Feeding‐related characters in basal pterosaurs: implications for jaw mechanism,dental function and diet

?si, A. 2011: Feeding‐related characters in basal pterosaurs: implications for jaw mechanism, dental function and diet. Lethaia, Vol. 44, pp. 136–152. A comparative study of various feeding‐related features in basal pterosaurs reveals a significant change in feeding strategies during the early evolutionary history of the group. These features are related to the skull architecture (e.g. quadrate morphology and orientation, jaw joint), dentition (e.g. crown morphology, wear patterns), reconstructed adductor musculature and post‐cranium. The most basal pterosaurs (Preondactylus, dimorphodontids and anurognathids) were small‐bodied animals with a wingspan no greater than 1.5 m, a relatively short, lightly constructed skull, straight mandibles with a large gape, sharply pointed teeth and well‐developed external adductors. The absence of extended tooth wear excludes complex oral food processing and indicates that jaw closure was simply orthal. Features of these basal‐most forms indicate a predominantly insectivorous diet. Among stratigraphically older but more derived forms (Eudimorphodon, Carniadactylus, Caviramus) complex, multicuspid teeth allowed the consumption of a wider variety of prey via a more effective form of food processing. This is supported by heavy dental wear in all forms with multicuspid teeth. Typical piscivorous forms occurred no earlier than the Early Jurassic, and are characterized by widely spaced, enlarged procumbent teeth forming a fish grab and an anteriorly inclined quadrate that permitted only a relatively small gape. In addition, the skull became more elongate and body size increased. Besides the dominance of piscivory, dental morphology and the scarcity of tooth wear reflect accidental dental occlusion that could have been caused by the capturing or seasonal consumption of harder food items. □Basal pterosaurs, heterodonty, dental wear, insectivory, piscivory.     

Preventive role of gallic acid on hepatic ischemia and reperfusion injury in rats

There is little information about the hepatoprotective effects of gallic acid against ischemia–reperfusion (I/R) damage. Animals were subjected to I/R. Gallic acid at doses of 50 and 100 mg/kg body weight (bw) were injected as a single dose prior to ischemia. Liver tissue homogenates were used for the measurement of malondialdehyde (MDA), catalase (CAT) and glutathione peroxidase (GPx) levels. At the same time alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were assayed in serum samples and compared statistically. While the ALT, AST, LDH activities and MDA levels were significantly increased, CAT and GPx activities significantly decreased in only I/R-induced control rats compared to normal control rats (P < 0.05). Treatment with gallic acid at a dose of 100 mg/kg bw significantly decreased the ALT, AST, LDH activities and MDA levels, and markedly increased activities of CAT and GPx in tissue homogenates compared to I/R-induced rats with no treatment group (P < 0.05). In oxidative stress generated by hepatic ischemia–reperfusion, gallic acid contributes partially an alteration in the delicate balance between the scavenging capacity of antioxidant defense systems and free radicals in favour of the antioxidant defense systems in the body.     

PTGS1, PTGS2, ALOX5, ALOX12, ALOX15, and FLAP SNPs: interaction with fatty acids in colon cancer and rectal cancer

