[The clinical spectrum of urea cycle defects in adult patients]. / Das klinische Spektrum von Harnstoffzyklusdefekten im Erwachsenenalter.

Urea cycle defects belong to the most common metabolic disorders with a cumulative incidence of 1:8000. A common trait of urea cycle defects is a disturbed detoxification of ammonia leading to hyperammonemia in the event of a high nitrogen load. Most patients develop symptoms in the neonatal period or in infancy, e. g. vomiting, seizures and disturbed consciousness. Depending on the affected enzyme and its residual activity, patients differ in the age at first presentation, the character and severity of symptoms and in the susceptibility to metabolic derangement. The presence of hyperammonemia and an altered plasma amino acid profile give the essential diagnostic clues. Since modern therapeutic measures have prolonged the life expectancy of these patients and provided the possibility of a first presentation in adulthood, patients with urea cycle defects have become an increasing challenge in internal medicine. The reported case series illustrates the heterogeneous clinical course of these disorders from childhood to adulthood.

Retrospective analysis of chronic hepatitis D in a West German University Clinic over two decades: migratory pattern, prevalence and clinical outcome.

BACKGROUND/AIMS: Epidemiology, clinical features and long term-course of chronic hepatitis D were addressed in a non-endemic Central European area. METHODS: Sixty-seven patients with chronic hepatitis D were identified among 1307 HBsAg carriers at the university hospital Düsseldorf during two decades (1989 - 2008) and followed for a mean of 7 +/- 6 years. Forty-one of these were treated with IFN-alfa for at least six months. RESULTS: Hepatitis D prevalence increased from 4.1 to 6.2 % among HBsAg carriers during the two decades (p < 0.06). Patients originating from the former Soviet Union (32.1 vs. 46.2 %) and Africa (0 vs. 17.9 %) became more frequent whereas the prevalence of patients from Southern Europe declined (46.5 vs.17.9 % p < 0.03). The time span between the diagnosis of hepatitis B and D was 4.8 +/- 7 years (p < 0.0001). A sustained virological response to interferon-alfa was achieved in 19.5 % of the patients. The yearly incidence rates for death, HCC and complications were 3.2 %, 2.7 % and 8 % among patients with liver cirrhosis. Estimated survival and complication-free survival during 12 years were 72 % and 45 % in cirrhotic compared to 100 % in non-cirrhotic patients (p < 0.008 and p < 0.0001, respectively). CONCLUSION: Hepatitis D in western Germany appears to be on the increase and has a migration background that should be considered in clinical practice. Clinical outcome and response to IFN are as poor as in endemic regions, indicating the need to improve early diagnosis.

Mechanisms of diarrhea in the interleukin-2-deficient mouse model of colonic inflammation.

Colitis in interleukin-2-deficient (IL-2(-/-)) mice resembles ulcerative colitis in humans. We studied epithelial transport and barrier function in IL-2(-/-) mice and used this model to characterize mechanisms of diarrhea during intestinal inflammation. (22)Na(+) and (36)Cl(-) fluxes were measured in proximal colon. Net Na(+) flux was reduced from 4.0 +/- 0.5 to 0.8 +/- 0.5 micromol.h(-1).cm(-2), which was paralleled by diminished mRNA and protein expression of the Na(+)/H(+) exchanger NHE3. Net Cl(-) flux was also decreased from 2.2 +/- 1.6 to -2.7 +/- 0.6 micromol.h(-1).cm(-2), indicating impaired Na(+)-Cl(-) absorption. In distal colon, aldosterone-induced electrogenic Na(+) absorption was 6.1 +/- 0.9 micromol.h(-1).cm(-2) in controls and was abolished in IL-2(-/-) mice. Concomitantly, mRNA expression of beta- and gamma-subunits of the epithelial sodium channel (ENaC) was reduced. Epithelial barrier was studied in proximal colon by impedance technique and mannitol fluxes. In contrast to ulcerative colitis, epithelial resistance was increased and mannitol fluxes were decreased in IL-2(-/-) mice. This was in accord with the findings of reduced ion transport as well as increased expression of tight junction proteins occludin and claudin-1, -2, -3, and -5. In conclusion, the IL-2(-/-) mucosa exhibits impaired electroneutral Na(+)-Cl(-) absorption and electrogenic Na(+) transport due to reduced mRNA and protein expression of NHE3 and ENaC beta- and gamma-subunit mRNA. This represents a model of early intestinal inflammation with absorptive dysfunction due to impaired transport protein expression/function while epithelial barrier is still intact. Therefore, this model is ideal to study regulation of transporter expression independent of barrier defects.

sICAM-1 and TNF-alpha induce MIP-2 with distinct kinetics in astrocytes and brain microvascular endothelial cells.

The dysfunction of the blood-brain barrier (BBB) occurring after traumatic brain injury (TBI) is mediated by intracerebral neutrophil accumulation, chemokine release (e.g., interleukin (IL)-8) and upregulation of adhesion molecules (e.g., intercellular adhesion molecule (ICAM)-1). In patients with severe TBI, we previously found that elevated cerebrospinal fluid (CSF) IL-8 and soluble (s)ICAM-1 correlate with BBB dysfunction, and this prompted us to concomitantly monitor IL-8, sICAM-1 and their stimulator tumor necrosis factor (TNF)-alpha in CSF. Potential mechanisms for upregulation of the IL-8 analogue, murine macrophage inflammatory protein (MIP)-2, and sICAM-1 at the BBB were studied using cultured mouse astrocytes and brain microvascular endothelial cells (MVEC). In CSF of seven patients, IL-8 and sICAM-1 were elevated for 19 days after severe TBI, whereas TNF-alpha exceeded normal values on 9 days. Stimulation of MVEC and astrocytes with TNF-alpha simultaneously induced the release of MIP-2 reaching saturation by 4-8 hr and of sICAM-1 increasing continuously from 2-4 hr to 12 hr. Augmented sICAM-1 production correlated with enhanced membrane-bound (m)ICAM-1 expression in both cell types (r(s) = 0.96 and 0.90, P < 0.0001), but was markedly higher in astrocytes. The release of sICAM-1 was not influenced by IL-8 or MIP-2, although astrocytes and MVEC expressed the IL-8/MIP-2 receptor (CXCR-2) as determined by FACS analysis. Instead, we found that sICAM-1 strongly induced MIP-2 secretion by both cell types with kinetics differing from those evoked by TNF-alpha. If added together, sICAM-1 and TNF-alpha synergistically induced MIP-2 production suggesting the involvement of two different pathways for MIP-2 regulation.