Systemic blockade of ACVR2B ligands prevents chemotherapy-induced muscle wasting by restoring muscle protein synthesis without affecting oxidative capacity or atrogenes.

Doxorubicin is a widely used and effective chemotherapy drug. However, cardiac and skeletal muscle toxicity of doxorubicin limits its use. Inhibiting myostatin/activin signalling can prevent muscle atrophy, but its effects in chemotherapy-induced muscle wasting are unknown. In the present study we investigated the effects of doxorubicin administration alone or combined with activin receptor ligand pathway blockade by soluble activin receptor IIB (sACVR2B-Fc). Doxorubicin administration decreased body mass, muscle size and bone mineral density/content in mice. However, these effects were prevented by sACVR2B-Fc administration. Unlike in many other wasting situations, doxorubicin induced muscle atrophy without markedly increasing typical atrogenes or protein degradation pathways. Instead, doxorubicin decreased muscle protein synthesis which was completely restored by sACVR2B-Fc. Doxorubicin administration also resulted in impaired running performance without effects on skeletal muscle mitochondrial capacity/function or capillary density. Running performance and mitochondrial function were unaltered by sACVR2B-Fc administration. Tumour experiment using Lewis lung carcinoma cells demonstrated that sACVR2B-Fc decreased the cachectic effects of chemotherapy without affecting tumour growth. These results demonstrate that blocking ACVR2B signalling may be a promising strategy to counteract chemotherapy-induced muscle wasting without damage to skeletal muscle oxidative capacity or cancer treatment.

Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy.

Many risk factors for progression in immunoglobulin A nephropathy (IgAN) have been found. We focused on renal leukocyte infiltrations and cytokines in IgAN. The subjects were 204 IgAN patients. Renal histopathological changes were semiquantitatively graded. Expression of tubulointerstitial Leukocyte common antigen (LCA), CD3, CD68, interleukin (IL)-1beta, and IL-10 was evaluated by immunohistochemistry. These parameters were correlated with progression of IgAN. The significance of these correlations was tested by a multivariate analysis. Glomerulosclerosis, tubular atrophy, interstitial inflammation, and hyaline arteriolosclerosis correlated with progression in all patients and also in patients with initially normal serum creatinine. Tubulointerstitial LCA, CD3, CD68, and IL-1beta expression correlated with progression. CD3 had the strongest correlation. In the multivariate analysis, tubulointerstitial CD3, hypertriglyceridemia, elevated serum creatinine concentration, and interstitial fibrosis were independently associated with progressive disease in all patients, and tubulointerstitial CD3 expression and hyaline arteriolosclerosis in patients with initially normal serum creatinine. We found parameters reflecting tubulointerstitial inflammation to predict deterioration of renal function in IgAN. This was also seen in patients whose serum creatinine was normal at the time of renal biopsy. Our findings show that, an immunohistochemical evaluation of tubulointerstitial inflammation seems to be a useful tool in determining the prognosis in IgAN.

Ten-year prognosis of Puumala hantavirus-induced acute interstitial nephritis.

Nephropathia epidemica (NE) is a hemorrhagic fever with renal syndrome caused by Puumala hantavirus. Its long-term prognosis is considered favorable. There are, however, some reports about subsequent hypertension, glomerular hyperfiltration, and proteinuria after previous hantavirus infection. Therefore, we studied 36 patients 5 and 10 years after acute NE, with 29 seronegative controls. Office blood pressure, ambulatory 24-h blood pressure (ABP), glomerular filtration rate (GFR), and proteinuria were examined. Hypertensive subjects were defined as those patients having increased ambulatory or office blood pressure, or receiving antihypertensive therapy. Office blood pressure was used to define hypertension only if ABP was not determined. At 5 years, the prevalence of hypertension was higher among NE patients than in controls (50 vs 21%, P=0.020). At 10 years, the difference between the groups was no more significant (39 vs 17%, P=0.098). Five years after NE, patients showed higher GFR (121+/-19 vs 109+/-16 ml/min/1.73 m(2), P=0.012) and urinary protein excretion (0.19 g/day, range 0.12-0.38 vs 0.14 g/day, range 0.09-0.24, P=<0.001) than controls. At 10 years, there were no more differences in GFR or protein excretion between the groups (GFR: 113+/-20 vs 108+/-17 ml/min/1.73 m(2), P=0.370; proteinuria: 0.14 g/day, range 0.07-0.24 vs 0.13 g/day, range 0.06-0.31, P=0.610). In conclusion, the 10-year prognosis of NE is favorable, as glomerular hyperfiltration and slight proteinuria detected at 5 years disappeared during the longer follow-up. However, the possibility exists that NE may predispose some patients to the development of hypertension.

