Differential Effects of Anionic,Cationic, Nonionic,and Physiologic Surfactants on the Dissociation, α-Chymotryptic Degradation,and Enteral Absorption of Insulin Hexamers

Various surfactants were investigated to compare their effects on insulin dissociation, -chymotryptic degradation, and rat enteral absorption. With a circular dichroism technique, sodium dodecyl sulfate (SDS) at a 5 mM concentration was found to completely dissociate procine-zinc insulin hexamers (0.5 mg/ml) into monomers. The catalytic activity of -chymotrypsin (0.5 µM) was also abolished by 5 mM SDS. When insulin was injected into the distal jejunum/ proximal ileum segment of the rat, 5 mM SDS greatly enhanced its pharmacological availability, from a negligible value to 2.8%. Being a cationic surfactant, hexadecyl trimethylammonium bromide (CTAB) also efficiently dissociated insulin hexamers at concentrations of 1–5 mM. However, extensive charge–charge interaction was observed below a CTAB concentration of 0.6 mM, leading to insulin precipitation at a molar CTAB:insulin ratio of 1:1 to 2:1. An -chymotryptic degradation study also revealed near-complete dissociation of insulin hexamers at 1 mM CTAB. Above 1 mM, however, CTAB acted as an enzyme inhibitor, most likely by means of charge repulsion. Enteral absorption studies showed a much lower pharmacological availability, only 0.29%. Nonionic surfactants such as Tween 80 and polyoxyethylene 9 lauryl ether were ineffective in dissociating insulin hexamers. Tween 80, at 5 mM, neither significantly altered the -chymotryptic degradation pattern nor enhanced the enteral absorption of insulin. The relative effectiveness of different species of bile salts on insulin hexamer dissociation appeared to be similar. Sodium glycocholate at a 30 mM concentration also significantly increased insulin pharmacological availability, to 2.3%. A morphological study did not reveal any significant alteration of the rat intestinal mucosal integrity after exposure to 5 mM SDS for 30 min. The results further emphasize the importance of the degree of insulin aggregation on its enteral transport.     

Superlattice-like structure and enhanced ferroelectric properties of intergrowth Aurivillius oxides

Aurivillius oxides with an intergrowth structures have been receiving increasing interest because of their special structures and potential outstanding ferroelectric properties. In this work, Bi₃LaTiNbFeO₁₂–Bi₅Ti₃FeO₁₅ and Bi₃TiNbO₉–Bi₃LaTiNbFeO₁₂ compounds were successfully synthetised using a simple solid-state reaction method. X-Ray diffraction patterns and scanning transmission electron microscopy high angle annular dark field (STEM-HAADF) images confirm the 2–3 and the 3–4 intergrowth structures in Bi₃TiNbO₉–Bi₃LaTiNbFeO₁₂ and Bi₃LaTiNbFeO₁₂–Bi₅Ti₃FeO₁₅ compounds, respectively. A superlattice-like distortion in these oxides was proposed resulting from the combination of sub-lattices with different a and b parameters, which was validated by XRD refinements and Raman spectra. Polarization-electric field tests and pulsed polarization positive-up negative-down measurements demonstrate that such superlattice-like structures can effectively enhance the intrinsic ferroelectric polarization and coercive field of these oxides, especially when compared with their component oxides Bi₃TiNbO₉, Bi₃LaTiNbFeO₁₂ and Bi₅Ti₃FeO₁₅. Simultaneously, ferroelectric Curie temperatures of Bi₃TiNbO₉–Bi₃LaTiNbFeO₁₂ and Bi₃LaTiNbFeO₁₂–Bi₅Ti₃FeO₁₅ oxides are lowered because of the internal stress in the superlattice-like structure. Nevertheless, the paramagnetism of the samples is hardly influenced by their structure, while mainly related to their iron content, in which iron has a similar effective magnetic moment around 3.4–3.9.

Aurivillius oxides with an intergrowth structures have been receiving increasing interest because of their special structures and potential outstanding ferroelectric properties.     

Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese

Background

A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the α-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese.

Methods

We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients.

Results

The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06–1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean±standard deviation ages at onset of GG, AG and AA carriers were 24.04±4.22, 25.76±4.75 and 25.78±4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects.

