Amel Karaa

Keratoacanthoma: a tumor in search of a classification

Keratoacanthoma (KA) is a unique epidermal tumor characterized by rapid, abundant growth and a spontaneous resolution, with the classic presentation in middle-aged, light-skinned individuals in hair-bearing, sun-exposed areas. Since the 1950s, controversies have arisen about the real nature of the tumor. Is this exophytic lesion a pseudomalignancy with self-regressing potential? Or a pseudo-benign tumor progressing into an invasive squamous cell carcinoma (SCC)?

A Homozygous Mutation in KCTD7 Links Neuronal Ceroid Lipofuscinosis to the Ubiquitin-Proteasome System

Neuronal ceroid lipofuscinosis (NCL) is a genetically heterogeneous group of lysosomal diseases that collectively compose the most common Mendelian form of childhood-onset neurodegeneration. It is estimated that ∼8% of individuals diagnosed with NCL by conservative clinical and histopathologic criteria have been ruled out for mutations in the nine known NCL-associated genes, suggesting that additional genes remain unidentified. To further understand the genetic underpinnings of the NCLs, we performed whole-exome sequencing on DNA samples from a Mexican family affected by a molecularly undefined form of NCL characterized by infantile-onset progressive myoclonic epilepsy (PME), vision loss, cognitive and motor regression, premature death, and prominent NCL-type storage material. Using a recessive model to filter the identified variants, we found a single homozygous variant, c.550C>T in KCTD7, that causes a p.Arg184Cys missense change in potassium channel tetramerization domain-containing protein 7 (KCTD7) in the affected individuals. The mutation was predicted to be deleterious and was absent in over 6,000 controls. The identified variant altered the localization pattern of KCTD7 and abrogated interaction with cullin-3, a ubiquitin-ligase component and known KCTD7 interactor. Intriguingly, murine cerebellar cells derived from a juvenile NCL model (CLN3) showed enrichment of endogenous KCTD7. Whereas KCTD7 mutations have previously been linked to PME without lysosomal storage, this study clearly demonstrates that KCTD7 mutations also cause a rare, infantile-onset NCL subtype designated as CLN14.

Neuronal Ceroid Lipofuscinosis: Impact of Recent Genetic Advances and Expansion of the Clinicopathologic Spectrum

Neuronal ceroid lipofuscinosis (NCL), first clinically described in 1826 and pathologically defined in the 1960s, refers to a group of disorders mostly diagnosed in the childhood years that involve the accumulation of lysosomal storage material with characteristic ultrastructure and prominent neurodegenerative features including vision loss, seizures, motor and cognitive function deterioration, and often times, psychiatric disturbances. All NCL disorders evidence early morbidity and treatment options are limited to symptomatic and palliative care. While distinct genetic forms of NCL have long been recognized, recent genetic advances are considerably widening the NCL genotypic and phenotypic spectrum, highlighting significant overlap with other neurodegenerative diseases. This review will discuss these recent advances and the expanded potential for increased awareness and new research that will ultimately lead to effective treatments for NCL and related disorders.

LPS inhibits endothelin-1-induced endothelial NOS activation in hepatic sinusoidal cells through a negative feedback involving caveolin-1.

During endotoxemia, liver microcirculation disruption is characterized by a hypersensitivity to the constrictor effects of endothelin 1 (ET‐1). The shift of ET‐1–mediated effects toward vasoconstriction may result from depressed ET‐1–mediated vasodilation through decreased ET‐1–induced nitric oxide (NO) production. We have previously shown that lipopolysaccharide (LPS) pretreatment abrogates ET‐1–induced endothelial nitric oxide synthase (eNOS) translocation, but its effects on eNOS activation are yet to be determined. Our aim was to assess the effects of LPS on ET‐1–mediated eNOS activation in hepatic sinusoidal endothelial cells (SECs) and to investigate the molecular mechanisms involved. SECs were treated with LPS (100 ng/mL) for 6 hours followed by 30 minutes ET‐1 (10 nmol/L) stimulation. LPS significantly inhibited ET‐1–mediated eNOS activation. This inhibition was associated with upregulation of Caveolin‐1 (CAV‐1) and a shift in ET‐1–mediated eNOS phosphorylation from an activation (Ser1177) to an inhibition (Thr495). LPS treatment has been shown to induce ET‐1 expression and secretion from endothelial cells. We therefore investigated the role of endogenous ET‐1 in the inhibition of ET‐1 activation of eNOS after LPS. Antagonizing ET‐1 effects and blocking its activation in LPS pretreated SECs decreased the LPS‐induced overexpression of CAV‐1 as well as the inhibition of ET‐1–induced NOS activity. Furthermore, 6 hours of ET‐1 treatment exerted the same effects on eNOS activity, phosphorylation, and CAV‐1 expression as LPS treatment. In conclusion, LPS‐induced suppression of ET‐1–mediated eNOS activation is ET‐1 dependent and suggest a pivotal role of CAV‐1 in eNOS induction inhibition under stress. (HEPATOLOGY 2006;43:182–190.)

