Diffuse alveolar hemorrhage in Colombian patients with systemic lupus erythematosus

Diffuse alveolar hemorrhage (DAH) is a rare life-threatening complication seen in patients with systemic lupus erythematosus (SLE). This paper describes the clinical features and outcome of seven SLE patients with DAH admitted to a medical intensive care unit (ICU) in a referral center. Of a total of 122 SLE patients, seven patients presented this complication (5.7%). Five patients were women (71.4%). Mean age was 24.3 (range 4–51 years). Mean duration of SLE before clinical DAH was 15.7 months (range 0–48 months). DAH was the initial manifestation of SLE in two patients (29%). DAH recurrence was seen in two patients (29%). Active lupus was present in all seven patients. Fever, glomerulonephritis, arthritis, myositis, and peripheral neuropathy were observed in six, four, four, three, and two patients, respectively. Five patients who underwent to bronchoscopy had positive findings of DAH (71.4%; i.e., bloody return on bronchoalveolar lavage—with hemosiderin-laden macrophages). Treatment options included intravenous methylprednisolone (10 mg kg⁻¹ day⁻¹—3 days) following by prednisolone 1 mg kg⁻¹ day⁻¹ and pulse cyclophosphamide (750 mg/m²). Plasmapheresis was added in four patients (57.1%) because of the persistence of DAH. All patients were treated in an ICU, six of them requiring mechanical respiratory support (85.1%). Mortality rate during ICU stay was 12% (one patient). Our results show that DAH is an uncommon complication in SLE patients, requiring a prompt and aggressive recognition and treatment with high-dose steroid, intravenous cyclophosphamide, and plasmapheresis. With all of these treatments, there is a trend to a low mortality rate in patients with SLE presenting DAH.     

Unusual presentation of non-Hodgkin lymphoma: polyarthritis and uveitis mimicking a rheumatologic disease

We report a case of 45-year-old male who presented with polyarthritis and posterior uveitis. He was given azathioprine (AZA) 150 mg day⁻¹ and methyl-prednisolone 48 mg day⁻¹ for his uveitis and polyarthritis. Eye and joint complaints improved with these medications within 1 month. Three months later, while he was on AZA, the patient presented with pain on his anterior chest wall associated with diffuse hyperemic and warm mass lesion. A wedge biopsy of the lesion was reported as diffuse large B-cell NHL. Here, we briefly discuss the relationship between arthritis, uveitis and lymphoproliferative disease.     

Suboptimal doses of low molecular weight heparin and acute venous thromboembolism. Data from the RIETE registry

The objective was to assess the use of suboptimal doses (60–149 UI kg⁻¹ day⁻¹) of low molecular weight heparin (LMWH) in the treatment of acute venous thromboembolism (VTE) in actual clinical practice and to evaluate the outcomes compared to standard doses (≥150 UI kg⁻¹ day⁻¹). Retrospective analysis of data from a multicenter registry of patients with VTE (RIETE; Registro Informatizado de Enfermedad TromboEmbólica). Patient characteristics, antithrombotic treatments, and 3-month outcomes were analyzed. We studied 12,302 patients with VTE; 10,524 patients were treated initially only with LMWH; 1,547 patients received suboptimal LMWH (mean = 122 UI kg⁻¹ day⁻¹), and 8,977 patients received full-dose LMWH (mean = 191 UI kg⁻¹ day⁻¹). The suboptimal group included significantly more patients with recent major bleeding, weight more than 100 kg, raised creatinine, or deep vein thrombosis. No significant differences in mortality rate (7.7 vs 7.8%), VTE recurrence (2.7 vs 2.3%), or fatal hemorrhage (0.6 vs 0.6%) occurred between the suboptimal and the standard group. Major bleeding episodes occurred more frequently in the patients with pulmonary embolism treated with suboptimal LMWH (4.5 vs 2.4%; p = 0.02). In the multivariate analysis, after adjusting for bleeding risk factors, major hemorrhage was not associated with the heparin dose. Suboptimal doses of LMWH are used in actual clinical practice in a reduced group of patients at an outcome rate not very different to that of standard doses. Bleeding episodes depend more on the patient’s characteristics than on the LMWH dose. Randomized trials should be performed to corroborate these results. A full list of the RIETE investigators is given in the Appendix.     

