The Overlap Subgroup of Functional Dyspepsia Exhibits More Severely Impaired Gastric and Autonomic Functions.

GOALS: A combination of multiple tests was introduced to noninvasively investigate the differences in pathophysiologies among functional dyspepsia (FD) subgroups, including postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlap. BACKGROUND: It has not been extensively evaluated whether different pathophysiologies are involved in FD subgroups. STUDY: This multicenter study included 364 FD patients fulfilling Rome IV criteria and 47 healthy controls. A combined noninvasive gastric and autonomic function test was performed: The electrogastrogram and electrocardiogram were recorded simultaneously in the fasting state and after a drink test. Symptoms after drinking were recorded using visual analog scale. RESULTS: (1) Compared with HC, FD patients showed a decreased maximum tolerable volume (MTV) ( P <0.01) and percentage of normal gastric slow waves [normal gastric slow waves (%NSW)] ( P <0.01), and increased postdrinking symptoms, anxiety ( P <0.01), and depression ( P <0.01). The drink reduced %NSW in both FD patients and HC; however, the effect was more potent in patients. (2) The PDS and overlap groups displayed a reduced MTV ( P <0.05). The overlap group exhibited a higher symptom score at 30 minutes after drinking, and higher anxiety and depression scores, and a higher sympathovagal ratio than the EPS ( P <0.05 for all) and PDS ( P <0.01 for all). (3) In the PDS subgroup, the MTV, postprandial sympathovagal ratio, and depression were associated with the overall dyspepsia symptom scale (DSS, P =0.034, 0.021, 0.043, respectively). No significant associations were found in the other 2 subgroups. CONCLUSIONS: The combination of multiple tests can detect pathophysiological abnormities in FD patients. Overall, patients with overlap symptoms display more severe pathophysiologies.

Investigating the relationship between fluctuations in daily milk yield as resilience indicators and health traits in Holstein cattle.

Disease-related milk losses directly affect dairy herds' profitability and the production efficiency of the dairy industry. Therefore, this study aimed to quantify phenotypic variability in milk fluctuation periods related to diseases and to explore milk fluctuation traits as indicators of disease resilience. By combining high-frequency daily milk yield data with disease records of cows that were treated and recovered from the disease, we estimated milk variability trends within a fixed period around the treatment day of each record for 5 diseases: udder health, reproductive disorders, metabolic disorders, digestive disorders, and hoof health. The average milk yield decreased rapidly from 6 to 8 d before the treatment day for all diseases, with the largest milk reduction observed on the treatment day. Additionally, we assessed the significance of milk fluctuation periods highly related to diseases by defining milk fluctuations as a period of at least 10 consecutive days in which milk yield fell below 90% of the expected milk production values at least once. We defined the development and recovery phases of milk fluctuations using 3,847 milk fluctuation periods related to disease incidences, and estimated genetic parameters of milk fluctuation traits, including milk losses, duration of the fluctuation, variation rate in daily milk yield, and standard deviation of milk deviations for each phase and their genetic correlation with several important traits. In general, the disease-related milk fluctuation periods lasted 21.19 ± 10.36 d with a milk loss of 115.54 ± 92.49 kg per lactation. Compared with the development phase, the recovery phase lasted an average of 3.3 d longer, in which cows produced 11.04 kg less milk and exhibited a slower variation rate in daily milk yield of 0.35 kg/d. There were notable differences in milk fluctuation traits depending on the disease, and greater milk losses were observed when multiple diseases occurred simultaneously. All milk fluctuation traits evaluated were heritable with heritability estimates ranging from 0.01 to 0.10, and moderate to high genetic correlations with milk yield (0.34 to 0.64), milk loss throughout the lactation (0.22 to 0.97), and resilience indicator (0.39 to 0.95). These results indicate that cows with lower milk losses and higher resilience tend to have more stable milk fluctuations, which supports the potential for breeding for more disease-resilient cows based on milk fluctuation traits. Overall, this study confirms the high effect of diseases on milk yield variability and provides insightful information about their relationship with relevant traits in Holstein cattle. Furthermore, this study shows the potential of using high-frequency automatic monitoring of milk yield to assist on breeding practices and health management in dairy cows.

