Niemann-Pick type C1 (NPC1) disease is an autosomal-recessive cholesterol-storage disorder characterized by liver dysfunction, hepatosplenomegaly, and progressive neurodegeneration. The NPC1 gene is expressed in every tissue of the body, with liver expressing the highest amounts of NPC1 mRNA and protein. A number of studies have now indicated that the NPC1 protein regulates the transport of cholesterol from late endosomes/lysosomes to other cellular compartments involved in maintaining intracellular cholesterol homeostasis. The present study characterizes liver disease and lipid metabolism in NPC1 mice at 35 days of age before the development of weight loss and neurological symptoms. At this age, homozygous affected (NPC1(-/-)) mice were characterized with mild hepatomegaly, an elevation of liver enzymes, and an accumulation of liver cholesterol approximately four times that measured in normal (NPC1(+/+)) mice. In contrast, heterozygous (NPC1(+/-)) mice were without hepatomegaly and an elevation of liver enzymes, but the livers had a significant accumulation of triacylglycerol. With respect to apolipoprotein and lipoprotein metabolism, the results indicated only minor alterations in NPC1(-/-) mouse serum. Finally, compared to NPC1(+/+) mouse livers, the amount and processing of SREBP-1 and -2 proteins were significantly increased in NPC1(-/-) mouse livers, suggesting a relative deficiency of cholesterol at the metabolically active pool of cholesterol located at the endoplasmic reticulum. The results from this study further support the hypothesis that an accumulation of lipoprotein-derived cholesterol within late endosomes/lysosomes, in addition to altered intracellular cholesterol homeostasis, has a key role in the biochemical and cellular pathophysiology associated with NPC1 liver disease.

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We present a case of failed prehospital treatment of fentanyl induced apnea with intranasal (IN) naloxone. While IN administration of naloxone is becoming more common in both lay and pre-hospital settings, older EMS protocols utilized intravenous (IV) administration. Longer-acting, higher potency opioids, such as fentanyl, may not be as easily reversed as heroin, and studies evaluating IN administration in this population are lacking. In order to contribute to our understanding of the strengths and limitations of IN administration of naloxone, we present a case where it failed to restore ventilation. We also describe peer reviewed literature that supports the use of IV naloxone following heroin overdose and explore possible limitations of generalizing this literature to opioids other than heroin and to IN routes of administration.

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This study sought to determine if the ability to label a flavor is associated with an improved ability to recall having tasted the flavor in preschool-aged children. A total of 120 3- to 6-year-old English-speaking children tasted and labeled 20 different flavors, blinded to color. Children's labels for the flavors were scored for consistency and accuracy. Recall for having tasted the flavor was tested. Both labeling ability and recall ability improved rapidly between the ages of 3 and 6 years in this cohort. Regression analysis indicated that independent of the child's age, consistent accurate labeling was positively associated with recall ability. Higher maternal education was an independent and marginal contributor to greater recall ability. The combination of consistent and accurate labeling, age, and maternal education accounted for 28% of the variance in flavor recall ability. Consistent but inaccurate labeling alone contributed little to the variance in flavor recall ability. We conclude from these findings that children's ability to recall having tasted a flavor develops rapidly during the preschool age range and that improved recall ability is associated with the ability to consistently and accurately label the flavor. We conclude that language mediates memory for flavors in young children.

The increasing prevalence of obesity in developed nations has far-reaching implications for medical toxicology. The management of obese patients is complicated by comorbid illnesses, changes in cardiovascular and respiratory physiology, alterations in pharmacokinetics, and a lack of studies to identify appropriate dosing for current therapeutics and antidotes. In this review article, we examine obesity-associated physiologic and pharmacokinetic changes that may increase the vulnerability of obese patients to overdose. Further research is needed to characterize the relationship between drug toxicity and obesity.

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A 61-year-old man was brought to the emergency department (ED) for shortness of breath, fatigue, frequent falls, and bluish discoloration of his skin. The primary care physician transferred the patient due to concern for cyanosis. On presentation to the ED, the patient was oriented but appeared fatigued. The patient was afebrile and had the following vital signs: blood pressure 161/88 mmHg, pulse 71/min, respiratory rate 16/min, and oxygen saturation 100 % on room air by fingertip pulse oximetry. On physical exam, pupils were 4 mm and reactive bilaterally, extraocular movements were intact, and there was no nystagmus. Anicteric sclerae were notable for blue pigmentation (Fig. 1). Heart sounds were regular, without murmurs, rubs, or gallops. Lung sounds were clear to auscultation bilaterally. Other than ataxia, the neurological exam was unremarkable. The skin had a generalized bluish tinge, especially on the arms, with darker pigmentation on the cheeks (Figs. 2, 3 and 4). There was acne on the back and facial rosacea. Bluish discoloration was also noted under the proximal nail beds (Fig. 5). When questioned about the skin discoloration, the patient and his family members described an insidious onset. Photographs of the patient from years ago confirmed that this was not congenital. Medical history included acne, orthostatic hypotension, and Parkinson's disease, for which a deep brain stimulator had been surgically implanted. A comprehensive medication list was not immediately available; however, the patient denied any recent medication additions or adjustments. The patient was unemployed, denied any recent travel, and no other members of his household were complaining of fatigue or similar blue skin discoloration.