The effect of spironolactone on diastolic function in haemodialysis patients.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m2 vs. 1.7 ± 14.1 ml/m2, p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m2 vs. + 2.7 ± 15.9 g/m2; p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.The trial has been registered at clinicaltrials.gov (NCT01691053; first posted Sep. 24, 2012).

[Idiopathic systemic capillary leak syndrome (Clarkson disease) : A rare cause of recurrent life-threatening edema]. / Idiopathisches systemisches Capillary-leak-Syndrom (Clarkson-Syndrom) : Eine seltene Ursache rezidivierender, vital bedrohlicher Ödeme.

This case report describes the episodic occurrence of severe generalized edema in a young female patient, who developed hypertension with a massive hemoconcentration (hematocrit >0.5, hemoglobin >20g/dl) and hypoalbuminemia during the course of these acute disease phases. After the first two disease exacerbations were overcome, there was a complete regression of symptoms. After a long symptom-free interval, a new exacerbation occurred as a result of which critical organ ischemia occurred due to the severe hypotension and massive edema. Despite all treatment measures a severe compartment syndrome of the lower extemities with subsequent rhabdomyelosis developed. The patient ultimately died as a result of treatment-refractory cardiovascular failure. The idiopathic systemic capillary leak syndrome (SCLS, also known as Clarkson disease) is a rare and potentially life-threatening disease with a high mortality. Since the first description of the disease only approximately 500 cases have been published worldwide. The pathophysiology of this disease remains unclear despite all previous attempts at clarification. Regulation processes of endothelial permeability seem to be essentially disturbed. Affected patients have a monoclonal gammopathy of undetermined signficance conspicuously often; however, the knowledge of the limited treatment options is of fundamental importance for the prognosis and overall survival of patients.

Evidence for gonadotrophin secretory and steroidogenic abnormalities in brothers of women with polycystic ovary syndrome.

STUDY QUESTION: Are there abnormalities in gonadotrophin secretion, adrenal steroidogenesis and/or testicular steroidogenesis in brothers of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Brothers of women with PCOS have increased gonadotrophin responses to gonadotrophin releasing hormone (GnRH) agonist stimulation and alterations in adrenal and gonadal steroidogenesis. WHAT IS KNOWN ALREADY: PCOS is a complex genetic disease. Male as well as female first-degree relatives have reproductive features of the syndrome. We previously reported that brothers of affected women have elevated circulating dehydroepiandrosterone sulfate levels. STUDY DESIGN, SIZE, DURATION: This was a case-control study performed in 29 non-Hispanic white brothers of 22 women with PCOS and 18 control men. PARTICIPANTS/MATERIALS, SETTING, METHODS: PCOS brothers and control men were of comparable age, weight and ethnicity. Adrenocorticotrophic hormone (ACTH) and GnRH agonist stimulation tests were performed. Gonadotrophin responses to GnRH agonist as well as changes in precursor-product steroid pairs (delta, Δ) across steroidogenic pathways in response to ACTH and GnRH agonist were examined. MAIN RESULTS AND THE ROLE OF CHANCE: Basal total (T) levels did not differ, but dehydroepiandrosterone (DHEA) levels (0.13 ± 0.08 brothers versus 0.22 ± 0.09 controls, nmol/l, P = 0.03) were lower in brothers compared with control men. ACTH-stimulated Δ17-hydroxypregnenolone (17Preg)/Δ17-hydroxyprogesterone (17Prog) (7.8 ± 24.2 brothers versus 18.9 ± 21.3 controls, P = 0.04) and ΔDHEA/Δandrostenedione (AD) (0.10 ± 0.05 brothers versus 0.14 ± 0.08 controls, P = 0.04) were lower in brothers than in the controls. GnRH agonist-stimulated Δ17Prog/ΔAD (0.28 ± 8.47 brothers versus 4.79 ± 10.28 controls, P = 0.003) was decreased and luteinizing hormone (38.6 ± 20.6 brothers versus 26.0 ± 9.8 controls, IU/l, P = 0.02), follicle-stimulating hormone (10.2 ± 7.5 brothers versus 4.8 ± 4.1 controls, IU/l P = 0.002), AD (1.7 ± 1.4 brothers versus 0.9 ± 1.5 controls, nmol/l, P = 0.02) and ΔAD/ΔT (0.16 ± 0.14 brothers versus 0.08 ± 0.12 controls, P = 0.005) responses were increased in brothers compared with controls. LIMITATIONS, REASONS FOR CAUTION: The modest sample size may have limited our ability to observe other possible differences in steroidogenesis between PCOS brothers and control men. WIDER IMPLICATIONS OF THE FINDINGS: Decreased ACTH-stimulated Δ17Preg/Δ17Prog and ΔDHEA/ΔAD responses suggested increased adrenal 3ß-hydroxysteroid dehydrogenase activity in the brothers. Decreased Δ17Prog/ΔAD and increased ΔAD/ΔT responses to GnRH agonist stimulation suggested increased gonadal 17,20-lyase and decreased gonadal 17ß-hydroxysteroid dehydrogenase activity in the brothers. Increased LH and FSH responses to GnRH agonist stimulation suggested neuroendocrine alterations in the regulation of gonadotrophin secretion similar to those in their proband sisters. These changes in PCOS brothers may reflect the impact of PCOS susceptibility genes and/or programming effects of the intrauterine environment. STUDY FUNDING/COMPETING INTERESTS: This research was supported by P50 HD044405 (A.D.), K12 HD055884 (L.C.T.), U54 HD034449 (A.D., R.S.L.) from the National Institute of Child Health and Development. Some hormone assays were performed at the University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core that is supported by U54 HD28934 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Partial support for some of the clinical studies was provided by UL1 RR025741 and UL1 TR000150 (Northwestern University Clinical and Translational Sciences Institute) from the National Center for Research Resources, National Institutes of Health, which is now the National Center for Advancing Translational Sciences. The authors have no conflict of interest to declare.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