Death rates and causes of death in patients with rheumatoid arthritis: a population-based study.

OBJECTIVE: To assess the mortality and causes of death in a cross-sectional population-based study of 1042 patients with rheumatoid arthritis (RA). METHODS: In 1988, 604 RA patients [470 females (F), 134 males (M)] and 457 age- and sex-matched controls (352 F, 105 M) were examined prospectively (participants) and 438 (183 F, 81 M) non-participant RA patients retrospectively. In 1999, vital status and causes of death were determined. Mortality in the total RA population was compared to that in the general population, and that among participant RA patients to their matched controls. RESULTS: A total of 384 (37%) RA patients and 71 (16%) controls died. RA patients had increased mortality compared to the general population (standardized mortality ratios SMR 2.64) or controls (1.71). This was observed in both sexes. Over 40% of deaths in all groups were due to cardiovascular diseases. RA patients were at increased risk of dying of urogenital, gastrointestinal, respiratory and cardiovascular diseases, infections, and cancers when compared to the general population or controls. CONCLUSIONS: Our results show that a cross-sectional cohort of RA patients had an increased risk of death from various causes.

Matrix metalloproteinase 9 (MMP-9) gene polymorphism and MMP-9 plasma levels in primary Sjogren's syndrome.

OBJECTIVES: To determine whether plasma matrix metalloproteinase 9 (MMP-9) and MMP9 (-1562C-->T) polymorphism have an effect on the disease phenotype in primary Sjogren's syndrome (pSS). METHODS: Plasma MMP-9 concentrations and polymorphism of the MMP9 gene were analysed in 66 patients with pSS. These data were studied in relation to the clinical data of the patients. The genetic data of patients were compared with the data of 66 healthy subjects. RESULTS: Plasma MMP-9 was higher in patients with definite pSS than in patients with possible pSS. This association was principally caused by higher plasma MMP-9 in patients with a positive Schirmer test and keratoconjunctivitis sicca. pSS patients with purpura, SS-A autoantibodies and RF had significantly lower plasma MMP-9 than patients without these characteristics. The overall MMP9 (-1562C-->T) allele frequencies were similar in patients and control subjects. The frequency of the allele T was higher in patients without Raynaud's phenomenon than in the control group. CONCLUSIONS: MMP9 (-1562C-->T) could not be used for risk assessment in pSS. The presence of the rarer allele T may decrease the risk of Raynaud's phenomenon in pSS. High plasma MMP-9 is indicative of definite pSS but may paradoxically have a preventive effect on the eruption of purpura and on the development of autoantibody reaction in pSS.

Presence of apolipoprotein E epsilon4 allele predisposes to early onset of primary Sjogren's syndrome.

BACKGROUND: Apolipoprotein E (apoE) polymorphism plays a central role in lipid metabolism, but has recently also been suggested to regulate inflammation, as judged by levels of serum C-reactive protein (CRP). OBJECTIVE: To establish whether polymorphism of the apoE genes affects susceptibility to primary Sjogren's syndrome (pSS), degree of inflammation or age of onset of pSS. METHODS: ApoE genotype distribution and allelic frequencies were analysed using PCR and the TaqMan system in 63 Finnish Caucasian patients with pSS and in 64 healthy controls matched for sex, ethnic origin and area of residence. The clinical and immunological data on the pSS patients were analysed in relation to the apoE genotypes. RESULTS: There was no difference between pSS patients and controls in apoE genotype and allelic frequencies. The apoE epsilon4 allele was significantly associated with early onset of pSS in the entire population and in female patients (Kaplan-Meier log rank test, P = 0.0407 and P = 0.0168, respectively). The average age (+/- S.D.) of onset of pSS in all apoE epsilon4 allele carriers was 46 +/- 12 and in other genotypes it was 53 +/- 10 yr (P = 0.031, t-test). ApoE polymorphism was not associated with signs of inflammation evaluated by such markers as concentration of plasma CRP, plasma interleukin-6, plasma TNF-alpha, immunoglobulin G and haemoglobin, or leucocyte count or ESR. CONCLUSIONS: ApoE polymorphism does not affect susceptibility to pSS or levels of plasma inflammatory indices in patients with pSS. However, a clear association prevails between apoE epsilon4 and early onset of pSS.