A new chronological framework for Chuandong Cave and its implications for the appearance of modern humans in southern China.

Chuandong Cave is an important Late Paleolithic site because it documents the early appearance of bone tools in southern China. We used the single-aliquot regenerative-dose protocol for optically stimulated luminescence dating to improve the precision of the chronology for the Chuandong Cave sedimentary sequence. The age of each layer was determined using a Bayesian modeling approach which combined optically stimulated luminescence ages with published AMS 14C dates. The results showed that Layer 10 began accumulating since 56 ± 14 ka and provides the upper age limit for all artifacts from the sequence. Bone awl tools from Layer 8, the earliest grinding bone tools in this site, were recovered within sediments between 40 ± 7 ka and 30 ± 4 ka. Layer 8 also indicates the appearance of modern humans in the Chuandong Cave sequence. Layers 4-2, ranging from 15 ± 3 ka until 11 ± 1 ka and including the Younger Dryas period, contain a few bone awls and an eyed bone needle. The shift from bone awls to eyed bone needles in the Chuandong Cave sequence indicates that modern humans adapted to the changing climate of southern China. We conclude that modern human behavior in bone tools appeared in southern China as early as 40 ± 7 ka, became more sophisticated during the Last Glacial Maximum, and spread more widely across southern China during the Younger Dryas.

Association Between Serum Homocysteine Levels and Severity of Diabetic Kidney Disease in 489 Patients with Type 2 Diabetes Mellitus: A Single-Center Study.

BACKGROUND This study from a single center aimed to investigate the association between serum homocysteine (Hcy) levels and severity of diabetic kidney disease (DKD) in 489 patients with type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS A total of 1163 patients with T2DM, including 674 T2DM without kidney disease (T2DM group) and 489 T2DM with DKD (DKD group), were evaluated. The DKD group was subdivided according to the chronic kidney disease (CKD) and albuminuria staging criteria in "Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline" to quantify the severity of DKD: CKD stage 1 (n=164), CKD stage 2 (n=103), CKD stage 3 (n=95), CKD stage 4 (n=71), and CKD stage 5 (n=56) and stage A1 (n=57), stage A2 (n=250), and stage A3 (n=182), respectively. Peripheral blood was collected after 8 hours of fasting to test Hcy levels. RESULTS In CKD stages, Hcy levels gradually increased with increasing DKD severity (CKD stage 1 to 5); while in albuminuria stages, Hcy levels did not gradually increase with increasing DKD severity (stage A1 to A3). Hcy was an independent risk factor for CKD stages 2-5 (P<0.05), and had no effect on the albuminuria stages (P>0.05), while it may indirectly affect the occurrence of albuminuria stages through its impact on estimated glomerular filtration rate. CONCLUSIONS The relationship between Hcy level and DKD severity was related to the different staging methods used. Hcy was an independent risk factor for CKD stages but not albuminuria stages.

Synthesis of the alkylated active metabolite of tipidogrel.

Tipidogrel (3), an effective anti-platelet drug candidate working by irreversibly inhibiting P2Y12 receptor, holds great promise in overcoming clopidogrel resistance and increasing bioavailability. As a prodrug like other thienopyridines, it metabolizes through thiophene ring opening to form active metabolites 3a and 3b, nevertheless they are easily to form disulfide bond. Derivatization of 3a and 3b via alkylation with MPBr can prevent disulfide conjugation and ensure reliable pharmacokinetic results. Thus, in order to support its pre-clinical studies on efficiencies in the formation of tipidogrel active metabolites, 13a and 13b were synthesized via seven steps of chemosynthesis and incubation with MPBr in rat plasma in vitro. The resulting crude productions were purified by semi-preparative HPLC to give Z configuration 13a and E configuration 13b. In LC-MS/MS spectra, they showed identical fragmentation pattern and retention time with M-13a and M-13b, the MPBr-derivatives of active metabolites of tipidogrel in rats. Thus, 13a and 13b were the anticipated alkylated active metabolite of tipidogrel. In addition, in the nucleophilic substitution of thioacetate with compound 11, besides the anticipated compounds 12a and 12b, their isomers compounds 12c and 12d were detected, whose structures were confirmed and the corresponding mechanism was presented.