Expression of the PAX8/PPARγ Fusion Protein Is Associated with Decreased Neovascularization In Vivo: Impact on Tumorigenesis and Disease Prognosis.

The PAX8/PPARγ fusion protein (PPFP) occurs in 36% of human follicular thyroid carcinoma (FTC) and is associated with favorable prognosis. To elucidate the function of PPFP in FTC, we analyzed the consequences of PPFP expression in immortalized thyrocytes in vitro and in vivo via xenograft tumorigenesis. While PPFP-expressing cells exhibited oncogenic hallmarks, including increased growth and decreased apoptosis, in vitro, xenograft tumors were initiated but not sustained in vivo. PPFP xenograft tumors exhibited reduced CD31 staining and VEGF expression, suggesting that PPFP modulates neovascularization. Microarray analysis demonstrated increased expression of tissue inhibitor of metalloproteinase (TIMP-3), an inhibitor of angiogenesis, in PPFP cells and tumors, a finding confirmed by quantitative PCR and immunohistochemistry. Immunohistochemical staining of archival human thyroid tumors demonstrates a significant decrease in CD31 staining in all adenomas and carcinomas containing the PAX8/PPARγ rearrangement. Decreased angiogenesis in PPFP-containing tumors is directly correlated with our observations in the xenograft model and provides evidence for the first time that PPFP may impact FTC tumorigenesis by modulating angiogenesis in vivo.

Different time courses of nephrogenic systemic fibrosis: Is there a role for pharmacokinetic aspects in explaining a new clinical entity?

OBJECTIVE: To report 3 cases of nephrogenic systemic fibrosis (NSF) focussing on the time course of clinical symptoms after exposure to gadolinium based contrast agents (GBCA) and to discuss pharmacokinetic aspects of commercially available GBCA. PATIENTS' DETAILS: All 3 patients (2 men, 1 woman, aged 51 - 54 years) suffered from end-stage renal disease (ESRD) and were on long-term dialysis. Linear GBCA compounds were given to all patients and NSF symptoms started 6 months, 1 and 4 years after the last GBCA exposure. In 2 patients, GBCA was administered after the occurrence of (unrecognized) NSF symptoms leading to worsening of clinical courses. 1 of the patients received multiple therapies (e.g. UV-A1 treatment, physical therapy) without significant improvement, 2 patients died from cardiac complications shortly after the diagnosis of NSF. CONCLUSION: NSF may develop after a longer period of time than generally reported and GBCA administration may aggravate or accelerate chronic, subclinical NSF symptoms.