Tonic and Phasic Pyloric Activity in Response to CCK-Octapeptide

Background The purpose of this study was to determine whether a high-resolution solid-state catheter system could detect regional pressure changes within the antrum and pylorus in response to CCK-octapeptide. Methods Subjects received a 30 min infusion of CCK-octapeptide at either 0.02 or 0.06 μg kg⁻¹ h⁻¹. Results Five males and two females were studied. Mean antral pressure during phase I MMC increased from 5.3 ± 2.1 to 9.9 ± 2.4 mmHg (P = 0.028) after infusion. At the pylorus, only the 0.06 μg kg⁻¹ h⁻¹ dose increased tonic pressure (8.8 ± 1.4 to 17.6 ± 2.0 mmHg; P = 0.01) as compared with the 0.02 μg kg⁻¹ h⁻¹ dose (4.7 ± 0.7 to 7.3 ± 0.4 mmHg; P = NS). The peak pressure of pyloric phasic pressure waves was 153 ± 28.4 mmHg and their frequency was 4.9 ± 1.1 contractions min⁻¹. Conclusions CCK-octapeptide elicits both tonic and phasic activity of the pyloric sphincter. The contractile response to a dose of 0.06 μg kg⁻¹ h⁻¹ is greater than the response to 0.02 μg kg⁻¹ h⁻¹.     

A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM

Summary In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two 12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect on serum potassium, uric acid, fasting glucose and HbA_{1 c} concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8 ± 2.9 vs 27.3 ± 3.5 μmol · kg^{− 1}· min^{− 1}, p < 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8 ± 3.6 vs 27.3 ± 3.5 μmol · kg^{− 1}· min^{− 1}, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg (11.7 ± 0.5 vs 10.2 ± 0.3 μmol · kg^{− 1}· min^{− 1}, p < 0.05) and suppressed to a lesser extent following insulin (4.0 ± 0.7 vs 2.0 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline (11.7 ± 0.5 vs 10.6 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p < 0.05) whereas bendrofluazide 1.25 mg did not (10.2 ± 0.3 vs 10.6 ± 0.4 μmol · kg^{− 1}· min^{− 1}, p = NS). At a dose of 1.25 mg bendrofluazide is as effective as conventional doses but has less adverse metabolic effects. In contrast to conventional doses which worsen both hepatic and peripheral insulin resistance, low-dose bendrofluazide has no effect on insulin action in non-insulin-dependent diabetic subjects. [Diabetologia (1995) 38: 853–859] Received: 6 September 1994 and in revised form: 29 December 1994     

Pharmacological manipulation of vascular endothelium function in non-diabetic and streptozotocin-diabetic rats: effects on nerve conduction,hypoxic resistance and endoneurial capillarization

