Biomedical subjects
Publications and source records attributed to B P Hazenberg.
A Turkish patient with episodic fever and thoracic pain is described in whom a homozygous M694V mutation of the MEFV gene confirmed the clinical diagnosis of familial Mediterranean fever. The role of DNA analysis is discussed with respect to understanding the pathogenesis of the fever and assessing the risk of amyloidosis in specific mutations of the MEFV gene.
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OBJECTIVES: To compare weight loss efficacy, safety and tolerability of sibutramine and placebo in mildly to moderately obese hypertensive subjects; to assess the effect of weight loss on blood pressure. DESIGN: Randomized, double-blind, parallel-group; 3-week placebo run-in and 12-week treatment phase. SETTING: Nine hospital outpatient clinics and general practices in the Netherlands. PARTICIPANTS: 127 men and women, 18-65 years old, with body mass indices (BMI) ranging from 27 to 40 kg/m(2) and stabilized hypertension - mean resting diastolic blood pressure of 90-120 mm Hg - with or without antihypertensive medication. INTERVENTIONS: Sibutramine 10 mg once daily; placebo. MAIN OUTCOME MEASURES: Body weight, blood pressure, routine laboratory and clinical safety monitoring. RESULTS: Of 113 evaluable patients, 54 received sibutramine and 59 placebo. Weight reduction was significantly greater with sibutramine from week 2 onwards (last observation carried forward): mean, 4.4 kg with sibutramine and 2.2 kg with placebo (p = 0.002); mean percentage weight reduction, 4.7 and 2.3%, respectively (p < 0.001); mean BMI reduction, 1.6 and 0.8 kg/m(2), respectively (p < 0.01). Reduction in excessive body weight was associated with a reduction in blood pressure in both groups, although the mean reduction in supine diastolic blood pressure was numerically, but not statistically significantly, greater in the placebo group (5.7 mm Hg) compared with the sibutramine group (4.0 mm Hg; p = 0.21). Similar reductions were seen in supine systolic blood pressure. Both treatments were well tolerated. CONCLUSIONS: Sibutramine 10 mg once daily is a useful, effective therapy for obesity in the presence of stable hypertension.
A Dutch family with familial amyloidotic polyneuropathy associated with the transthyretin mutation Val71Ala is described. This is the third reported family with this mutation, causing at the protein level an unstable TTR monomer and at the clinical level progressive wasting, polyneuropathy, autonomic dysfunction and vitreous opacities.
OBJECTIVE: To describe a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue and to compare it with smears stained with Congo red. METHODS: After extraction of at least 30 mg of abdominal fat tissue in guanidine, the amyloid A protein concentration was measured by a monoclonal antibody-based sandwich ELISA. RESULTS: The concentrations in 24 patients with arthritis and AA amyloidosis (median 236, range 1.1-8530 ng/mg tissue) were higher (p < 0.001) than in non-arthritic controls, uncomplicated rheumatoid arthritis, and other types of systemic amyloidosis (median 1.1, range 1.1-11.6 ng/mg tissue). Patients with extensive deposits, according to Congo red staining, had higher concentrations than patients with minute deposits. CONCLUSION: This is a new, quantitative, and reproducible method for detecting deposits of amyloid A protein in aspirated fat tissue of patients with arthritis, even when minute deposits are present as detected in smears stained with Congo red.
Autonomic neuropathy is a well-known and prognostically important feature of systemic amyloidosis. In other conditions, autonomic function is commonly assessed by cardiovascular reflex tests, described by Ewing, but the feasibility of these tests has not been investigated in patients with systemic amyloidosis. We studied autonomic function in amyloidotic patients using cardiovascular tests and assessed their feasibility. Patients with AA, AL and ATTR amyloidosis participated. In all patients, cardiovascular reflex testing (mental arithmetic stress test and head-up tilting, besides the Ewing-tests) was performed. Of the 46 patients included, only 28 patients could perform all 4 Ewing-tests. In particular, patients with AA amyloidosis secondary to rheumatoid arthritis could not perform standing up and the isometric handgrip test. However, when the mental stress test replaced the handgrip test and head-up tilting replaced standing up, in 45 of the 46 patients, autonomic function could be assessed with cardiovascular reflex tests. Half of the patients with AA amyloidosis had signs of autonomic neuropathy--which was more than expected. We propose to replace the isometric handgrip test with the mental arithmetic stress test and standing up with head-up tilting if a patient is not able to perform these tests.
