Intestinal polypoid arteriovenous malformation: unusual presentation in a child and review of the literature

Aim: We report a jejuno‐jejunal intussusception with a polypoid arteriovenous malformation as a lead point in a 12‐year‐old boy, presenting with lower abdominal pain and non‐bloody non‐projectile vomiting. Methods: A computed tomography scan of the abdomen and pelvis showed proximal jejuno‐jejunal intussusception in the right upper quadrant. Exploratory laparotomy revealed a 5.5 × 2.5 × 2 cm polypoid mass within the wall of the jejunum. Consequently, jejunal segment resection was performed with end to end jejunostomy. Our case is distinctive because it involves a rare vascular lesion at an atypical site, the jejunum, in a child with an unusual presentation of intussusception treated surgically. Conclusion: Many paediatric benign and surgical conditions present with similar clinical symptoms; the physician in the emergency department should try to narrow the differential diagnosis and recognize surgical emergencies to avoid any delay in intervention that could be life‐threatening.     

Applying the taguchi method to optimize sumatriptan succinate niosomes as drug carriers for skin delivery

Niosomes formulated from different nonionic surfactants (Span® 60, Brij® 72, Span® 80, or Eumulgin® B 2) with cholesterol (CH) molar ratios of 3:1 or 4:1 with respect to surfactant were prepared with different sumatriptan amount (10 and 15 mg) and stearylamine (SA). Thin‐film hydration method was employed to produce the vesicles, and the time lapsed to hydrate the lipid film (1 or 24 h) was introduced as variable. These factors were selected as variables and their levels were introduced into two L18 orthogonal arrays. The aim was to optimize the manufacturing conditions by applying Taguchi methodology. Response variables were vesicle size, zeta potential (Z), and drug entrapment. From Taguchi analysis, drug concentration and the time until the hydration were the most influencing parameters on size, being the niosomes made with Span® 80 the smallest vesicles. The presence of SA into the vesicles had a relevant influence on Z values. All the factors except the surfactant–CH ratio had an influence on the encapsulation. Formulations were optimized by applying the marginal means methodology. Results obtained showed a good correlation between mean and signal‐to‐noise ratio parameters, indicating the feasibility of the robust methodology to optimize this formulation. Also, the extrusion process exerted a positive influence on the drug entrapment. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3845–3863, 2012     

Osteoporosis in chronic liver disease: a case–control study

Osteoporosis has become an increasingly recognized complication among patients with chronic liver disease (CLD). The aim of the present study was to assess the prevalence and risk factors of osteoporosis in patients with CLD (primary biliary cirrhosis and chronic viral hepatitis B or C patients) in comparison with a group of age- and sex-matched controls. Sixty-four patients with CLD (mean age 51.66 ± 11.54 years), 48 females and 16 males were included. Age- and sex-matched individuals from the general population served as controls. Osteoporosis was evaluated by dual energy X-ray absorptiometry (bone mineral density below ?2.5 T score) at the lumbar spine (LS) and total hip (TH). Vertebral fractures were established by densitometric morphometry (vertebral fracture assessment). Bone turnover was assessed by intact parathyroid hormone, osteocalcin and C-telopeptides of type I collagen in the serum. Prevalence of osteoporosis in either the LS or the TH was 45.3%, twice as high as in the controls (19.6%) (RR 2.31, 95% CI 1.42–3.75, P < 0.001). Age, menopausal status, cirrhosis and advanced histological stage are not determinant factors for developing osteoporosis in patients with CLD. However, female sex, cholestasis, lower weight and height but not body mass index seem to play predominant role. Three (5.3%) patients had dorsal and LS fractures. It was concluded that osteoporosis is effectively a complication of CLD. Cholestasis in addition to female sex and lower weight and height are risk factors of osteoporosis in CLD.     

The highly selective mGlu2 receptor positive allosteric modulator LY‐487,379 alleviates l‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat model of Parkinson's disease

l ‐3,4‐Dihydroxyphenylalanine (l ‐DOPA) is the most effective treatment for Parkinson's disease (PD), but its use over a long period is marred by motors complications such as dyskinesia. We previously demonstrated that selective metabotropic glutamate 2/3 (mGlu_2/3) receptor activation with LY‐354,740 alleviates dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐lesioned marmoset and the 6‐hydroxydopamine (6‐OHDA)‐lesioned rat. Here, we sought to determine the role played by selective mGlu₂ activation in the anti‐dyskinetic effect of mGlu_2/3 stimulation and have investigated the effect of the highly selective mGlu₂ positive allosteric modulator LY‐487,379 at alleviating established, and preventing the development of, l ‐DOPA‐induced dyskinesia in the 6‐OHDA‐lesioned rat. First, dyskinetic 6‐OHDA‐lesioned rats were administered l ‐DOPA in combination with LY‐487,379 (0.1, 1 and 10 mg/kg) or vehicle, and the severity of dyskinesia was determined. Second, 6‐OHDA‐lesioned rats were administered LY‐487,379 (0.1 or 1 mg/kg), started concurrently with l ‐DOPA, once daily for 22 days, and dyskinesia severity was evaluated weekly for four consecutive weeks. We also assessed the effect of LY‐487,379 on l ‐DOPA anti‐parkinsonian effect. We found that acute challenges of LY‐487,379 0.1 mg/kg in combination with l ‐DOPA, significantly diminished dyskinesia severity, by ≈54% (p < .01), when compared to vehicle. Moreover, animals treated with l ‐DOPA/LY‐487,379 0.1 and 1 mg/kg during the dyskinesia induction phase exhibited milder dyskinesia, by ≈74% and ≈61%, respectively (both p < .01), when compared to l ‐DOPA/vehicle. LY‐487,379 did not impair l ‐DOPA anti‐parkinsonian activity. These results suggest that mGlu₂ activation may be an effective and promising therapeutic strategy to alleviate the severity and prevent the development of dyskinesia.     

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.