[The Effect of Chronic Intermittent Hypoxia on Cognitive Function and Prefrontal Cortex Neurons in Rats].

OBJECTIVE: To determine the effect of chronic intermittent hypoxia on cognitive function and prefrontal cortex neurons in rats. METHODS: 48 adult male Wistar rats were randomly divided into two groups: control group and 50 mL/L intermittent hypoxia group (50 mL/L CIH). Rats in the CIH group were placed in the low oxygen tank, simulating intermittent hypoxia environment. At 7 d, 14 d, 21 d, and 28 d, the learning and memory ability of the rats was assessed with the Morris water maze (MWM) test; the expressions of cysteinyl aspartate specific protease (caspase)-8 protein in their prefrontal cortex were determined using Western blot method; the apoptosis of neurons was detected by the TdT mediated UTP nick end labeling (TUNEL) method. RESULTS: Compared with the controls, the CIH rats had significantly prolonged escape latency at 14 d, 21 d, and 28 d (P<0. 05) and decreased target quadrant time (P<0. 05). The prolonged escape latency increased and target quadrant time shortened with length of exposure to hypoxia (P<0. 05). Compared with controls, the CIH rats had gradually increased caspase-8 in their frontal cortex neurons, peaked at 28 d (P<0. 05). The CIH rats showed obvious structural damage and reduced neuron density in their frontal cortex neurons. They had higher levels of nerve cell apoptosis (P<0. 05), with apoptosis index increasing with length of exposure to hypoxia (P<0. 05). CONCLUSION: Severe chronic intermittent hypoxia can lead to pathological changes of frontal,cortex of rats, possibly

Lugol chromoendoscopic screening for esophageal dysplasia/early squamous cell carcinoma in patients with esophageal symptoms in low-risk region in China.

Detection of esophageal dysplasia/early esophageal squamous cell carcinoma (ESCC) is essential for improving 5-year survival. The aim of this prospective study was to evaluate whether Lugol chromoendoscopy improves the detection of esophageal dysplasia/early ESCC in patients with esophageal symptoms in a low-incidence region in China. Eligible patients were randomly assigned into two groups who received routine endoscopy or Lugol chromoendoscopy. During endoscopy, between one and five biopsies were taken from visible lesions for routine endoscopy, or unstained areas of >0.5 cm in diameter for Lugol chromoendoscopy. In total, 812 patients were enrolled, 395 for routine endoscopy and 417 for Lugol chromoendoscopy. The overall detection rate of esophageal dysplasia/early ESCC was 10.6% (86/812), the detection rates were 7.3% (29/395) and 13.7% (57/417) in routine and chromoendoscopy groups, respectively (χ2=8.58, P=0.003). The detection rates were 8.3% (48/580), 17.2% (17/99) and 16.5% (22/133), respectively, in patients with reflux, dysphagia and globus sensation symptoms. In the chromoendoscopy group, 213 patients had unstained lesions of >0.5 cm, the detection rates of dysplasia/early carcinoma were 5.3% (4/76) in those with lesions of 0.5-1.0 cm, and 37.2% (51/137) in those with lesions >1.0 cm (χ2=21.46, P<0.001). These results indicate that Lugol chromoendoscopy improves the detection rate of esophageal dysplasia/early carcinoma in patients with esophageal symptoms compared with routine endoscopy. We propose that Lugol chromoendoscopy must therefore be considered in addition to routine endoscopy in patients with esophageal symptoms.

Design, synthesis and fungicidal activity of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e] azepine-6-one derivatives.

