[Thromboembolic complications in nephrotic syndrome]. / Thromboembolische Komplikationen bei nephrotischem Syndrom.

Thromboembolic complications are among the most important extrarenal consequences of nephrotic syndrome (NS). In addition to deep vein thrombosis in the legs and pulmonary embolism, NS is very frequently accompanied by renal vein thrombosis. Due to enhanced procoagulatory and antifibrinolytic potential and reduced anticoagulatory potential, multifactor disruption of hemostatic equilibrium leads to hypercoagulability in NS patients, which is aggravated by an increase in blood viscosity and endothelial dysfunction. Circulating antibodies against α-enolase, a plasmin(ogen)-binding protein, and the possibility of certain molecules being renally eliminated in specific manner are discussed as reasons for the particular frequency of thromboembolic complications in patients with idiopathic membranous nephropathy. Serum albumin concentration is an indicator for the risk of thrombosis in NS patients. When applying the current KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for glomerulonephritis to NS patients with a serum albumin concentration of less than 25 g/l and at least one additional thrombogenic risk factor, primary prophylactic anticoagulation ("conditioned prophylaxis") with an orally administered vitamin K antagonist (target INR 2-3) is recommended as long as the serum albumin concentration is less than 30 g/l.

Predictive factors for breast cancer in patients diagnosed with ductal intraepithelial neoplasia, grade 1B.

BACKGROUND: For ductal intraepithelial neoplasia, grade 1B, studies that predict breast cancer risk after an 11-gauge vacuum-assisted breast biopsy have yielded contradictory results. In order to identify a predictive model of breast cancer risk, we assessed the underestimation rate according to radiological and clinical findings. PATIENTS AND METHODS: Our study involved 212 patients. We compared the area under the receiver operating characteristic curves and the clinical utility of a logistic regression and partitioning model. RESULTS: Overall upgrade to malignancy occurred in 42 (19.8%) out of the 212 cases. The area under the curve for the logistic regression and partitioning model were 0.65 (95% confidence interval=0.61-0.70) and 0.58 (95% confidence interval=0.54-0.62), respectively. The lowest predicted underestimation rate obtained with the logistic regression model was 9.5%. CONCLUSION: From this large series, we were unable to define any accurate safety model for breast cancer. Surgery should be thus recommended.

[The need to revise the hemoglobin threshold value in the German Quality Assurance Directive for Dialysis]. / Die Notwendigkeit zur Revision des Hämoglobingrenzwerts in der deutschen Qualitätssicherungs-Richtlinie Dialyse.

The German Quality Assurance Directive for Dialysis (QSD-RL) stipulates that no more than 15 % of all patients treated in a dialysis unit in any quarter may have a hemoglobin (Hb) value lower than 10 g/dl. For approximately 90 % of dialysis patients, this Hb threshold value can be simply achieved by administering erythropoiesis-stimulating agents (ESA). However, the question is raised as to wether this Hb threshold accords with the current state of knowledge. It is now evident from four randomized controlled trials (above all the TREAT study) and three meta-analyses that an ESA-induced increase in Hb does not produce any significant survival benefit in cases of chronic kidney disease (CKD), but may actually be detrimental. Critical attention must be focused in this regard on the higher risk of cardiovascular and cerebrovascular events, as well as malignoma-associated risks. In 2011, in response to these findings, the American Food and Drug Administration (FDA), the Drug Directive (AM-RL) of the German Federal Joint Committee and KDIGO (Kidney Disease: Improving Global Outcomes) amended guidelines for the treatment of renal anemia. Very restrictive recommendations were made regarding the use of ESA in CKD, according to which the Hb threshold value of 10 g/dl stipulated in the Quality Assurance Directive is now obsolete, thus necessitating prompt revision of the Directive. Two alternatives are available in this regard: either the 10 g/dl Hb threshold value applicable hitherto is withdrawn without replacement, and individualized treatment of renal anemia is practised ("individualization") instead, or a threshold value of 9 g/dl (modified "standardization") is applied in future.

Scoring to predict the possibility of upgrades to malignancy in atypical ductal hyperplasia diagnosed by an 11-gauge vacuum-assisted biopsy device: an external validation study.