Renal disease as a predictor of increased mortality among patients with rheumatoid arthritis.

AIMS AND METHODS: Mortality among RA patients and controls was analyzed with special attention to renal disease in population-based material (originally screened in 1988) of 604 patients with RA (470 females, 134 males) and 457 age- and sex-matched controls (352 females, 105 males). In the original RA population, isolated hematuria (HU) was observed in 54, isolated proteinuria (PU) in 27, combined hematuria and proteinuria (HUPU) in 7, chronic renal failure (CRFtot) in 36 and isolated chronic renal failure without HU or PU (CRFisol) in 15 patients. Among the controls, HU was observed in 39, PU in 11, CRFtot in 32 and CRFisol in 16 subjects. HUPU was not observed in any of the controls. Microalbuminuria (20-200 microg/min) was observed in 34 RA patients and in 27 controls. Histologically confirmed amyloidosis was found in 13 RA patients and mesangial glomerulonephritis (MesGN) in 17 patients. The mortality was evaluated in 1999 from data of the Statistical Office of Finland. Statistical analysis was performed by Cox regression analysis. RESULTS: Mortality was significantly increased in the RA population as compared to controls: hazard ratio (HR) 1.78 (95% CI 1.34-2.31) for all RA patients; HR 2.12 (1.52-2.94) for females; HR 1.15 (0.75-1.77) for males. In the RA material, increased mortality was detected in patients with HUPU (HR 4.45; 1.54-12.84), PU (HR 3.54; 1.88-6.65), CRFtot (HR 3.74; 2.55-5.56) or microalbuminuria (HR 2.77; 1.64-4.69) when compared to those with normal clinical renal findings, whereas HU (HR 1.49; 0.88-2.52), CRFisol (HR 1.71; 0.82-3.54), bacteriuria (HR 0.96; 0.35-2.59) or pyuria (HR 0.65; 0.09-4.65) did not predict mortality. Renal amyloidosis was associated with an over twofold mortality rate (HR 2.31; 1.03-5.15), whereas mortality was within expected limits in RA patients with MesGN (HR 1.61; 0.49-5.24). CONCLUSION: Our results show that nephropathy presenting with combined hematuria and proteinuria, proteinuria, microalbuminuria or histologically confirmed amyloidosis is associated with increased mortality in RA patients, whereas mortality is within expected limits in those with isolated hematuria or mesangial glomerulonephritis.

Natriuretic peptide and echocardiography after operation of atrial septal defect.

Patients benefit from surgical seclusion of atrial septal defect but have excessive cardiovascular morbidity after the operation. We evaluated haemodynamics and looked for abnormalities of cardiac structures and function late after surgical seclusion of the defect. Serum N-terminal natriuretic peptide measurement and transthoracic and transoesophageal echocardiography were performed in 61 patients aged 43+/-15 years (mean+/-standard deviation) 21+/-5 years after surgery. The findings were compared with 67 control subjects. The patients had higher serum N-terminal atrial natriuretic peptide concentration than the control subjects (0.40+/-0.32 vs. 0.24+/-0.12 nmol/l, P=0.0001). Peptide levels correlated with current age (P=0.0001) and age at operation (P=0.0014), but not with age in the control subjects. In the patients, echocardiography measurements of cardiac dimensions correlated with hormone levels (atrial natriuretic peptide concentration with left atrial end-systolic diameter (P=0.042), left ventricular end-diastolic (P=0.021) and end-systolic diameter (P=0.042). There were only 10 patients (16%) without any abnormality in echocardiography. Their peptide concentration was 0.25+/-0.18 nmol/l (P=not significant compared to the control subjects). The association between increasing N-terminal atrial peptide levels and operation age together with echocardiography findings support the clinical consensus of treating atrial septal defect patients in their childhood and adolescence.

