Acrodermatitis acidaemica.

Methylmalonic acidaemia (MMA) is an inborn error of amino acid metabolism that may be associated with cutaneous manifestations mimicking other diagnoses, including staphylococcal scalded skin syndrome (SSSS), psoriasis and acrodermatitis enteropathica. Whether this is due to the underlying metabolic disorder itself or occurs as a consequence of dietary restriction has yet to be elucidated. Skin biopsies typically show histological features shared by a number of other metabolic disorders and nutritional deficiency-associated diseases. Some presentations, especially SSSS-like eruptions, may be associated with acute metabolic decompensation. An underlying metabolic disorder, such as MMA, should be considered in a diagnosed adult or undiagnosed child presenting with skin eruptions that resemble those listed above, so that specialist management may be initiated early.

Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice.

BACKGROUND: Metabolic function is regulated by the interplay of central and peripheral factors that ultimately regulate food intake (FI) and energy expenditure. The tachykinin substance P (SP) has been identified as a novel regulator of energy balance, however, the mechanisms underlying this effect are ill-defined and conflicting data regarding the role of SP on FI have been reported by different groups. OBJECTIVE: To further characterize the metabolic role of the Tac1 gene products (SP and neurokinin A) in mice through a series of genetic, metabolic and behavioral studies in Tac1-deficient mice. RESULTS: Tac1-/- mice are leaner than controls and display reduced FI and altered feeding circadian rhythm, supported by disrupted expression of the clock genes Cry1/2, Per1/2 in the suprachiasmatic nucleus, mediobasal hypothalamus (MBH) and liver, as well as increased proopiomelanocortin expression in the MBH. Tac1 ablation induced resistance to obesity, improved glucose tolerance, prevented insulin resistance under high-fat diet, increased activation of brown adipose tissue and improved hepatic steatosis. Moreover, deletion of Tac1 in ob/ob mice ameliorated body weight gain in females only but was sufficient to decrease fat and triglyceride content in the liver of males. CONCLUSIONS: These results provide further evidence that Tac1 controls circadian feeding behavior and metabolism in mice through mechanisms that involve the regulation of the melanocortin system. In addition, these studies suggest that the blockade of SP may offer a new method to treat metabolic syndrome.

Exosome-associated AAV vector as a robust and convenient neuroscience tool.

Adeno-associated virus (AAV) vectors are showing promise in gene therapy trials and have proven to be extremely efficient biological tools in basic neuroscience research. One major limitation to their widespread use in the neuroscience laboratory is the cost, labor, skill and time-intense purification process of AAV. We have recently shown that AAV can associate with exosomes (exo-AAV) when the vector is isolated from conditioned media of producer cells, and the exo-AAV is more resistant to neutralizing anti-AAV antibodies compared with standard AAV. Here, we demonstrate that simple pelleting of exo-AAV from media via ultracentrifugation results in high-titer vector preparations capable of efficient transduction of central nervous system (CNS) cells after systemic injection in mice. We observed that exo-AAV is more efficient at gene delivery to the brain at low vector doses relative to conventional AAV, even when derived from a serotype that does not normally efficiently cross the blood-brain barrier. Similar cell types were transduced by exo-AAV and conventionally purified vector. Importantly, no cellular toxicity was noted in exo-AAV-transduced cells. We demonstrated the utility and robustness of exo-AAV-mediated gene delivery by detecting direct GFP fluorescence after systemic injection, allowing three-dimensional reconstruction of transduced Purkinje cells in the cerebellum using ex vivo serial two-photon tomography. The ease of isolation combined with the high efficiency of transgene expression in the CNS, may enable the widespread use of exo-AAV as a neuroscience research tool. Furthermore, the ability of exo-AAV to evade neutralizing antibodies while still transducing CNS after peripheral delivery is clinically relevant.

Controlling brain tumor growth by intraventricular administration of an AAV vector encoding IFN-beta.

Glioblastoma multiforme (GBM) is the most aggressive type of all primary brain tumors, with an overall median survival <1 year after diagnosis. Despite introduction of multimodal treatment approaches, the prognosis has not improved significantly over the past 50 years. In this study we investigated the effect of intracerebroventricular (ICV) injection of an adeno-associated virus (AAV) vector encoding human interferon-beta (AAV-hIFN-beta) on glioblastoma growth. Recently, we found that peritumoral parenchymal transduction with an AAV-hIFN-beta was exceptionally efficient in eradicating GBM brain tumors. However, the extensive infiltration and migration displayed by glioblastoma cells in patients may leave a significant number of tumor cells outside a local therapeutic zone created by intraparenchymal delivery of AAV vectors. Here we show that pretreatment of mice by ICV infusion of an AAV-IFN-beta completely prevents tumor growth in an orthotopic model of GBM. Furthermore, ICV infusion of AAV-IFN-beta into mice bearing preestablished U87 intracranial tumors improved their survival compared to mice infused through the same route with a control AAV vector. These data suggest that ICV injection of AAV vectors encoding antitumor proteins is a promising approach deserving further consideration for the treatment of GBM.

Ontogeny of glucose homeostasis in low birth weight infants.

Suppression of the endogenous glucose production rate (Ra) is the adult response to glucose infusion. Persistent Ra (greater than or equal to 1 mg.kg-1min-1 or less than 80% decrease in basal Ra) in response to glucose infusion is evidence of a transitional homeostatic state in the neonate during the first days after birth. To determine whether postnatal development produces an adultlike response, Ra was measured in 11 infants (birth weight 1716 +/- 48 g, gestational age 33 +/- 0.3 weeks) at 2 to 5 weeks of age. In these paired studies, 4 micrograms.kg-1min-1 D-(U-13C)glucose tracer was infused by prime constant infusion to determine Ra, during infusion of either saline solution or glucose, the latter at a rate of 5.3 +/- 0.2 mg.kg-1min-1 (mean +/- SEM). When the results of the saline infusion turnover period were compared with those of the glucose infusion turnover period, plasma glucose concentration increased significantly, from 88 +/- 3 mg/dL to 101 +/- 4 mg/dL (P less than 0.001). Plasma insulin concentration remained unchanged (12 +/- 5 microU/mL vs 8 +/- 3 microU/mL). Ra was heterogenous during glucose infusion, and persistent Ra was present in six of 11 infants. Of the five infants who had decreased Ra during glucose infusion, three received glucose at a rate exceeding basal Ra. Of the remaining six infants who evidenced persistent Ra during glucose infusion, three received glucose at a rate equal to or in excess of basal Ra. We conclude that glucose homeostasis in low birth weight infants is transitional throughout the neonatal period.