Dietary polyunsaturated fatty acids (PUFAs) can be converted to prostaglandins and leukotrienes. Oxygenation of omega-6 PUFAs generally results in the production of pro-inflammatory mediators, whereas oxygenated products of omega-3 (n-3) PUFAs generally have lower inflammatory activity. We hypothesize that elevated n-3 PUFA intakes from fish are associated with lower risk of colorectal cancer among those with genetic variants that result in higher levels of pro-inflammatory mediators. In population-based case–control studies of colon (case n = 1,574) and rectal cancer (case n = 791) and disease-free controls (n = 2,969), we investigated interactions between dietary fatty acid intake and 107 candidate polymorphisms and tagSNPs in PTGS1, PTGS2, ALOX12, ALOX5, ALOX15, and FLAP. The two studies used an identical genotyping protocol. We observed interactions and statistically significant increases in colon cancer risk for low docosahexaenoic acid intake among those with the PTGS1 rs10306110 (−1,053 A > G) variant genotypes (OR = 1.6, 95 % confidence interval = 1.1–2.3, adj. p = 0.06) and rectal cancer risk for low total fat intake among those with the variant PTGS1 rs10306122 (7,135 A > G) (OR_vs.wt = 1.80, 1.02–2.99; adj. p = 0.08). The ALOX15 rs11568131 (10,339 C > T) wild type in combination with a high inflammation score (low EPA intake, high AA intake, no regular NSAID use, high BMI, smoking) was associated with increased colon cancer risk (OR = 2.28, 1.7–3.07). Rectal cancer risk was inversely associated with a low inflammation score among PTGS2 rs4648276 (3,934 T > C) variant allele carriers (OR = 0.49, 0.25–0.75). Overall, these data provide some modest evidence for interactions between dietary fat intake and genetic variation in genes involved in eicosanoid metabolism and colorectal cancer risk.

Electronic supplementary material

The online version of this article (doi:10.1007/s12263-012-0302-x) contains supplementary material, which is available to authorized users.     

A delicate interplay of structure, dynamics, and thermodynamics for function: a high pressure NMR study of outer surface protein A

Outer surface protein A (OspA) is a crucial protein in the infection of Borrelia burgdorferi causing Lyme disease. We studied conformational fluctuations of OspA with high-pressure ¹⁵N/¹H two-dimensional NMR along with high-pressure fluorescence spectroscopy. We found evidence within folded, native OspA for rapid local fluctuations of the polypeptide backbone in the nonglobular single layer β-sheet connecting the N- and C-terminal domains with τ << ms, which may give the two domains certain independence in mobility and thermodynamic stability. Furthermore, we found that folded, native OspA is in equilibrium (τ >> ms) with a minor conformer I, which is almost fully disordered and hydrated for the entire C-terminal part of the polypeptide chain from β8 to the C-terminus. Conformer I is characterized with ΔG⁰ = 32 ± 9 kJ/mol and ΔV⁰ = −140 ± 40 mL/mol, populating only ∼0.001% at 40°C at 0.1 MPa, pH 5.9. Because in the folded conformer the receptor binding epitope of OspA is buried in the C-terminal domain, its transition into conformer I under in vivo conditions may be critical for the infection of B. burgdorferi. The formation and stability of the peculiar conformer I are apparently supported by a large packing defect or cavity located in the C-terminal domain.     

Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci

Psoriasis (PS) and Crohn disease (CD) have been shown to be epidemiologically, pathologically, and therapeutically connected, but little is known about their shared genetic causes. We performed meta-analyses of five published genome-wide association studies on PS (2,529 cases and 4,955 controls) and CD (2,142 cases and 5,505 controls), followed up 20 loci that showed strongest evidence for shared disease association and, furthermore, tested cross-disease associations for previously reported PS and CD risk alleles in additional 6,115 PS cases, 4,073 CD cases, and 10,100 controls. We identified seven susceptibility loci outside the human leukocyte antigen region (9p24 near JAK2, 10q22 at ZMIZ1, 11q13 near PRDX5, 16p13 near SOCS1, 17q21 at STAT3, 19p13 near FUT2, and 22q11 at YDJC) shared between PS and CD with genome-wide significance (p < 5 × 10⁻⁸) and confirmed four already established PS and CD risk loci (IL23R, IL12B, REL, and TYK2). Three of the shared loci are also genome-wide significantly associated with PS alone (10q22 at ZMIZ1, p_rs1250544 = 3.53 × 10⁻⁸, 11q13 near PRDX5, p_rs694739 = 3.71 × 10⁻⁰⁹, 22q11 at YDJC, p_rs181359 = 8.02 × 10⁻¹⁰). In addition, we identified one susceptibility locus for CD (16p13 near SOCS1, p_rs4780355 = 4.99 × 10⁻⁸). Refinement of association signals identified shared genome-wide significant associations for exonic SNPs at 10q22 (ZMIZ1) and in silico expression quantitative trait locus analyses revealed that the associations at ZMIZ1 and near SOCS1 have a potential functional effect on gene expression. Our results show the usefulness of joint analyses of clinically distinct immune-mediated diseases and enlarge the map of shared genetic risk loci.     