The significance of mannan-binding lectin gene alleles in patients with primary Sjögren's syndrome.

OBJECTIVE AND METHODS: To investigate the significance or mannan-binding lectin (MBL) gene alleles in patients with primary Sjogren's syndrome (pSS). Genotypes were determined in 65 pSS patients and 138 controls. RESULTS: No difference in MBL genotype or allele frequencies was detected between the pSS patients and controls. However, when the effect of MBL genotypes on the diagnostic findings in pSS patients was assessed, none of the eight patients with 52/w genotype fulfilled four (definite) Californian criteria (P = 0.007). Among these eight the Chisholm-Mason histological grade was > or = 3 in only three (P = 0.017). Furthermore, the MBL concentration was lower in patients with 52/w genotype compared to those with wild-type (w/w) genotype (P = 0.035). CONCLUSION: Our findings suggest that MBL structural gene polymorphisms do not influence on susceptibility to pSS. However, MBL may be associated with salivary gland destruction in pSS, and its concentration may be comparable with the intensity of inflammatory reaction. Further studies are warranted to clarify the possible mechanisms involved.

Time course of serum prolactin and sex hormones following successful renal transplantation.

BACKGROUND: Chronic renal failure is commonly associated with disturbances in hypothalamic-pituitary-gonadal function. METHODS: The gonadotrophins, prolactin and estradiol or testosterone levels were measured immediately before renal transplantation, at discharge from the transplantation unit (19 +/- 8 days after Tx) and 6 months after transplantation in 21 patients, 7 females and 14 males, age range 21-60 years. RESULTS: The mean prolactin level was high during uremia and decreased rapidly after transplantation, from 441 to 167 mU/l in males and from 1,057 to 521 mU/l in females. Hypergonadotrophism was seen in most uremic patients, with the mean LH and FSH levels of 14.2 and 6.0 U/l in males and 14.7 and 4.0 U/l in females, respectively. A temporary change to hypogonadotrophic hypogonadism took place 2-3 weeks after transplantation and was followed by normalization of the hypothalamic-gonadal function. The levels of circulating sex steroids were suppressed when the patients were discharged from the transplantation unit but returned to the normal range at 6 months. CONCLUSIONS: We conclude that renal transplantation corrects the hyperprolactinemia induced by uremia and is followed by rapid onset of restoration of the hypothalamic-pituitary-gonadal axis.

Methylenetetrahydrofolate reductase gene polymorphism, hyperhomocysteinemia and occlusive retinal vascular disease in type 2 diabetic and non-diabetic subjects.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphism may cause hyperhomocysteinemia, which affects the vascular endothelium and may induce occlusive vascular disease (OVD). Hypertension thickens small-sized arterial walls and attenuates intramural blood flow. Such OVD can be studied in retinal angiograms as a decrease in the arterio-venous ratio (AVR). Diabetes, by altering microvascular structure and function, in many ways modifies this AVR. OBJECTIVE: To assess whether MTHFR gene polymorphism (C677T) by causing hyperhomocysteinemia affects the retinal AVR in type 2 diabetic and non-diabetic subjects. METHODS: Eighty-four recently diagnosed (< 1 year) type 2 diabetic and 115 non-diabetic subjects were included in the study. Retinal fluoresceine angiograms were recorded and the mean AVR was calculated by measuring transverse vessel diameters at 6 locations. The mean AVR was used as a marker of OVD. The MTHFR VV, VA and AA genotypes were determined by PCR and plasma homocysteine by high-pressure liquid chromatography. RESULTS: In the diabetic subjects with the VV, VA and AA genotypes, the plasma homocysteine levels were 16.5 +/- 7, 12.5 +/- 4.6 and 11.3 +/- 4.9 microM, respectively (p = 0.008, ANCOVA). The corresponding values in controls were 14.6 +/- 3.8, 13.7 +/- 5.7 and 11.6 +/- 4.4 (p = 0.08). Correspondingly, in the diabetic subjects, the AVR values were 0.71 +/- 0.07, 0.75 +/- 0.07 and 0.73 +/- 0.1 (p = NS, ANOVA) and in the control subjects they were 0.8 +/- 0.14, 0.81 +/- 0.12 and 0.76 +/- 0.09 (p = NS, ANOVA). Multiple linear regression analysis (best model chi2 = 18.2, R2 = 0.10, p < 0.001) showed that AVR was related to diastolic blood pressure (t = -3.7, p < 0.001) and GFR (t = -2.2, p = 0.03). There was no relation between the AVR and plasma homocysteine levels. CONCLUSION: In the present study of recently diagnosed type 2 diabetic and non-diabetic subjects, MTHFR gene polymorphism (C677T mutation) slightly affected the plasma homocysteine level but did not alter the arterio-venous ratio.