Summary We examined the potential for some of the abnormalities of vascular endothelium found in diabetes mellitus to cause neuropathic changes. Non-diabetic rats were treated for 2 months with the cyclo-oxygenase inhibitor flurbiprofen (5 mg·kg⁻¹·day⁻¹) to reduce prostacyclin production, the nitric oxide synthase inhibitor N^G-nitro-L-arginine (5 or 25 mg·kg⁻¹·day⁻¹), or combined treatment. There were dose-dependent reductions in sciatic motor and saphenous sensory conduction velocity. The two inhibitors acted synergistically, thus, the 5–6% motor conduction deficits (p<0.01) produced by either flurbiprofen or N^G-nitro-l-arginine (5 mg·kg⁻¹·day⁻¹) increased to 17% (p<0.001) for combined treatment. With N^G-nitro-l-arginine (25 mg·kg⁻¹·day⁻¹) and flurbiprofen, motor and sensory conduction velocity were reduced by 23% (p<0.001) and 12% (p<0.001), respectively, matching the deficits following 2-month streptozotocin diabetes. N^G-nitro-l-arginine (25 mg·kg⁻¹·day⁻¹) and flurbiprofen together produced a 13% prolongation of the time taken for 80% hypoxic conduction failure in vitro (p<0.05) and a 10% reduction in sciatic capillary density. A second investigation tested an alternative hypothesis that overproduction of nitric oxide was responsible for vascular-related complications in diabetes, the prediction being that N^G-nitro-L-arginine (5 mg·kg⁻¹·day⁻¹) would prevent nerve dysfunction. However, rather than prophylaxis during 2-month streptozotocin diabetes, treatment exacerbated nerve abnormalities. Thus, N^G-nitro-L-arginine worsened (8%,p<0.001) the motor conduction deficit, there was an 11% increase in hypoxic conduction failure time (p<0.01) and an 11% reduction in endoneurial capillary density (p<0.01). We conclude that overproduction of nitric oxide is unlikely to be involved in the aetiology of experimental diabetic neuropathy. However, endothelial dysfunction resulting in impaired nitric oxide and prostacyclin synthesis could make a substantial contribution.     

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia,hypoglycaemia and post-hypoglycaemic hyperglycaemia

Aims/hypothesis The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids. Materials and methods Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg⁻¹ min⁻¹) and eu-, hypo- and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low- or high-dose alanine, or saline. Results With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181 ± 16 ng l⁻¹ min⁻¹) and high-dose alanine (238 ± 20 ng l⁻¹ min⁻¹) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112 ± 5 ng l⁻¹ min⁻¹). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu- or hyperglycaemia. Conclusions/interpretation In type 1 diabetes, the usually deficient responses of glucagon to hypoglycaemia may improve after increasing the concentration of plasma amino acids. Amino acid-enhanced secretion of glucagon in response to hypoglycaemia remains under physiological control since it is regulated primarily by the ambient plasma glucose concentration. These findings might be relevant to improving counter-regulatory defences against insulin-induced hypoglycaemia in type 1 diabetes.     

The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM

Summary A pig model of insulin-dependent diabetes was used to examine the importance of the portal-systemic insulin gradient for whole-body metabolic control. Six pigs had jugular vein, portal vein, and carotid artery cannulae implanted before being made diabetic (150 mg kg^{− 1} streptozotocin). Each animal received 4 weeks of portal and 4 weeks of peripheral insulin delivery in random order. The blood glucose target range was 5–10 mmol · l^{− 1}, and serum fructosamine and fasting and postprandial blood glucose concentrations were not different between peripheral and portal insulin infusion. Insulin requirement was not different between the 4 week infusion periods, but fasting peripheral insulin levels after peripheral delivery (124 ± 16 (mean ± SEM) pmol · l^{− 1}) were significantly higher (p < 0.05) than in portally infused (73.8 ± 5.4 pmol · l^{− 1}) or pre-diabetic control animals (68.4 ± 3.6 pmol · l^{− 1}). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 ± 0.4 mg · kg^{− 1}· min^{− 1}) than in portally infused animals (2.9 ± 0.4 mg · kg^{− 1}· min^{− 1}) or controls (3.0 ± 0.3 mg · kg^{− 1}· min^{− 1}). Clamp glucose metabolic clearance rate was, however, not different between the peripheral and portal insulin delivery routes (8.1 ± 1.0 vs 9.0 ± 0.7 ml · kg^{− 1}· min^{− 1}), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 ± 1.0 ml · kg^{− 1}· min^{− 1}). Lipid profiles and subfractions were similar in all three groups. It is concluded that the portal route of delivery is superior to the peripheral in maintaining more appropriate insulin concentrations and control of hepatic glucose output, although in the absence of euglycaemia it is still associated with significant metabolic abnormalities. [Diabetologia (1997) 40: 1125–1134] Received: 25 February 1997 and in revised form: 23 May 1997     

