[Application value of neutrophil lymphocyte ratio combined with age in the diagnosis of dual-phenotype hepatocellular carcinoma].

Objective: This study retrospectively analyzed the clinical medical records of patients with dual phenotypic liver cancer (DPHCC) and those (non-DPHCC) in the same period to seek quick and effective biomarkers for differential diagnosis. Methods: A retrospective study was conducted on 164 patients who underwent radical hepatocellular carcinoma resection at Affiliated Hospital of Nantong University from May 2017 to May 2020, including 29 patients with DPHCC, accounting for 17.7% (age: 53.9±10.0). There were 135 non-DPHCC patients, accounting for 82.3% (age, 62.6±9.1). The clinical records of the above patients were collected,including the basic information of the patients, clinical symptoms and signs, history of infection, laboratory test indexes one day before surgery, postoperative pathological report and other relevant data, The follow-up time was 18 months and the data were complete. By analyzing the clinical data of DPHCC patients and non-DPHCC patients in the same period, to find quick and effective differential diagnostic indicators, and to explore the indicators indicating poor prognosis of DPHCC patients. Results: One-way ANOVA showed significant differences in age, AFP[143(4.8-984.8) vs 9.9(2.8-71.3) µg/L], NLR (3.650±1.924 vs 2.220±1.486), neutrophil count, lymphocyte count, vascular infiltration rate, TNM stage, Chinese Hepatocellular carcinoma Staging (CNLC), Child grade, and Japanese General Staging Score (JIS) (P<0.05). Multivariate logistic regression analysis identified age(OR score:0.967,95%CI:0.860-0.957) and NLR(OR score:1.564,95%CI:1.205-2.029) as independent risk factors for DPHCC differential diagnosis. The receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficiency of NLR, and the best cut-off value was 2.586. The combination of age at onset improved the efficiency of differential diagnosis. When reaching the maximum diagnostic efficiency, the area under curve(AUC) was 0.836, the sensitivity was 89.66%, and the specificity was 65.93%. Conclusion: NLR combined with the age of disease has certain feasibility in predicting DPHCC and may be an effective index to distinguish DPHCC from non-DPHCC patients.

[Time to initial diagnosis of imported malaria and its influencing factors in Jiangsu Province].

OBJECTIVE: To investigate the health-seeking behaviors of imported malaria cases after returning to China, and to investigate the factors affecting the time to initial diagnosis, so as to provide the scientific evidence for early identification of imported malaria cases and prevention of severe cases development and secondary transmission. METHODS: The individual demographic features, and the disease onset and the time to initial diagnosis of imported malaria cases in Jiangsu Province in 2019 were captured from the National Notifiable Disease Report System and the Information Management System for Parasitic Disease Control in China. The characteristics of health-seeking behaviors and epidemiological features of imported malaria cases were descriptively analyzed, and the factors affecting the time to initial diagnosis of imported malaria cases after returning to China were identified using multivariate logistic regression analysis. RESULTS: A total of 244 imported malaria cases were reported in Jiangsu Province in 2019, and the time to initial diagnosis of the cases were 1-12 days, with mean time of (1.53 ± 1.65) days, with median time of one day. The highest number of malaria cases seeking healthcare services were found on the day of developing primary symptoms (76 cases, 31.1%), followed by on the second day (68 cases, 27.9%), on the third day (46 cases, 18.9%), and 54 cases (22.1%) received initial diagnosis 3 days following presence of primary symptoms, including 3 cases with initial diagnosis at more than one week. High proportions of imported malaria cases with a delay in the time to initial diagnosis were seen in migrant workers who returned to China in January (14 cases, 5.7%) and December (13 cases, 5.3%) and those aged between 41 and 50 years (32 cases, 13.1%). Multivariate logistic regression analysis showed relative short time to initial diagnosis among imported malaria cases returning to China on March [odds ratio (OR) = 0.16, P = 0.03, 95% confidence interval (CI): (0.03, 0.85)] and those with a history of overseas malaria parasite infections [OR = 0.36, P = 0.001, 95% CI: (0.19, 0.67)]. CONCLUSIONS: Timely health-seeking behaviors should be improved among imported malaria cases in Jiangsu Province, patients with a history of overseas malaria infections require faster health-seeking activities.