Skeletal deposition of clodronate is related to parathyroid function and bone turnover in dialysis patients.

AIMS: Bisphosphonates inhibit osteoclastic bone resorption, and in the future, they may also have a role in the therapy of renal osteodystrophy. Our aim was to study whether the severity of hyperparathyroidism has an effect on the clearance of clodronate via routes other than dialysis or kidneys (nonrenal, non-dialysis clearance, CL(NRD)), which most likely represents the deposition of the drug in the skeleton. METHODS: We studied 31 dialysis patients (9 female/22 male, aged 28 - 79, median 58 years), 18 on hemodialyis (HD) and 13 on peritoneal dialysis (PD). HD patients were studied on a non-dialysis day. An intravenous infusion of 300 mg clodronate was given during 60 min at 8:00 a.m. Blood, urine and PD fluid samples were collected for 1 + 24 h, and pharmacokinetic parameters were calculated. RESULTS: In PD patients, 7% of the infused drug was excreted into PD fluid within 24 h, and in those HD or PD patients with residual diuresis 11% was excreted via the kidneys. The highest CL(NRD) was seen in patients with the most severe hyperparathyroidism. There was a positive correlation between CL(NRD) and plasma intact PTH (r = 0.79, p < 0.001). CL(NRD) was also related to the serum levels of bone markers PINP (procollagen type I N-terminal propeptide, r = 0.81, p < 0.001), osteocalcin (r = 0.65, p < 0.001) and ICTP (type I collagen cross-linked telopeptide, r = 0.68, p < 0.001). However, even in the patients with normal PTH, more than one-third of the infused drug was taken up by bone. CONCLUSION: In dialysis patients, the skeletal deposition of clodronate is related to bone turnover being highest in severe hyperparathyroidism. However, even in the case of low turnover, the uptake of the drug in bone takes place in amounts that might be clinically significant.

Renal ultrasound findings and their clinical associations in nephropathia epidemica. Analysis of quantitative parameters.

PURPOSE: To evaluate renal US findings in patients with nephropathia epidemica (NE) and to determine whether changes in these findings are related to the clinical course of NE. MATERIAL AND METHODS: Renal US was undertaken in 23 hospital-treated NE patients during the acute phase of their disease (first study). The second US study was performed 3-6 months later. RESULTS: The resistive index (RI) was abnormal in 12 patients and fluid collections (perirenal, pleural, pericardial, ascites) were found in 13 patients in the first study. Renal length decreased in every patient, cortical parenchymal thickness in 19 patients and RI in 18 patients from the first to the second studies. The mean change was significant in all parameters. Increased RI and presence of fluid collections in the first study as well as a greater change in length and RI between the first and the second studies were associated with high maximum daily urine excretion, substantial change in body weight between the anuric and polyuric phases, high maximum serum creatinine and urea concentration, high blood leukocyte count and low hematocrit value. CONCLUSION: Renal US changes occurred in every patient with NE. The severity of the findings was associated with fluid volume overload and degree of clinical renal insufficiency.

Isolated ultrafiltration affects dynamic vectorcardiographic ischemia monitoring parameters.