ONYX-411, a conditionally replicative oncolytic adenovirus, induces cell death in anaplastic thyroid carcinoma cell lines and suppresses the growth of xenograft tumors in nude mice.

Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer variant, accounting for 1-2% of all cases, but 33% of deaths, and exhibiting an average life expectancy of 5 months. ATC is largely unresponsive to radioactive iodine, chemotherapy, external beam radiation or surgery, underscoring the need for new and effective therapies. We evaluated the therapeutic potential of an oncolytic adenovirus, ONYX-411, that replicates selectively in and kills cells with dysfunction of the retinoblastoma (RB) pathway. In the present study, we report that ONYX-411 is able to induce cell death in eight human anaplastic carcinoma cell lines in vitro. The cytopathic effect of the virus is specific to cells with RB dysfunction, which appears to be frequent in ATC. We confirmed the expression of the coxsackie adenovirus receptor, CAR, in all ATC cell lines, demonstrating the potentially universal application of this oncolytic viral therapy to ATC. In addition, the growth of xenograft tumors induced in athymic mice with the ARO and DRO cell lines was significantly reduced by ONYX-411 treatment. These results indicate that ONYX-411 can be a potential therapeutic agent for the treatment of ATC, rendering this class of conditionally replicating adenoviruses an attractive candidate for clinical trials.

Most multifocal papillary thyroid carcinomas acquire genetic and morphotype diversity through subclonal evolution following the intra-glandular spread of the initial neoplastic clone.

Papillary thyroid carcinoma (PTC) is frequently multifocal (mPTC), with synchronous tumour foci often showing varied morphology. The genetic mechanisms underlying the development of multiple and histologically diverse tumour foci remain uncertain. Different tumour foci might develop either through intrathyroidal dissemination of a single malignant clone, with morphotype differentiation occurring as a result of subclonal progression, or they may stem from independent transformational events involving multiple progenitor clones. To determine the clonal derivation of multiple tumour foci and to map their clonal relationships and genetic progression in mPTC, we evaluated genome-wide allelic imbalances (AI) and BRAF V600E mutation status in 55 synchronous tumour foci from 18 mPTC patients. For apparently monoclonal tumours, we calculated the probabilities of monoclonal derivation and used phylogenetic analysis to model clonal evolution. Genome-wide allelotyping and BRAF mutation analysis showed genetic alterations consistent with monoclonal origin in 83% of cases, mostly with evidence of subclonal evolution. BRAF V600E mutations were early events during clonal evolution of most, but not all cases. MPTC with morphologically diverse tumour foci also arose through monoclonal derivation in 75% of cases, demonstrating that morphotype-determining genetic changes can be acquired during clonal diversification, subsequent to the spread of the original malignant progenitor clone. In 17% of patients, discordant AI or BRAF V600E profiles implied that mPTCs can occasionally develop from distinct transformation events. This study suggests that mPTC originates usually from neoplastic transformation and subsequent intrathyroidal spread of a single malignant progenitor clone. Clonal progression and morphotype differentiation occur through progressive acquisition of genetic alterations subsequent to the initial intra-glandular spread. In monoclonal BRAF V600E-positive mPTCs, BRAF V600E is not always present in all tumour foci, indicating that other tumour-genetic factors in the primary progenitor clone can also trigger PTC neoplastic transformation.