BACKGROUND: Ko's scoring system was developed to predict malignancy upgrades in patients diagnosed with atypical ductal hyperplasia by core needle biopsy. The Ko algorithm was able to identify a subset of patients who were eligible for exclusively clinical follow-up. The current study statistically investigated the patient outcomes to determine whether this scoring system could be translated and used safely in clinical practice. METHODS: We tested the statistical performance of the Ko scoring system against an external independent multicentre population. One hundred and seven cases of atypical ductal hyperplasia diagnosed by an 11-gauge biopsy needle were available for inclusion in this study. The discrimination, calibration and clinical utility of the scoring system were quantified. In addition, we tested the underestimation rate, sensitivity, specificity, and positive and negative predictive values according to the score threshold. RESULTS: The overall underestimation rate was 19% (20/107). The area under the receiver operating characteristic curve for the logistic regression model was 0.51 (95% confidence interval: 0.47-0.53). The model was not well calibrated. The lowest predicted underestimation rate was 11%. The sensitivity, specificity, positive predictive value, and negative predictive values were 90%, 22%, 20%, and 89%, respectively, according to the most accurate threshold proposed in the original study. CONCLUSION: The scoring system was not sufficiently accurate to safely define a subset of patients who would be eligible for follow-up only and no additional treatment. These results demonstrate a lack of reproducibility in an external population. A multidisciplinary approach that correlates clinicopathological and mammographic features should be recommended for the management of these patients.

[Klinefelter syndrome: spermatogenesis and quality of gametes]. / Syndrome de Klinefelter : qualité des gamètes et spermatogenèse.

Klinefelter syndrome is defined by the presence of a supernumerary X chromosome in a phenotypic male. It is the most frequent gonosomic anomaly in infertile men with an incidence of 0.1 to 0.2% in newborn males. The presence of an additional X chromosome induces spermatogenic failure but when gametes are present, they are usually normal. The risk of transmission of the chromosomal anomaly remains low. In the literature, only one 47,XXY foetus resulting from more than a hundred births from fathers with Klinefelter syndrome, has been reported. One can estimate, that a TESE performed in half of the patients with non-mosaic 47,XXY will be positive and may enable IVF/ICSI to be achieved.

[Fluoroquinolone-induced Achilles tendon rupture]. / Fluorochinolon-induzierte Achillessehnenruptur.

HISTORY AND ADMISSION FINDINGS: A 72-year-old female dialysis patient with insulin-dependent diabetes mellitus who was under long-term medication with oral prednisolone due to chronic obstructive pulmonary disease was given levofloxacin for one week to treat an acute bronchitis (one 500 mg dose on the first day, 125 mg/day orally from second day onwards). One day after the end of levofloxacin treatment, the patient complained about a constant dragging pain above the right heel that receded under local application of diclofenac ointment and inactivity of the right foot. Twelve days after ending administration of levofloxacin, strong pains in the right calf were suddenly felt during normal walking, and active plantar flexion was lost. Palpation showed the right calf to be soft; a distinct gap was found in the middle third of the Achilles tendon. The Thompson test was positive, and the patient was unable to stand on her right toes. INVESTIGATIONS AND DIAGNOSIS: Ultrasonography showed a discontinuity of the right Achilles tendon. A spontaneous Achilles tendon rupture after taking fluoroquinolone was diagnosed. TREATMENT AND COURSE: Conservative treatment was applied due to the reduced general condition. Initial treatment involved a below-knee plaster cast in equinus position; the cast was replaced on the fourth day by a pneumatic walker, which was also worn during mobilisation by physiotherapy. CONCLUSION: A typical feature of fluoroquinolone-induced tendinopathy (FIT) is a considerable latency period in some cases between the commencement of treatment with a fluoroquinolone and the onset of FIT symptoms. In addition to fluoroquinolone intake, there are three other predisposing risk factors for tendinopathy: age over 60 years, long-term treatment with systemic glucocorticoids, and chronic kidney disease. The patient showed a combination of all the aforementioned risk factors. In patients with these risk factors, especially among people with a combination of said risk factors - which is frequently the case with nephrologic and dialysis patients, especially -, fluoroquinolones should be administered only after critical evaluation and with a dosage that is adapted to renal function.

Randomised controlled trial of essential fatty acid supplementation in phenylketonuria.