AIMS: The present study was undertaken to assess the role of isolated ultrafiltration (UF phase) and hemodialysis with minimal ultrafiltration (HD phase) in changes in parameters reflecting myocardial ischemia: QRS vector difference (QRS-VD), ST change vector magnitude (STC-VM) and ST vector magnitude (ST-VM6) registered by MIDA (myocardial infarction dynamic analysis). PATIENTS AND METHODS: Twelve patients on maintenance hemodialysis were first ultrafiltrated for 2.5 h without dialysis (UF) followed by a 2.5-hour session of hemodialysis with minimal ultrafiltration (HD). Computerized vectorcardiography (VCG) was used for on-line dynamic analysis of ST segment and QRS complex changes. Blood volume (BV) changes were monitored non-invasively and continuously with the CRIT-LINE instrument. Whole-body bioelectric impedance analysis (BIA) was used for extracellular water (ECW) estimation. RESULTS: During the UF phase QRS-VD and STC-VM showed a statistically significant increasing linear trend (time effect for both QRS-VD and STC-VM p < 0.0001, while no changes were noted in ST-VM6; time effect p = 0.986). During the HD phase none of these parameters changed (time effect for QRS-VD p = 0.855, for STC-VM p = 0.275 and for ST-VM6 p = 0.976). During the UF, phase changes in QRS-VD were in close relation to those in ECW. CONCLUSION: Isolated ultrafiltration leads to an increase in the VCG ischemia monitoring parameters QRS-VD and STC-VM. The increase of QRS-VD is related to changes in ECW. Hemodialysis with minimal ultrafiltration has no effect on VCG ischemia monitoring parameters.

Thyroid hormone substitution therapy rapidly enhances left-ventricular diastolic function in hypothyroid patients.

OBJECTIVE: Alterations in thyroid status may lead to changes in both systolic and diastolic function of the heart. Pulsed Doppler echocardiography is a reliable non-invasive means of assessing left-ventricular (LV) diastolic function. The aim of the present study was to evaluate LV diastolic function in patients with primary hypothyroidism receiving thyroxine therapy. METHODS: Twelve patients (all females, mean age 47 +/- 17, range 16-69 years) with primary hypothyroidism were studied by pulsed Doppler echocardiography. The first examination was made before the start of thyroxine substitution and the second at 37-68 (mean 53 +/- 10) days after commencing thyroxine treatment (mean dose 136 +/- 22 microg/day). RESULTS: During thyroxine substitution therapy, the hypothyroid patients became clinically euthyroid and serum T4 increased from 51 +/- 21 to 119 +/- 24 nmol/l; TSH decreased from 50.4 +/- 55.3 to 1.2 +/- 1.5 mU/l. During therapy, heart rate increased from 61 +/- 8 to 68 +/- 10 (p = 0.05). The LV posterior wall (7.8 +/- 1.0 mm) and interventricular septum thickness (8.0 +/- 1.4 mm) were significantly greater in hypothyroid patients than in the control subjects (6.4 +/- 1.0 mm, p = 0.007 and 6.8 +/- 1.0 mm, p = 0.04, respectively). There was no significant change in LV dimensions and wall thickness during follow-up. E/A(max) increased significantly during treatment (from 1.679 +/- 0.432 to 1.947 +/- 0.335, p = 0.006). The isovolumic relaxation time shortened significantly (from 88 +/- 23 ms to 75 +/- 24 ms, p = 0.005). CONCLUSIONS: The present study shows that LV diastolic function as assessed by pulsed Doppler echocardiography in hypothyroid patients is enhanced by thyroxine therapy during a rather short follow-up period.

Mesangiocapillary glomerulonephritis caused by Puumala hantavirus infection.

Nephropathia epidemica induced by Puumala hantavirus typically causes acute reversible renal function impairment. A typical renal biopsy finding is acute tubulointerstitial nephritis with slight glomerular mesangial changes. We describe here 5 patients who developed the nephrotic syndrome during the convalescent phase of an otherwise typical acute febrile nephropathia epidemica. Renal biopsy of all patients disclosed type I mesangiocapillary glomerulonephritis (MCGN). A clinical remission of the nephrotic syndrome was observed in 4 patients during the follow-up period, and 1 entered into chronic renal failure. Three patients had microscopic hematuria and proteinuria and 2 elevated blood pressure at the latest assessment visit. No patient had clinical or laboratory findings compatible with chronic bacterial, parasitic or viral infections (hepatitis B or C), malignancies, or other disorders known to be associated with MCGN. In conclusion, Puumala hantavirus has to be added to the list of potential agents associated with type I MCGN. Further studies are necessary to establish the incidence of MCGN caused by various hantavirus infections.