Synergistic antinociception between ZC88, an N-type voltage-dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain.

BACKGROUND: A combination of analgesic agents with different mechanisms can induce additive or synergistic analgesia. The N-type voltage-dependent calcium channel (N-VDCC) is a novel therapeutic target for pain control. In addition to providing effective pain relief when used alone, N-VDCC blockers produce synergistic analgesia when used in combination with opiates. However, the interaction between N-VDCC blockers and nonsteroidal anti-inflammatory drugs (NSAIDs) remains unclear. METHODS: Using isobolographic analysis and composite additive curve analysis, the antinociceptive interaction between ZC88, a selective N-VDCC blocker and ibuprofen, a classical NSAID, was investigated in two mouse models of visceral and somatic inflammatory pain. RESULTS: In the acetic acid writhing test, both ZC88 (10.5-42 mg/kg, intraperitoneally) and ibuprofen (50-200 mg/kg, orally) produced dose-dependent antinociception, with ED50 values of 27.2 and 100.5 mg/kg, respectively. ZC88 in combination with ibuprofen (ZC88 + ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimental ED50 (ED50 mix ) of this combination (34.5 mg/kg) was significantly lower than the theoretical ED50 (ED50 add ; 63.8 mg/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test, ZC88 or ibuprofen alone significantly reduced late-phase rather than early-phase pain, with ED50 values of 31.3 and 123.9 mg/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception of ZC88 + ibuprofen (40.6 mg/kg of ED50 mix vs. 77.6 mg/kg of ED50 add ). CONCLUSION: ZC88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain. SIGNIFICANCE: Because ZC88 + ibuprofen achieves the same antinociceptive effect at lower doses, the use of this combination could result in fewer dose-related untoward effects. The potentiation of ZC88 on ibuprofen-induced antinociception indicates that N-VDCC blocker has potential benefit to treat severe inflammatory pain.

The structure of greylag goose oxy haemoglobin: the roles of four mutations compared with bar-headed goose haemoglobin.

The greylag goose (Anser anser), which lives on lowlands and cannot tolerate hypoxic conditions, presents a striking contrast to its close relative the bar-headed goose (A. indicus), which lives at high altitude and possesses high-altitude hypoxia adaptation. There are only four amino-acid residue differences at alpha18, alpha63, alpha119 and beta125 between the haemoglobins of the two species. The crystal structure of greylag goose oxy haemoglobin was determined at 3.09 A resolution. Its quaternary structure is slightly different from that of the bar-headed goose oxy haemoglobin, with a rotation of 2.8 degrees in relative orientation of the two dimers. Of the four mutations, those at alpha119 and beta125 produce contact changes in the alpha(1)beta(1) interface and may be responsible for the differences in intrinsic oxygen affinity between the two species; those at alpha18 and alpha63 may be responsible for the differences in quaternary structure between the two species.

Crystallization and preliminary crystallographic studies of antibacterial polypeptide LCI expressed in Escherichia coli.

LCI is a type of novel antibacterial polypeptide secreted by a Bacillus subtilis strain. It consists of 47 residues with a molecular weight of 5468 Da. Using bioengineering, LCI was expressed in Escherichia coli DH5alpha with recombinant plasmid pBVAB16. It was crystallized using PEG 4000 as a precipitant. The crystal belongs to space group P6(2)22 or P6(4)22, with unit-cell parameters a = b = 29.30, c = 187.09 A, and diffracts to 2.44 A. A set of diffraction data to 2.8 A was collected.

Avian haemoglobins and structural basis of high affinity for oxygen: structure of bar-headed goose aquomet haemoglobin.