Variation in the functioning of autonomous self-pollination, pollinator services and floral traits in three Centaurium species

Background and Aims

Reproductive assurance through autonomous selfing is thought to be one of the main advantages of self-fertilization in plants. Floral mechanisms that ensure autonomous seed set are therefore more likely to occur in species that grow in habitats where pollination is scarce and/or unpredictable.

Methods

Emasculation and pollen supplementation experiments were conducted under laboratory conditions to investigate the capacity for, and timing of autonomous selfing in three closely related Centaurium species (Centaurium erythraea, C. littorale and C. pulchellum). In addition, observations of flower visitors were combined with emasculation and pollen addition experiments in natural populations to investigate the degree of pollinator limitation and pollination failure and to assess the extent to which autonomous selfing conferred reproductive assurance.

Results

All three species were capable of autonomous selfing, although this capacity differed significantly between species (index of autonomous selfing 0·55 ± 0·06, 0·68 ± 0·09 and 0·92 ± 0·03 for C. erythraea, C. littorale and C. pulchellum, respectively). The efficiency and timing of autogamous selfing was primarily associated with differences in the degree of herkogamy and dichogamy. The number of floral visitors showed significant interspecific differences, with 1·6 ± 0·6, 5·4 ± 0·6 and 14·5 ± 2·1 floral visitors within a 2 × 2 m² plot per 20-min observation period, for C. pulchellum, C. littorale and C. erythraea, respectively. Concomitantly, pollinator failure was highest in C. pulchellum and lowest in C. erythraea. Nonetheless, all three study species showed very low levels of pollen limitation (index of pollen limitation 0·14 ± 0·03, 0·11 ± 0·03 and 0·09 ± 0·02 for C. erythraea, C. littorale and C. pulchellum, respectively), indicating that autonomous selfing may guarantee reproductive assurance.

Conclusions

These findings show that limited availability of pollinators may select for floral traits and plant mating strategies that lead to a system of reproductive assurance via autonomous selfing.     

Oxygen-binding characteristics of three extra-cellular haemoglobins of Artemia salina

The oxygen-binding characteristics of the three extracellular haemoglobins of brine shrimp (Artemia salina) were studied in vitro by using highly purified preparations. Haemoglobin I is induced last in the development of brine shrimps when functional gills are formed. It has the lowest oxygen affinity (p₅₀ 5.34mmHg), an intermediate Bohr effect (ø −0.09 at 20°C) above pH8 and a temperature-sensitivity (ΔH −44.8 to −45.6kJ/mol at pH8–9) comparable with those observed with other invertebrate haemoglobins [Weber & Heidemann (1977) Comp. Biochem. Physiol. A 57, 151–155]. Haemoglobin II, which is the first to be induced, soon after hatching of nauplius larvae, persists generally throughout the whole adult life. It has an intermediate oxygen affinity (p₅₀ 3.7mmHg), the highest Bohr effect (ø −0.21 at 20°C) above pH8 and a similar temperature-sensitivity (ΔH −46.0 to −54.8kJ/mol at pH8–9) as haemoglobin I. However, haemoglobin III, which is induced second several hours after the induction of haemoglobin II but disappearing from the haemolymph in the middle of adult life, has the highest oxygen affinity (p₅₀ 1.8mmHg), the lowest Bohr effect (ø −0.03 at 20°C) above pH8.5 and a high resistance against temperature variation between 10 and 25°C at pH8.5–9 (ΔH −22.6 to −23.0kJ/mol). At pH7.5–8, haemoglobin III exhibits a similar temperature-sensitivity under 30°C as do other haemoglobins. All three haemoglobins have a rather low co-operativity, with Hill coefficients (h 1.6–1.9 at pH8.5), which are dependent on both pH and temperature. The highest co-operativity was observed at 20°C and pH9 for haemoglobins I and II, whereas it was at 27°C and pH8.5 for haemoglobin III. Thus the oxygen-binding behaviour of haemoglobin III in vitro is significantly different from those of haemoglobins I and II and indicates possibly its specific physiological role in vivo in the adaptive process in the natural environment.     

