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The chemokine receptors CCR2 and CCR5 play important roles in the recruitment of monocytes/macrophages and T cells. To better understand the role of both receptors in murine models of inflammatory diseases and to recognize potential problems when correlating these data to humans, we have generated mAbs against murine CCR2 and CCR5. In mice CCR2 is homogeneously expressed on monocytes and on 2--15% of T cells, closely resembling the expression pattern in humans. In contrast to humans, murine NK cells are highly CCR5 positive. In addition, CCR5 is expressed on 3--10% of CD4 and 10--40% of CD8-positive T cells and is weakly detectable on monocytes. Using a model of immune complex nephritis, we examined the effects of inflammation on chemokine receptor expression and found a 10-fold enrichment of CCR5(+) and CCR2(+) T cells in the inflamed kidneys. The activity of various chemokines and the antagonistic properties of the mAbs were measured by ligand-induced internalization of CCR2 and CCR5 on primary leukocytes. The Ab MC-21 (anti-CCR2) reduced the activity of murine monocyte chemotactic protein 1 by 95%, whereas the Ab MC-68 (anti-CCR5) blocked over 99% of the macrophage-inflammatory protein 1alpha and RANTES activity. MC-21 and MC-68 efficiently blocked the ligand binding to CCR2 and CCR5 with an IC(50) of 0.09 and 0.6--1.0 microg/ml, respectively. In good correlation to these in vitro data, MC-21 almost completely prevented the influx of monocytes in thioglycollate-induced peritonitis. Therefore, both Abs appear as useful reagents to further study the role of CCR2 and CCR5 in murine disease models.

Over the past 25 years, nailfold capillary microscopy (NCM) has gained diagnostic value in the field of rheumatology based on descriptive data from patients with distinct connective tissue diseases (CTD). We prospectively analysed NCM findings from 116 patients selected for NCM by one of the following indications: (1) suspected diffuse or limited scleroderma or dermatomyositis, (2) evaluation of Raynaud's phenomenon (RP) or (3) suspected small-vessel vasculitis. Nailfold haemorrhages, and enlarged and tortuous nailfold capillaries ('lupus pattern') were found to comparable degrees in patients with CTD and primary RP. Only giant loops, bushy capillaries and avascular areas indicated CTD; 92% of patients with Wegener's granulomatosis (WG) had avascular areas. From all nailfold capillary abnormalities, only bushy capillaries, giant loops and avascular areas support a suspected CTD. A lupus-like pattern is not diagnostic. Avascular areas are a typical abnormality in patients with WG, for which NCM findings have not been described previously.

The estimation of glomerular filtration rate is important for the medical treatment of patients with rheumatoid arthritis (RA). However, the determination of endogenous creatinine clearance (Clcr) from a 24-h urine collection is an unreliable and time-consuming procedure. We therefore tested the accuracy of six equations and one nomogram for the prediction of Clcr from serum creatinine (Scr) in 38 patients with RA and 20 controls. A positive correlation was found for all methods in the controls (r = 0.83-0.94) and RA patients (r = 0.51-0.69). The methods did not overestimate Clcr in RA. In the RA group the simple formula published by Cockcroft [Clcr = ((140 - age) x body weight)/(72 x Scr), x 0.85 for females] showed the best correlation with the measured Clcr. In RA the Cockroft formula can reliably be used to predict Clcr from Scr.

Myocardial involvement in polymyositis is commonly suspected in noninvasive studies, but symptomatic cardiac disease is rare. We describe a 27-year-old woman with a 6 year history of severe polymyositis and persistent elevation of creatine phosphokinase-MB isoenzyme who suddenly developed congestive heart failure and bradycardia-tachycardia syndrome. Autopsy revealed severe myocardial fibrosis without inflammatory cell infiltrates concomitant to active polymyositis of the skeletal muscles despite intensive longterm immunosuppressive therapy.