Haemoglobin from the bar-headed goose (Anser indicus) has higher oxygen affinity than that from its lowland relatives such as greylag goose (A. anser). The crystal structure of bar-headed goose aquomet haemoglobin was determined at 2.3 A resolution and compared with the structures of the goose oxy, human, horse and other avian haemoglobins and the sequences of other avian haemoglobins. Four amino-acid residues differ between greylag goose and bar-headed goose haemoglobins, among which Alaalpha119 and Aspbeta125 in bar-headed goose haemoglobin reduces the contacts between the alpha(1) and beta(1) subunits compared with Pro and Glu, respectively, and therefore may increase the oxygen affinity by loosening the alpha(1)beta(1) interface. Compared with human oxy haemoglobin, the relative orientation of two alphabeta dimers in the bar-headed goose aquomet and oxy Hbs are rotated by about 4 degrees, indicating a unique quaternary structural difference from the typical R state. This new 'R(H)' state is probably correlated with the higher oxygen affinity of bar-headed goose haemoglobin.

Transthyretin, thyroxine, and retinol-binding protein in human cerebrospinal fluid: effect of lead exposure.

Transthyretin (TTR), synthesized by the choroid plexus, is proposed to have a role in transport of thyroid hormones in the brain. Our previous studies in animals suggest that sequestration of lead (Pb) in the choroid plexus may lead to a marked decrease in TTR levels in the cerebrospinal fluid (CSF). The objectives of this study were to establish in humans whether TTR and thyroxine (T(4)) are correlated in the CSF, and whether CSF levels of Pb are associated with those of TTR, T(4), and/or retinol-binding protein (RBP). Eighty-two paired CSF and blood/serum samples were collected from patients undergoing clinical diagnosis of CSF chemistry. Results showed that the mean value of CSF concentrations for TTR was 3.33 +/- 1.60 microg/mg of CSF proteins (mean +/- SD, n = 82), for total T(4) (TT(4)) was 1.56 +/- 1.68 ng/mg (n = 82), for RBP was 0.34 +/- 0.19 microg/mg (n = 82), and for Pb was 0.53 +/- 0.69 microg/dl (n = 61 for those above the detection limit). Linear regression analyses revealed that CSF TTR levels were positively associated with those of CSF TT(4) (r = 0.33, p < 0.005). CSF TTR concentrations, however, were inversely associated with CSF Pb concentrations (r = -0.29, p < 0.05). There was an inverse, albeit weak, correlation between CSF TT(4) and CSF Pb concentrations (r = -0.22, p = 0.09). The concentrations of TTR, TT(4), and Pb in the CSF did not vary as the function of their levels in blood or serum, but RBP concentrations in the CSF did correlate to those of serum (r = 0.39, p < 0.0005). Unlike TTR, CSF RBP concentrations were not influenced by PB: These human data are consistent with our earlier observations in animals, which suggest that TTR is required for thyroxine transport in the CSF and that Pb exposure is likely associated with diminished TTR levels in the CSF.

Crystallization and preliminary crystallographic studies of bar-headed goose fluoromethaemoglobin with inositol hexaphosphate.

Bar-headed goose fluoromethaemoglobin (fluoromet-Hb) complexed with inositol hexaphosphate (IHP) has been crystallized using PEG 6000 as precipitant. The crystal belongs to space group P2(1), with unit-cell parameters a = 59.8, b = 72.0, c = 79.8 A, beta = 102.1 degrees, and diffracts to 2.5 A resolution. To prove the presence of IHP, the structure was determined by the molecular-replacement method. IHP was observed at the entrance to the central cavity between the N and C termini of two beta subunits.

Impaired glucose tolerance, diabetes, and cardiovascular disease risk factor profiles in the elderly. The Honolulu Heart Program.