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents.

A series of novel pazopanib derivatives, 7a-m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by (1)H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

Synthesis and biological evaluation of substituted desloratadines as potent arginine vasopressin V2 receptor antagonists.

Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

Crystal structure of 9-(4-bromo-but-yl)-9H-fluorene-9-carb-oxy-lic acid.

The title compound, C18H17BrO2, is a key inter-mediate in the synthesis of lomitapide mesylate, a microsomal triglyceride transfer protein inhibitor. Its asymmetric unit contains two independent mol-ecules with slightly different conformations; the mean planes of the 4-bromo-butyl and carboxyl-ate groups in the two mol-ecules form dihedral angles of 24.54 (12) and 17.10 (18)°. In the crystal, carboxyl-ate groups are involved in O-H⋯O hydrogen bonding, which leads to the formation of two crystallographically independent centrosymmetric dimers. Weak inter-molecular C-H⋯O inter-actions further link these dimers into layers parallel to the bc plane.

5-(2-Cyano-benz-yl)-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-2-yl acetate.

In the title mol-ecule, C17H16N2O2S, the tetra-hydro-pyridine ring exhibits a half-chair conformation. The mean planes of the ester chain and benzene ring are twisted by 5.5 (1) and 81.32 (5)°, respectively, from the plane of thio-phene ring. In the crystal, weak C-H⋯O inter-actions link mol-ecules related by translation along [100] into chains.

1-(4,5,6,7-Tetra-hydro-thieno[3,2-c]pyridin-5-yl)-2-{4-[3-(trifluoro-meth-yl)phen-yl]piperazin-1-yl}ethanone.

In the title mol-ecule, C(20)H(22)F(3)N(3)OS, the piperazine ring has a chair conformation, and the N-C(=O)-C-N torsion angle is -59.42 (14)°. In the crystal, weak C-H⋯O and C-H⋯π inter-actions link the mol-ecules into layers parallel to (101).

5-(2-Chloro-benz-yl)-4,5,6,7-tetra-hydro-thieno[3,2-c]pyridin-2-yl acetate.

In the title compound, C(16)H(16)ClNO(2)S, the benzene and thio-phene rings make a dihedral angle of 72.60 (4)°. In the crystal, weak C-H⋯O inter-actions are observed.

1,3-Dimethyl-1H-indazol-6-amine.

The mol-ecular skeleton of the title compound, C(9)H(11)N(3), is almost planar, with a maximum deviation of 0.0325 (19) Šfor the amino N atom. In the crystal, N-H⋯N hydrogen bonds establish the packing.

Exploring milk loss and variability during environmental perturbations across lactation stages as resilience indicators in Holstein cattle.