Low-dose epoprostenol improved pulmonary hypertension in a patient with systemic lupus erythematosus

A 43-year-old Japanese woman was referred to our hospital in 1997 because of Raynaud’s phenomenon. Systemic lupus erythematosus was diagnosed on the basis of the presence of antinuclear antibody (1:1,280), anti-DNA antibody (1:640), anti-Sm antibody, antiphospholipid antibody, lymphopenia, and proteinuria. She developed pulmonary fibrosis in 1999 and pulmonary hypertension in 2001. In October 2002, a 24-hr continuous infusion of epoprostenol was started. Dyspnea, Raynaud’s phenomenon, and pulmonary hypertension improved with low-dose epoprostenol (3.0 to 4.0 ng kg⁻¹ min⁻¹). The patient could not tolerate larger doses of epoprostenol so 4.0 ng kg⁻¹ min⁻¹ was selected as the maintenance dose. The clinical course was uneventful at this dosage. It appears that pulmonary hypertension can be controlled with low-dose epoprostenol such as 3.0 to 4.0 ng kg⁻¹ min⁻¹ in some rheumatic patients.     

Acute blockade by endothelin-1 of haemodynamic insulin action in rats

Aims/hypothesis Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing to insulin resistance. Materials and methods The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1 (50 pmol min⁻¹ kg⁻¹ for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min⁻¹ kg⁻¹ for 2 h). Insulin clamps (10 or 15 mU min⁻¹ kg⁻¹) were performed after 30 min of saline infusion. Results Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p < 0.05) and blood pressure by 20% (p < 0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1 with 10 mU min⁻¹ kg⁻¹ insulin caused a decrease in insulin clearance from 0.35 ± 0.6 to 0.19 ± 0.02 ml/min (p = 0.02), resulting in significantly higher plasma insulin levels (10 mU min⁻¹ kg⁻¹ insulin: 2,120 ± 190 pmol/l; endothelin-1 + 10 mU min⁻¹ kg⁻¹ insulin: 4,740 ± 910 pmol/l), equivalent to 15 mU min⁻¹ kg⁻¹ insulin alone (4,920 ± 190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary recruitment and glucose uptake were blocked by endothelin-1. Conclusions/interpretation Endothelin-1 blocks insulin’s haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery.     

The Effect of the Phytoestrogen Genistein on Myocardial Protection, Preconditioning and Oxidative Stress

Introduction We have previously shown that estrogen administered in ovariectomized female rabbits significantly reduce myocardial infarct size. We now investigated whether the phytoestrogen genistein similarly protects ischemic myocardium and whether this is associated with its antioxidant properties. In addition, we examined whether genistein abolishes preconditioning, since at high doses, it inhibits tyrosine kinase. Materials and methods We studied five groups of New Zealand white female rabbits. Group A (n = 12) were normal controls, group B (n = 14) were ovariectomized 4 weeks prior to the experiment, group C (n = 10) were ovariectomized and treated with genistein (0.2 mg kg⁻¹ day⁻¹ subcutaneously) for 4 weeks before the experiment, group D (n = 12) had intact gonads and were treated with genistein (0.2 mg kg⁻¹ day⁻¹ subcutaneously) for 4 weeks before the experiment and group E (n = 8) were ovariectomized 4 weeks prior to the experiment and treated with a single dose of genistein (0.2 mg kg⁻¹ day⁻¹ subcutaneously) just prior to the experiment. All animals underwent 30 min of heart ischemia and 120 min of reperfusion, with (subgroup I) or without (subgroup II) preconditioning. Malondialdehyde (MDA) concentration just before the experiment was determined. Results We found significant differences between the groups—p < 0.0001 in factorial ANOVA. The groups with preconditioning had significant smaller infarcts compared to those without—AI vs AII (10.66 ± 1.42% vs 43.22 ± 2.67%), BI vs BII (18.53 ± 2.36% vs 43.05 ± 8.37%), CI vs CII (10.17 ± 2.07% vs 44.5 ± 5.47%), DI vs DII (14.98 ± 2.36% vs 37.79 ± 3.92%) and EI vs EII (17.11 ± 3.24% vs 42.08 ± 3.42%), p < 0.0005. Ovariectomy was not associated with larger myocardial infarctions—AII vs BII, p = NS. Genistein, for 4 weeks, did not protect ischemic myocardium in either ovariectomized or non-ovariectomized animals—BII vs CII and AII vs DII, p = NS. There was no significant difference between the preconditioned animals, with intact gonads or ovariectomized (AI vs BI, p = NS), ovariectomized with or without genistein (BI vs CI, p = NS) and non-ovariectomized whether treated with genistein or not (AI vs DI, p = NS). A single dose of genistein did not offer any protection (EII vs BII, p = NS), nor did it modify the preconditioning effect (EI vs BI, p = NS). We found no significant difference in MDA plasma levels between the groups. Conclusion Genistein, at this dose, does not reduce infarct size per se nor abolishes the protection induced by preconditioning, in both ovariectomized and non-ovariectomized animals. Preconditioning offers myocardial protection in animals with intact gonads as well as estrogen deprived; bilateral ovariectomy, at least during short-term, is not associated with larger myocardial infarcts compared to control animals. In addition estrogen deprivation, during short term, as well as genistein do not modify oxidative stress.     

