Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome

Objective

To present long-term respiratory function outcomes from an open-label, multi-center, phase 3 extension study (MOR-005) of elosulfase alfa enzyme replacement therapy (ERT) in patients with Morquio A syndrome.

Methods

In part 1 of MOR-005, patients initially randomized to ERT in the 24-week pivotal study (MOR-004) remained on their regimen (2.0 mg/kg/week or every other week); placebo patients were re-randomized to one of the two regimens. During part 2, all patients received elosulfase alfa 2.0 mg/kg/week. Respiratory function was one of the efficacy endpoints evaluated in MOR-005. Change from MOR-004 baseline to 120 weeks of treatment for the combined population was determined and compared with results from untreated patients from a Morquio A natural history study (MorCAP).

Results

Maximum voluntary ventilation (MVV) improved up to week 72 and then stabilized; forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV₁) increased continuously over 120 weeks. Mean increases in the modified per-protocol population was 9.2 % for FVC, 8.8 % for FEV₁, and 6.1 % for MVV after 120 weeks. All patients ≤14 years showed respiratory improvements, presumably in part related to growth; however, these were greater in treated patients. For those >14 years, treated patients showed improvements, while deterioration occurred in untreated. Altogether, the improvements were significantly greater (P?<?0.05) in treated patients.

Conclusions

Long-term ERT is associated with sustained improvements in respiratory function in Morquio A. In younger patients (≤14 years), some improvement may be ascribed to growth. In older patients, other mechanisms, e.g., decreased glycosaminoglycan storage, are likely involved.

     

Small bowel of patients with asthma and allergic rhinitis: absence of inflammation despite the presence of major cellular components of allergic inflammation.

Eosinophils participate in the pathogenesis of inflammatory diseases of the respiratory tract and the gut. We investigated the constitutive presence of eosinophils and mononuclear cells in the macroscopically normal duodenal mucosa of patients with asthma and allergic rhinitis. Macroscopically normal duodenal specimens were obtained at routine endoscopy for upper gastrointestinal symptoms from 16 patients with asthma and 13 patients with allergic rhinitis. Twelve nonatopic patients with irritable bowel syndrome were studied as controls. Specimens were analyzed by immunohistochemistry using a panel of antibodies to human eosinophil cationic protein clone EG1 (EG1) and clone EG2 (EG2), anti-human interleukin (anti-hIL)-5, anti-hIL-4, anti-CD4, and anti-CD68. Significantly increased numbers of eosinophils stained with EG1 and EG2 were found in the duodenum of patients with asthma and allergic rhinitis compared with controls. IL-5+ cells and IL-4+ cells were detected in significantly increased numbers in the duodenal mucosa of patients with asthma and rhinitis compared with controls. Mononuclear cells expressing CD4 (helper T cells) and CD68 (macrophages) also were significantly increased in the duodenal mucosa of asthma and rhinitis compared with controls. Accumulation of eosinophils in conjunction with IL-4+ cells and IL-5+ cells in the noninflamed duodenal mucosa may reflect a predominant T helper cell subset 2 systemic immune response in patients with asthma and allergic rhinitis. The absence of intestinal inflammation despite the marked presence of cells implicated in the allergic inflammation suggests that local mechanisms might determine the state of nonresponsiveness in the gut mucosa of patients with asthma and allergic rhinitis.     

Synthetic Cannabinoids: Use and Predictors in a Community Sample of Young Adults

Background: Synthetic cannabinoids (SCs) are a class of drugs of abuse with deleterious consequences. Despite governmental regulations related to distribution and sale, SC variants are still available online. More research is needed to determine SC use prevalence and factors associated with SC use, especially among young adults. Methods: One thousand eighty individuals, 18–25 years old, were surveyed, between January 2012 and July 2013, during recruitment for a randomized controlled trial investigating health behaviors in young adults. Advertisements were placed online and in community locations seeking individuals “who had recently used marijuana or alcohol.” Respondents were queried about their use of alcohol and drugs, including SCs, in the last month. Results: Participants averaged 21.4 years old and were 53.4% male. Nearly 59% were non-Hispanic white, 15% were African American, 15% were Hispanic, and 11% identified as other. Approximately 9% reported SC use in the last month, a level higher than the reported use of opioids, cocaine, or hallucinogens. SC use was significantly associated with male gender, not being enrolled in school, and with use of cigarettes, binge alcohol drinking, daily and weekly marijuana use, and other drugs of abuse. There was a significant decrease in SC use after the federal ban in July 2012. Conclusions: SC use was common in the past month and often overlaps with other drug use, particularly marijuana use, and should be asked about during clinical encounters with young adults.     