Kinetic and Thermodynamic Characterization of Glucoamylase from Colletotrichum sp. KCP1

Extracellular glucoamylase of Colletotrichum sp. KCP1 produced through solid state fermentation was purified by two steps purification process comprising ammonium sulphate precipitation followed by gel permeation chromatography (GPC). The Recovery of glucoamylase after GPC was 50.40 % with 19.3-fold increase in specific activity. The molecular weight of enzyme was found to be 162.18 kDa by native-PAGE and was dimeric protein of two sub-units with molecular weight of 94.62 and 67.60 kDa as determined by SDS-PAGE. Activation energy for starch hydrolysis was 26.45 kJ mol⁻¹ while temperature quotient (Q₁₀) was found to be 1.9. The enzyme was found to be stable over wide pH range and thermally stable at 40–50 °C up to 120 min while exhibited maximum activity at 50 °C with pH 5.0. The pKa₁ and pKa₂ of ionisable groups of active site controlling V_max were 3.5 and 6.8, respectively. V_max, K_m and K_cat for starch hydrolysis were found to be 58.82 U ml⁻¹, 1.17 mg (starch) ml⁻¹ and 449 s⁻¹, respectively. Activation energy for irreversible inactivation (E_a(d)) of glucoamylase was 74.85 kJ mol⁻¹. Thermodynamic parameters of irreversible inactivation of glucoamylase and starch hydrolysis were also determined.     

B vitamins, methionine and alcohol intake and risk of colon cancer in relation to BRAF mutation and CpG island methylator phenotype (CIMP)

Background

One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain.

Methods

Utilizing incident colon cancers in a large prospective cohort of women (the Nurses'' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.

Results

Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53–1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P_{heterogeneity} = 0.73). Neither vitamin B₆, methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.

Conclusions

This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations.     

Did pterosaurs feed by skimming? Physical modelling and anatomical evaluation of an unusual feeding method

Similarities between the anatomies of living organisms are often used to draw conclusions regarding the ecology and behaviour of extinct animals. Several pterosaur taxa are postulated to have been skim-feeders based largely on supposed convergences of their jaw anatomy with that of the modern skimming bird, Rynchops spp. Using physical and mathematical models of Rynchops bills and pterosaur jaws, we show that skimming is considerably more energetically costly than previously thought for Rynchops and that pterosaurs weighing more than one kilogram would not have been able to skim at all. Furthermore, anatomical comparisons between the highly specialised skull of Rynchops and those of postulated skimming pterosaurs suggest that even smaller forms were poorly adapted for skim-feeding. Our results refute the hypothesis that some pterosaurs commonly used skimming as a foraging method and illustrate the pitfalls involved in extrapolating from limited morphological convergence.     

Morphological and genomic evidence for a new species of Corallorhiza (Orchidaceae: Epidendroideae) from SW China

Corallorhiza sinensis, a new species of mycoheterotrophic orchid from western Sichuan, China, is described and illustrated based on molecular and morphological evidence. It is morphologically similar to Corallorhiza trifida, but can be distinguished by bigger flowers, both sepals and petals with 3 veins, and longer lateral lobes of lip. To distinguish the new Corallorhiza species and explore its phylogenetic position within subtribe Calypsoinae, this study employed sequences of the nuclear ribosomal DNA (nrDNA) and whole plastome assembled from the genome skimming approach. The plastome is 148,124 bp in length, including a pair of inverted repeats (IRs) of 26,165 bp, a large single-copy region (LSC) of 82,207 bp, and a small single-copy region (SSC) of 13,587 bp. Further, phylogenetic analyses were performed using nrDNA sequence and 79 coding sequences (CDSs) from 26 complete plastomes of subtribe Calypsoinae. The phylogenetic tree based on nrDNA sequence suggested that Corallorhiza is a monophyletic group, and strongly support C. sinensis as sister to the rest species of Corallorhiza. The plastid tree showed that 10 Corallorhiza species grouped into two clades and C. sinensis is most closely related to the North American C. striata and C. bentleyi instead of Oreorchis foliosa and O.angustata in the same clade. The plastid tree and nrDNA tree indicate Oreorchis is a paraphyletic. Although the topological conflicts are displayed between plastome and nrDNA phylogenies of C. sinensis, it is still the most closely related to Corallorhiza. Comparative analysis showed that C. sinensis populations are characteristic of the intermediate morphological traits between Corallorhiza and Oreorchis. The finding of this new species from China shed new light on the phylogeny of Oreorchis and Corallorhiza.     