Contraindication for osmotic mini-pump in the abdominal cavity to study muscarinic cholinergic control of pancreatic enzyme secretion and muscarinic receptors

Summary Alzet mini-pumps were used to study modulation of rat pancreatic muscarinic receptors and the acinic secretory response to long-termN-methylscopolamine. (NMS) treatment. Infused intraperitoneally (i.p.), NMS, 25 mg·kg⁻¹·day⁻¹ for 14 days, resulted in a shift to the left in the amylase dose-response curve to carbamylcholine (Cch) and an increase in receptor concentration compared to saline-in-fused group. Compared to previously published control data [4,5] the saline-infused group exhibited desensitization with increased EC₅₀ for secretion. An alternative mode of saline treatment, subcutaneous (s.c.) infusion showed normal pancreatic secretory response. Desensitization by i.p. saline infusion was prevented by NMS infusion. In conclusion, a foreign body such as a mini-pump in the abdominal cavity can cause desensitization of the pancreatic secretory function under neural cholinergic control.     

Comparison of the Cardiac Electrophysiology and General Toxicology of Two Formulations of Intravenous Amiodarone in Dogs

Intravenous amiodarone (AIV) must be administered slowly after dilution to avoid hypotension, which is due to the cosolvents polysorbate 80 and benzyl alcohol used in its formulation. PM101 is a formulation of amiodarone devoid of these cosolvents, which enables bolus administration. We evaluated any potential toxicity or exaggerated adverse cardiac electrophysiologic effects of PM101 compared with AIV and control. Beagle dogs were treated with the human-equivalent amiodarone loading dose (2.14 mg/kg) with PM101 (bolus push) or AIV (10 min infusion in the toxicology study and bolus push in the electrophysiology study) followed by maintenance infusion (0.014 mg kg⁻¹ min⁻¹ through 6 h followed by 0.007 mg kg⁻¹ min⁻¹ through 14 days) or a control. General toxicology was assessed in conscious dogs over 14 days. Cardiac electrophysiology was assessed in a separate cohort of anesthetized dogs during the first 20 min of dosing. In the toxicology study, dosing in all animals in the AIV group was terminated within 17 min of initiation due to a severe hypersensitivity reaction. There were no acute adverse clinical signs in the PM101 or control groups. There were no significant effects on body weight or ECG parameters, and no adverse histomorphologic changes were seen in dogs that received PM101 or AIV. No significant exaggerated cardiac electrophysiologic effects of the approved doses PM101 or AIV were observed. PM101 may represent a formulation of intravenous amiodarone that could be administered rapidly without dilution in the setting of life-threatening cardiac arrhythmias.     

