Clinical phenotype,biochemical profile,and treatment in 19 patients with arginase 1 deficiency

Background

Arginase 1 (ARG1) deficiency is a rare urea cycle disorder (UCD). This hypothesis-generating study explored clinical phenotypes, metabolic profiles, molecular genetics, and treatment approaches in a cohort of children and adults with ARG1 deficiency to add to our understanding of the underlying pathophysiology.

Methods

Clinical data were retrieved retrospectively from physicians using a questionnaire survey. Plasma aminoacids, guanidinoacetate (GAA), parameters indicating oxidative stress and nitric oxide (NO) synthesis as well as asymmetric dimethylarginine (ADMA) were measured at a single study site.

Results

Nineteen individuals with ARG1 deficiency and 19 matched controls were included in the study. In patients, paraparesis, cognitive impairment, and seizures were significantly associated suggesting a shared underlying pathophysiology. In patients plasma GAA exceeded normal ranges and plasma ADMA was significantly elevated. Compared to controls, nitrate was significantly higher, and the nitrite:nitrate ratio significantly lower in subjects with ARG1 deficiency suggesting an advantage for NO synthesis by inducible NO synthase (iNOS) over endothelial NOS (eNOS). Logistic regression revealed no significant impact of any of the biochemical parameters (including arginine, nitrates, ADMA, GAA, oxidative stress) or protein restriction on long-term outcome.

Conclusion

Three main hypotheses which must be evaluated in a hypothesis driven confirmatory study are delineated from this study: 1) clinical manifestations in ARG1 deficiency are not correlated with arginine, protein intake, ADMA, nitrates or oxidative stress. 2) GAA is elevated and may be a marker or an active part of the pathophysiology of ARG1 deficiency. 3) Perturbations of NO metabolism merit future attention in ARG1 deficiency.

     

A multistate outbreak of Shiga toxin-producing Escherichia coli O26:H11 infections in Germany,detected by molecular subtyping surveillance

In the spring of 2000, a cluster of indistinguishable Shiga toxin-producing Escherichia coli (STEC) O26:H11 was identified in Germany by molecular subtyping surveillance. An investigation was prompted to identify a common source of exposure. A case subject was defined as a person having a polymerase chain reaction-confirmed STEC O26 infection between March and April 2000, irrespective of clinical signs, and whose isolate was indistinguishable from the index strain by use of pulsed-field gel electrophoresis. Eleven case subjects were found in 5 institutions that were supplied by 4 kitchens located in 3 states. The median age was 2 years (range, 2-31 years). No bloody diarrhea was reported, and 5 persons remained asymptomatic. Comparison of invoices revealed a certain type of beef ("Seemerrolle") as possible source of infection. This is, to our knowledge, the first multistate outbreak associated with a non-O157 STEC detected by laboratory-based surveillance. Molecular subtyping was pivotal, as disease occurrence was sporadic or family-related.     

Biological relevance of anti-recombinant hirudin antibodies--results from in vitro and in vivo studies

This article provides an overview of the clinically relevant characteristics of antibodies directed toward recombinant (r) hirudin, with emphasis on the different ways in which these antibodies may influence pharmacokinetics and pharmacodynamics of r-hirudin. A high incidence of anti-hirudin antibody (AHAb) formation, mainly of the immunoglobulin G (IgG) subclass, was reported in up to 74% of patients treated with r-hirudin for more than 5 days. Like other drug-induced antibodies, AHAb may be responsible for accumulation or neutralization of the drug. Current clinical data support this assumption with reports on reduced metabolism, enhanced activity, and accumulation and neutralization of r-hirudin in the presence of AHAb. By examining AHAb developed in patients, we were able to demonstrate that AHAbs are capable of neutralizing r-hirudin in vitro. In addition, the anticoagulant activity of r-hirudin administered to Sprague-Dawley rats was almost completely abolished when a monoclonal mouse AHAb with known r-hirudin neutralizing capacity in vitro was injected intravenously. Because r-hirudin is mainly eliminated via the kidneys, formation of r-hirudin-AHAb complexes may, due to their size, result in accumulation of r-hirudin. We investigated filtration of r-hirudin incubated with monoclonal mouse AHAb by using high-flux hemodialyzers in a suitable in vitro model. Whereas sieving coefficients (SC) were high in the absence of AHAb, they were minimal (SC < 0.05) in the presence of AHAb. These findings may also be important when AHAb-positive patients treated with r-hirudin undergo hemofiltration procedures, which have recently been described as a rescue measure in case of r-hirudin overdosage. In vivo, the influence of a non-neutralizing monoclonal mouse AHAb on r-hirudin pharmacokinetics was examined in rats. Pharmacokinetic data compared with those of a control group without AHAb administration revealed that r-hirudin elimination half-life was significantly prolonged (59 +/- 25 minutes versus 142 +/- 25 minutes). This was accompanied by a decrease of total plasma clearance of r-hirudin. The volume of distribution of r-hirudin was significantly decreased (275 +/- 112 mL/kg versus 35 +/- 3 mL/kg), indicating that r-hirudin bound by AHAb is mainly distributed to the intravascular compartment. Taken together, both the half-life prolongation and the decrease of the volume of distribution contribute to r-hirudin accumulation and may explain respective findings in patients. In summary, two different effects of AHAbs seem to be clinically relevant: decreasing anticoagulant activity of r-hirudin by neutralization and accumulation of r-hirudin by reducing renal clearance. Formation of AHAbs has not yet been correlated with enhanced major bleeding complications. However, close monitoring of coagulation parameters is recommended in AHAb-positive patients during r-hirudin treatment.     

