In silico design of novel proton-pump inhibitors with reduced adverse effects.

The development of new proton-pump inhibitors (PPIs) with less adverse effects by lowering the pKa values of nitrogen atoms in pyrimidine rings has been previously suggested by our group. In this work, we proposed that new PPIs should have the following features: (1) number of ring II = number of ring I + 1; (2) preferably five, six, or seven-membered heteroatomic ring for stability; and (3) 1 < pKa1 < 4. Six molecular scaffolds based on the aforementioned criteria were constructed, and R groups were extracted from compounds in extensive data sources. A virtual molecule dataset was established, and the pKa values of specific atoms on the molecules in the dataset were calculated to select the molecules with required pKa values. Drug-likeness screening was further conducted to obtain the candidates that significantly reduced the adverse effects of long-term PPI use. This study provided insights and tools for designing targeted molecules in silico that are suitable for practical applications.

Multipronged Therapeutic Effects of Chinese Herbal Medicine Qishenyiqi in the Treatment of Acute Myocardial Infarction.

Background: Based on global gene expression profile, therapeutic effects of Qishenyiqi (QSYQ) on acute myocardial infarction (AMI) were investigated by integrated analysis at multiple levels including gene expression, pathways involved and functional group. Methods: Sprague-Dawley (SD) rats were randomly divided into 3 groups: Sham-operated, AMI model (left anterior descending coronary artery ligation) and QSYQ-treated group. Cardiac tissues were obtained for analysing digital gene expression. Sequencing and transcriptome analyses were performed collaboratively, including analyses of differential gene expression, gene co-expression network, targeted attack on network and functional grouping. In this study, a new strategy known as keystone gene-based group significance analysis was also developed. Results: Analysis of top keystone QSYQ-regulated genes indicated that QSYQ ameliorated ventricular remodeling (VR), which is an irreversible process in the pathophysiology of AMI. At pathway level, both well-known cardiovascular diseases and cardiac signaling pathways were enriched. The most remarkable finding was the novel therapeutic effects identified from functional group analysis. This included anti-inflammatory effects mediated via suppression of arachidonic acid lipoxygenase (LOX) pathway and elevation of nitric oxide (NO); and amelioration of dyslipidaemia mediated via fatty acid oxidation. The regulatory patterns of QSYQ on key genes were confirmed by western blot, immunohistochemistry analysis and measurement of plasma lipids, which further validated the therapeutic effects of QSYQ proposed in this study. Conclusions: QSYQ exerts multipronged therapeutic effects on AMI, by concurrently alleviating VR progression, attenuating inflammation induced by arachidonic acid LOX pathway and NO production; and ameliorating dyslipidaemia.

A Comparison of the Nutritional Value of Cow's Milk and Nondairy Beverages.

OBJECTIVES: Nondairy beverages are advertised as a healthy alternative to cow's milk. There is an increased availability and consumption of nondairy beverages and a decrease in consumption of cow's milk. The aim of the present study is to review and compare the contents and nutritional value of nondairy beverages to cow's milk. METHODS: Information about the nondairy beverages on the shelves at stores in Buffalo, New York was collected. The Web pages of several manufacturers were assessed for product contents. The nutrient contents including the protein quality of the nondairy beverages and cow's milk were compared. The nutrient contents of nondairy beverages and cow's milk were also compared to recommended dietary allowance or adequate intake for toddlers and young children. RESULTS: Commonly available nondairy beverages are derived from almond, cashew, coconut, hazelnut, hemp, oat, rice, and soy. Cow's milk has higher protein content and quality compared with most of these products. It was noted that most of these beverages are fortified with calcium and vitamin D. The bioavailability of these substances after fortification is, however, not available. CONCLUSIONS: Nondairy milk beverages vary in their nutritional profiles. These should not be considered nutritional substitutes for cow's milk until nutrient quality and bioavailability are established.

Feeding Intolerance and Poor Growth in Infants with Gastroschisis: Longitudinal Experience with Consecutive Patients over Thirteen Years.

OBJECTIVES: 1) To investigate in-hospital factors associated with delayed tolerance of full volume enteral nutrition and 2) To assess longitudinal growth in a contemporary population of infants with gastroschisis. DESIGN: Retrospective single-center study of all infants with gastroschisis Setting: Level III neonatal intensive care unit in a free-standing Children's Hospital Duration: 13.5 years MATERIALS & METHODS: Detailed data regarding demographics, nutritional support, growth, and infant outcomes was collected for all infants with gastroschisis. Linear regression was used to investigate in-hospital factors associated with feeding intolerance and poor growth. RESULTS: For 52 infants, the median gestational age at birth was 36 weeks, the median postnatal age to achieve full feeds was 22 days, and median in-hospital weight gain was 18 gm/day. With linear regression, there was a positive association between time to full feeds and both hospital length of stay (adjusted R2=0.503, p < 0.0001) and (unexpectedly) in-hospital weight gain (adjusted R2=0.125, p=0.0248). There was a negative association between in-hospital weight gain and preterm birth (adjusted R2=0.125, p=0.0356). For infants with longitudinal growth data, 35% had a weight < 5th percentile (of whom 67% were preterm). CONCLUSIONS: Many infants with gastroschisis have poor growth before and after hospital discharge. Aggressive feeding advancement may be a contributing factor to this finding and preterm infants may be at greater risk for poor growth than term infants.

Long-term neuropsychological effects of opioid use in children: a descriptive literature review.

BACKGROUND: Use of opioids in the management of pain and its consequences in children presents a substantial challenge. A significant concern in pediatric pain management is the long-term neuropsychological consequences of opioids. OBJECTIVES: The authors aim to provide a descriptive review of the current literature surrounding the neuropsychological impact of opioid use in children, along with possible extrapolations from their use in adults and animal models. STUDY DESIGN: Systematic review of published literature. SETTING: Various universities in the United States. METHODS: The electronic review for papers published between January 1992 and December 2012 was conducted using Medline/Pubmed, PsychInfo, CINAHL, the Cochrane Library database, and Google Scholar. RESULTS: Findings assessing pediatric pain patients treated with opioids demonstrated no significant differences in intelligence, behavior, vocabulary, or motor skills. One study reported a decrease in a visuo-constructional ability, which measured higher order executive function. Studies from prenatal illicit opioid exposure found poorer performance on measures of language, verbal ability, mathematics, reading, impulse control, and school readiness skills. The literature from adult prescribed opioid users has mixed results. Some showed impairment in the neuropsychological domains of memory, decision-making, attention, concentration, information processing, psychomotor speed, visual special skills, and hand-eye coordination, while others found no differences or revealed improved perceptual-cognitive status, possibly due to the removal of pain as a stressor. LIMITATIONS: Very few studies looked into the long term neuropsychological and cognitive effects of the opioids in pediatric population. In an attempt to extrapolate from other groups, this review also included literature from adult patients, prenatal opioid exposure, and animal studies. CONCLUSION: Opioid medications have the potential to produce long-lasting neuropsychological side effects. However, given the negative consequences of untreated pain, the potential benefit may offset their risk. More studies are needed to clarify this complex interaction.