Effect of mycophenolate mofetil on kidney graft function and body weight in patients with chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN) is the most common cause of late graft loss. A beneficial effect of mycophenolate mofetil (MMF) on CAN was observed, although, due to the loss of body weight (BW) under MMF, serum creatinine (sCr) and reciprocal sCr may be unsuitable markers of graft function. METHODS: In 17 kidney transplant patients with CAN, azathioprine (Aza) was replaced by MMF. The remaining therapy was not changed; specifically, the cyclosporine (CsA) dose was not decreased. The mean values and regression coefficients of reciprocal sCr, CCr, urinary creatinine excretion (uCr x V), proteinuria, BW, blood pressure (BP), serum cholesterol (sChol), and serum triglycerides (sTG) versus time were analyzed 12 months before and after institution of MMF by a paired-comparison t test. RESULTS: The mean regression coefficient of reciprocal sCr differed significantly before and after conversion to MMF (mean -0.01 +/- 0.01 vs +0.012 +/- 0.029 mg/dL per month), suggesting improved graft function. However, the mean values of BW (74 +/- 15 vs 71 +/- 15 kg, P <.001) and uCr x V (1152 +/- 321 vs 1065 +/- 266 mg per 24 hours, P=.0897) decreased, making the increase in CCr less significant (mean -1.16 +/- 2.69 vs 0.40 +/- 1.79 mL/min per month, P <.05). BP, sChol, sTG, and proteinuria before and after conversion did not differ significantly. Among patients with long-term stable graft function at 36.5 +/- 16.9 months after conversion to MMF there was an almost significant improvement in renal protein excretion. CONCLUSIONS: MMF improved graft function, although this effect was overestimated using reciprocal sCr. Other risk factors, such as BP, sChol, and sTG, showed no significant differences, suggesting that MMF accounted for the improvement in CAN. The course of proteinuria under MMF seems to be of prognostic significance.

Immune monitoring in organ transplantation using neopterin.

Transplantation has become an established and successful therapy. Rejections and infections are the principal immune-related complications in the post-transplant course. A reliable and early diagnosis is necessary to prevent graft failure and patient morbidity. Despite the immunologic nature of these complications the diagnostic procedures still rely on functional tests and organ biopsies. Non-invasive monitoring remains to be one of the major goals in transplant medicine. Neopterin is a sensitive marker of the cellular immune response. It reflects the activation of macrophages and can be easily measured in serum, plasma, urine or other body fluids. This review summarises studies on the diagnostic value of neopterin in transplant medicine. Based on these results key factors for immune monitoring in regard to neopterin are evaluated. In particular the unspecificity of diagnostic immune markers, the kinetics of the immune response, the importance of adjustment of neopterin to kidney function, and quantitative differences in immune pathways against viruses and allografts are discussed. Reflecting these points a concept to use neopterin for non-invasive immune monitoring in the clinical routine is presented. This approach calculates probabilities for specific post-transplant complications based on daily measurements of neopterin, a combination with the acute phase reactant amyloid A, and a modification of the likelihood ratio concept.

Assessment of cytomegalovirus infections using neopterin and a new immunoblot.

Human cytomegalovirus (HCMV) infections are a major cause of morbidity and mortality in immunocompromised patients despite advances in diagnostic tests and antiviral therapies. The underlying study investigates the diagnostic value of the immune marker neopterin and a recently developed HCMV-specific western blot to detect HCMV infections and to differentiate them into either syndromes or diseases. The mean period of observation was 1428 days. Thirteen HCMV diseases and nine syndromes were diagnosed retrospectively. The first appearance of clinical signs or symptoms was always associated with a marked increase of serum and urine neopterin. The HCMV-specific IgM response followed in the mean 9 days later. Median values and the course of the neopterin levels were significantly higher during the HCMV diseases. In addition, the strength of the humoral immune response was related to the severity of the HCMV infection. Patients with HCMV diseases developed antibodies against a higher number of epitopes. The anti-HCMV IgM response persisted in more than 80% of the patients for longer than 3 years. In conclusion, combining the HCMV-specific western blot and neopterin permit detection of the immune response against HCMV, reflect the severity of the infection and might guide the anti-viral therapy.

Oral shark cartilage does not abolish carcinogenesis but delays tumor progression in a murine model.