UNLABELLED: In systemic amyloidosis, widespread amyloid deposition interferes with organ function, frequently with fatal consequences. Diagnosis rests on demonstrating amyloid deposits in the tissues, traditionally with histology although scintigraphic imaging with radiolabeled serum amyloid P component (SAP) has lately been developed as a specific noninvasive alternative. We report a detailed analysis of the abnormal turnover of SAP in patients with systemic amyloidosis and an assessment of its clinical value. METHODS: Iodine-123-labeled human SAP (200 MBq) SAP was injected intravenously into 49 patients with histologically proven systemic AA- or AL- amyloidosis and in 7 control subjects. Plasma clearance and whole-body retention of labeled SAP were analyzed over 48 hr using plasma sampling, whole-body gamma camera imaging and measurement of radioactivity in the urine. The rate of SAP synthesis and interstitial exchange were determined, and the size of the amyloid compartment was compared with clinical estimates of whole-body amyloid load and patient survival. RESULTS: All plasma time-activity curves were biphasic. In comparison with control subjects, patients with amyloidosis showed significantly faster plasma disappearance [4-hr value: AA 48% +/- 18%, AL 45% +/- 15% versus 65% +/- 8% (p < 0.05)], higher total-body retention 48 hr p.i. [AA 74% +/- 14%, AL 73% +/- 17% versus 46% +/- 15% (p < 0.01)] and especially higher extravascular retention 48 hr p.i. [AA 59% +/- 16%, AL 58% +/- 19% versus 30% +/- 14% (p < 0.01)]. Extravascular retention correlated with clinical estimation of the amyloid load. If extravascular retention values in patients with AL amyloidosis were over 60%, survival was decreased (median 4 versus 23 mo, p < 0.001). Markedly increased interstitial exchange rates were present in amyloidosis (AA 64 +/- 61, AL 50 +/- 37 versus 18 +/- 8 mg/hr), whereas the SAP synthesis rate did not differ from the control values (AA 5.0 +/- 3.0, AL 5.5 +/- 3.2 versus 4.5 +/- 1.4 mg/hr). CONCLUSION: The presence of systemic amyloidosis is characterized by accelerated initial clearance of 123I-SAP from the plasma and increased interstitial exchange rate and extravascular retention. These findings reflect reversible binding of radiolabeled SAP to amyloid deposits and provide clinically useful information for diagnosis, monitoring of therapy and prognosis in patients with systemic amyloidosis.
Radiographs of hand and hip joints of 15 hemodialysis patients taken annually over at least 15 years were evaluated in this retrospective study. We looked for signs of A beta 2M-amyloidosis such as lucencies, erosions, and soft tissue swelling. The femoral head-soft tissue distance (FHSTD) was used to estimate the soft tissue swelling of the hips. The number and size of lucencies, the number of erosions, and the FHSTD increased during dialysis. Both hyperparathyroidism and failure of renal allograft transplantation influenced the development of lucencies and erosions after 15 years. The FHSTD at the start of the dialysis appeared to be an independent prognostic factor for the lucencies of the hips and hands. We conclude that the radiological signs of A beta 2M-amyloidosis are influenced not only by the duration of dialysis, but also by age, failure of renal transplantation, hyperparathyroidism and the FHSTD at the start of dialysis.
Approach to the management of AA amyloidosis complicating RA. (A) In case of proteinuria or loss of renal function a rectal biopsy or a subcutaneous fat biopsy is a suitable screening method for the detection of amyloidosis. If in any doubt, try to ascertain the diagnosis by renal biopsy. Adequate staining with alkaline Congo red and preferably immunohistochemical staining with anti-AA antibodies should be performed. Beware of renal pathology other than amyloidosis even in the presence of a positive rectal biopsy. (B) A vigorous attempt to control disease activity of the RA should be made in order to eliminate the production of SAA, an acute phase protein. The response to treatment should be monitored by serial measurements of CRP and preferably SAA. (C) The function of some vital organs should be evaluated: (a) endogenous creatinine clearance and the extent of proteinuria; (b) electrocardiogram and optional echocardiography; (c) thyroid function and adrenocortical function; (d) intestinal absorption tests; (e) optional--SAP scintigraphy and turnover studies. (D) Attention should be given to adequate supportive treatment: (a) blood pressure control; (b) treatment of intercurrent infections; (c) corticosteroids during major surgical procedures; (d) pay attention to the possible effect of NSAID on proteinuria and renal function. (E) In case of total renal failure or uncontrollable proteinuria: (a) consider the possibility of primary renal transplantation; (b) otherwise regular haemodialysis is indicated.
This article describes the use of granulocyte macrophage colony stimulating factor and granulocyte colony stimulating factor in two patients with drug induced granulocytopenia. A granulocyte count > 1 x 10(9)/l was obtained after 7 days' treatment. These results suggest that the haematopoietic growth factors shortened the period of agranulocytosis and subsequently may improve the survival of these patients.
Extensive deposition of amyloid was detected in the digestive tract of a Somali woman aged 20 yr with abdominal pain, diarrhoea and cachexia. Immunohistochemical characterisation showed that the amyloid protein involved was of the AA type. Elevated levels were also found for serum amyloid A (SAA), an acute-phase protein which is the precursor of AA amyloid. The underlying inflammatory disease was peritoneal tuberculosis. The normalisation of the SAA levels and the recovery of the small intestine during tuberculostatic therapy showed that the tuberculosis was the cause of the enteropathy. This case report highlights the importance of early detection and effective treatment of the underlying inflammatory disease in case of AA amyloidosis.