Biochemical and immunohistochemical analysis of glycosaminoglycans in inflamed and non-inflamed intestinal mucosa of patients with Crohn’s disease

OBJECTIVES: Changes in extracellular matrix glycosaminoglycans (GAGs) of the intestinal mucosa have been associated with inflammatory bowel disease. The aim of the present study was to follow the changes in GAGs metabolism during the progression from non-inflamed to inflamed intestinal colon of patients with Crohn's disease (CD), using direct biochemical analysis and specific immunohistochemistry against chondroitin/dermatan sulfate and heparan sulfate. DESIGN AND METHODS: The content of GAGs from inflamed and non-inflamed colon of eight patients with active CD was estimated by uronic acid per dry weight of tissue and analyzed by agarose gel electrophoresis and ion-exchange chromatography. Intestinal sections were stained using antibodies against dermatan sulfate/chondroitin 4-sulfate (DS/CS), heparan sulfate (HS), and ICAM-1 (CD54), and analyzed by confocal microscopy. RESULTS: There was a reduction in the amount of GAGs in the non-inflamed colon of patients with CD. In the inflamed colon, HS, CS and DS showed increased concentrations compared with the non-inflamed colon. GAGs showed a diffuse distribution in the lamina propria and in the basement membrane of both inflamed and non-inflamed mucosa of patients with CD. CONCLUSION: We observed a marked reduction in GAGs with altered patterns of distribution in the non-inflamed colon of patients with CD. The increase in the synthesis of GAGs observed in the inflamed colon may be a compensatory mechanism for the restoration of the integrity of the intestinal mucosa.     

Dysregulated mTORC1 renders cells critically dependent on desaturated lipids for survival under tumor-like stress

Solid tumors exhibit heterogeneous microenvironments, often characterized by limiting concentrations of oxygen (O₂), glucose, and other nutrients. How oncogenic mutations alter stress response pathways, metabolism, and cell survival in the face of these challenges is incompletely understood. Here we report that constitutive mammalian target of rapamycin complex 1 (mTORC1) activity renders hypoxic cells dependent on exogenous desaturated lipids, as levels of de novo synthesized unsaturated fatty acids are reduced under low O₂. Specifically, we demonstrate that hypoxic Tsc2^−/− (tuberous sclerosis complex 2^−/−) cells deprived of serum lipids exhibit a magnified unfolded protein response (UPR) but fail to appropriately expand their endoplasmic reticulum (ER), leading to inositol-requiring protein-1 (IRE1)-dependent cell death that can be reversed by the addition of unsaturated lipids. UPR activation and apoptosis were also detected in Tsc2-deficient kidney tumors. Importantly, we observed this phenotype in multiple human cancer cell lines and suggest that cells committed to unregulated growth within ischemic tumor microenvironments are unable to balance lipid and protein synthesis due to a critical limitation in desaturated lipids.     

Perceived barriers to implementation of injury prevention programs among collegiate women’s soccer coaches

ObjectivesKnee injury prevention programs (IPPs) reduce knee and anterior cruciate ligament (ACL) injury rates in female athletes, however, implementation of IPPs is low. The purpose of this study was to identify barriers to implementation of IPPs among collegiate women’s soccer coaches.DesignCross-sectional survey.MethodsA custom survey based on the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework and existing literature was sent to 151 out of 153 women’s National Collegiate Athletic Association (NCAA) soccer coaches in the NCAA’s Eastern Region.ResultsTen respondents reported that they did not use an IPP (Non-users), and nineteen respondents reported that they did use an IPP (Users). “Cost” was the most highly ranked barrier (median rank: 2) to implementing an IPP among Non-users. For the statement, “Who should be responsible for completing an IPP,” Users said “Coaches” (47%) and “Other” (21%), while Non-users said “Strength and conditioning” (50%) and “Athletic trainers” (30%). Respondents who marked “Other”, elaborated that it was the responsibility of coaches, athletes, and additional staff members.ConclusionsCost was the primary barrier to implementation of an IPP. Since the majority of Non-users indicated that implementation of an IPP was the responsibility of a non-coaching staff member, cost may be a surrogate for the expense of hiring an additional staff member rather than the cost of performing the IPP itself. Additionally, using a team-based approach that encompasses athletes, coaches, and non-coaching staff members may support long-term implementation of IPPs.     