Effects of dietary protein restriction on albumin and fibrinogen synthesis in macroalbuminuric type 2 diabetic patients

Aims/hypothesis Diabetic nephropathy is associated with hypoalbuminaemia and hyperfibrinogenaemia. A low-protein diet has been recommended in patients with diabetic nephropathy, but its effects on albumin and fibrinogen synthesis are unknown. Methods We compared the effects of a normal (NPD; 1.38 ± 0.08 g kg⁻¹ day⁻¹) or low (LPD; 0.81 ± 0.04 g kg⁻¹ day⁻¹) -protein diet on endogenous leucine flux (ELF), albumin and fibrinogen synthesis (l-[5,5,5,-²H₃]leucine infusion), and markers of inflammation in nine type 2 diabetic patients with macroalbuminuria. Six healthy participants on NPD served as control participants. Results In comparison with healthy participants, type 2 diabetic patients on an NPD had similar ELF, reduced serum albumin (38 ± 1.1 vs 42 ± 0.8 g/l; p < 0.05), similar fractional synthesis rates (FSR) and absolute synthesis rates (ASR) of albumin, and both increased plasma fibrinogen concentration [10.7 ± 0.6 vs 7.2 ± 0.5 μmol/l (3.64 ± 0.22 vs 2.45 ± 0.18 g/l); p < 0.05] and fibrinogen ASR [11.03 ± 1.17 vs 6.0 ± 1.8 μmol 1.73 m⁻² day⁻¹ (3.7 ± 0.4 vs 1.9 ± 0.3 g 1.73 m⁻² day⁻¹); p < 0.01]. After LPD, type 2 diabetic patients had the following changes in comparison with NPD: reduced proteinuria (2.74 ± 0.4 vs 4.51 ± 0.8 g/day; p < 0.05), ELF (1.93 ± 0.08 vs 2.11 ± 0.08 μmol kg⁻¹ min⁻¹; p < 0.05) and total fibrinogen pool; increased serum albumin (42 ± 1 vs 38 ± 1 g/l; p < 0.01) and albumin ASR (14.1 ± 1 vs 9.9 ± 1 g 1.73 m⁻² day⁻¹; p < 0.05); and reduced plasma IL-6 levels, which were correlated with albumin ASR (r = −0.749; p < 0.05). Conclusions/interpretation LPD in type 2 diabetic patients with diabetic nephropathy reduces low-grade inflammatory state, proteinuria, albuminuria, whole-body proteolysis and ASR of fibrinogen, while increasing albumin FSR, ASR and serum concentration. ISRCTN ID no: CCT-NAPN-16911     

Phase II trial of biochemotherapy with interferon α, dacarbazine, cisplatin and tamoxifen in metastatic melanoma: a Southwest Oncology Group trial

The therapeutic benefit of adding interferon α (IFNα) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNα, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNα plus dacarbazine over dacarbazine alone, we treated patients with an “induction” regimen of IFNα, 15 mU m⁻² day⁻¹ intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNα, 5 mU m⁻² day⁻¹ subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m⁻² day⁻¹ and cisplatin 33 mg m⁻² day⁻¹ for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNα and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%–20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma. Received: 11 August 1998 / Accepted: 21 December 1998     

Induction of apoptosis in metastatic foci from human gastric cancer xenografts in nude mice and reduction of circulating tumor cells in blood by 5-FU and 1-hexylcarbamoyl-5-fluorouracil

