[Investigation of pregestational diabetes mellitus in 15 hospitals in Guangdong province].

Objective: To investigate the morbidity, diagnostic profile and perinatal outcome of pregestational diabetes mellitus (PGDM) in 15 hospitals in Guangdong province. Methods: A total of 41 338 women delivered in the 15 hospitals during the 6 months, 195 women with PGDM (PGDM group) and 195 women with normal glucose test result (control group) were recruited from these tertiary hospitals in Guangdong province from January 2016 to June 2016. The morbidity and diagnostic profile of PGDM were analyzed. The complications during pregnancy and perinatal outcomes were compared between the two groups. In the PGDM group, pregnancy outcomes were analyzed in women who used insulin treatment (n=91) and women who did not (n=104). Results: (1) The incidence of PGDM was 0.472%(195/41 338). Diabetes mellitus were diagnosed in 59 women (30.3%, 59/195) before pregnancy, and 136 women (69.7%,136/195) were diagnosed as PGDM after conceptions. Forty-six women (33.8%) were diagnosed by fasting glucose and glycohemoglobin (HbA1c) screening. (2) The maternal age, pre-pregnancy body mass index (BMI) , prenatal BMI, percentage of family history of diabetes, incidence of macrosomia, concentration of low density lipoprotein were significantly higher in PGDM group than those in control group (all P<0.05). Women in PGDM group had significantly higher HbA1c concentration ((6.3±1.3)% vs (5.2±0.4)%) , fasting glucose [(6.3±2.3) vs (4.8±1.1) mmol/L], oral glucose tolerance test (OGTT) -1 h glucose ((12.6±2.9) vs (7.1±1.3) mmol/L) and OGTT-2 h glucose [(12.0±3.0) vs (6.4±1.0) mmol/L] than those in control group (P<0.01). (3) The morbidity of preterm births was significantly higher (11.3% vs 1.0%, P<0.01), and the gestational age at delivery in PGDM group was significantly smaller [(37.6±2.3) vs (39.2±1.2) weeks, P<0.01]. Cesarean delivery rate in the PGDM group (70.8% vs 29.7%) was significantly higher than the control group (P<0.01). There was significantly difference between PGDM group and control in the neonatal male/female ratio (98/97 vs 111/84, P=0.033). The neonatal birth weight in PGDM group was significantly higher ((3 159±700) vs (3 451±423) g, P<0.01) . And the incidence of neonatal hypoglycemia in the PGDM group was higher than the control group (7.7% vs 2.6%, P=0.036). (4) In the PGDM group, women who were treated with insulin had a smaller gestational age at delivery [(36.9±2.9) vs (37.9±2.5) weeks, P<0.01], and the neonates had a higher neonatal ICU (NICU) admission rate (24.2% vs 9.6%, P<0.01). Conclusions: The morbidity of PGDM in the 15 hospitals in Guangdong province is 0.472%. The majority of PGDM was diagnosed during pregnancy; HbA1c and fasting glucose are reliable parameters for PGDM screening. Women with PGDM have obvious family history of diabetes and repeated pregnancy may accelerate the process of diabetes mellitus. Women with PGDM have higher risk for preterm delivery and neonatal hypoglycemia. Unsatisfied glucose control followed by insulin treatment may increase the need for NICU admission.

Prognostic significance of preoperative albumin-to-globulin ratio in patients with cholangiocarcinoma.

BACKGROUND: This study aimed to assess the prognostic value of the serum albumin to globulin ratio (AGR) in cholangiocarcinoma patients after surgery. METHODS: We retrospectively enrolled 123 cholangiocarcinoma patients who underwent surgical treatment between June 2003 and September2014 at the Third Affiliated Hospital of Sun Yat-sen University. Univariate and multivariate analyses using the Cox regression model were performed to determine the prognostic value of AGR. RESULTS: Univariate analysis suggested that AGR was a predictive factor for (overall survival) OS but not for recurrence free survival (RFS). After adjustment for other risk factors, multivariate analysis showed that AGR remained independently associated with OS. The optimal cut-off point for AGR was determined to be 1.44. Kaplan-Meier curves showed that there was a significantly lower mean survival time in the low AGR group compared to the high AGR group. A low AGR was found to be significantly associated with high alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin levels and an advanced American Joint Committee on Cancer TNM stage, but a low hemoglobin level. CONCLUSION: In summary, patients with higher AGRs have better outcomes than those with lower AGRs. Preoperative AGR can be a reliable marker for evaluating the prognosis of cholangiocarcinoma patients.