Limitations

The relative small sample size in BD group should be considered a limitation of this study.

Conclusions

Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility.     

Interrelationships Between BDNF,Superoxide Dismutase,and Cognitive Impairment in Drug-Naive First-Episode Patients With Schizophrenia

The pathogenesis and etiology of schizophrenia (SCZ) remains unclear. Accumulating studies showed that complex interrelationships between brain-derived neurotrophic factor (BDNF) and an imbalanced redox system has a crucial role in the psychopathology of SCZ. However, the influence of the interrelationships of BDNF and superoxide dismutase (SOD) on cognitive impairment and clinical symptomatology in drug-naive first-episode (DNFE) SCZ patients has not been studied thoroughly. Serum BDNF levels, plasma total SOD, manganese-SOD (Mn-SOD), copper/zinc-containing SOD (CuZn-SOD) activities, and malondialdehyde (MDA) levels were measured in 327 DNFE patients with SCZ and 391 healthy controls. Cognitive functions were measured using the Repeatable Battery for the Assessment of Neuropsychological status (RBANS) and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). Compared with the controls, the DNFE patients had increased activities of total SOD and CuZn-SOD, and reduced levels of BDNF and MDA. BDNF levels were positively correlated with CuZn-SOD activity in patients. In addition, we found that elevated Mn-SOD and CuZn-SOD activities were related to PANSS depression factor. Moreover, an interactive effect of BDNF levels and Mn-SOD activity was associated with attentional index score in the patients. Therefore, our findings suggested that interrelationships between BDNF and antioxidant mechanisms might underlie the pathological mechanisms of cognitive impairments and symptomatology in the DNFE patients with SCZ.     

壳聚糖改性丝素合金膜的制备及其相关性质研究

以无毒氧化葡萄糖醛作交联剂 ,采用溶液共混交联法制备壳聚糖改性丝素合金膜。用 FTIR、DSC表征其结构 ,测定其等电点、力学性能、不同 p H条件下的溶胀率和对模型药物 5 - Fu的渗透性。结果表明 :改性丝素合金膜中丝素和壳聚糖分子间存在着强烈的氢键相互作用及良好的相容性。改性膜的等电点对应的 p H值是 5 .35 ,而丝素膜的等电点是 4 .5。改性膜的力学性能优于单组分膜 ,当壳聚糖含量为 4 0 %～ 6 0 %时 ,具有最大的抗张强度和拉伸率 ,分别为 71.4～ 72 .7MPa和 2 .96～ 3.82 %。改性丝素合金膜对 5 - Fu的渗透量与壳聚糖的含量和时间成正相关关系 ,渗透系数随 p H值增大 (5→ 9)先逐渐减小然后略有增大 ,在 p H=7时最小。     

CNS involvement in CMTX1 caused by a novel connexin 32 mutation: a 6-year follow-up in neuroimaging and nerve conduction

X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) is one of the most common inherited neurological disorders. Obvious CNS involvement is relatively rare in CMTX1 patients. A 24-year-old male with CMTX1 presented with three transient stroke-like attacks, and was followed up regularly for 6 years with brain MRI and electrophysiological examination. Transient symmetrical high signals on T2 imaging and restricted diffusion were found in bilateral deep white matter. Electrophysiological measurement revealed a sensorimotor peripheral neuropathy with slightly reduced nerve conduction velocities. A novel thymine to cytosine mutation at nucleotide position 445 in the connexin 32 allele of the GJB1 gene was identified. During the 6-year longitudinal study, patient’s motor and sensory function did not worsen; radiological abnormalities correlated with episodes of CNS dysfunction and resolved after clinical recovery; electrophysiological records showed no obvious change. Little change in the patient’s clinical, radiological and electrophysiological results over the follow-up reflected a slow disease progression.     