Leptin, the ob gene product, has been proposed as a mediator of inflammatory cytokine-dependent decreased food intake and cachexia in rodents. In humans, leptin serum levels increase after administration of tumor necrosis factor-alpha (TNF-alpha) or interleukin-2 or during septicemia. However, the effect of human chronic inflammatory disease on serum leptin is unknown. We therefore determined the serum leptin level (radioimmunoassay), body mass index (BMI), percent body fat ([%BF] bioelectrical impedance analysis), and disease activity (Disease Activity Score [DAS]) in 58 patients with rheumatoid arthritis (RA) and 16 controls. The BMI, %BF, serum leptin, and ratio of leptin to %BF (leptin/%BF) did not differ significantly in 25 patients with moderate RA activity (DAS, 3.6 +/- 0.5), 33 patients with low RA activity (DAS, 1.8 +/- 0.5), and controls. A positive correlation for serum leptin and %BF was detected in all groups. Our data indicate that in RA, a human chronic cytokine-mediated inflammatory disease, the serum leptin level is directly related to %BF but not to disease activity.

Scleroderma renal crisis is characterized by intimal thickening of the afferent glomerular arterioles resulting in hypertension and fibrinoid necrosis of the capillary tuff. We report a 67-year-old man with long-standing systemic sclerosis who developed normotensive progressive renal failure, proteinuria, and a nephritic urinary sediment with serum myeloperoxidase-antineutrophil cytoplasmatic antibodies (MPO-ANCA). Renal biopsy showed pauci-immune crescentic glomerulonephritis but none of the typical vascular changes of scleroderma renal crisis. Because comparable cases have recently been reported from Japan, normotensive MPO-ANCA-positive crescentic glomerulonephritis may form an entity of progressive renal failure in scleroderma.

Cytomegalovirus (CMV) infection is one of the most important opportunistic infections in AIDS. The most common manifestation of neurological CMV disease in HIV infection is retinitis followed by encephalitis, polyradiculopathy, and multifocal neuropathy. Untreated necrotizing retinitis proceeds to blindness but can readily be diagnosed by ophthalmological examination. CMV polyradiculopathy presents as subacute leg weakness, paraesthesia, and urinary retention. Untreated patients develop ascending paralysis and die within weeks. Multifocal neuropathy commonly affects the radial, ulnar, and peroneal nerves but cranial nerves may also be involved. Confusion, cranial nerve palsies, and hyperreflexia are signs of ventriculoencephalitis, whereas the presentation of diffuse micronodular encephalitis is often asymptomatic. The diagnostic approach relies on the detection of CMV DNA in the cerebrospinal fluid for polyradiculopathy, encephalitis, and neuropathy. Neuroimaging can exclude other causes of encephalitis and polyradiculopathy. Ganciclovir, foscarnet, and cidofovir monotherapy are current medical treatment options. Intraocular administration can be used for refractory retinitis, but additional systemic prophylaxis is required to suppress extraocular disease. Ganciclovir and foscarnet have improved the prognosis of multifocal neuropathy and polyradiculopathy, but response rates for encephalitis are low. However, despite therapy survival of central nervous CMV disease is still limited to months. Recently highly active antiretroviral therapy (HAART) has decreased the overall incidence of CMV disease in AIDS. Furthermore (HAART) has become a mainstay for CMV therapy by improving the patient's immunocompetence against CMV.

In patients with acquired immune deficiency syndrome (AIDS), hypoosmolality is frequently observed, whereas hypernatremia is distinctly rare. We report two patients with advanced AIDS and cytomegalovirus (CMV) encephalitis, who developed severe hypernatremia without any thirst sensation, that is, adipsic hypernatremia. Both developed severe hypernatremia of up to 164 and 162 mmol/L, with serum osmolalities of 358 and 344 mOsmol/kg while remaining alert and denying thirst. Serum antidiuretic hormone (ADH) levels were 0.9 and 1.5 pg/mL, inappropriately low for the concomitant serum osmolalities. Vital signs were stable. During hypernatremia, urine osmolalities were 327 and 340 mOsmol/kg, and urine Na+ levels were 56 and 119 mmol/L, respectively. Periventricular white matter lesions were seen on cerebral nuclear magnetic resonance imaging (NMRI) in case 1, but the pituitary appeared normal in both cases. Survival after onset of hypernatremia was 6 and 4 weeks, respectively. Autopsy in case 1 showed typical findings of CMV encephalitis but normal pituitary, confirming that infection with HIV or CMV most likely caused the dysfunction of the central osmostat.

