Phototherapy-induced Purpuric Eruption in a Neonate.

Phototherapy is commonly utilized in the treatment of neonatal jaundice. The authors observed a rare cutaneous complication of visible blue light phototherapy in a neonate with hyperbilirubinemia. A three-day-old neonate was evaluated for a purpuric rash after initiation of phototherapy for treatment of hyperbilirubinemia. Cutaneous examination revealed purpuric, nonblanching, well-demarcated lesions on the chest, abdomen, arms, and chin with sparing at shielded sites. The history, physical examination, and laboratory results support the diagnosis of purpuric phototherapy-induced eruption. The authors present a case report of this uncommon cutaneous eruption in a transfused neonate undergoing phototherapy for treatment of hemolytic disease of the newborn.

Pseudoxanthoma elasticum, the paradigm of heritable ectopic mineralization disorders - can diet help?

Pseudoxanthoma elasticum (PXE) is a heritable multi-system disorder manifesting with characteristic cutaneous lesions, associated with ocular findings and cardiovascular involvement. The skin lesions, yellowish papules which coalesce into plaques of inelastic and leathery skin, demonstrate by histopathologic and ultrastructural examinations ectopic mineralization of dermal connective tissues, primarily the elastic structures. PXE is inherited in an autosomal recessive fashion due to mutations in the ABCC6 gene. Significant insights into the pathogenesis of PXE have been recently obtained from observations on the Abcc6(-/-) knockout mouse which mimics the genetic, histopathologic and ultrastructural features of PXE. This mouse model has provided a platform to test various treatment modalities to counteract the mineralization phenotypes. One of the intriguing findings emanating from these studies is that supplementation of the mouse diet with magnesium, at levels that are ∼5-fold higher than those in control diet, completely inhibits the development of tissue mineralization. These and related observations suggest that changes in the diet might counteract the progression of PXE and improve the quality of life of patients with this, currently intractable, disease.

Pseudoxanthoma elasticum: a streamlined, ethnicity-based mutation detection strategy.

Pseudoxanthoma elasticum (PXE), an autosomal recessive multisystem disorder, is caused by mutations in the ABCC6 gene, and approximately 300 distinct mutations representing >1000 mutant alleles have been disclosed thus far. Few population-based studies have reported mutational hotspots in some geographic areas. In this study, we attempted to correlate recurring mutations with the individuals' ethnic origin. Specifically, we plotted our international database of 70 families from distinct or mixed ethnic backgrounds against their mutations. The frequent p.R1141X mutation was distributed widely across Europe, while deletion of exons 23-29 (del23-29) was encountered in Northern Europe and in Northern Mediterranean countries. p.R1138W may be a marker for French descent, evidenced by its presence also in French Canadians. The splice site transition mutation 3736-1G→A was seen in the neighboring countries Greece and Turkey, whereas 2542 delG occurs only in the Japanese. Two mutations seem to be present worldwide without evidence of a founder effect, p.Q378X and p.R1339C, suggesting the presence of mutational hotspots. Knowledge of this distribution will allow us to streamline mutation screening through a targeted, stepwise approach when the ethnicity of a patient is known. This will facilitate the identification of individuals at risk, improving their care to prevent ophthalmological and vascular disease.

Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-/-)).

Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder characterized by ectopic connective tissue mineralization, with clinical manifestations primarily in the skin, eyes, and cardiovascular system. There is considerable, both intra- and interfamilial, variability in the spectrum of phenotypic presentation. Previous studies have suggested that mineral content of the diet may modify the severity of the clinical phenotype in PXE. In this study, we utilized a targeted mutant mouse (Abcc6(-/-)) as a model system for PXE. We examined the effects of changes in dietary phosphate and magnesium on the mineralization process using calcification of the connective tissue capsule surrounding the vibrissae as an early phenotypic biomarker. Mice placed on custom-designed diets either high or low in phosphate did not show changes in mineralization, which was similar to that noted in Abcc6(-/-) mice on control diet. However, mice placed on diet enriched in magnesium (fivefold) showed no evidence of connective tissue mineralization in this mouse model of PXE. The inhibitory capacity of magnesium was confirmed in a cell-based mineralization assay system in vitro. Collectively, our observations suggest that assessment of dietary magnesium in patients with PXE may be warranted.

Magnesium carbonate-containing phosphate binder prevents connective tissue mineralization in Abcc6(-/-) mice-potential for treatment of pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic mineralization of connective tissues primarily in the skin, eyes, and the cardiovascular system. PXE is caused by mutations in the ABCC6 gene. While PXE is associated with considerable morbidity and mortality, there is currently no effective or specific treatment. In this study, we tested oral phosphate binders for treatment of a mouse model of PXE which we have developed by targeted ablation of the corresponding mouse gene (Abcc6(-/-)). This "knock-out" (KO) mouse model recapitulates features of PXE and demonstrates mineralization of a number of tissues, including the connective tissue capsule surrounding vibrissae in the muzzle skin which serves as an early biomarker of the mineralization process. Treatment of these mice with a magnesium carbonate-enriched diet (magnesium concentration being 5-fold higher than in the control diet) completely prevented mineralization of the vibrissae up to 6 months of age, as demonstrated by computerized morphometric analysis of histopathology as well as by calcium and phosphate chemical assays. The magnesium carbonate-enriched diet also prevented the progression of mineralization when the mice were placed on that experimental diet at 3 months of age and followed up to 6 months of age. Treatment with magnesium carbonate was associated with a slight increase in the serum concentration of magnesium, with no effect on serum calcium and phosphorus levels. In contrast, concentration of calcium in the urine was increased over 10-fold while the concentration of phosphorus was markedly decreased, being essentially undetectable after long-term (> 4 month) treatment. No significant changes were noted in the serum parathyroid hormone levels. Computerized axial tomography scan of bones in mice placed on magnesium carbonate-enriched diet showed no differences in the bone density compared to mice on the control diet, and chemical assays showed a small increase in the calcium and phosphate content of the femurs by chemical assay, in comparison to mice on control diet. Similar experiments with another experimental diet supplemented with lanthanum carbonate did not interfere with the mineralization process in Abcc6(-/-) mice. These results suggest that magnesium carbonate may offer a potential treatment modality for PXE, a currently intractable disease, as well as for other conditions characterized by ectopic mineralization of connective tissues.