Results of ajmaline testing in patients with arrhythmogenic right ventricular dysplasia-cardiomyopathy

An association between arrhythmogenic right ventricular dysplasia-cardiomyopathy (ARVD/C) and Brugada syndrome can be supposed according to several case reports. In order to examine a possible link between ARVD/C and Brugada syndrome, systematic ajmaline testing with 1 mg/kg body weight intravenously, was done in 55 patients (32 males, mean age 46.7+/-12.3 years) with ISFC/ESC criteria of ARVD/C. In nine patients ajmaline testing could demonstrate coved ST segment elevation of at least 2 mm in at least two right precordial leads. Three of these patients had recurrent syncopes. Electrophysiological study revealed non-sustained ventricular tachycardia with left bundle branch block configuration and inferior axis in only one case. Systematic ajmaline testing could demonstrate a definite link between ARVD/C and Brugada syndrome.     

Natural Course of Functional Dyspepsia After <Emphasis Type="Italic">Helicobacter pylori</Emphasis>Eradication: A Seven-Year Survey

The role of Helicobacter pylori(Hp) in functional dyspepsia (FD) is controversial and previously published data do not help to clarify whether Hp eradication affects the natural course of FD. The aim of this study was to assess the clinical course of FD during a long follow-up period of 7 years in a homogeneous sample of Hp-eradicated patients. Among patients referred between 1991 and 1996, patients with FD and infected with Hp were enrolled. Patients were administered a structured symptom questionnaire and evaluated after Hp eradication at each 12-month time points. Patients were divided into three FD subgroups: predominantly ulcer-like, dismotility-like, and reflux-like symptom clusters. A composite symptom score ranging from 0 (no symptom) to 3 (severe symptoms) was assigned to each FD cluster. Of the 1685 screened patients, 405 had FD and 211 of them (52.1%) were also Hp-positive. During the follow-up, the amount of missing information varied from 10% to 17.5% within the first 6 years and was 30.8% at 7 years. The rates of improved patients ranged from 33% (reflux-like) to 34.9% (dismotility-like) to 47.3% (ulcer-like). However, only a proportion of 10%–50% of them was symptom-free after eradication and also at each 12-month evaluation, whereas the other patients became symptomatic at different times. FD symptoms slightly improve after Hp eradication over a long period of time but a large percentage of these improved patients may experience FD symptoms again, even after some years of well-being after Hp eradication. This study was not supported by any pharmaceutical company, government agency, or other grants: under the auspices of Roberto Farini Foundation for Gastroenterological Research. The data were analyzed by G. Leandro, MD. Preliminary versions of this paper were presented in abstract form at the 16th International Workshop of Gastrointestinal Pathology and Helicobacter, September 3–6, 2003, Stockholm Sweden; the 11th United European Gastroenterology Week, November 1–5, 2003, Madrid, Spain; the 10th National Congress on Digestive Diseases, March 27–31, 2004, Torino, Italy; and Digestive Disease Week, May 15–20, 2004, New Orleans, Louisiana, USA.     

Cefotaxime versus penicillin in the late stage of lyme disease — prospective,randomized therapeutic study

Summary The low responsiveness of Lyme arthritis to high dose intravenous penicillin G therapy has evoked the demand for new drugs for the treatment of late stage borreliosis. As can be deduced fromin vitro susceptibility data, third generation cephalosporins are far more effective onBorrelia burgdorferi spirochetes than penicillin G. The study presented here was designed to compare cefotaxime at a dosage of 2 × 3 g/day with penicillin G at a dosage of 2 × 10 megaunits/day, for ten days in a prospective randomized trial. A total of 135 patients were included in the study. They were diagnosed to suffer from late stage Lyme borreliosis on the basis of defined clinical symptoms compatible with stage three borreliosis manifestations of at least six months' duration and positive antibody titers againstB. burgdorferi. Final outcomes were recorded after a 24 month post-treatment observation period with re-examination at three-month-intervals. Cefortaxime proved to be significantly superior to penicillin G with 87.9% versus 61.3% of treatments resulting in full or incomplete remission of symptoms (p=0.002). Clinical remission was accompanied by declining antibody titers. Herxheimer-like reactions were observed in 20% of the patients of the penicillin group and in 40.5% of the patients of the cefotaxime group and may be interpreted as an indication of a response to therapy.

