Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs

Seventy-six dogs with clinical acquired atrioventricular valvular disease were evaluated to determine the efficacy of pimobendan (n=41) versus benazepril hydrochloride (n=35) in a randomized, positive-controlled, multicenter study. The study was divided into 56-day and long-term evaluation periods. In a subgroup of dogs with concurrent furosemide treatment (pimobendan [n=31], benazepril [n=25]), the Heart Insufficiency Score improved in favor of pimobendan (P=0.0011), equating to a superior overall efficacy rating (P<0.0001) at day 56. Long-term median survival (i.e., death or treatment failure) for dogs receiving pimobendan was 415 days versus 128 days for dogs not on pimobendan (P=0.0022).

Detection of Progressive Deterioration in Early Onset Schizophrenia with a New Statistical Method

Much controversy exists over whether the course of schizophrenia, as defined by the lengths of repeated community tenures, is progressively ameliorating or deteriorating. This article employs a new statistical method proposed by Wang and Chen (2000) to analyze the Denmark registry data in Eaton, et al (1992). The new statistical method correctly handles the bias caused by induced informative censoring, which is an interaction of the heterogeneity of schizophrenia patients and long-term follow-up. The analysis shows a progressive deterioration pattern in terms of community tenures for the full registry cohort, rather than a progressive amelioration pattern as reported for a selected sub-cohort in Eaton, et al (1992). When adjusted for the long-term chronicity of calendar time, no significant progressive pattern was found for the full cohort.

High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.

Multiple B-cell clones producing antibodies directed to the spacer and disintegrin/thrombospondin type-1 repeat 1 (TSP1) of ADAMTS13 in a patient with acquired thrombotic thrombocytopenic purpura

BACKGROUND: The cysteine-rich/spacer domains of ADAMTS13 contain a major binding site for antibodies in patients with acquired thrombotic thrombocytopenic purpura (TTP). OBJECTIVE: To study the heterogeneity of the antibody response towards these domains an immunoglobulin V-gene phage-display library was constructed to isolate monoclonal anti-ADAMTS13 antibodies from the immunoglobulin repertoire of a patient with acquired TTP. METHODS: Combined variable heavy chain (VH) and variable light chain (VL) segments, expressed as single-chain Fv fragments (scFv), were selected for binding to an ADAMTS13 fragment consisting of the disintegrin/thrombospondin type-1 repeat 1 (TSP1)/cysteine-rich/spacer domains. RESULTS: Seven different scFv antibody clones were identified that were assigned to four groups based on their homology to VH germline gene segments. Epitope-mapping revealed that scFv I-9 (VH1-69), I-26 (VH1-02), and I-41 (VH3-09) bind to an overlapping binding site in the ADAMTS13 spacer domain, whereas scFv I-16 (VH3-07) binds to the disintegrin/TSP1 domains. The affinity of scFv for the disintegrin/TSP1/cysteine-rich/spacer domain was determined by surface plasmon resonance analysis and the dissociation constants ranged from 3 to 254 nM. The scFv partially inhibited ADAMTS13 activity. However, full-length IgG prepared from the variable domains of scFv I-9 inhibited ADAMTS13 activity more profoundly. Plasma of six patients with acquired TTP competed for binding of scFv I-9 to ADAMTS13. CONCLUSION: Our data indicate that multiple B-cell clones producing antibodies directed against the spacer domain are present in the patient analyzed in this study. Our findings also suggest that antibodies with a similar epitope specificity as scFv I-9 are present in plasma of other patients with acquired TTP.