Sublingual buprenorphine for treatment of neonatal abstinence syndrome: a randomized trial.

OBJECTIVE: In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial mu-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered. METHODS: We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 mug/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system. RESULTS: Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to approximately 0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated. CONCLUSIONS: Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.

Aprepitant for the prevention of nausea and vomiting associated with chemotherapy and postoperative recovery.

Chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) can negatively impact patient quality of life, functional performance and activities of daily living. Although the development of serotonin receptor antagonists has greatly improved the control of acute emesis, delayed CINV remains a significant clinical issue. Aprepitant (Emend(®)) is the first commercially available drug from a new class of agents, the neurokinin-1 receptor antagonists. Elucidation of its mechanism of action has produced a greater understanding of the pathophysiology of nausea and vomiting. Oral aprepitant, in combination with a selective serotonin (5-HT3) receptor antagonist and corticosteroids, is indicated for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy in adults. Aprepitant alone or in combination only with dexamethasone does not optimally control acute emesis compared with triple combination therapy. By contrast, aprepitant as monotherapy is indicated for the prevention of PONV. Aprepitant represents an emerging class of agents and its addition to standard therapy provides an advanced benefit in the prevention and treatment of CINV and PONV. Investigations of aprepitant for other indications are ongoing.

Ectopic mineralization of connective tissue in Abcc6-/- mice: effects of dietary modifications and a phosphate binder--a preliminary study.

Pseudoxanthoma elasticum (PXE), a heritable multisystem disorder, is caused by mutations in the ABCC6 gene. We have developed a murine model for PXE by targeted inactivation of the corresponding mouse gene. A feature of this mouse model is ectopic mineralization of connective tissue capsule surrounding the bulb of vibrissae. This study was designed to investigate the effect of dietary sevelamer hydrochloride (Renagel), a phosphate binder, and specific mineral modifications on ectopic mineralization of connective tissue in Abcc6-/- mice. Three groups were fed a specific diet: (i) a standard rodent diet, (ii) a standard rodent diet supplemented with sevelamer hydrochloride, and (iii) a custom experimental diet with specific mineral modifications (high phosphorus, low calcium and low magnesium). The degree of mineralization was determined in hematoxylin-eosin-stained sections using computerized morphometric analysis and by chemical assays to measure the calcium and phosphorus content of the vibrissae. The results indicated increased mineralization in the Abcc6-/- mice fed a standard diet or a diet with mineral modifications as compared with control mice fed a standard diet. However, feeding Abcc6-/- mice with diet supplemented with sevelamer hydrochloride did not improve mineralization, in comparison to mice fed with normal diet. Collectively, these results suggest that the mineralization process in PXE may be exacerbated by changes in mineral intake. The role of dietary minerals, and phosphorus in particular, as well as that of phosphate binders, in ectopic mineralization of PXE, merits further investigation.

Targeted ablation of Abcc1 or Abcc3 in Abcc6(-/-) mice does not modify the ectopic mineralization process.

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic mineralization of connective tissues, with considerable intra- and interfamiliar phenotypic variability. PXE is caused by mutations in the ABCC6 gene, which encodes a transporter protein, MRP6, and targeted ablation of Abcc6 in mice recapitulates the manifestations of PXE. In this study, we examined the hypothesis that the expression of other members of the Abcc family may be altered in Abcc6 null mice, possibly explaining the phenotypic variability because of the functional overlap of these transporters. Analysis of the transcript levels of Abcc1-10 and 12 in the liver of Abcc6 (-/-) mice by quantitative RT-PCR indicated that the levels of other C family mRNAs were not significantly different from wild-type mice. Next, we developed Abcc6/1(-/-) and Abcc6/3(-/-) double null mice and examined them for tissue mineralization. Histopathologic examination, coupled with computerized morphometric analysis, and chemical assay of calcium x phosphate product in the muzzle skin of Abcc1(-/-) and Abcc3(-/-) mice did not reveal evidence of mineralization. Abcc6/1(-/-) and Abcc6/3(-/-) double knock-out mice exhibited connective tissue mineralization similar to that in Abcc6 (-/-) mice. These results emphasize the importance of the Abcc6 gene in the ectopic mineralization process and further suggest that other members of the Abcc family, particularly Abcc1 and Abcc3, do not modulate the effects of Abcc6 in this mouse model.