BACKGROUND: Macrocyclic compounds with an oxime ether side chain, discovered in Wang's group, showed good fungicidal activity. However, the long synthetic route makes the cost too high for them to be developed further as practical fungicides. Alternative compounds with good fungicidal activity and an easier synthesis than the above-mentioned macrolactams were sought, and a series of 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) were designed and bioassayed. RESULTS: The structures were confirmed by (1) H NMR, (13) C NMR and LC-MS. The bioassay showed that about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) displayed good fungicidal activity against Sclerotinia sclerotiorum (Lib.) de Bary, with EC50 values <15 µg mL(-1) . 11-(n-Butyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-05), 11-(4-nitrobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-12) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of <2.5 µg mL(-1) , much better than the commercial fungicide chlorothalonil with an EC50 value of 7.16 µg mL(-1) . In addition, about half of the 11-alkoxyimino-5,6-dihydro-dibenzo[b,e]azepine-6-one derivatives (4) had good fungicidal activity against Botrytis cinerea (De Bary) Whetzel, with EC50 values of <10 µg mL(-1) . 11-(2-Fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-16), 11-(3-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-17) and 11-(2-chloro-6-fluorobenzyloxyimino)-5,6-dihydro-dibenzo[b,e]azepine-6-one (4A-21) displayed excellent fungicidal activity, with EC50 values of 3.73, 2.54 and 3.20 µg mL(-1) respectively, comparable with the commercial fungicide procymidon with an EC50 value of 2.45 µg mL(-1) . Their structure-activity relationship is discussed. CONCLUSIONS: The present work demonstrates that the title compounds show promise as fungicides.

Synthesis, fungicidal activity, and structure-activity relationship of spiro-compounds containing macrolactam (macrolactone) and thiadiazoline rings.

Two series of novel spiro-compounds containing macrolactam or macrolactone and thiadiazoline rings, 1-thia-2-alkylimino-3,4,9-triaza-10-oxospiro[4.15]eicosyl-3-ene (4F) and 1-thia-2-alkylimino-3,4-diaza-9-oxa-10-oxospiro[4.15]eicosyl-3-ene (4G), were synthesized from 12-oxo-1,15-pentadecanlactam and 12-oxo-1,15-pentadecanlactone, respectively. Their structures were confirmed by elemental analysis, (1)H NMR, and (13)C NMR. The conformation of compounds 4F was determined via the crystal structure of a representative compound (4F(6)). The bioassay showed that compounds 4F have much better fungicidal activity against five fungi ( Botrytis cinerea Pers., Sclerotinia sclerotiorum , Rhizoctonia solani Kuhn., Phomopsis asparagi Sacc., and Pyricularia oryzae Cav.) than compounds 4G. The fact above showed that the presence of a hydrogen-bonding donor for the fungicidal activity of macrocyclic compounds is very important. 4F(6) showed excellent fungicidal activity against P. oryzae, which is much better than the commercial fungicide isoprothiolane, and 4F(13) showed excellent fungicidal activity against P. oryzae and good fungicidal activity against P. asparagi.

Determination of 7B3 residues in cotton plants by liquid chromatography/mass spectrometry.

A method was developed for the determination of 7B3 (12-propyloxyimino-1,15-pentadecanlactam), a novel macrolactam fungicide, by liquid chromatography/mass spectrometry (LC/MS) with positive electrospray ionization (ESI+). The method used a reversed-phase C18 column and acetonitrile-water (60 + 40, v/v) mobile phase. The quick, easy, cheap, effective, rugged, and safe method was used for extraction of 7B3 from cotton plants, which involved the extraction of 10 g homogenized sample with 10 mL acetonitrile, followed by the addition of 4 g anhydrous MgSO4 and 1.0 g NaCl. After centrifugation, 1 mL of the buffered acetonitrile extract was transferred into a tube containing 50 mg primary secondary amine sorbent and 100 mg anhydrous MgSO4. After shaking and centrifugation, the final extract was transferred to an autosampler vial for concurrent analysis by LC/MS. The results of 7B3 determined by LC/MS in the selective ion monitoring mode were linear, and the matrix effect of the method was evaluated. The average recoveries of 7B3 fortified at different levels were within 84.1-100.2%, and the relative standard deviations were <7.5% for all samples analyzed. The method limit of detection and the limit of quantitation values were 0.03 and 0.1 mg/kg, respectively. The proposed method was successfully applied to determine 7B3 residues in practical samples. This method is sensitive, accurate, reliable, simple, and safe.

Synthesis and herbicidal activity of 12-(aryloxyacyloxyimino)-1,15-pentadecanlactone derivatives.