A 57-year-old woman was admitted because of weakness, fatigue, abdominal discomfort, easy bruising and splenomegaly. A highly elevated leukocyte count with hairy-cell-like cells was found, the cells being positive for the monoclonal antibodies CD19, FMC7, CD11c and B-ly-7 and negative for CD24 and CD25. Blood and bone marrow were investigated not only in our own laboratory but also in several other laboratories resulting in a variety of possible diagnoses. Only after combining all data could a definitive diagnosis of variant hairy cell leukaemia be made. The patient was treated initially with a splenectomy and later on with interferon-alpha-2b, resulting in a steady decrease in the leukocyte count. After a follow-up of 2 years a nearly complete remission was obtained with a good quality of life. The differential diagnosis of this rare disorder is discussed with emphasis on the relative contribution of different diagnostic procedures.
Two patients are described with Weil's disease as a rare cause of jaundice. We discuss some features that can lead to early diagnosis. This concerns the apparently aspecific flu-like syndrome that precedes the icteric phase of the disease, as well as the typical pattern of liver function tests in the jaundiced patient: serum bilirubin is markedly elevated as compared with the liver enzymes. Another clue to the diagnosis can be obtained by enquiring not only about the patient's profession, but also about his leisure activities, since both patients acquired the disease in their leisure time.
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OBJECTIVE: To study the patterns of plasma concentrations of endotoxin, tumor necrosis factor-alpha (TNF), interleukin-6 (IL-6), plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A during the treatment of human sepsis. DESIGN: A prospective case series study. SETTING: ICU of the Department of Internal Medicine, University Hospital Groningen, The Netherlands. PATIENTS: Twenty consecutive patients (11 female, 9 male, mean age 67 yrs) with clinically defined sepsis. Eighteen patients were admitted from the outpatient emergency ward; two patients were already inpatients. The control group (n = 7) comprised patients with nonseptic shock. MEASUREMENTS AND MAIN RESULTS: Ten (50%) septic patients had detectable endotoxemia (greater than 5 (ng/L). TNF concentrations on admission were increased in 94% of the septic patients, whereas IL-6 and plasminogen activator inhibitor plasma concentrations were increased in all septic patients. The septic group showed significantly (p less than .05) higher concentrations of TNF, IL-6, plasminogen activator inhibitor-1, C-reactive protein, and serum amyloid A compared with the nonseptic patients. In the septic group, we found a correlation of both IL-6 and plasminogen activator inhibitor concentrations with severity of illness (r2 = .33, p less than .05; r2 = .22, p less than .05, respectively). After the start of antibiotic treatment, high concentrations of TNF and plasminogen activator inhibitor persisted in the nonsurvivors in contrast to decreasing concentrations in most of the survivors. After an initial increase in seven patients, IL-6 concentrations decreased in all septic patients and also in nonsurvivors. CONCLUSIONS: This study confirms previous findings that: a) TNF is a major mediator involved in the pathogenesis of septic shock; b) plasminogen activator inhibitor activity is significantly increased in septic patients and might be involved in the pathogenesis of disseminated intravascular coagulation associated with sepsis; and c) IL-6 is involved in the pathophysiology of septic shock, although further studies are needed to determine whether IL-6 is directly involved in mediating the lethal complications of septic shock or whether it should be considered an "alarm hormone" that reflects endothelial cell injury. Our findings also suggest that the concentrations and trends of these mediators during treatment are valuable for monitoring septic patients.
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We report the use of granulocyte-macrophage colony stimulating factor (GM-CSF) in a case of rheumatoid arthritis with sulfasalazine induced agranulocytosis, leading to a rapid bone marrow recovery within 7 days. This case and 2 others reported in the literature emphasize the need for further research into the possible role of GM-CSF in the treatment of drug induced agranulocytosis.
Interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF) are considered as important mediators for the modulation of liver synthesis of acute phase proteins. However, studies of the direct effect of individual or a combination of these cytokines on the synthesis of acute phase proteins in human hepatocytes are still very limited. In this study, we have examined the synthesis of C-reactive protein (CRP) and serum amyloid A (SAA) in primary cultures of human hepatocytes exposed to recombinant(r)IL-1 alpha (100 U/ml), rIL-6 (2000 U/ml), rTNF alpha (30 U/ml) and to various combinations of these cytokines in the presence of 1 microM dexamethasone. Monoclonal antibodies to rTNF alpha and monospecific anti-rIL-6 sheep antiserum were also used to investigate the possible endogenous production of TNF or IL-6. The findings indicate: (1) IL-1 and IL-6 are stimulatory cytokines for the liver synthesis of CRP and SAA. Anti IL-6 abolishes the stimulatory effect of IL-1. These findings support the previous observation and indicate that IL-1 exerts its action on the enhanced synthesis of CRP and SAA at least in part via IL-6 production in the liver cell. (2) TNF is an inhibitory cytokine for the liver synthesis of CRP. It inhibits also the stimulatory effect of IL-1 and IL-6 on the synthesis of CRP and SAA. (3) Since anti-TNF enhances the stimulatory effect of IL-6 on the synthesis of CRP and SAA, it seems likely that TNF is also produced by the human hepatocytes. However, further studies for more direct evidence of the liver cell production of TNF, such as the detection of TNF messenger RNA are required.