Chronic ethanol sensitizes the liver to endotoxin via effects on endothelial nitric oxide synthase regulation

In vivo studies have shown that chronic alcohol consumption sensitizes the liver to endotoxemic shock, leading to liver microcirculation disruption. In the present study, we investigated the molecular mechanisms involved, focusing on endothelial nitric oxide synthase (eNOS) activity and regulation, which represents one of the major vasodilatory pathways. Male Sprague-Dawley rats were fed an alcohol liquid diet or a control isocaloric diet for 5 weeks. Priming effects of ethanol were studied in a model with or without a 24-h LPS treatment (1 mg/kg body weight). At the end of the diet, liver tissue was harvested for western blot, reverse transcriptase-PCR, histological analysis, and immunostaining and blood for serum alanine aminotransferase analysis. Chronic ethanol and LPS alone induced a mild hepatitis and infiltration, respectively. Combined, LPS and chronic ethanol feeding showed a synergistic effect on the liver, leading to extensive steatohepatitis with extensive focal necrosis associated with significantly higher levels of serum ALT. Chronic ethanol and LPS significantly inhibited eNOS activity, but exerted their effects through different mechanisms. Caveolin-1, an eNOS inhibitory protein, was upregulated after LPS and chronic alcohol consumption. Additionally, chronic alcohol consumption down-regulated endothelin B receptor, eNOS protein levels, and eNOS phosphorylation. In conclusion, chronic ethanol consumption and LPS share a similar pathophysiology and both lead to the impairment of eNOS activity, but through distinct molecular mechanisms. The presence of focal necrosis in a mild stress model could provide a good animal study to investigate the advanced stages of alcoholic liver diseases.

Remote trauma sensitizes hepatic microcirculation to endothelin via caveolin inhibition of eNOS activity

This study addresses the microvascular mechanisms by which a remote, mild stress such as blunt trauma sensitizes the liver to injury. Rats received closed femur fracture (FFx), and 24 h later livers were isolated and perfused at a similar starting flow rate for assessment of vascular response to endothelin-1 (ET-1). Sinusoidal volumetric flow (QS), red blood cell velocity (VRBC), and sinusoidal diameter (Ds) were determined by intravital microscopy. Baseline portal resistance in livers from FFx rats was not changed. The FFx group showed a lower baseline VRBC (322.9 ± 26.4 and 207.3 ± 17.2 μm/s in sham and FFx,) and QS (28.4 ± 4.2 and 17.6 ± 2.1 pL/s in sham and FFx, P < 0.05). ET-1 caused a decrease in the VRBC in sham but no change after FFx. In contrast, Ds was unchanged by ET-1 in sham but decreased in FFx (10.3 ± 0.4 to 10.7 ± 0.5 vs. 10.6 ± 0.4 to 9.0 ± 0.4 μm at 10 min in sham and FFx groups, P < 0.05). The overall result of these changes was a greater decrease in sinusoidal flow in FFx compared with sham. There was no significant change in mRNA for ET-1, endothelin A (ETA) receptor, or iNOS (inducible nitric oxide synthase) in FFx compared with sham. However, endothelin B (ETB) receptor mRNA and eNOS (endothelial nitric oxide synthase) mRNA were increased in the FFx group (ETB, 54.81 ± 8.08 in sham vs. 83.28 ± 8.19 in FFx; eNOS, 56.11 ± 2.53 in sham vs. 83.31 ± 5.51 in FFx; P < 0.05) while the levels of these proteins remained unchanged. Caveolin-1 (cav-1) protein levels were elevated in FFx, and coimmunoprecipitation with both ETB and eNOS showed increased associations with these proteins, suggesting a possible inactivation of eNOS. The eNOS activity was also blunted in FFx animals in the presence of increased cav-1 expression. Taken together, these results demonstrate that remote trauma sensitizes the liver to the sinusoidal constrictor effect of ET-1. We propose that this hyperresponsiveness occurs as a result of uncoupling of the ETB receptor from eNOS activity mediated by interaction of eNOS and possibly the ETB receptor with increased caveolin-1. This vascular sensitization that occurs after FFx may contribute to the exacerbation of injury during subsequent stresses.