OBJECTIVE: The long-chain polyunsaturated fatty acids (LC-PUFA) status of children with PKU is often compromised. LC-PUFA, which are important fatty acids in the development of the CNS, can be synthesised endogenously from the parent essential fatty acids (EFA) provided dietary intakes are adequate. This study was designed to assess the biochemical effect over a 20-week period of a phe-free protein substitute that has been supplemented with a balanced blend of n-3 and n-6 EFAs on LC-PUFA status of children with PKU. DESIGN, SETTING AND SUBJECTS: Fifty three community-living children aged 1-10 years diagnosed with PKU in the newborn period were recruited from seven tertiary centres in the UK and France and randomised to a fat-free control formula or the EFA-supplemented test-treatment formula in an open, prospective study. Forty four children completed the study (20 controls, 24 test-treatments). Fatty acid status was assessed at entry and 20-weeks follow-up. Three day dietary diaries were recorded at 20 weeks' follow-up. The safety, efficacy and palatability of the test-treatment formula were also assessed. RESULTS: The test-treatment group had significantly higher intakes of fat and EFA than the control group. There was a significant between group difference (P=0.04) in increases in median docosahexaenoic acid (DHA) concentrations in erythrocyte phospholipids, which increased by 19% in the test-treatment group and by 0.5% in the control group over the study period. Growth and phe control were satisfactory in all subjects. CONCLUSIONS: Supplementing the diets of children with PKU with a balanced blend of n-6 and n-3 EFA improves DHA status without compromising AA status.

[Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. / Consensus national sur la prise en charge des enfants dépistés avec une hyperphénylalaninémie.

Phenylketonuria (PKU) is an inherited metabolic disease affecting about one birth out of 15 000. From 1978, a national systematic neonatal screening was set up in France with a regional organisation. French rational and guidelines have been established by the national PKU group with the collaboration of all the physicians responsible for the regional centres. These guidelines specify the minimal diagnosis procedures leading to an optimal treatment of all patients. A low-phenylalanine diet must be started as soon as possible in the neonatal period for all newborns whose phenylalanine levels are above 10 mg/dl. The dietary control must keep the phenylalanine plasma levels between 2 and 5 mg/dl until 10 years of age. After this age, several data argue for a progressive and controlled relaxation of the diet, keeping the phenylalanine level below 15 mg/dl until the end of the adolescence and below 20 to 25 mg/dl in adulthood. All PKU patients must be followed up for life, in order to screen those who may not bear the diet relaxation and in order to strictly prevent maternal PKU deleterious consequences.

Abnormal expression of gastric mucin in human and rat aberrant crypt foci during colon carcinogenesis.

Colorectal cancer is a major cause of death in Europe and the USA, and much effort is therefore devoted to improve its early detection. In this article, we report the abnormal expression of gastric mucin in aberrant crypt foci (ACF) that appear in the colon mucosae removed from colorectal cancer patients and rats treated with methyl-N'-nitro-N-nitroso-guanidine (MNNG). We performed the immunoperoxidase test using monoclonal antibodies raised against gastric M1 mucin encoded by the MUC5AC gene and against rat gastric mucins (MAb 660), respectively. In both human and rat colon, these anti-gastric mucin MAbs stained specifically goblet cells within ACF. In humans, the M1/MUC5AC mucin was expressed in the upper part of the glands in hyperplastic ACF and in the typical ACF. In addition, the anti-gastric mucin MAbs stained some rare, scattered, histologically normal glands in the human and rat colon mucosae. These glands may be regarded as precursors of ACF. The abnormal expression of the MUC5AC gene constitutes a novel change in addition to genetic modifications already observed in ACF, and supports our previous findings demonstrating the potential of this gastric mucin as an early marker of human and rat colon carcinogenesis.

Neonatal screening and long-term follow-up of phenylketonuria: the French database.

BACKGROUND: In France, neonatal screening of phenylketonuria (PKU) started in 1966. A national association was created in 1978 in order to organise the neonatal screening program and to control the efficacy of the screening and patients' follow-up. AIMS: To evaluate the results of the French PKU screening program in terms of hyperphenylalaninaemia epidemiology, efficacy of the screening procedure, management and outcome of the patients. STUDY DESIGN: The national database has been filled-up first with the answers to questionnaires that were sent each year by the PKU patients' physicians, and second with the results of an additional inquiry, which was set up in 1994 in order to investigate diagnosis, treatment, and school outcome of all French PKU patients. RESULTS: PKU was diagnosed in 81.6% of patients with hyperphenylalaninaemia (HPA), non-PKU HPA in 17.2% and cofactor deficiency in 1.1%. From 1980, incidence of PKU has been stable: 1 per 17,124 live births. Sensitivity of the screening procedure was 99.3%. Age at diet initiation regularly decreased to reach 14 days as a median in 1996. Until 1990, median age at diet discontinuation was 6 years of age. Later, strict diet was continued longer (at least, up to 8-10 years). PKU patients who entered to secondary school at normal age were characterised by an earlier age at diagnosis and at diet initiation and a later age at diet discontinuation, compared to those who entered 1 year or more behind normal age. CONCLUSION: These data confirm the benefit of a nationwide organised screening program. They emphasise the importance of an early neonatal diagnosis and diet initiation in PKU patients and are consistent with the benefit of a longer period of strict diet in childhood.