OBJECTIVE: The relationship between glucose tolerance status and other cardiovascular disease (CVD) risk factors was evaluated in a cohort of Japanese-American men (n = 3,741) ages 71-93 years who participated in the fourth examination of the Honolulu Heart Program in 1991-1993. RESEARCH DESIGN AND METHODS: In this cross-sectional study, subjects were classified by reported diabetes and glucose tolerance status using questionnaires and the World Health Organization (WHO) criteria, respectively. RESULTS: The prevalence of reported diabetes was 17%. Among the men who completed an oral glucose tolerance test and had no history of diabetes (n = 1,900), 23% were diagnosed as diabetic and 39% had impaired glucose tolerance (IGT) by WHO criteria. The CVD risk factor profiles of men with IGT and diabetes were significantly more adverse compared with men with normal glucose tolerance after adjustment for age. The rates of hypertension, mean levels of BMI, waist-to-hip ratio, triglycerides, and fasting insulin were higher in men with IGT and diabetes compared with normal subjects. Opposite trends were observed for HDL cholesterol. Two-hour insulin was significantly higher among men with IGT and previously undiagnosed diabetes. Men with known diabetes had a lower physical activity index and higher fibrinogen levels than normal subjects. No significant differences were observed for current smoking and alcohol intake. Differences in risk factor levels by glucose tolerance status remained after adjustment for age, physical activity, BMI, and waist-to-hip ratio. CONCLUSIONS: These findings show that among elderly men of Japanese ancestry, impaired glucose tolerance and undiagnosed and known diabetes are highly prevalent, and these conditions are associated with adverse CVD factor profiles.

Preliminary three-dimensional model for nematode thick filament core.

Understanding the structure and the mechanism of assembly of thick filaments have been long-standing problems in the field of muscle biology. Cores which represent the backbones of thick filaments and consist of paramyosin and associated proteins were isolated from the nematode Caenorhabditis elegans. Electron microscopy of negatively stained and frozen hydrated cores was performed. The resulting images were analyzed by computing their Fourier transforms, three-dimensional reconstruction, and by modeling. A preliminary three-dimensional model is proposed in which the paramyosin constitutes an outer sheath of seven subfilaments about a set of inner 54-nm-long tubules which repeat every 72 nm. The subfilaments are not closely packed but require cross-linking by the internal tubules. Each subfilament consists of two strands of paramyosin molecules which are staggered by 72 nm with respect to one another. This stagger introduces a 22-nm gap between consecutive paramyosin molecules in each strand. An offset of the center of the inner tubules relative to the center of the gap of 6 nm was consistent with the images and their transforms. This model suggests that the nonhelical ends of paramyosin and the unpaired gap between adjacent paramyosin molecules contain sites for the interaction with the inner tubular proteins. The molecular interactions at this locus would appear to be critical in the assembly of thick filaments and their regulation.

Studies on quinazolines. 5. 2,3-dihydroimidazo[1,2-c]quinazoline derivatives: a novel class of potent and selective alpha 1-adrenoceptor antagonists and antihypertensive agents.

A series of 2-[(substituted phenylpiperazin-1-yl)methyl]- and 2-[(substituted phenylpiperidin-1-yl)methyl]-2,3-dihydroimidazo[1,2- c]quinazolin-5(6H)-ones or -5(6H)-thiones, and 3-[(substituted phenylpiperazin-1-yl)methyl]-2,3-dihydroimidazo[1,2-c]quinaz oline derivatives were synthesized, as conformationally restricted analogues of SGB-1534 and ketanserin, for evaluation as alpha-antagonists and antihypertensive agents. Most compounds containing a (substituted phenylipiperazinyl)methyl side chain displayed high binding affinity for alpha 1-adrenoceptor with no significant activity at alpha 2-sites. Compounds having a (substituted phenylpiperazinyl)methyl at the 3-position of 2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ring system had a better activity than those with the same substituent at the 2-position. Structure-activity relationships for alpha 1-adrenoceptor affinity are presented and indicate that compounds with substitution at the ortho position on the benzene ring of the phenylpiperazine side chain moiety are more potent than those without substitution and/or substitutions at the 3- and 4-positions. Computer-assisted superimposition of SGB-1534 and 20b showed little structural correspondence between the quinazolinone and 2,3-dihydroimidazo[1,2-c]quinazoline nucleus, and specific interactions of these molecular fragments with the receptor protein appear unlikely. Antihypertensive activity was evaluated via intravenous administration of each compound to spontaneously hypertensive rats, and compounds (16a, 16b, 20b, and 28b) illustrated similar efficacy to SGB-1534 when assessed after 6 h. The pA2 value for 16a against phenylephedrine in rat aorta was much higher than that of prazosin. On the basis of alpha 1-adrenoceptor affinity/selectivity in vitro and duration of antihypertensive action in vivo, compounds 20b and 28b warrant further evaluation.