BACKGROUND: Shark cartilage and shark cartilage extracts have been reported to have anti-angiogenic and anti-neoplastic properties. This study reports the effects of oral administration of powdered shark cartilage on tumor progression in a murine renal tumor model. MATERIALS AND METHODS: Renal tumors were induced in CBA female mice by a single bolus of IV streptozotocin. 57 mice were fed shark cartilage and the numbers and rate of development of dysplastic convoluted tubules, papillary and solid renal epithelial tumors was compared with 57 control mice over an 88 week follow-up period. RESULTS: In the shark cartilage fed group dysplasia was first observed after 23 weeks (control 19 weeks), papillary tumors after 24 weeks (control 23 weeks) and solid tumors after 55 weeks (control 19 weeks). There was no significant difference in the rate of development of dysplastic tubules between test and control animals. The development of papillary and solid tumors was significantly delayed in the test group. CONCLUSIONS: In this tumor model oral shark cartilage delays, but does not abolish, tumor progression.

Amidolytic heparin activity and values for several hemostatic variables after repeated subcutaneous administration of high doses of a low molecular weight heparin in healthy dogs.

OBJECTIVE: To determine effects of SC administration of repeated doses of a low molecular weight heparin (LMWH) in dogs. ANIMALS: 5 healthy dogs. PROCEDURE: Each dog received 6 injections (each injection, 150 U of anti-factor-Xa [anti-FXal/kg of body weight, SC) at 8-hour intervals. Blood samples were collected before and 2 hours after the first, second, third, and sixth injections to measure heparin activity, thrombin time, activated partial thromboplastin time (APTT), antithrombin activity, Hct, and platelet count. RESULTS: Heparin activity varied between 0.36+/-0.10 and 0.77+/-0.08 U of anti-FXa/ml (before and 2 hours after the third injection) and between 0.46+/-0.11 and 0.82+/-0.15 U of anti-FXa/ml (before and 2 hours after the sixth injection). Thrombin time and APTT were influenced only slightly. Platelet count, Hct, and antithrombin activity started to decrease significantly 2 hours after the second LMWH injection. Because of the increased consumption of antithrombin, antithrombin activity continuously decreased from 102.1+/-6.3% before the study to 91.0+/-3.0% at the end of the study. CONCLUSIONS AND CLINICAL RELEVANCE: Heparin plasma activity was only slightly higher than that recommended for LMWH treatment of humans, and none of the dogs had signs of increased bleeding. Thus, administration of heparin in accordance with this dosing regimen can be recommended for use in clinical studies. The screening tests investigated were not suitable for use in monitoring LMWH treatment of dogs. Assays that use chromogenic substrates are necessary to reliably monitor LMWH plasma concentrations in dogs.

[Improved diagnosis through digital mammography with the assistance of computer algorithms]. / Verbesserte Diagnosefindung durch den Einsatz von Computeralgorithmen in der digitalen Mammographie.

OBJECTIVE: The aim of this survey was to determine improved diagnostics through digital mammography with assistance of computer algorithms and new investigation techniques. MATERIAL AND METHODS: In general, the presented procedures are practicable with all digital mammography procedures. In our clinic the largest clinical experience exists with the only FDA certified full field mammography device Senograph 2000D (GE Medical Systems). RESULTS: First results from initial studies are shown, which are to evaluate the new procedures. The so-called post processing with visualization of microcalcifications, computer-assisted diagnosis, tomosynthesis, energy subtraction, contrast media in mammography and teleradiology are considered in particular. CONCLUSION: Digital mammography represents a promising procedure, opening new possibilities for improved diagnostic in mammography.

A prospective randomized trial on heart rate variability of the surgical team during laparoscopic and conventional sigmoid resection.