Objectives: To study the prevalence and possible mechanisms of hypocalcaemia in HIV infection and AIDS., Subjects: 828 patients with HIV infection or AIDS and 549 controls., Interventions: Measurements of total serum calcium and albumin levels. Parameters of calcium homeostatis were determined in a subgroup of 21 hypocalcaemic AIDS patients., Results: Mean serum calcium was 2.34 +/- 0.13 mmol L-1 in the HIV group vs. 2.46 +/- 0.10 mmol L-1 in controls (P < 0.0001). After adjusting for serum albumin, hypocalcaemia was present in 6.5% of the HIV group vs. 1.1% of controls. Mean serum calcium was declining according to CDC groups, and differed significantly from controls in each group. Regression coefficients of cacium vs. albumin were 0.147 amongst HIV-infected patients and 0.106 for controls. In the subgroup of hypocalcaemic patients with AIDS, 10/21 had vitamin D deficiency, six of these with low ionized calcium levels. Low serum PTH was found in 2/21 patients. Magnesium deficiency in 1/21. Of the remaining eight patients, only one had secondary hyperparathyroidism, while the other seven lacked an adequate PTH response, despite low ionized calcium levels in four subjects., Conclusions: Mean serum calcium concentrations were lower through all CDC stages, irrespective of albumin, resulting in a higher prevalence of hypocalcaemia in HIV-positive patients compared with controls. In a considerable number, this seems to be caused by vitamin D deficiency and potentially a lack of adequate PTH secretion, but further studies are needed to confirm this.

Using the MEDLINE database, we evaluated 103 cases of AIDS-related cytomegalovirus (CMV) polyradiculopathy (PRP). In 13% of cases, PRP was the initial manifestation of AIDS. Hyporeflexia was present in 100% of cases; lower limb weakness, in 100%; urinary retention, in 94%; paresthesia, in 79%; sensory loss, in 80%; and a Babinski's sign, in 16%. Mean cerebrospinal fluid (CSF) parameters +/- SD were as follows: white blood cell count, 651 +/- 1,053 x 10(6)/L; protein level, 2.28 +/- 1.78 g/L; and CSF/serum glucose ratio, 0.48 +/- 0.17. Gadolinium enhancement of meninges on a magnetic resonance image and abnormalities on a myelogram were noted in 31% and 17% of cases, respectively. Mean survival time +/- SD was 5.4 +/- 1.8 weeks for untreated patients and 14.6 +/- 9.4 weeks for patients treated with ganciclovir (P < .0001), but it was only 7.2 +/- 3.0 weeks for patients receiving ganciclovir treatment at the onset of PRP. CMV-related PRP is an uncommon but distinctive complication of AIDS. Early diagnosis is possible, and other causes can be excluded by lumbar magnetic resonance imaging and by the presence of typical CSF changes, as shown by polymerase chain reaction of CMV. Retrospectively, survival time for naive patients was increased by ganciclovir therapy and may even be underestimated in this evaluation of historical reports.