Birth seasons and heights among girls and boys below 12 years of age: lasting effects and catch-up growth among native Amazonians in Bolivia

Background: Seasons affect many social, economic, and biological outcomes, particularly in low-resource settings, and some studies suggest that birth season affects child growth.

Aim: To study a predictor of stunting that has received limited attention: birth season.

Subjects and methods: This study uses cross-sectional data collected during 2008 in a low-resource society of horticulturists-foragers in the Bolivian Amazon, Tsimane’. It estimates the associations between birth months and height-for-age Z-scores (HAZ) for 562 girls and 546 boys separately, from birth until age 11?years or pre-puberty, which in this society occurs ～13–14?years.

Results: Children born during the rainy season (February–May) were shorter, while children born during the end of the dry season and the start of the rainy season (August–November) were taller, both compared with their age–sex peers born during the rest of the year. The correlations of birth season with HAZ were stronger for boys than for girls. Controlling for birth season, there is some evidence of eventual partial catch-up growth, with the HAZ of girls or boys worsening until?～?age 4–5?years, but improving thereafter. By age 6?years, many girls and boys had ceased to be stunted, irrespective of birth season.

Conclusion: The results suggest that redressing stunting will require attention to conditions in utero, infancy and late childhood.     

Assessment of in vitro cytotoxicity of imidazole ionic liquids and inclusion in targeted drug carriers containing violacein

Violacein (Viol) is a pigment produced by several Gram-negative bacteria with many bioactivities, such as anticancer, virucide, and antiparasitic. However, violacein is insoluble under physiological conditions preventing its potential therapeutic uses. Surface-active ionic liquids (SAILs) based on the cation 1-alkylimidazolium ([C_nHim]) with n = 10 to 16 alkyl carbon side chain lengths and acetate, bromide, methanesulfonate (S) or trifluoroacetate (F) as counterions were synthesized and screened to dissolve Viol in micellar aqueous media and for toxicological studies on the human lung carcinoma A549 cell line. Screening allowed the selection of 1.5 × 10⁻³% (w/v) [C₁₆Him]-S because it combines low cytotoxicity with 71.5% cell viability and good interaction with 95.2% of the violacein kept in micellar solution for at least 48 h. [Viol-([C₁₆Him]-S)] complex was used to develop an efficient hybrid solid lipid nanoparticle (SLN) carrier based on myristyl myristate and poloxamer 188 and tailored with folate to target cancer cells. Cellular SLN uptake was evaluated with fluorescent DiOC₁₈ on A549, HCT-116, and HeLa cell lines expressing or not the folate receptor. The results showed fivefold incorporation of Viol nanoparticles in HCT-116 and HeLa cell cultures, displaying a high level of folate receptor. Biophysical characterization of the hybrid solid lipid carrier containing Viol was performed by dynamic light scattering, Fourier transform infrared, X-ray diffraction and X-ray photoelectron spectroscopies, and by transmission electron and cryo-transmission microscopies.

Violacein (Viol) is a pigment produced by several Gram-negative bacteria with many bioactivities, such as anticancer, virucide, and antiparasitic.     

The Effects of Inattention/Impulsivity and Aggression on the Development of Toddlers with Autism Spectrum Disorder

Autism spectrum disorder (ASD) frequently co-occurs with additional symptoms of psychopathology and challenging behaviors. While aggressive behaviors are often associated with attention deficits and hyperactivity in children with ASD, there is limited research on the impact that inattention/impulsivity and aggressive behaviors have on the developmental functioning of toddlers with ASD. However, identifying comorbidities is necessary for proper intervention. The aim of the current study was to examine the effects of inattention/impulsivity and aggressive behaviors on several domains of developmental functioning in infants and toddlers with ASD as measured by the Battelle Developmental Inventory, Second Edition (BDI-2). This study compared four groups consisting of 29 toddlers each: without inattention/impulsivity or aggressive behaviors (i.e., -I/-A), with inattention/impulsivity but without aggressive behaviors (i.e.,?+?I/-A), without inattention/impulsivity but with aggressive behaviors (i.e., –I/?+?A), and with both inattention/impulsivity and aggressive behaviors (i.e.,?+?I/?+?A). The results of the current study revealed significant group differences in Personal-Social, Communication, Motor, and Cognitive domains of the BDI-2. The significance and implications of the present study are discussed.