small joints, or, less commonly, as mono-or oligoarthritis, usually of the large joints. HCV arthritis usually runs a relatively benign course that, in contrast to ‘true’ rheumatoid arthritis (RA), is typically non-deforming and is not associated with articular bony erosions. In addition, unlike ‘classic’ RA, erythrocyte sedimentation rate is elevated only in about half of the patients and subcutaneous nodules are absent. In about two-thirds of the affected individuals morning stiffness may be severe, resolving after more than an hour. Several pathogenetic mechanisms may be involved: HCV arthritis may be part of the syndrome of mixed cryoglobulinaemia, or may be directly or indirectly mediated by HCV. Such possible, but yet not proven, mechanisms include direct invasion of synovial cells by the virus eliciting local inflammatory response, cytokine-induced disease or immune complex disease, particularly in genetically susceptible individuals.The diagnosis of HCV arthritis in patients with positive rheumatoid factor and chronic inflammatory polyarthritis may be difficult. Positive HCV antibody and HCV RNA, and the absence of bony erosions, subcutaneous nodules and antikeratin antibodies, may be useful in distinguishing between HCV-related arthritis and RA. The optimal treatment of HCV-related arthritis has not yet been established. Concerns may be raised regarding the use of immunosuppressive or potentially hepatotoxic drugs. However, it may be suggested that once the diagnosis of HCV-associated arthritis is made, combination antiviral treatment with interferon-α and ribavirin should be initiated as part of the therapeutic armamentarium. Low dose oral corticosteroids, nonsteroidal anti-inflammatory drugs, hydroxychloroquine or sulfasalazine in addition to the antiviral therapy can be used to control arthritis-related symptoms. Some patients may need long term anti-inflammatory treatment in various combinations, along with antiviral therapy. In patients with severe, disabling or life-threatening cryoglobulinaemiarelated symptoms refractory to antiviral or anti-inflammatory treatment, high dose corticosteroids (including pulse therapy) and/or plasmapheresis may be needed.

Arterial occlusive disease in occult cancer

Thromboembolism frequently complicates advanced cancer. The incidence of TE as one of the initial manifestations of occult cancer and the diagnostic value of TE as a signal of a possible unrecognized tumor were the subjects of recent studies. TE may precede the diagnosis of cancer by several months or years. The polymorphism of manifestations of paraneoplastic TE has been described previously. An accelerated course of intermittent claudication and of ischemic heart disease has been described in patients with cancer and probably represents additional variants of Trousseaus syndrome. Recently, clues for the presence of occult neoplasms in patients with TE have been proposed. Their value in the stratification of patients needs to be established in prospective studies. That cancer may be responsible for a precipitated course of coronary or peripheral arterial disease raises the question of whether work-up is recommended to uncover a silent malignancy in a patient who has been referred for treatment of these severe ischemic syndromes.

Quantitative liver-spleen scan using single photon emission computerized tomography (SPECT) for assessment of hepatic function in cirrhotic patients

BACKGROUND/AIMSnAccurate quantitative determination of liver function is critical in cirrhotic patients in order to predict outcome, particularly in patients who undergo hepatic resection or non-hepatic surgery. As colloid uptake by perfused Kupffer cells is proportional to perfused hepatocyte mass, quantitative liver spleen scan may be used as an index of perfused hepatocyte mass. Thus, this study was conducted to evaluate quantitative single photon emission computerized tomography (SPECT) of Tc-99mm-phytate colloid uptake by the liver as a test for hepatic function in cirrhotic patients.nnnMETHODSnQuantitative SPECT was used to measure liver volume, quantitative colloid uptake by the liver and percentage of injected dose/ml of liver tissue in cirrhotic patients (n=75), non-cirrhotic patients with chronic liver disease (n=52) and patients without liver disease (n=36).nnnRESULTSnAlthough liver volume was similar among the three groups, the cirrhotic patients had significantly lower total quantitative uptake and quantitative uptake/ml compared to groups 2 and 3 (P<0.001). Quantitative liver uptake in the cirrhotic patients was highly correlated with Child-Pugh score (r=-0.64, P<0.0001) and with indocyanine green retention at 15 min (r=-0.84, P<0.0001).nnnCONCLUSIONSnQuantitative SPECT of the liver may be an additional, useful, non-invasive quantitative test for assessment of hepatic function and severity of liver disease in cirrhotic patients.

The Fasciitis-Panniculitis Syndrome: Clinical Spectrum and Response to Cimetidine

The term fasciitis-panniculitis syndrome (FPS) is proposed as a novel compilation encompassing several disorders, common to which is subcutaneous induration caused by cicatrizing fasciitis as well as septal and lobular panniculitis and perimysial fibrosis. Included herein are Shulmans eosinophilic fasciitis, morphea profunda, lupus profundus, venous lipodermatosclerosis, toxic oil syndrome, altered tryptophane-related eosinophilic myositis, graft-versus-host reaction, and fasciitis reactive to subjacent basal cell carcinoma. FPS should be differentiated from scleroderma, which primarily affects the dermal structures and in which arterioles are injured. In contrast, vasculopathy of the subcutaneous medium-sized veins accompanies the hypodermal lesions of FPS. The importance of recognizing and grouping these disorders lies in their different histopathology, characterization as reactive phenomena, enhanced responsiveness to treatment, and better prognosis than scleroderma. In view of the excellent prognosis of FPS, steroid treatment is not warranted. Long-term therapy with cimetidine appears to benefit the majority of patients.

Lymph-Node—Based Malignant Lymphoma and Reactive Lymphadenopathy in Eosinophilic Fasciitis

BACKGROUNDnLymph node enlargement in patients with eosinophilic fasciitis is a rare occurrence and its clinical significance is unknown.nnnMETHODSnThe literature and authors registries were searched for eosinophilic fasciitis associated with lymphadenopathy. Clinical data, time sequence of appearance of either disorder, and pathological diagnoses were analyzed.nnnRESULTSnSix patients presenting with eosinophilic fasciitis had a lymph-node-based lymphoma and 4 patients had a reactive lymphadenopathy. The patients with lymphoma were elderly and the subcutaneous induration preceded the lymphadenopathy by 2 to 36 months. The patients with eosinophilic fasciitis and reactive lymphadenopathy were young and the onset of subcutaneous induration and lymph node enlargement coincided with one another. Favorable response of the eosinophilic fasciitis to prednisone therapy was attained in 3 of 3 patients with reactive lymphadenopathy and in 4 of the 6 cases with lymphoma.nnnCONCLUSIONSnEosinophilic fasciitis is rarely associated with clinically significant lymph node enlargement. Subcutaneous induration preceding the lymphadenopathy by 6 months or more, especially in elderly patients, suggests an underlying lymphoma. A favorable response of the subcutaneous induration to prednisone treatment does not exclude the diagnosis of lymphoma; therefore, it does not supersede the need of a pathological evaluation. A lymph node biopsy is mandatory in all cases.