[Application of a modified tympanic membrane surgical knife with suction and tube device in myringotomy with ventilation tube placement].

Objective:To explore the efficacy of a modified tympanic membrane surgical knife with suction and tube device in myringotomy with ventilation tube placement for the treatment of secretory otitis media.Method:From June of 2014 to December of 2015, 87 cases of secretory otitis media were randomly divided into two groups: One group was treated by general approach to achieve tympanic membrane tube insertion, and another group with modified method. The total effective rate，the rate of tube detachment at 3 months postoperatively, the rate of scar formation or tympanic membrane atrophy, the operation time and the success rate of tube insertion for the first time in two groups were analyzed retrospectively. Result:There was no significantly difference between two groups about the total effective rate，the rate of tube detachment and the rate of scar formation or tympanic membrane atrophy（P>0.05）.However, the duration of operation in general method groupï¼»(11.4±4.3 min）］was significantly longer than that in modified method groupï¼»(8.1±3.6)minï¼½(t=5.412，P<0.05）.In addition, the success rate of tube insertion in general group（81.2%） was significantly lower than that in modified group（93.7%）(χ²=5.397，P<0.05）. Conclusion:The modified method contributed to shorten the duration of operation, improved the success rate of tube insertion and avoided the injury of tympanic membrane and external auditory canal caused by repeated operation.

Distribution of the cytoskeletal protein, Nestin, in acute leukemia.

Nestin is a neuroepithelial stem cell marker that is expressed in some types of tumor cells. Recent reports suggest that Nestin may be closely related to malignant cell proliferation and migration. Acute leukemia (AL) is characterized by a lack of differentiation, which results in uncontrolled proliferation in the bone marrow and accumulation of immature cells. The expression and function of Nestin in AL is unclear. We investigated Nestin immunohistochemical patterns of 87 patients that included 47 cases of acute myeloid leukemia (AML) and 40 cases of acute lymphoblastic leukemia (ALL), and 20 patients in complete remission (CR) from AML or ALL. We also investigated the clinico-pathological features of 87 cases of AL and their CR and overall survival (OS). Nestin was expressed in leukemic blasts and mature granulocytic cells in most cases (39/47) of AML. Conversely, Nestin was expressed in mature granulocytic cells in fewer cases (6/40) of ALL, but not in blasts. Nestin expression appeared in leukemic blasts of AML, but not ALL. Nestin expression in AML blast cells was not associated with CR or OS. We provide evidence that Nestin is expressed in AL and might be a useful immunohistochemical marker for identifying AML and ALL.

Chloride ion transport and fate in oilfield wastewater reuse by interval dynamic multimedia aquivalence model.

A surface flow constructed wetland was built up to dispose of oilfield wastewater with a high level of inorganic salt ions. Chlorine ion (Cl(-)) was selected as an indicator of soil secondary salinization, and an interval dynamic multimedia aquivalence (IDMA) model was developed to investigate the dynamic multimedia environmental (air, water, soil, flora, and groundwater) effects of Cl(-) in the wastewater irrigation process between 2002 and 2020. The modeled Cl(-) concentrations were in good agreement with the measured ones, as indicated by the interval average logarithmic residual errors (IALREs) being generally lower than 0.5 logarithmic units. The model results showed that the temporal trends of Cl(-) concentrations in the multimedia environments represented a relatively steady state. More than 97.00% of the mass exchange was finished between soil and groundwater compartments, and Cl(-) finally outputted the environmental system by the pathways of advection outflows in the water (71.03%) and groundwater (24.02%). Soil (59.17%) was the dominant sink of Cl(-). It was revealed that the high level of Cl(-) in oilfield wastewater was well treated by the constructed wetland, and there was not a significant environmental effect of soil secondary salinization in the oilfield wastewater reused for the constructed wetland irrigation.