HYPOTHESIS: Mental strain measured by heart rate variability differs during laparoscopic and conventional sigmoid resections. DESIGN: Prospective randomized study. SETTING: University hospital. PARTICIPANTS: Two surgeons performed 10 conventional and 10 laparoscopic sigmoid resections, alternating roles as primary surgeon and assistant. The kind of technique was randomly chosen each time. INTERVENTION: Electrocardiograms of the surgeon and assistant were continuously recorded during the procedures and heart rate variability was analyzed off-line. The first 10 procedures (5 laparoscopic and 5 conventional) were performed by the more experienced and the next 10 by the less experienced surgeon. MAIN OUTCOME MEASURES: Heart rate variability was determined by power spectral analysis as heart rate in beats per minute, high frequency (HF) and low frequency (LF) components in normalized units, and LF/HF ratio. RESULTS: Results are given for heart rate, HF, LF, and LF/HF ratio for the following variables: laparoscopic surgery: 87.9, 14.7, 90.1, 7.5; conventional surgery: 90.2, 17.1, 87.6, 6.4; surgeon: 94.0, 13.5, 91.4, 8.4; first assistant: 84.1, 17.8, 86.3, 5.6; more experienced surgeon: 93.1, 16.5, 87.8, 6.4; and less experienced surgeon: 85.0, 14.8, 90.0, 7.5. The LF/HF ratio was significantly higher (P<.05) for laparoscopic compared with conventional surgery and for the surgeon compared with the assistant (P<.001), but not between the less and the more experienced surgeons. CONCLUSION: Performing laparoscopic colorectal surgery causes higher mental strain in surgeons than performing conventional surgery.

Anticoagulant effects of repeated subcutaneous injections of high doses of unfractionated heparin in healthy dogs.

OBJECTIVE: To evaluate s.c. administration of unfractionated heparin (UFH) in accordance with a dosing regimen for high-dose treatment in dogs. ANIMALS: 10 healthy adult Beagles. PROCEDURES: Two groups of dogs (5 dogs/group) were given 6 injections of heparin (500 units of UFH/kg of body weight, s.c.) at intervals of 8 (experiment 1) and 12 (experiment 2) hours. Blood samples were collected before and 4 hours after heparin injections to determine amidolytic heparin activity, activated partial thromboplastin time (APTT), thrombin time, antithrombin activity, platelet count, and Hct. RESULTS: For experiments 1 and 2, mean +/- SD heparin activities before (experiment 1, 1.32 +/- 0.20 U/ml; experiment 2, 0.69 +/- 0.174 U/ml) and 4 hours after the last heparin injection (experiment 1, 1.71 +/- 0.30 U/ml; experiment 2, 1.10 +/- 0.30 U/ml) were higher than values calculated for the regimen used in experiment 1. Results of the investigated thrombin time test system with low thrombin activity were frequently beyond the measurement range, even with UFH activities > or = 0.6 U/ml. Moreover, a severe decrease of antithrombin activity became evident during both experiments (eg, in experiment 2 from 95.6 +/- 4.8 to 59.2 +/- 6.6%). In each treatment group, 2 dogs developed hematomas. CONCLUSIONS AND CLINICAL RELEVANCE: Calculations of the course of heparin activity after a single injection do not result in a reliable dosing regimen for high-dose heparin treatment in dogs. High-dose treatment must be monitored for each dog. Thrombin time measured with low thrombin activity is unsuitable for this purpose.

Evolving classification of renal cell neoplasia.

The development of consensus classifications for renal epithelial neoplasia in 1996 and 1997 led to the recognition of renal adenoma, renal oncocytoma and metanephric adenoma/adenofibroma as benign tumors and conventional (clear cell) renal cell carcinoma (RCC), papillary RCC, chromophobe RCC and collecting duct carcinoma as malignant morphotypes. While the overwhelming majority of renal adenomas and metanephric adenomas are benign, malignant transformation of both types have been described and genetic predictors of malignant transformation are as yet unknown. The main groups of malignant renal tumors are associated with characteristic genetic changes; conventional RCC (-3p), papillary RCC (+7, +17, -Y), chromophobe RCC (hypodiploid). Recent studies have also shown focal loss of heterozygosity of 3p segments in papillary and chromophobe RCC, indicating that 3p mutations are not confined to the conventional RCC morphotype and suggesting the presence of an important tumor suppressor gene at this site. Sarcomatoid metaplasia may occur in any morphotype and this is associated with a poor prognosis. More recently additional varieties of conventional RCC (multilocular cystic RCC), collecting duct carcinoma (medullary renal carcinoma) and papillary RCC (Types 1 and 2), each showing a characteristic morphology, have been recognized.