多发性抽动症的临床与脑电图特征分析

目的：探讨多发性抽动症（tourette syndrome,TS）的临床及脑电图（EEG）特征。方法：对164例多发性抽动症患儿的临床及脑电图资料进行回顾性分析。结果：EEG异常36例,异常率22％,其中32例表现为枕区基本节律慢化,α波指数减少,α波调节调幅不良,阵发高幅θ节律等非特异性异常。另4例表现为典型的癫痫样放电。结论：部分TS患儿有EEG的异常改变,且EEG的异常与病程的长短及严重程度存在一定的对应关系,EEG可作为评估病变严重程度的客观依据之一。     

慢性肾功能衰竭患者血清甲状腺激素水平与血脂代谢关系的临床探讨

目的探讨慢性肾功能衰竭（CRF）患者血清甲状腺激素水平的变化对血脂代谢的影响及其临床意义。方法采用放射免疫法（RIA）检测56例CRF患者和35名正常对照者血清总三碘甲状腺原氨酸（TT3）、总甲状腺素（TT4）、游离三碘甲状腺原氨酸（FT3）、游离甲状腺素（FT4）、高敏促甲状腺素（h-TSH）的含量，同时测定其血清总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A-Ⅰ（apo A-Ⅰ）、载脂蛋白B（apo B）及肌酐（Cr）、β2微球蛋白（β2-MG）和白蛋白（A1b）等，并分析各指标的相关性。结果CRF患者血清TT3、FT3显著低于对照组（P〈0．01），TT4、FT4、h-TSH虽低于对照组，但差异无统计学意义（P〉0．05）；血清TG、LDL-C和apo B显著高于对照组（P〈0．01、P〈0．05、P〈0．05），HDL-C明显低于对照组（P〈0．05），TC和apo A-Ⅰ虽略高于对照组，但无统计学意义（P〉0．05）；血清Cr、β2-MG明显高于对照组（P〈0．01），A1b明显低于对照组（P〈0．01）。直线回归和相关性分析显示，CRF患者血清TT3、FT3均分别与Cr、TG、LDL-C、apo B呈显著负相关（P〈0．01），而与HDL-C呈显著正相关（P〈0．01），h-TSH与Cr、TG、HDL-C、LDL-C和apo B均无显著相关性（P〉0．05）。结论血清甲状腺激素水平降低与肾功能损害程度密切相关，与CRF患者血脂代谢紊乱有一定的关系。因此，CRF患者血清甲状腺激素水平的监测具有一定的临床价值。     

Transport and degradation characteristics of methotrexate dialkyl ester prodrugs across tape-stripped hairless mouse skin

A series of methotrexate dialkyl esters were examined with respect to their permeability across tape-stripped hairless mouse skin. The dialkyl esters showed a parabolic permeability versus side chain length relationship with the dimethyl ester being the most permeable compound. These compounds were also found to undergo an increased degree of degradation with increased ester chain length during the diffusion process, while with substantially reduced degradation occuring with the branched chain diisopropyl ester. No measurable methotrexate was formed during the course of the experiment, apparently due to the chemical and enzymatic stability of the intermediate - and -γ-monoesters.     

Cocrystal Formation during Cogrinding and Storage is Mediated by Amorphous Phase

Purpose The purpose of this work was to investigate the mechanisms of cocrystal formation during cogrinding and storage of solid reactants, and to establish the effects of water by cogrinding with hydrated form of reactants and varying RH conditions during storage.Methods The hydrogen bonded 1:1 carbamazepine–saccharin cocrystal (CBZ–SAC) was used as a model compound. Cogrinding of solid reactants was studied under ambient and cryogenic conditions. The anhydrous, CBZ (III), and dihydrate forms of CBZ were studied. Coground samples were stored at room temperature at 0% and 75% RH. Samples were analyzed by XRPD, FTIR and DSC.Results Cocrystals prepared by cogrinding and during storage were similar to those prepared by solvent methods. The rate of cocrystallization was increased by cogrinding the hydrated form of CBZ and by increasing RH during storage. Cryogenic cogrinding led to higher levels of amorphization than room temperature cogrinding. The amorphous phase exhibited a T _g around 41°C and transformed to cocrystal during storage.Conclusions Amorphous phases generated by pharmaceutical processes lead to cocrystal formation under conditions where there is increased molecular mobility and complementarity. Water, a potent plasticizer, enhances the rate of cocrystallization. This has powerful implications to control process induced transformations.