[Evaluation of 47,213 infants in neonatal screening for cystic fibrosis, using pancreatitis-associated protein and immunoreactive trypsinogen assays]. / Evaluation sur 47,213 enfants d'une stratégie de dépistage néonatal de la mucoviscidose associant les dosages de pancreatitis-associated protein et de trypsinogène immunoréactive.

OBJECTIVES: The increasing evidence of the benefits of neonatal screening for cystic fibrosis (CF) indicates that this procedure could soon be implemented throughout France. The screening strategy currently used involves the detection of infants with elevated levels of immunoreactive trypsinogen (IRT) (approximately 1% of the population), followed by the detection of CFTR gene mutations. However, genetic analysis has certain drawbacks, the most important of which being the management of heterozygotes, and in France the requirement by law of previous informed consent. In cases of CF, pancreatic alterations are already present in utero. A previous study has demonstrated the value of pancreatitis-associated protein (PAP) as a screening test for CF, and has indicated that a feasible two-stage strategy could involve the following: 1) selection of infants with elevated PAP levels; 2) in this group of infants, subsequent detection of those with elevated IRT levels for direct CF diagnosis by the sweat test thereby avoiding the use of genetic analysis. The study aim was to evaluate this strategy in a large number of neonates. METHODS AND RESULTS: The aforementioned strategy was evaluated in a prospective study involving 47,213 infants in the Provence region of France. In infants with a PAP > 7.5 ng/mL (1.28%), 176 had an elevated IRT level > 700 ng/mL (0.37%). In this limited population sample (0.37% of the total), the sweat test diagnosed five cases of CF. A sixth case involving the monozygous twin of an infant with diagnosed CF remained undetected, probably because of a registration error. Genetic analysis confirmed the diagnosis, and also detected another case in an infant with two CFTR mutations but with a normal phenotype at 20 months of age. As the observed incidence was similar to that which had previously been reported, and as no further case was subsequently detected two years after the end of the study, this indicated that the sensitivity of this screening strategy was satisfactory. Its specificity makes the direct diagnosis of CF cases by the sweat test feasible, without further selection by genetic analysis. CONCLUSION: The PAP/IRT technique for CF detection seems to be suitable for mass screening, without the drawbacks of genetic testing.

Blood concentrations of pancreatitis associated protein in neonates: relevance to neonatal screening for cystic fibrosis.

AIM: To determine whether pancreatitis associated protein (PAP) is a marker for cystic fibrosis which could be used in neonatal screening for the disease. METHODS: PAP was assayed on screening cards from 202,807 neonates. Babies with PAP > or = 15 ng/ml, or > or = 11.5 ng/ml and immunoreactive trypsinogen (IRT) > or = 700 ng/ml were recalled for clinical examination, sweat testing, and cystic fibrosis transmembrane regulator (CFTR) gene analysis. RESULTS: Median PAP value was 2.8 ng/ml. Forty four cases of cystic fibrosis were recorded. Recalled neonates (n = 398) included only 11 carriers. A receiver operating characteristic curve analysis showed that PAP above 8.0 ng/ml would select 0.76% of babies, including all those with cystic fibrosis, except for one with meconium ileus and two with mild CFTR mutations. Screening 27,146 babies with both PAP and IRT showed that only 0.12% had PAP > 8.0 ng/ml and IRT > 700 ng/ml, including all cases of cystic fibrosis. CONCLUSION: PAP is increased in most neonates with cystic fibrosis and could be used for CF screening. Its combination with IRT looks promising.

[Rational hemostatic screening]. / Rationelles Hämostase-Screening.

BACKGROUND: In order to exclude hemorrhagic diathesis, e.g. before diagnostic measures carrying the risk of bleeding or in preoperative situations, a graded screening is advisable. PROCEDURE: During the first stage, besides the anamnesis, clinical examination and classification of relevant concomitant diseases (e.g. liver cirrhosis or renal insufficiency), basic laboratory examinations such as prothrombin time, activated partial thromboplastin time (aPTT) and platelet count must be carried out. Should all these measures produce no noteworthy results, no further examinations are necessary. However, in the case of test results within normal limits accompanied by an unsatisfactory anamnesis and/or conspicuous clinical findings, the second stage should include examination of bleeding time according to Mielke to exclude a relevant platelet dysfunction. Should this be inconspicuous a third stage should follow in which successive implementation is made of fibrinogen according to Clauss, the Rumpel-Leede test (to exclude heightened capillary fragility), factor XIII and alpha 2-antiplasmin. The methodical snares of the parameters mentioned will be explained in full.