Pushed to the limit: consequences of climate change for the Araucariaceae: a relictual rain forest family

Background and Aims

Under predicted climate change scenarios, increased temperatures are likely to predispose trees to leaf and other tissue damage, resulting in plant death and contraction of already narrow distribution ranges in many relictual species. The effects of predicted upward temperatures may be further exacerbated by changes in rainfall patterns and damage caused by frosts on trees that have been insufficiently cold-hardened. The Araucariaceae is a relictual family and the seven species found in Australia have limited natural distributions characterized by low frost intensity and frequency, and warm summer temperatures. The temperature limits for these species were determined in order to help understand how such species will fare in a changing climate.

Methods

Experiments were conducted using samples from representative trees of the Araucariaceae species occurring in Australia, Agathis (A. atropurpurea, A. microstachya and A. robusta), Arauacaria (A. bidwilli, A. cunninghamii and A. heterophylla) and Wollemia nobilis. Samples were collected from plants grown in a common garden environment. Lower and higher temperature limits were determined by subjecting detached winter-hardened leaves to temperatures from 0 to –17 °C and summer-exposed leaves to 25 to 63 °C, then measuring the efficiency of photosystem II (F_v/F_m) and visually rating leaf damage. The exotherm, a sharp rise in temperature indicating the point of ice nucleation within the cells of the leaf, was measured on detached leaves of winter-hardened and summer temperature-exposed leaves.

Key Results

Lower temperature limits (indicated by FT₅₀, the temperature at which PSII efficiency is 50 %, and LT₅₀ the temperature at which 50 % visual leaf damage occurred) were approx. –5·5 to –7·5 °C for A. atropurpurea, A. microstachya and A. heterophylla, approx. –7 to –9 °C for A. robusta, A. bidwillii and A. cunninghamii, and –10·5 to –11 °C for W. nobilis. High temperature damage began at 47·5 °C for W. nobilis, and occurred in the range 48·5–52 °C for A. bidwillii and A. cunninghamii, and in the range 50·5–53·5 °C for A. robusta, A. microstachya and A. heterophylla. Winter-hardened leaves had ice nucleation temperatures of –5·5 °C or lower, with W. nobilis the lowest at –6·8 °C. All species had significantly higher ice nucleation temperatures in summer, with A. atropurpurea and A. heterophylla forming ice in the leaf at temperatures >3 °C higher in summer than in winter. Wollemia nobilis had lower FT₅₀ and LT₅₀ values than its ice nucleation temperature, indicating that the species has a degree of ice tolerance.

Conclusions

While lower temperature limits in the Australian Araucariaceae are generally unlikely to affect their survival in wild populations during normal winters, unseasonal frosts may have devastating effects on tree survival. Extreme high temperatures are not common in the areas of natural occurrence, but upward temperature shifts, in combination with localized radiant heating, may increase the heat experienced within a canopy by at least 10 °C and impact on tree survival, and may contribute to range contraction. Heat stress may explain why many landscape plantings of W. nobilis have failed in hotter areas of Australia.     