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Cefotaxim im Vergleich zu Penicillin zur Therapie der Lyme-Borreliose im Spätstadium. Prospektive, randomisierte Studie

Zusammenfassung Die geringe Ansprechrate der Lyme-Arthritis auch bei intravenöser und hochdosierter Gabe von Penicillin G hat das Interesse an neueren Antibiotika zur Behandlung der Lyme-Borreliose im Spätstadium erhöht. Wie schon auf Grund vorliegender In-vitro-Daten zur Empfindlichkeit vonBorrelia burgdorferi erwartet werden konnte, sind Cephalosporine der dritten Generation sehr viel effektiver als Penicillin G. In der hier vorgestellten randomisierten prospektiven Untersuchung wurde deshalb Cefotaxim in einer Dosierung von 2 × 3 g täglich mit Penicillin G in einer Dosierung von 2 × 10 Mega-Einheiten verglichen. 135 Patienten, bei denen eine definierte klinische Symptomatik im Sinne einer Stadium-3-Borreliose für mindestens sechs Monate bestanden hatte und bei denen Antikörper gegenB. burgdorferi nachweisbar waren, wurden in die Studie aufgenommen. Die Patienten wurden 24 Monate nachbeobachtet und im Abstand von drei Monaten reevaluiert. Die mit Cefotaxim behandelten Patienten zeigten ein signifikant besseres Therapieergebnis. Während in der Penicillin-Gruppe nur 61,3% der Patienten eine Voll- oder Teilremission ihrer Beschwerden zeigten, konnte dies bei der Cefotaxim-Gruppe bei 87,9% der Patienten erreicht werden (p=0,002). Parallel zum klinischen Effekt war ein Absinken der Antikörpertiter im Immunfluoreszenztest zu beobachten. Herxheimer-artige Reaktionen waren bei 20% der Patienten der Penicillin-Gruppe und bei 40,5% der Patienten der Cefotaxim-Gruppe zu beobachten. Diese Reaktion kann als Hinweis auf ein Ansprechen der Therapie gewertet werden.

     

The effect of iron depletion on chronic hepatitis C virus infection

Increasing evidence exists that iron overload, a common finding in chronic hepatitis C virus (HCV) infection, plays an important role in the pathophysiology of this disease. The mechanisms by which iron excess induces liver damage along with the benefit of iron depletion via phlebotomy on biochemical and histological outcomes in patients with chronic HCV infection have been discussed in this review. Finally, we focus on the effect of iron reduction on the rate of response to interferon antiviral therapy. An erratum to this article can be found at     

EuroSCORE predicts mid-term outcome after combined valve and coronary bypass surgery

BACKGROUND AND AIM OF THE STUDY: EuroSCORE is widely used to assess operative risk. Combined cardiac procedures carry increased perioperative mortality, but the influence of preoperative factors on mid-term outcome is not well known for these patients. The study aim was to determine if EuroSCORE risk influences mid-term survival after combined coronary artery bypass grafting (CABG) and valve surgery. METHODS: Follow up (mean 23.7 months) was obtained in 258 consecutive hospital survivors (148 males, 110 females; median age 72.29 years; mean EuroSCORE 7 points) operated on between January 1998 and March 2001. CABG + aortic valve replacement (AVR) was performed in 171 patients, CABG + mitral surgery in 72, and CABG + double valve surgery in 15. Kaplan-Meier estimates were calculated for survival and combined freedom from death and NYHA class III/IV. The Cox regression model was applied to prove the influence of EuroSCORE risk and a number of preoperative and operative variables on mid-term outcome. RESULTS: Thirty patients (11.63%) died during follow up, and 34 (13.17%) were in NYHA class III/IV. Freedom from death and NYHA class III/IV was 89.3%, 74.7% and 55.2% at 12, 24 and 36 months, respectively. The significant predictor for combined death and NYHA class III/IV was EuroSCORE risk (p = 0.0004). In the subgroup of patients with CABG + mitral valve surgery, age was identified as a significant risk factor for death (p = 0.0346), whereas in the subgroup of patients with CABG + AVR EuroSCORE was detected as significant risk factor for combined death and NYHA class III/IV. CONCLUSION: EuroSCORE is an important predictor for poor mid-term outcome after combined CABG and valve surgery.