Severe gastrointestinal hemorrhage due to Mycobacterium avium complex in a patient receiving immunosuppressive therapy.

Intense immunosuppressive therapy is used frequently for treatment of systemic vasculitides, collagenoses, rapidly progressive glomerulonephritis, and after organ transplantation. Numerous serious treatment-related side effects include localized or disseminated opportunistic infections, and require careful monitoring of immunosuppressed patients. Gastrointestinal infections with Mycobacterium avium complex (MAC) or other nontuberculous mycobacteria have been previously identified in HIV seropositive patients only. We now report the first case of an HIV seronegative patient who received immunosuppressive therapy for rapidly progressive glomerulonephritis. The patient presented with severe lower gastrointestinal bleeding and was diagnosed to have ulcerative colitis due to infection with MAC. The patient recovered promptly after administration of antimycobacterial therapy. MAC infection should be included in the differential diagnosis of gastrointestinal bleeding in all immunodeficient patients. The significance of repeated colonoscopy to obtain multiple biopsy specimens with histological examination for foam cells and specific staining for acid-fast organisms is emphasized.

Platelet function deficiency in Duchenne muscular dystrophy.

Platelet function and plasmatic coagulation of 51 patients with Duchenne muscular dystrophy (DMD) were studied in order to find an explanation for the known substantial blood loss in spinal surgery of these very patients. A normal plasmatic coagulation and a slight but not significant increase of bleeding time was found. However, a significant deficiency of platelet adhesion and ristocetin induced aggregation (P < 0.001) as well as a marked reduction of expression of glycoprotein i.v. (synonyms: GPIV, GPIIIb, CD36) to 50% were detected. We conclude from our study, that this finding of deficiency of platelet function in DMD patients is of no importance in everyday life and minor operations, e.g. lower limb surgery. In major spinal surgery, however, the platelet function deficiency occurs. A decompensation of platelet adhesion as well as aggregation capacity can be assumed due to the unavoidable intraoperative dilution effect by the inevitable volume replacement.

Hemostasis activation markers in acute renal failure.

Fibrinopeptide A and thrombin-antithrombin III complex were used respectively as markers for in vivo thrombin formation and beta-thromboglobulin as a marker for platelet activation. In cases of acute renal failure (ARF) a heightened plasma concentration in the hemostasis activation markers may occur, because of a renal elimination disturbance, without a previous activation of the hemostasis. In order to check the validity of fibrinopeptide A, thrombin-antithrombin III complex and beta-thromboglobulin as markers for the hemostasis activation in cases of ARF we examined 32 patients prior to renal replacement therapy. A significant rise in fibrinopeptide A (x +/- SD: 34 +/- 22 ng/mL, ref < 3.0), thrombin-antithrombin III complex (19 +/- 15 ng/mL, ref 1.0-4.0) and beta-thromboglobulin (149 +/- 58 U/mL, ref 10-40) was found. None of the parameters examined showed a correlation to the serum creatinine. A correlation was observed respectively between fibrinopeptide A (r = 0.34, p < .05), beta-thromboglobulin (r = 0.39, p < .05) and the beta-thromboglobulin/creatinine coefficient (0.50 +/- 0.30, r = 0.72, p < .001) on the one side and the thrombin-antithrombin III complex on the other. A greater rise in the concentration of all parameters in patients with disseminated intravascular coagulation (DIC) was established, in contrast to patients without DIC (fibrinopeptide A: 44 +/- 31 vs. 32 +/- 20 ng/mL, beta-thromboglobulin: 169 +/- 57 vs. 144 +/- 60 U/mL, thrombin-antithrombin III complex 40 +/- 21 vs. 14 +/- 7 ng/mL, p < .05). Fibrinopeptide A and beta-thromboglobulin/creatinine coefficient in combination with the thrombin-antithrombin III complex can be employed as markers for the activation of hemostasis in cases of ARF there is no direct relationship between restricted kidney function in ARF and the plasma concentration of these markers, which behave similarly in spite of their varying elimination patterns.