The 2.3-A resolution structure of the maltose- or maltodextrin-binding protein, a primary receptor of bacterial active transport and chemotaxis.

The three-dimensional structure of the maltose- or maltodextrin-binding protein (Mr = 40,622) with bound maltose has been obtained by crystallographic analysis at 2.8-A resolution. The structure, which has been partially refined at 2.3 A, is ellipsoidal with overall dimensions of 30 x 40 x 65 A and divided into two distinct globular domains by a deep groove. Although each domain is built from two peptide segments from the amino- and carboxyl-terminal halves, both domains exhibit similar supersecondary structure, consisting of a central beta-pleated sheet flanked on both sides with two or three parallel alpha-helices. The groove, which has a depth of 18 A and a base of about 9 x 18 A, contains the maltodextrin-binding site. We have previously observed the same general features in the well-refined structures of six other periplasmic receptors with specificities for L-arabinose, D-galactose/D-glucose, sulfate, phosphate, leucine/isoleucine/valine, and leucine. The bound maltose is buried in the groove and almost completely inaccessible to the bulk solvent. The groove is heavily populated by polar and aromatic groups many of which are involved in extensive hydrogen-bonding and van der Waals interactions with the maltose. All the disaccharide hydroxyl groups, which form a peripheral polar surface approximately in the plane of the sugar rings, are tied in a total of 11 direct hydrogen bonds with six charged side chains, one Trp side chain, and one peptide backbone NH, and five indirect hydrogen bonds via water molecules. The maltose is wedged between four aromatic side chains. The resulting stacking of these aromatic residues on the faces of the glucosyl units provides a majority of the van der Waals contacts in the complex. The nonreducing glucosyl unit of the maltose is involved in approximately twice as many hydrogen bonds and van der Waals contacts as the glucosyl unit at the reducing end. The binding protein-maltose complex shows the best example of the extensive use of polar and aromatic residues in binding oligosaccharides. The tertiary structure of the maltodextrin-binding protein, along with the results of genetic studies by a number of investigators, has also enabled us for the first time to map the different regions on the surface of the protein involved in the interactions with the membrane-bound protein components necessary for transport of and chemotaxis toward maltodextrins. These sites permit distinction of the "open cleft" (without bound sugar) and closed (with bound sugar) conformations of the binding protein by the chemotactic signal transducer with which the maltodextrin-binding protein interacts.(ABSTRACT TRUNCATED AT 250 WORDS)

Crystal structure determination of mung bean trypsin inhibitor Lys fragment-bovine trypsin complex--molecular replacement, electron density map at 3.0 angstron resolution.

The orientation and position of the trypsin molecule in the complex crystal cell mung bean trypsin inhibitor Lys fragment (MBILF)-bovine trypsin (BTRY) have been successfully determined by molecular replacement method with the model of the refined bovine trypsin molecule. Starting from the BTRY coordinates which were oriented and located in the correct azimuth and position in the complex cell according to the result from rotation function and translation function, sim-weighted Fourier map with coefficients 2/Fo/-/Fc/ at 3.0 A resolution was calculated. Besides the electron density which is obviously attributed to itself, in the vicinity of the active site of BTRY the dense contour levels corresponding to the MBILF and and its boundary could be clearly seen in this map. The size of MBILF was approximately estimated at 15 x 15 x 25 A.