Antimetastatic effects of 5-FU and its derivative, 1-hexylcarbamoyl-5-fluorouracil (HCFU) on human gastric cancer micrometastasis and their mode of action were evaluated, using a spontaneous lung metastasis model (HY-1) in nude mice. Metastases were first detected in the lung from 4 weeks after subcutaneous transplantation, growing intravascularly and forming micrometastases at 100% incidence by 6 weeks after implantation. Lung metastasis in mice bearing subcutaneous tumors was significantly inhibited by HCFU at doses of 100–150 mg kg⁻¹ day⁻¹ without severe toxic side-effects, when orally administered three times per week either from week 4 or week 6 to 9 weeks after implantation. Spontaneous lung metastasis was also inhibited by the administration of 5-FU, but to lesser extent than with HCFU at equimolar low doses. Apoptosis within primary tumors and lung metastatic foci, as detected by the terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling method, was found to be significantly enhanced by HCFU as well as 5-FU administration at doses of more than 100 mg kg⁻¹ day⁻¹ and 50 mg kg⁻¹ day⁻¹ respectively. However, proliferating activity of the metastatic foci, as evaluated by MIB-1 immunostaining, was not significantly suppressed by HCFU or 5-FU treatment. Furthermore, polymerase chain reaction analysis using human specific primers for the β-globin gene, which proved to be capable of detecting 10 tumor cells/ml mouse blood, revealed that circulating tumor cells in the peripheral blood of mice bearing primary tumors were reduced by HCFU or 5-FU administration. These results indicate that circulating tumor cells in blood and micrometastases in the lung are sensitive to these chemotherapeutic agents, and suggest that the anti-metastatic effect of these agents is mediated, at least in part, by enhanced apoptosis rather than by inhibition of cell proliferation. Received: 7 April 1999 / Accepted: 2 June 1999     

Insulin resistance is associated with high plasma ouabain-like immunoreactivity concentration in NIDDM

Summary The aim of the present study was to elucidate the pathophysiologic significance of circulating ouabain as a link between insulin resistance (IR) and hypertension (HT) in NIDDM. Euglycaemic (4.5 mmol/l) hyperinsulinaemic (360–580 pmol/l) clamping was performed using an artificial endocrine pancreas. Plasma ouabain-like immunoreactivity (OLI) was determined by radioimmunoassay using a highly specific antibody to ouabain. HT was defined as systolic blood pressure > 140 mm Hg and/or diastolic > 90 mm Hg or being treated with antihypertensive agents. The values (mean ± SEM) of glucose infusion rate (GIR) and plasma OLI were compared among the four groups classified using IR and HT as factors. Group I (IR−/HT−, n = 15):GIR 7.20 ± 0.36 mg · kg⁻¹· min⁻¹, OLI 130.8 ± 20.9 pmol/l, which was not different from that in eight normal control subjects (7.69 ± 0.40 mg · kg⁻¹· min⁻¹ and 142.6 ± 32.3 pmol/l, respectively); Group II (IR−/HT+, n = 13): 5.89 ± 0.36 mg · kg⁻¹· min⁻¹, 172.5 ± 35.0 pmol/l; Group III (IR+/HT−, n = 14) 1.91 ± 0.28 mg · kg⁻¹· min⁻¹, 576.6 ± 161.5 pmol/l (p < 0.01 vs Group I and II); Group IV (IR+/HT+, n = 15) 1.79 ± 0.22 mg · kg⁻¹· min⁻¹, 703.1 ± 170.1 pmol/l (p < 0.01 vs Group I and II), respectively. Six of 57 NIDDM patients studied exhibited very high (> 1500 pmol/l) plasma OLI concentrations, showed marked insulin resistance and were all hypertensive. When analysed as a whole, plasma OLI was negatively correlated with GIR (p < 0.001), but was not correlated with arterial blood pressure. These results demonstrate that plasma concentration of OLI is closely associated with the severity of IR but not with blood pressure elevation. It is, however, possible that in some fraction of NIDDM patients with insulin resistance, the elevation of blood pressure may be causally related to circulating OLI. [Diabetologia (1995) 38: 792–797] Received: 13 September 1994 and in revised form: 9 December 1994     

Dissociation between pancreatic enzyme secretory and synthetic dose-responses to cholecystokinin in man