Recommendations for the Management of Strokelike Episodes in Patients With Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes.

IMPORTANCE Strokelike episodes are a cardinal feature of several mitochondrial syndromes, including mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). Recent advances in the understanding of the pathophysiologic mechanisms of strokelike episodes in MELAS have led to improved treatment options. OBSERVATIONS Current understanding of the cause of strokelike episodes in MELAS and present recommendations to assist in the identification and treatment of patients with MELAS who present with stroke are presented. Mounting evidence points toward a benefit of the nitric oxide precursors, arginine, to both prevent and reduce the severity of strokes in patients with MELAS. CONCLUSIONS AND RELEVANCE Although much information is still needed regarding the appropriate dosing and timing of arginine therapy in patients with MELAS, urgent administration of nitric oxide precursors in patients with MELAS ameliorates the clinical symptoms associated with strokelike episodes.

Differential Effects of Oxidative Stress on Hepatic Endothelial and Kupffer Cell Eicosanoid Release in Response to Endothelin‐1

Objective: The vasoconstrictor endothelin‐1 can induce vasomodulators release like nitric oxide in the liver. Here the authors explored whether endothelin‐1 can stimulate endothelial and Kupffer cells release of other vasomodulators under normal and stress conditions.

The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes

Primary mitochondrial diseases refer to a group of heterogeneous and complex genetic disorders affecting 1:5000 people. The true prevalence is anticipated to be even higher because of the complexity of achieving a diagnosis in many patients who present with multisystemic complaints ranging from infancy to adulthood. Diabetes is a prominent feature of several of these disorders which might be overlooked by the endocrinologist. We here review mitochondrial disorders and describe the phenotypic and pathogenetic differences between mitochondrial diabetes mellitus (mDM) and other more common forms of diabetes mellitus.

Inhibition of endothelin-1-mediated up-regulation of iNOS by bosentan ameliorates endotoxin-induced liver injury in cirrhosis.

ABSTRACT Endothelin-1 (ET-1) has been shown to regulate the expression of various genes in addition to its vasoconstrictor role in the liver. Elevated levels of ET-1 during cirrhosis play an important role in the observed microcirculatory dysfunction; however, its role as a transcription regulator remains unclear. This study aimed to determine the role of ET-1 in the hepatic gene expression of vasomediators after cirrhosis in response to LPS. Cirrhosis was induced by bile duct ligation (BDL) for 1 or 3 weeks in male Sprague-Dawley rats. Following 1 or 3 weeks of BDL or sham operation (sham), rats received an intravenous (i.v.) injection of bosentan, a dual-selective ETA/B receptor antagonist (30mg/kg bw) or saline, and an intraperitoneal (i.p.) injection of LPS (1 mg/kg bw). Plasma alanine aminotransferase (ALT) levels were significantly elevated in 1- and 3-week BDL animals. Six hours following LPS, the elevated ALT levels were markedly exacerbated in 3-week BDL animals, which were significantly ameliorated with bosentan treatment. LPS resulted in increased ET-1, inducible nitric oxide synthase (iNOS), and cyclooxygenase (COX)-2 mRNA expressions in both sham and BDL rats. Bosentan significantly inhibited the up-regulations of ET-1, iNOS, and COX-2 mRNA. Our data strongly suggest that ET-1 plays an important role in up-regulating the expression of iNOS, COX-2, and ET-1 itself in hepatic tissue following LPS challenge, which may contribute to the observed hepatocellular injury during endotoxemia in cirrhosis. Thus, due to significant increases in ET-1 levels during cirrhosis, ET-1 receptor blockade may prove to be of great therapeutic value in the treatment of cirrhotic patients exposed to secondary injuries such as endotoxemia.