Analysis and mapping of CACNB4, CHRNA1, KCNJ3, SCN2A and SPG4, physiological candidate genes for porcine congenital progressive ataxia and spastic paresis

The cause of porcine congenital progressive ataxia and spastic paresis (CPA) is unknown. This severe neuropathy manifests shortly after birth and is lethal. The disease is inherited as a single autosomal recessive allele, designated cpa. In a previous study, we demonstrated close linkage of cpa to microsatellite SW902 on porcine chromosome 3 (SSC3), which corresponds syntenically to human chromosome 2. This latter chromosome contains ion channel genes (Ca(2+), K(+) and Na(+)), a cholinergic receptor gene and the spastin (SPG4) gene, which cause human epilepsy and ataxia when mutated. We mapped porcine CACNB4, KCNJ3, SCN2A and CHRNA1 to SSC15 and SPG4 to SSC3 with the INRA-Minnesota porcine radiation hybrid panel (IMpRH) and we sequenced the entire open reading frames of CACNB4 and SPG4 without finding any differences between healthy and affected piglets. An anti-epileptic drug treatment with ethosuximide did not change the severity of the disease, and pigs with CPA did not exhibit the corticospinal tract axonal degeneration found in humans suffering from hereditary spastic paraplegia, which is associated with mutations in SPG4. For all these reasons, the hypothesis that CACNB4, CHRNA1, KCNJ3, SCN2A or SPG4 are identical with the CPA gene was rejected.

Pathophysiology and diagnosis of nephrocalcinosis

Nephrocalcinosis is the result of a myriad of hereditary or acquired diseases in the calcium, phosphate or oxalate metabolism that lead to deposition of calcium containing precipitates within the kidney. Nephrocalcinosis and nephrolithiasis are pathophysiologically tightly related and often co-exist. In the case of recurrent nephrolithiasis, nephrocalcinosis has to be excluded. Stone analysis can yield important clues to the underlying disease process. The best way to diagnose nephrocalcinosis and an accompanying nephrolithiasis is by native computer tomography scans. Untreated, nephrocalcinosis will lead to a progressive decline in renal function and eventually to end stage renal disease. Thus, for each case, the underlying disease process has to be determined and a causative therapy initiated.

Reduced neuronal efficacy in progressive mild cognitive impairment: a prospective fMRI study on visuospatial processing

Mild cognitive impairment (MCI) often refers to the preclinical stage of dementia, where the majority develop Alzheimer's disease (AD). Given that neurodegenerative burden and compensatory mechanisms might exist before accepted clinical symptoms of AD are noticeable, the current prospective study aimed to investigate the functioning of brain regions in the visuospatial networks responsible for preclinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Eighteen MCI patients were evaluated and clinically followed for approximately 3 years. Five progressed to AD (PMCI) and eight remained stable (SMCI). Thirteen age-, gender- and education-matched controls also participated. An angle discrimination task with varying task demands was used. Brain activation patterns as well as task demand-dependent and -independent signal changes between the groups were investigated by using an extended general linear model including individual performance (reaction time [RT]) of each single trial. Similar behavioral (RT and accuracy) responses were observed between MCI patients and controls. A network of bilateral activations, e.g. dorsal pathway, which increased linearly with increasing task demand, was engaged in all subjects. Compared with SMCI patients and controls, PMCI patients showed a stronger relation between task demand and brain activity in left superior parietal lobules (SPL) as well as a general task demand-independent increased activation in left precuneus. Altered brain function can be detected at a group level in individuals that progress to AD before changes occur at the behavioral level. Increased parietal activation in PMCI could reflect a reduced neuronal efficacy due to accumulating AD pathology and might predict future clinical decline in patients with MCI.

Sequential immunosuppressive therapy in progressive IgA nephropathy

BACKGROUNDS: Cyclophosphamide and high-dose steroids have been used as limited induction therapy in progressive IgA nephropathy (IgAN) to reduce the loss of renal function and proteinuria. We evaluated the effect of cyclophosphamide pulses (CyP) and mycophenolic acid (MPA) as sequential therapy on renal function in patients with progressive IgAN. METHODS: Twenty patients with progressive IgAN and advanced renal failure (median GFR 22 ml/min per 1.73 m2) and further disease activity (triangle downGFR -0.8 ml/min per month) after cyclophosphamide (CyP; n = 18) or steroid pulse therapy (n = 2) were treated with mycophenolate mofetil 1 g per day for a median of 27 months. RESULTS: The monthly loss of renal function was significantly reduced in linear regression analysis from -2.4 ml/min before CyP to -0.12 ml/min with CyP/MPA (p = 0.0009). Estimated renal survival time was significantly prolonged by a median of 65 months (p = 0.0014). Proteinuria decreased significantly from 1.7 to 0.4 g/l during MPA treatment (p = 0.015). In Cox regression analysis, only proteinuria >1.0 g/l was an independent risk factor for doubling of creatinine during CyP/MPA treatment (p = 0.03). CONCLUSION: A sequential therapy with CyP/MPA may arrest or slow down the loss of renal function and reduces proteinuria even in patients who passed the so called 'point of no return' with progressive IgAN.

Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma

AIM: To compare the plasma levels of endothelin-1 (ET-1) between patients with primary open angle glaucoma with visual field progression despite normal or normalised intraocular pressure and patients with stabile visual fields in a retrospective study. METHODS: The progressive group consisted of 16 primary open angle glaucoma patients and the group with stable visual field consisted of 15 patients. After a 30 minute rest in a supine position, venous blood was obtained for ET-1 dosing. Difference in the plasma level of ET-1 between two groups was compared by means of analysis of covariance (ANCOVA), including age, sex, and mean arterial blood pressure as covariates. RESULTS: ET-1 plasma levels were found to be significantly increased in patients with deteriorating (3.47 (SD 0.75) pg/ml) glaucoma when compared to those with stable (2.59 (SD 0.54) pg/ml) visual fields (p = 0.0007). CONCLUSIONS: Glaucoma patients with visual field progression in spite of normal or normalised intraocular pressure have been found to have increased plasma endothelin-1 levels. It remains to be determined if this is a secondary phenomenon or whether it may have a role in the progression of glaucomatous damage.

[Community-acquired pneumonia--pathogens and assessment]

Pneumonia is one of the most important infectious diseases, both in terms of incidence as well as potential severity. Streptococcus pneumoniae remains the most prevalent etiologic agent, accounting for about two-thirds of bacteremic cases. Diagnostic procedures include chest radiography, blood culture, Gram staining and culture of expectorated sputum, urine antigen assays for Legionella pneumophila and pneumococci, and asservation of an initial serum sample for comparative serologic investigations. Molecular biology techniques continue to gain importance for the diagnosis of Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionellae and viral respiratory infections, however, their availability at present is mainly restricted to research and reference laboratories.

Susceptibility of Escherichia coli strains isolated from outpatient children with community-acquired urinary tract infection in southern Switzerland

BACKGROUND: Based on antimicrobial resistance patterns found in Swiss university hospitals, treatment with a third-generation cephalosporin is currently advised for Swiss children with urinary tract infection. OBJECTIVE: The aim of this study was to prospectively assess the susceptibility of Escherichia coli strains isolated from children with symptomatic community-acquired urinary tract infection. METHODS: The antimicrobial susceptibility of E coli strains causing symptomatic community-acquired urinary tract infections was assessed in outpatient children attending the emergency management unit at the Department of Pediatrics, Mendrisio and Bellinzona Hospitals, Switzerland. Strains from children receiving antimicrobial prophylaxis or prescribed antimicrobials in the previous 4 weeks were excluded. Clinical and Laboratory Standards Institute methods were used for culture and identification of pathogens. E coli susceptibility testing was performed using the disk diffusion technique. RESULTS: Strains from 100 consecutive outpatient children (73 girls, 27 boys; aged 5 weeks-17 years [median, 33 months]; 100% white) were assessed. High rates of ampicillin and cotrimoxazole resistance (39 and 21 strains, respectively) and low rates of nitrofurantoin resistance (4 strains) were identified. No resistance was identified for coamoxiclav or third-generation cephalosporins. CONCLUSIONS: In these Swiss outpatient children with symptomatic community-acquired urinary tract infection, without antimicrobial prophylaxis or recent prescription of antimicrobials, uropathogenic E coli strains resistant in vitro to ampicillin and cotrimoxazole were common. However, in vitro resistance to nitrofurantoin, coamoxiclav, and third-generation cephalosporins was uncommon.