Summary The effect of varying the intensity of pancreatic stimulation on the synthesis of human pancreatic enzymes has not previously been studied. We have measured the secretion and synthesis of pancreatic enzymes in response to either secretin alone (1 Cu·kg⁻¹·h⁻¹) or secretin plus increasing doses of cholecystokinin (CCK) (0.25, 0.5 or 1.0 IDU·kg⁻¹·h⁻¹). Enzyme synthesis was measured using the incorporation of⁷⁵Se-methionine (0.15 mCi (5.6 kBq)·kg⁻¹·h⁻¹) into the trichloracetic acid-insoluble fraction of the duodenal aspirate. Outputs of trypsin, chymotrypsin, lipase and protein showed a bell-shaped dose response to increasing doses of cholecystokinin, with maximal outputs occurring in response to secretin plus cholecystokinin 0.5 IDU·kg⁻¹·h⁻¹. The rate of incorporation of⁷⁵Se-methionine increased with increasing doses of cholecystokinin and was maximal in response to secretin plus cholecystokinin 1.0 IDU·kg⁻¹·h⁻¹. There was therefore dissociation between the secretory and synthetic responses to increasing doses of cholecystokinin.     

Restless Legs Syndrome in Patients with Irritable Bowel Syndrome: Response to Small Intestinal Bacterial Overgrowth Therapy

Background Small intestinal bacterial overgrowth (SIBO) occurs in irritable bowel syndrome (IBS) and fibromyalgia. Since restless legs syndrome (RLS) occurs with fibromyalgia, a link between IBS, SIBO, and RLS was studied. Methods BS patients with abnormal lactulose breath tests received rifaximin 1,200 mg day⁻¹ for 10 days, followed by tegaserod 3 mg, long-term, and 1 month of zinc 220 mg day⁻¹ and once-daily probiotic (N = 11) or rifaximin monotherapy (N = 2). IBS symptom improvement was assessed after rifaximin. RLS symptoms, IBS symptoms, and overall IBS global improvement were assessed at last posttreatment visit: 8/10 patients were followed long-term (mean, 139 days; range, 54–450 days). Results Ten of 13 patients exhibited ≥80% improvement from baseline in RLS symptoms. Five maintained complete resolution of RLS symptoms. Global gastrointestinal symptom improvement was great (n = 6), moderate (n = 5), or mild (n = 2). Conclusion This study suggests that SIBO associated with IBS may be a factor in some RLS patients and SIBO therapy provides long-term RLS improvement.     

Evidence that insulin can directly inhibit hepatic glucose production

Summary In order to evaluate the role of portal insulin in the modulation of hepatic glucose production (HGP), measurements of plasma glucose and insulin concentrations and both HGP and peripheral glucose disappearance rates were made following an infusion of a dose of tolbutamide (0.74 mg · m⁻²· min⁻¹) in healthy volunteers that does not result in an increase in peripheral vein insulin concentrations or metabolic clearance rate of glucose. The results showed that the infusion of such a dose of tolbutamide was associated with a significant and rapid decline in both HGP (from 9.0 ± 0.5 to 7.7 ± 0.5 μmol · kg⁻¹· min⁻¹ or Δ = − 13.8 ± 4.5 %; p < 0.001 compared to saline) and plasma glucose concentration (from 5.1 ± 0.2 to 4.4 ± 0.1 mmol/l or Δ = − 13.0 ± 2.1 %; p < 0.01 compared to saline). Since neither HGP nor fasting glucose fell when tolbutamide-stimulated insulin secretion was inhibited by the concurrent administration of somatostatin, it indicated that tolbutamide by itself, does not directly inhibit HGP. Finally, HGP fell by 26.3 ± 6.0 % at 10 min after a dose of tolbutamide that elevated both peripheral and portal insulin concentrations, at a time when HGP had barely increased (Δ = + 6.9 ± 5.3 %). The difference in the magnitude of the two responses was statistically significant (p < 0.03), providing further support for the view that insulin can directly inhibit HGP, independent of any change in flow of substrates from periphery to liver. [Diabetologia (1997) 40: 1300–1306] Received: 8 April 1997 and in revised form: 20 June 1997