Genetic selection for resilience is essential to improve the long-term sustainability of the dairy cattle industry, especially the ability of cows to maintain their level of production when exposed to environmental disturbances. Recording of daily milk yield provides an opportunity to develop resilience indicators based on milk losses and fluctuations in daily milk yield caused by environmental disturbances. In this context, our study aimed to explore milk loss traits and measures of variability in daily milk yield, including log-transformed standard deviation of milk deviations (Lnsd), lag-1 autocorrelation (Ra), and skewness of the deviations (Ske), as indicators of general resilience in dairy cows. The unperturbed dynamics of milk yield as well as milk loss were predicted using an iterative procedure of lactation curve modeling. Milk fluctuations were defined as a period of at least 10 successive days of negative deviations in which milk yield dropped at least once below 90% of the expected values. Genetic parameters of these indicators and their genetic correlation with economically important traits were estimated using single-trait and bivariate animal models and 8,935 lactations (after quality control) from 6,816 Chinese Holstein cows. In general, cows experienced an average of 3.73 environmental disturbances with a milk loss of 267 kg of milk per lactation. Each fluctuation lasted for 19.80 ± 11.46 days. Milk loss traits are heritable with heritability estimates ranging from 0.004 to 0.061. The heritabilities differed between Lnsd (0.135-0.250), Ra (0.008-0.058), and Ske (0.001-0.075), with the highest heritability estimate of 0.250 ± 0.020 for Lnsd when removing the first and last 10 days in milk in a lactation (Lnsd2). Based on moderate to high genetic correlations, lower Lnsd2 is associated with less milk losses, better reproductive performance, and lower disease incidence. These findings indicate that among the variables evaluated, Lnsd2 is the most promising indicator for breeding for improved resilience in Holstein cattle.

Synthesis and antihistamine evaluations of novel loratadine analogues.

A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H(1) antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.

[Synthesis of thienopyridine derivatives and its anti-platelet activity in vivo].

To explore novel ADP receptor inhibitors with anti-thrombotic activity, eighteen compounds were synthesized and their structures were confirmed by 1H NMR and MS. The results showed that the activity of compound C1 was superior to ticlopidine in platelet aggregation inhibition tests in vivo and worthy for further investigation. Compounds A4, B2, C4 and C7 possessed moderate platelet aggregation inhibitory activities.

2-(Thio-phen-2-yl)ethyl 4-methyl-benzene-sulfonate.

In the title mol-ecule, C(13)H(14)O(3)S(2), the thio-phene and benzene rings form a dihedral angle of 13.86 (13)°. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into layers parallel to the ab plane.

1-[4-(3-{[5-(4-Chloro-phen-yl)furan-2-yl]methyl-idene-amino}-2,5-dioxoimidazol-idin-1-yl)but-yl]-4-methyl-piperazine-1,4-diium dichloride hemihydrate.

The title compound, C(23)H(30)ClN(5)O(3) (2+)·2Cl(-)·0.5H(2)O, was synthesized by N-alkyl-ation of 1-({[5-(4-chloro-phen-yl)-2-furan-yl]methyl-ene}amino)-2,4-imidazolidinedione with 1-bromo-4-chloro-butane, and N-methyl-piperazine. In the crystal, the cations, anions and water mol-ecules are linked by O-H⋯Cl and N-H⋯Cl hydrogen bonds.

1-(2-Nitro-benz-yl)-1H-pyrrole-2-carbaldehyde.

In the title compound, C(12)H(10)N(2)O(3), the five- and six-membered rings form a dihedral angle of 83.96 (6)°. The nitro group is twisted by 5.92 (8)° from the plane of the attached benzene ring. In the crystal, weak inter-molecular C-H⋯O hydrogen bonds link the mol-ecules into columns in the [100] direction, with a short distance of 3.725 (3) Šbetween the centroids of benzene rings inside these columns.

N-(5-Ethylsulfanyl-1,3,4-thiadiazol-2-yl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyri-din-5-yl)acetamide.

In the title compound, C(13)H(16)N(4)OS(3), a thienopyridine-derivative, the tetra-hydro-pyridine ring exhibits a half-chair conformation, and the folded conformation of the mol-ecule is defined by the N-C-C-N torsion angle of -78.85 (16)°. The crystal packing features inter-molecular C-H⋯N, N-H⋯N and C-H⋯O hydrogen bonds.

2-Methyl-6-nitro-2H-indazole.

In the title compound, C(8)H(7)N(3)O(2), the mol-ecular skeleton is almost planar with a maximum deviation of 0.0484 (9) Šfor the methyl C atom. In the crystal, weak inter-molecular C-H⋯N and C-H⋯O hydrogen bonds help to establish the packing.