Ante-partum and post-partum markers of metabolic syndrome in pre-eclampsia.

It is rare for a study to address immediate metabolic change in pre-eclamptic pregnancy. Our aim is to study the ante-partum and post-partum metabolic markers in pre-eclampsia. A total of 33 pre-eclamptic and 200 uncomplicated women with singleton pregnancies were recruited for the prospective research. Immediately ante-partum and 24-48 h postpartum venous blood samples were collected for the analysis of metabolic markers. In the pre-eclamptic group, the ante-partum fasting glucose, fasting insulin, triglyceride and free fatty acid levels were found to be higher than in the control group; however, ante-partum high-density lipoprotein level was lower. Interestingly, fasting glucose and insulin levels decreased by 24-48 h post-partum in both groups and no significant differences were found. Pre-eclamptic patients had lower post-partum high-density lipoprotein (P=0.02), higher triglyceride (P<0.001), higher free fatty acid (P=0.02) and higher apolipoprotein B levels (P=0.01) than the control group. Dyslipidemia lasts from ante-partum to immediate post-partum in pre-eclamptic women in the form of increased triglyceride, higher free fatty acid and decreased high-density lipoprotein levels. We speculate that women with dyslipidemia and higher baseline blood pressure tend to develop pre-eclampsia during pregnancy. Hence, the development of pre-eclampsia may be a 'marker' of possible future cardiovascular or metabolic disease.

Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats.

The current study describes the neuroprotective effects of an endogenous diketopiperazine, cyclo-glycyl-proline (cyclic GP), in rats with hypoxic-ischemic brain injury and the pre-clinical development of an analogue, cyclo-L-glycyl-L-2-allylproline (NNZ 2591), modified for improved bioavailability. The compounds were given either intracerebroventricularly or subcutaneously 2h after hypoxia-ischemia. Histology, immunohistochemistry and behavior were used to evaluate treatment effects. The central uptake of NNZ 2591 was also examined in normal and hypoxic-ischemic injured rats by HPLC-mass spectrometry. Central administration of cyclic GP or NNZ 2591 reduced the extent of brain damage in the lateral cortex, the hippocampus and the striatum (p<0.001), with NNZ 2591 being more potent. NNZ 2591 was stable in the plasma and crossed the blood-brain barrier independent of hypoxic-ischemic injury. The level of NNZ 2591 in the CSF was maintained for 2 h after a single subcutaneous dose, and modest neuroprotection was seen after a bolus subcutaneous administration (overall p<0.001). Treatment with NNZ 2591 for 5 d subcutaneously improved somatosensory-motor function (p<0.05) and long-term histological outcome (overall p<0.0001). NNZ 2591 treatment not only reduced both caspase-3 mediated apoptosis and microglial activation but also enhanced astrocytic reactivity, which may mediate its protective effect. The pharmacokinetic profile and potent long-term protective effects of NNZ 2591 suggests its utility for the treatment of ischemic brain injury and other neurological conditions requiring chronic intervention.

Enhancing absorption of fluorescein and LHRH across hindgut epithelia in a marsupial, the common brushtail possum Trichosurus vulpecula.

We have identified differences in transport properties of intestinal epithelia in the marsupial brushtail possum, compared to eutherian mammals. To determine whether differences in its permeability to hydrophilic compounds also occur, the absorption of sodium fluorescein and luteinizing hormone releasing hormone (LHRH) was assessed in vitro and the ability of chemical enhancers and a metabolic inhibitor to promote their absorption investigated. The apparent permeability of colonic and caecal tissues to fluorescein and LHRH and transepithelial resistance (Rt) in the absence or presence of ethylenediamine tetra-acetic acid (EDTA), sodium deoxycholic acid (SDA), dithiothreitol (DTT), polyacrylic acids (PAA), or the inhibitor bacitracin were determined. The effects of SDA and/or DTT on adherent mucus and the release of lactate dehydrogenase (LDH) were also assessed. In the absence of treatment, both tissues had comparable amounts of adherent mucus, Rt and low permeabilities to fluorescein and LHRH. All chemical enhancers increased fluorescein permeability, but SDA at concentrations >0.5 mM also induced LDH release. DTT alone and in combination with SDA reduced the amount of adherent mucus. Bacitracin inhibited LHRH metabolism and increased LHRH permeability. These data indicate that the possum hindgut epithelium represents a significant barrier to the uptake of hydrophilic compounds, similar to that in eutherians.