Microarray analysis revealed different gene expression patterns in HepG2 cells treated with low and high concentrations of the extracts of Anacardium occidentale shoots

In this study, the effects of low and high concentrations of the Anacardium occidentale shoot extracts on gene expression in liver HepG2 cells were investigated. From MTT assays, the concentration of the shoot extracts that maintained 50% cell viability (IC₅₀) was 1.7 mg/ml. Cell viability was kept above 90% at both 0.4 mg/ml and 0.6 mg/ml of the extracts. The three concentrations were subsequently used for the gene expression analysis using Affymetrix Human Genome 1.0 S.T arrays. The microarray data were validated using real-time qRT–PCR. A total of 246, 696 and 4503 genes were significantly regulated (P < 0.01) by at least 1.5-fold in response to 0.4, 0.6 and 1.7 mg/ml of the extracts, respectively. Mutually regulated genes in response to the three concentrations included CDKN3, LOC100289612, DHFR, VRK1, CDC6, AURKB and GABRE. Genes like CYP24A1, BRCA1, AURKA, CDC2, CDK2, CDK4 and INSR were significantly regulated at 0.6 mg/ml and 1.7 mg but not at 0.4 mg/ml. However, the expression of genes including LGR5, IGFBP3, RB1, IDE, LDLR, MTTP, APOB, MTIX, SOD2 and SOD3 were exclusively regulated at the IC₅₀ concentration. In conclusion, low concentrations of the extracts were able to significantly regulate a sizable number of genes. The type of genes that were expressed was highly dependent on the concentration of the extracts used.     

Identity of Squalius (Actinopterygii, Cyprinidae) from Istra Peninsula in Croatia (Adriatic Sea basin)

A chub of previously ambiguous identity from the Boljunscica and Pazincica rivers (south-eastern Istra Peninsula) was studied and compared with geographically close Squalius squalus, Squalius zrmanja, and Squalius janae recently described from the Dragonja River drainage in the Adriatic Sea basin in Slovenia. It was shown that the chub from the south-eastern Istra Peninsula differs from all know species of Squalius but one: Squalius janae. Three samples examined from Boljunscica and Pazincica rivers and Squalius janae from its type locality, Dragonja River, show the following characters typical for the latter species: a long head (the head length 27–32% SL); a pointed conical snout with a clearly projecting upper jaw; a long straight mouth cleft, the lower jaw length (39–45% HL) exceeding the caudal peduncle depth; a large eye; commonly 9? branched anal-fin rays; commonly 44 total vertebrae (24+20 or 25+19); bright silvery colouration, scales easily lost; iris, pectoral, pelvic and anal fin pigmentation with yellow shades. The data on the distribution of Squalius chubs in the northern Adriatic basin support the assumption that the range of Squalius janae is determined by the geology of the Trieste Flysch Basin and the Pazin Flysch Basin forming the base of the Istra Peninsula. The distribution pattern of this species does not support a simple model of fish dispersal and a complete connectivity within the whole Palaeo-Po historical drainage. Indeed, it indicates a disrupted surface palaeohydrography that was heavily fragmented by karstification in the whole Dinaric area.     

Development of Controlled-Release Matrix Tablet of Risperidone: Influence of Methocel®- and Ethocel®-Based Novel Polymeric Blend on <Emphasis Type="Italic">In Vitro</Emphasis> Drug Release and Bioavailability

Controlled-release (CR) matrix tablet of 4 mg risperidone was developed using flow bound dry granulation–slugging method to improve its safety profile and compliance. Model formulations F1, F2, and F3, consisting of distinct blends of Methocel® K100 LV-CR and Ethocel® standard 7FP premium, were slugged. Each batch of granules (250–1,000 μm), obtained by crushing the slugs, was divided into three portions after lubrication and then compressed to 9-, 12-, and 15-kg hard tablets. In vitro drug release studies were carried out in 0.1 N HCl (pH 1.2) and phosphate buffer (pH 6.8) using a paddle dissolution apparatus run at 50 rpm. The CR test tablet, containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness, exhibited pH-independent zero-order release kinetics for 24 h. The drug release rate was inversely proportional to the content of Ethocel®, while the gel layer formed of Methocel® helped in maintaining the integrity of the matrix. Changes in the hardness of tablet did not affect the release kinetics. The tablets were reproducible and stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. Risperidone and its active metabolite, 9-hydroxyrisperidone, present in the pooled rabbit’s serum, were analyzed with HPLC-UV at λ_max 280 nm. The CR test tablet exhibited bioequivalence to reference conventional tablet in addition to the significantly (p < 0.05) optimized peak concentration, C_max, and extended peak time, T_max, of the active moiety. There was a good association between drug absorption in vivo and drug release in vitro (R² = 0.7293). The successfully developed CR test tablet may be used for better therapeutic outcomes of risperidone.KEY WORDS: controlled release, dry granulation slugging method, risperidone     