A series of novel 12-(aryloxyacyloxyimino)-1,15-pentadecanlactone derivatives (3) were synthesized, and their structures including configuration of C=N bond were confirmed by (1)H NMR, elemental analysis and X-ray diffraction analysis. The bioassay showed that some of them exhibited excellent herbicidal activity against Amaranthus tricolor L. The activity of compounds 3 except compounds 3A1-2 was much higher than the commercial herbicide 2,4-D and the activity of about half of compounds 3 was comparable to the commercial herbicide tribenuron-methyl. The further bioassay showed that the representative of compounds 3, 3A1-12, exhibited excellent herbicidal activity not only against dicotyledon, such as Amaranthus tricolor L., Cucumis sativus L., Glycine max L., and Phaseolus radiatus L., but also against monocotyledon, such as Zea mays L. and Oryza sativa L.

2-(4-Methoxyphenoxy)-6-methyl-3-oxo-3,6-dihydro-2H-pyran-4-yl benzoate.

The title compound, C(20)H(18)O(6), has been synthesized from 4-methoxy-phenyl 3-O-benzo-yloxy-α-l-rhamnopyran-oside by oxidation on treatment with pyridinium dichromate in the presence of acetic anhydride. In the mol-ecule, the pyran ring adopts an envelope conformation with the O atom at the flap position. Weak inter-molecular C-H⋯O hydrogen bonding is present in the crystal structure.

Design, synthesis, and fungicidal activity of macrolactones and macrolactams with a sulfonamide side chain.

Four series of novel macrolactones and macrolactams12-alkylsulfonamido-1,15-pentadecanlactones ( 5), 12-alkylsulfonamido-15-methyl-1,15-pentadecanlactones ( 6), 12-alkylsulfonamido-1,15-pentadecanlactams ( 7), and N-(alkylsulfonamidoethyl)-1,12-dodecanlactams ( 8)were designed and synthesized from readily available 2-nitrocyclododecanone or cyclododecanone. Their structures were confirmed by (1)H NMR, IR, and elemental analysis. The bioassay showed that these compounds displayed fair to excellent fungicidal activity against Rhizoctonia solani Kuhn and have a gradual increase of fungicidal activity in the order of 6, 7, 8, and 5. Among them, compounds 5a, 5b, and 5c displayed excellent fungicidal activity against R. solani comparable with the commercial fungicide carbendazim. Above results illustrated that the rule on the relationship between the activity and hydrogen-bonding, namely the macrocyclic compounds with a hydrogen-bonding acceptor and a hydrogen-bonding donor on the ring and having a three methylenes distance between two polarizable groups have the best fungicidal activity against R. solani, has a general suitability to the macrocyclic compounds, and pesticide molecules may combine with a target enzyme by hydrogen-bonding. The facts, which compound 6 has a much lower fungicidal activity against R. solani than compound 5 but their difference in chemical structure is only that there is a methyl group on the C15 for compound 6 and none but hydrogen atom on the C15 for compound 5, indicated that a methyl group plays an inhibitory role to the fungicidal activity. It suggests that the existence of a methyl group with a great volume between two polarizable groups would interfere in the interaction of pesticide molecules and the target enzyme.

2-(Methyl-sulfan-yl)cyclo-dodeca-none tosyl-hydrazone.

The title compound, C(20)H(32)N(2)O(2)S(2), has been synthesized by the reaction of α-methyl-sulfanylcyclo-dodeca-none and p-toluene-sulfonyl-hydrazine. In the crystal structure, the conformation of the non-benzenoid ring is [3333] and the methyl-sulfanyl group is in the α-side exo position. The mol-ecules are linked by inter-molecular N-H⋯S hydrogen bonds.

Synthesis and fungicidal activity of macrolactams and macrolactones with an oxime ether side chain.