Role of ATP-binding cassette drug transporters in the intestinal absorption of tanshinone IIB, one of the major active diterpenoids from the root of Salvia miltiorrhiza.

There is an increasing use of herbal medicines worldwide, and the extracts from the root of Salvia miltiorrhiza are widely used in the treatment of angina and stroke. In this study, we investigated the mechanism for the intestinal absorption of tanshinone IIB (TSB), a major constituent of S. miltiorrhiza. The oral bioavailability of TSB was about 3% in rats with less proportional increase in its maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC) with increasing dosage. The time to C(max) (T(max)) was prolonged at higher oral dosage. In a single pass rat intestinal perfusion model, the permeability coefficients (P(app)) based on TSB disappearance from the lumen (P(lumen)) were 6.2- to 7.2-fold higher (p < 0.01) than those based on drug appearance in mesenteric venous blood (P(blood)). The uptake and efflux of TSB in Caco-2 cells were also significantly altered in the presence of an inhibitor for P-glycoprotein (PgP) or for multi-drug resistance associated protein (MRP1/2). TSB transport from the apical (AP) to basolateral (BL) side in Caco-2 monolayers was 3.3- to 5.7-fold lower than that from BL to AP side, but this polarized transport was attenuated by co-incubation of PgP or MRP1/2 inhibitors. The P(app) values of TSB in the BL-AP direction were significantly higher in MDCKII cells over-expressing MDR1 or MRP1, but not in cells over-expressing MRP2-5, as compared with the wild-type cells. The plasma AUC(0-24hr) in mdr1a and mrp1 gene-deficient mice was 10.2- to 1.7-fold higher than that in the wild-type mice. Furthermore, TSB significantly inhibited the uptake of digoxin and vinblastine in membrane vesicles containing PgP or MRP1. TSB also moderately stimulated PgP ATPase activity. Taken collectively, our findings indicate that TSB is a substrate for PgP and MRP1 and that drug resistance to TSB therapy and drug interactions may occur through PgP and MRP1 modulation.

Central penetration and stability of N-terminal tripeptide of insulin-like growth factor-I, glycine-proline-glutamate in adult rat.

Insulin-like growth factor-I is a neurotrophic factor and can prevent neurons from ischemic brain injury. However, the large molecular weight and metabolic effects can be problematic in its central delivery. Glycine-proline-glutamate (GPE) is the N-terminal tripeptide of insulin-like growth factor-I, which is naturally cleaved in the plasma and brain tissues. GPE reduces neuronal loss from hypoxic-ischemic brain injury following central administration. Central penetration and the stability of GPE in the plasma and central nervous system were examined in rats using radioimmunoassay and HPLC. GPE was rapidly metabolised in the plasma (8 min) after intraperitoneal administration. Despite having a short half-life in plasma, GPE was detected in the cerebrospinal fluid up to 40 min after intraperitoneal administration. With present of peptidase inhibitors, GPE existed in the brain tissue up to 3 h after intracerebroventricular administration, suggesting a role for peptolysis in its stability. The endopeptidase inhibitors 4- (2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) reduced GPE metabolism in the brain tissue while acid peptidase inhibitor pepstatin-A decreased GPE metabolism in the plasma. GPE reduced neuronal loss in the CA1-2 sub-region of the hippocampus given (intraperitoneally) after 30 min of hypoxic-ischemic injury in adult rats, further suggested the effectiveness of GPE central uptake. These results indicated that GPE crosses the blood-CSF and the functional CSF-brain barriers. The longer half-life of GPE in the CNS may be due to its unique enzymatic stability.

A particle swarm optimizer with passive congregation.