Objective: The long-term effects and mechanisms of early started angiotensin converting enzyme (ACE) inhibition post myocardial infarction (MI) are not well understood. Chronic effects of early ACE inhibition on hemodynamics, left ventricular diastolic wall stress and remodeling were, therefore, compared to that of angiotensin AT1-receptor subtype blockade in rats with experimental myocardial infarction. The contribution of bradykinin potentiation to both ACE inhibitor and angiotensin AT1-receptor subtype blockade was assessed by cotreatment of rats with a bradykinin B2-receptor antagonist., Methods: MI was produced by coronary artery ligation in adult male Wistar rats. The ACE inhibitor, quinapril (6 mg/kg per day), or the angiotensin AT1-receptor subtype blocker, losartan (10 mg/kg per day), administered by gavage, and the bradykinin B2-receptor antagonist, Hoe-140 (500 micrograms/kg per day s.c.), administered either alone or in combination with quinapril or losartan, were started 30 min after MI and continued for eight weeks., Results: Quinapril and losartan reduced left ventricular end-diastolic pressure and global left ventricular diastolic wall stress only in rats with large MI. Pressure volume curves showed a rightward shift in proportion to MI size that was not prevented by quinapril or losartan treatment. Only the ACE inhibitor reduced left ventricular weight and this effect was prevented by cotreatment with the bradykinin antagonist. Baseline and peak cardiac index and stroke volume index, as determined using an electromagnetic flowmeter before and after an acute intravenous volume load, were restored by quinapril, whereas losartan had no effects., Conclusion: Treatments starting 30 min after coronary artery ligation, with either quinapril or losartan, reduced preload only in rats with large MI. Despite this unloading of the heart, structural dilatation was not prevented by this early treatment. Only quinapril improved cardiac performance and reduced left ventricular weight and this effect was abolished by cotreatment with Hoe-140, suggesting an angiotensin II blockade-independent, but bradykinin potentiation-dependent, mechanism.

Enlargement of the thyroid is common, especially in areas of endemic iodine deficiency. Substernal enlargement of a goitre can cause compression of several mediastinal structures. As a consequence of tracheal compression and tracheomalacia, syndromes of chronic respiratory distress occur and intercurrent upper respiratory infections may lead to acute respiratory failure. Superior vena cava syndrome secondary to compression by a substernal goitre may be complicated by venous thrombosis. Although dysphagia is the most frequent oesophageal symptom of a substernal goitre, upper gastrointestinal bleeding from 'downhill' oesophageal varices may be an initial presentation. Arterial compression or thyrocervical steal syndrome by large substernal goitres occasionally cause cerebral hypoperfusion and stroke. Recurrent and phrenic nerve palsies, as well as Horner's syndrome, occur secondary to non-malignant mediastinal goitres and may resolve after surgery. Substernal goitres rarely cause therapy-resistant pleural effusions, chylothorax and pericardial effusion. In conclusion, although cervical goitres are easily recognised, the initial presentation of mainly substernal goitres may be unusual.

Cytomegalovirus (CMV) polyradiculopathy is a rare complication of AIDS in which ascending motor weakness, sensory loss and urinary retention are associated with polymorphonuclear pleocytosis and positive CMV polymerase chain reaction in the cerebrospinal fluid (CSF). We describe three patients with this syndrome. One patient's paresis improved after ganciclovir therapy. Another patient deteriorated despite foscarnet treatment, but improved after ganciclovir was added. The third patient died from ascending paralysis despite ganciclovir-foscarnet combination. Reviewing the literature, we conclude that antiviral treatment reduced mortality from 100 to 22%. In patients with ascending paralysis treatment, failure may be caused by viral drug resistance, at least in some patients. Risk factors for treatment failure are preceding monotherapy for other CMV diseases or persistent CSF pleocytosis on serial CSF analysis. We suggest that these patients should therefore be treated with the alternative drug or a ganciclovir-foscarnet combination therapy.

Adverse drug reactions to trimethoprim-sulfamethoxazole (TMP/SMX) are common in HIV-positive patients. However, only one case of TMP/SMX-related rhabdomyolysis has been reported, so far. We report a 55-year old-man with asymptomatic rhabdomyolysis after oral high-dose TMP/SMX for suspected PCP. Laboratory changes settled after discontinuation of the drug.

In the past workers have isolated several pseudomonad strains which have been used for studies of anaerobic aromatic metabolism. The best studied of these strains are strains KB 740T (T = type strain) and K 172T. The taxonomic positions of these two organisms were determined by classical methods, including experiments to determine substrate spectrum, quinone type, and total fatty acid composition. Our results clearly excluded these strains from the authentic genus Pseudomonas, which belongs to the gamma subclass of the Proteobacteria. Instead, the properties of these organisms indicated that they belong to the beta subclass of the Proteobacteria. The sequences of the 16S ribosomal DNA genes confirmed this conclusion and indicated that strain K 172T represents a new species of the genus Thauera, Thauera aromatica, and that strain KB 740T represents a new species of the genus Azoarcus, Azoarcus evansii.