Three series of novel macrolactams and macrolactones--12-alkoxyimino-tetradecanlactam, 12-alkoxyiminopentadecanlactam, and 12-alkoxyiminodecanlactone derivatives (7A, 7B, and 7C)--were synthesized from corresponding 12-oxomacrolactams and 12-oxomacrolactone. Their structures were confirmed by 1H NMR and elemental analysis. The Z and E isomers of 7A and 7B were separated, and their configurations were determined by 1H NMR. These compounds showed fair to excellent fungicidal activities against Rhizoctonia solani Kühn. It is interesting that the Z and E isomers of most of the compounds have quite different fungicidal activities. The fact that the compounds have a gradual increase of fungicidal activity in the order of 7A, 7C, and 7B indicated that the macrocyclic derivatives with a hydrogen-bonding acceptor (=N-O-) and a hydrogen-bonding donor (-CONH-) on the ring, and a three methylenes distance (CH2CH2CH2) between these two functional groups, exhibited the best fungicidal activity. The bioassay also showed that 7B not only has good fungicidal activity but also may have a broad spectrum of fungicidal activities.

Synthesis and fungicidal activity of novel 2-oxocycloalkylsulfonylureas.

A series of 2-oxocycloalkylsulfonylureas (2) have been synthesized in a six-step, three-pot reaction sequence from readily available cyclododecanone, cycloheptanone, and cyclohexanone. Their structures were confirmed by IR, 1H NMR, and elemental analysis. The bioassay indicated that some of them possess certain fungicidal activity against Gibberella zeae Petch. In general, compounds containing a 12-membered ring (2A) are more active than those containing a 6- or 7-membered ring (2B, 2C). In the series 2A, the compounds in which R is a disubstituted phenyl or pyrimidyl showed better activity than those in which R is a monosubstituted phenyl or pyrimidyl, and aryl-substituted compounds have somewhat higher activity than those substituted by pyrimidyl. The further bioassay showed that the representative of 2A, 2A15, has good fungicidal activities against not only G. zeae Petch but also Botrytis cinerea Pers, Colletotrichum orbiculare Arx, Pythium aphanidermatum Fitzp, Fusarium oxysporum Schl. f. sp. Vasinfectum, etc.

A Randomised, Controlled Comparison of Low-Dose Polyethylene Glycol 3350 plus Electrolytes with Ispaghula Husk in the Treatment of Adults with Chronic Functional Constipation.

OBJECTIVE: To compare the efficacy and safety of polyethylene glycol (PEG) 3350 plus electrolytes (PEG+E; Movicol((R))) with that of ispaghula husk (psyllium; Konsyl((R))) in the treatment of constipation. PATIENTS: Male or female adults with chronic functional constipation. METHODS: This was a randomised, controlled, open-label, parallel-group trial. Study treatment was either PEG+E 13.8g/sachet dissolved in water twice daily or ispaghula husk 3.5g/sachet dissolved in water twice daily for a period of 2 weeks. Assessments were at baseline and after 1 and 2 weeks' therapy and by patient daily diary card. The primary outcome measures were weekly defaecation rate, stool consistency according to the Bristol Stool Form scale, time to first defaecation, and overall efficacy, which combined defaecation rate, stool consistency and difficulty on defaecation. Adverse effects were recorded and laboratory assessments were performed before and at the end of the treatment period. RESULTS: Sixty-three patients were randomised to each treatment group. Treatment was highly effective in 50/63 patients in the PEG+E group compared with 26/63 in the ispaghula husk group, and the overall efficacy rates were 92% and 73%, respectively (p = 0.005). PEG+E increased the mean weekly defaecation rate from 1.18 (SD 0.77) at baseline to 7.95 (SD 3.49) after 1 week and 8.48 (SD 3.55) after 2 weeks. In the ispaghula husk group the mean weekly defaecation rate increased from 1.33 (SD 0.68) at baseline to 5.33 (SD 2.81) after 1 week and to 5.71 (SD 2.49) after 2 weeks. The treatment differences for defaecation rates were all statistically significant (p < 0.001). Two weeks of treatment with PEG+E or ispaghula husk normalised stools in 55/63 (87.3%) and 42/63 (66.7%) of patients (p < 0.001). The incidence of adverse effects did not differ between groups and none were serious or required any treatment. Laboratory evaluations found no adverse effect from either treatment. CONCLUSION: The present study demonstrated that low-dose PEG 3350 plus electrolytes is more effective and more rapid in its onset of action than ispaghula husk, and is equally well tolerated.