This paper presents a particle swarm optimizer (PSO) with passive congregation to improve the performance of standard PSO (SPSO). Passive congregation is an important biological force preserving swarm integrity. By introducing passive congregation to PSO, information can be transferred among individuals of the swarm. A particle swarm optimizer with passive congregation (PSOPC) is tested with a set of 10 benchmark functions with 30 dimensions and compared to a global version of SPSO (GSPSO), a local version of SPSO (LSPSO), and PSO with a constriction factor (CPSO), respectively. Experimental results indicate that the PSO with passive congregation improves the search performance on the benchmark functions significantly.

Pharmacokinetics of glycine-proline-glutamate, the N-terminal tripeptide of insulin-like growth factor-1, in rats.

Glycine-proline-glutamate (GPE) is the N-terminal tripeptide of insulin-like growth factor-1 and has been shown to be neuroprotective following ischemia-induced brain injury. The pharmacokinetics of GPE were studied in adult rats since GPE is a candidate for use in neuroprotection therapies. To measure plasma concentrations of GPE a novel radioimmunoassay was developed whereby GPE was initially derivatized with Bolton and Hunter reagent before use in a standard homologous assay against the Bolton and Hunter iodinated form. The derivatized GPE radioimmunoassay showed a 83% recovery of unlabeled GPE and complete parallel displacement with rat plasma. The simplicity and speed of the assay described here indicate an exciting new use for a previously described technology. The pharmacokinetic studies were conducted in adult rats using a single bolus intravenous injection of GPE at 30 or 100 mg/kg and showed that GPE was rapidly cleared from the circulation. In addition, evidence of the route of the metabolic degradation of GPE is presented. The findings presented here are the first description of the pharmacokinetics of GPE and suggest that, because of its very short half-life in plasma, continuous intravenous infusion of GPE may be the preferred route of administration for use in future neuroprotection therapies.

Inhibition of proteolysis in luminal extracts from the intestine of the brushtail possum.

The proteolytic activity of luminal extracts from five regions (duodenum, jejunum, ileum, caecum and colon) of the brushtail possum intestine towards bovine serum albumin (BSA) and human luteinizing hormone releasing hormone (LHRH) was investigated. There were no significant differences in degradation rates between fresh and previously frozen extracts from any region of the possum intestine. The inhibition of degradation of BSA by luminal extracts from two regions (jejunum and ileum) and of LHRH from four regions (jejunum, ileum, caecum and colon) was evaluated. Soybean trypsin-chymotrypsin inhibitor (SBTI), sodium deoxycholate, Carbopol 934P, bacitracin and bestatin significantly inhibited the degradation of both LHRH and BSA (P < 0.05). SBTI almost totally inhibited the proteolysis of BSA and the peptidolysis of LHRH in extracts from the small intestine. This finding suggests that serine proteases such as chymotrypsin are responsible for the protein and peptide degradation in luminal extracts. It is concluded that including serine protease inhibitors in a formulation may enhance oral delivery of bioactive peptides and proteins to possums.

Enzymatic degradation of luteinizing hormone releasing hormone (LHRH) by mucosal homogenates from the intestine of the common brushtail possum (Trichosurus vulpecula).

The peptidolytic activity of fresh and frozen mucosal homogenates from five regions (duodenum, jejunum, ileum, caecum and colon) of possum intestine from Trichosurus vulpecula towards human Luteinizing Hormone Releasing Hormone (LHRH) was investigated. The rank of order of specific peptidolytic activity of the mucosal homogenates was jejunum > ileum > caecum> duodenum = colon, with a 3 to 4 fold difference between the least and the most active segment in both frozen and fresh samples. The formation of peptides LHRH (1-3), LHRH (1-4) and LHRH (1-5) suggest endopepetidase-24.18, endopeptidase-24.15 and angiotensin converting enzyme (ACE) might be responsible for the peptide degradation in mucosal homogenates. The inhibition of LHRH degradation by mucosal homogenates was evaluated in four regions (jejunum, ileum, caecum and colon) of possum intestine. Ethylenediaminetetraacetic acid (EDTA, 5 mM), sodium deoxycholate (SDA, 10 mM) and bacitracin (3.5 or 9 mM) inhibited the degradation of LHRH in mucosal homogenates from small intestine and hindgut. However, the serine protease inhibitor, soybean trypsin-chymotrypsin inhibitor (SBTI), did not prevent degradation of LHRH. It is concluded that combining peptides with inhibitors may enhance oral delivery of bioactive peptides or proteins to possums.