Controlled Release Matrix Tablets of Olanzapine: Influence of Polymers on the <Emphasis Type="Italic">In Vitro</Emphasis> Release and Bioavailability

Controlled-release (CR) tablet formulation of olanzapine was developed using a binary mixture of Methocel® K100 LV-CR and Ethocel® standard 7FP premium by the dry granulation slugging method. Drug release kinetics of CR tablet formulations F1, F2, and F3, each one suitably compressed for 9-, 12-, and 15-kg hardness, were determined in a dissolution media of 0.1 N HCl (pH 1.5) and phosphate buffer (pH 6.8) using type II dissolution apparatus with paddles run at 50 rpm. Ethocel® was found to be distinctly controlling drug release, whereas the hardness of tablets and pH of the dissolution media did not significantly affect release kinetics. The CR test tablets containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness exhibited pH-independent zero-order release kinetics for 24 h. In vivo performance of the CR test tablet and conventional reference tablet were determined in rabbit serum using high-performance liquid chromatography coupled with electrochemical detector. Bioavailability parameters including C_max, T_max, and AUC_0–48 h of both tablets were compared. The CR test tablets produced optimized C_max and extended T_max (P < 0.05). A good correlation of drug absorption in vivo and drug release in vitro (R² = 0.9082) was observed. Relative bioavailability of the test tablet was calculated as 94%. The manufacturing process employed was reproducible and the CR test tablets were stable for 6 months at 40 ± 2°C/75 ± 5% relative humidity. It was concluded that the CR test tablet formulation successfully developed may improve tolerability and patient adherence by reducing adverse effects.Key words: bioavailability, controlled release, Ethocel®, olanzapine     

Association Between rs1344706 of ZNF804A and Schizophrenia:A Meta-analysis

Schizophrenia is one of the most serious mental diseases found in humans. Previous studies indicated that the single nucleotide polymorphism（SNP） rs1344706 in the gene ZNF804 A encoding zinc finger protein 804 A was associated with schizophrenia in Caucasian population but not in Chinese Han population. However, current results are conflicting in Asian population. In the present study, a meta-analysis was performed to revisit the association between rs1344706 and the risk of schizophrenia in Asian, Caucasian and other populations. Electronic search of Pub Med database identified 25 case–control studies with available genotype frequencies of rs1344706 for the meta-analysis,involving a total of 15,788 cases and 22,654 controls. A pooled odds ratio（OR） with 95% confidence interval（CI） was used to assess the association. The current meta-analysis showed an association between rs1344706 and schizophrenia in Caucasian populations（P = 0.028, OR = 1.138, 95% CI：1.014–1.278; P = 0.004 for heterogeneity） and Asian populations（P = 0.008, OR = 1.092, 95%CI： 1.023–1.165; P = 0.001 for heterogeneity）, but not in other populations（P = 0.286,OR = 1.209, 95% CI： 0.853–1.714, P = 0.120 for heterogeneity）. Egger’s test（P 〉 0.05） and Begg’s test（P 〉 0.05） are both suggestive of the lack of publication bias for the included studies. Thus, the absence of association in other populations suggests a genetic heterogeneity in the susceptibility of schizophrenia and demonstrates the difficulties in replicating genome-wide association study findings regarding schizophrenia across different ethnic populations. To validate the association between rs1344706 and schizophrenia, further studies with larger participant populations worldwide are needed.