Protein and peptide degradation in the intestine of the common brushtail possum (Trichosurus vulpecula).

A protein (bovine serum albumin: BSA) and a peptide (luteinizing hormone releasing hormone: LHRH) were used to evaluate proteolytic activity in the intestine of common brushtail possums (Marsupiala, Trichosurus vulpecula). Luminal and mucosal extracts were isolated from the duodenum, jejunum, ileum, caecum, proximal colon and distal colon, their protein content assessed and specific activities in metabolising LHRH and BSA determined in vitro. The degradation of LHRH by luminal extracts was compared with that by the pancreatic enzymes, chymotrypsin, trypsin, and elastase. The protein concentration (microg x mg-1) of mucosal extract in the duodenum was higher ( P<0.05) than in the proximal colon, but that of luminal extracts did not differ significantly between regions. Proteolytic activity of luminal extracts was greater ( P<0.01) in the jejunum and ileum than in the hindgut. In the small intestine, proteolytic activity of luminal enzymes far exceeded that of mucosal enzymes ( P<0.05). All three pancreatic enzymes hydrolysed LHRH, but chymotrypsin had the greatest activity. This study has demonstrated that, in possums, proteolysis occurs primarily in the small intestine through luminal enzymes, with chymotrypsin playing a major role. The possum hindgut contributes little to the metabolism of peptides and proteins, identifying it as a potential site to target for their absorption following oral delivery.

Olfactory associative learning in Caenorhabditis elegans is impaired in lrn-1 and lrn-2 mutants.

The C. elegans mutants, lrn-1 and lrn-2, are impaired in associative learning using conditioned taste cues. Both mutants are defective in associative learning about appetitive and aversive events, indicating that lrn-1 and lrn-2 exert effects across motivational boundaries. In a new olfactory associative learning paradigm, in which wild type worms learn to avoid a previously attractive diacetyl odor after it has been paired with an aversive acetic acid solution, lrn-1 and lrn-2 are impaired. Although defective in associative learning using a conditioned olfactory cue, nonassociative learning (habituation and dishabituation) using this same olfactory cue is unaffected. The discovery that lrn-1 and lrn-2 are defective in associative learning with both taste and olfactory cues may suggest that associative learning in different sensory modalities converges on a common genetic pathway in C. elegans that is subserved by lrn-1 and lrn-2.

Mutations that prevent associative learning in C. elegans.

The nematode Caenorhabditis elegans offers a promising system for the reductionist study of learning and memory. In this article, classical conditioning in C. elegans is demonstrated with a variety of associative learning assays. These assays allowed for the isolation and behavioral characterization of 2 mutant C. elegans lines impaired in associative learning. Both lines show no short-term or long-term associative conditioning; however, they appear relatively normal in tests of nonassociative learning and sensorimotor function. In combination with the well-described genetics and neuroanatomy of C. elegans, the isolation of mutants selectively, yet completely, blocked in associative learning provides the basis for an effective characterization of the cellular and molecular aspects of associative learning.

Satellite cell proliferation in the adult rat trigeminal ganglion results from the release of a mitogenic protein from explanted sensory neurons.

Explant of trigeminal ganglia neurons in adult rats induces perineuronal glial proliferation of primarily satellite cells as opposed to Schwann cells. This proliferation begins at 15 h after explant culture and by 27 h there is a significant increase in glial proliferation as measured by scintillation counts of [3H]thymidine. Blocking protein synthesis between 0 and 3.5 h after explant culture (early) results in an enhanced proliferative response, while blocking protein synthesis between 3.5 and 7 h (late) causes a complete block of the proliferative response assessed at 27 h. Conditioned media experiments demonstrate that both the mitogenic and inhibitory signals are diffusible and heat labile. Finally, the addition of neurotrophic factors to rescue injured ganglionic neurons attenuates the proliferative glial response suggesting that injured neurons produce and release signals that induce glial proliferation.