Impact of COVID-19 on acute ischemic stroke presentation and prognosis in a county-level stroke center.

OBJECTIVE: The COVID-19 pandemic has influenced regular medical procedures and health-seeking behaviors. In this study, we aimed to investigate the influence of the COVID-19 pandemic on the presentation and prognosis of acute ischemic stroke (AIS) patients in county-level stroke centers. PATIENTS AND METHODS: We retrospectively collected AIS patients during the strict lockdown period (January 24, 2020, to March 27, 2020) and the corresponding "new normal" period (2021) of the COVID-19 pandemic. Patients seen during the same timeframe in 2019 were enrolled as controls. Statistical analysis was conducted to compare the clinical characteristics of AIS patients who presented during the lockdown and new normal periods and those who presented during the pre-COVID-19 pandemic period. RESULTS: A total of 134 AIS patients presented during the lockdown period (the 2020 group), 207 patients in the pre-COVID-19 period (the 2019 group) and 201 patients in the "new normal" period (the 2021 group). Compared to the 2019 group, there was approximately 1/3 reduction in the number of patients who presented during the lockdown period, while the number of patients who received IVT or EVT was similar between the two groups. The number of patients, baseline characteristics, workflow intervals and clinical outcomes presented during the "new normal" period were similar between the 2019 and 2021 groups. Logistic regression showed that lockdown or new normal status were not risk factors associated with a poor outcome at 90 days. CONCLUSIONS: In county-level city stroke centers, the COVID-19 lockdown resulted in a reduction in the number of patients with AIS admitted to the hospital but had no effect on patients treated with IVT or EVT. Lockdown or new normal status did not influence the prognosis of AIS patients.

Apolipoprotein E Polymorphism and Frailty: Apolipoprotein ε4 Allele Is Associated with Fatigue but Not Frailty Syndrome in a Community-Dwelling Older Population Cohort.

OBJECTIVE: Frailty is known to be influenced by genetics, however, little evidence on the association of Apolipoprotein E (ApoE) genotype and frailty exists which we aim to investigate. DESIGN: This study is a cross-sectional analysis from a prospective longitudinal study cohort. SETTING AND PARTICIPANTS: Community-dwelling individuals aged 55 years and older from Beijing region in China. MEASUREMENTS: A total of 3,569 older adults with a mean age of 75.06(±6.79) years were included. We investigated the association between ApoE polymorphism and frailty syndrome using the frailty index (FI) and frailty phenotype (including association with individual components of the frailty phenotype). Logistic regressions were performed to investigate the relation between ApoE variants and frailty. RESULTS: There was no significant association between ApoE variants and frailty as assessed by the FI. In the age and sex-adjusted model, compared to the ApoE e3/e3 carriers ApoE e4 carriers had almost 1.5 times higher odds of being frail as assessed by the frailty phenotype. However, the significance was lost on the model with adjustment for cognitive impairment. Compared to the ApoE e3/e3 carriers ApoE e4 carriers had almost two times higher odds of fatigue. ApoE e4 heterozygotes had higher odds of fatigue compared to ApoE e4 non-carriers. No significant association was found between ApoE variants and other components of frailty phenotype. CONCLUSIONS: Our findings do not support an association between ApoE genotype and frailty irrespective of the frailty assessment tools. Fatigue in older adults is the only component of frailty phenotype influenced by ApoE genotype.

[A possible mechanism for low-level viremia occurrence in nucleos(t)ide analog-treated chronic hepatitis B patients].

The first-line nucleos(t)ide analogs (NAs) based antiviral drugs can effectively inhibit HBV replication and slow down the progression of chronic hepatitis B. However, about 20% of patients receiving standard NAs antiviral therapy will still develop low-level viremia (LLV). Therefore, understanding the occurrence mechanism of LLV will help to optimize antiviral treatment regimens and improve the prognosis of patients with chronic hepatitis B. This article systematically summarizes the possible mechanisms of LLV occurrence, and the important factor of NAs failure. Taking into account the unique limitations of NAs competitive inhibition of virus replication, weakening host's immune response is not enough to directly eliminate infected hepatocytes. This makes it difficult to achieve a complete virological response in some patients with the active compensatory proliferation of residual infected hepatocytes and the accompanying effective removal or dilution of covalent, closed, circular DNA (cccDNA) pools. Therefore, it is speculated that activating host immunity can eliminate infected liver cells and may be more conducive to address LLV.

Measures to prevent goggles from fogging during the treatment of Coronavirus Disease 2019.

During these challenging and unprecedented times for the global communities as they battle the COVID-19 pandemic, we found a simple and effective way to prevent the goggles fogging. We hope that it will help the healthcare professionals who are still troubled by the problem of fogging goggles.

[Clinical effects of vacuum sealing drainage in the treatment of alkali burn wounds].

Objective: To preliminarily observe the clinical effects of vacuum sealing drainage (VSD) in the treatment of alkali burn wounds. Methods: From June 2016 to March 2020, 60 male patients with alkali burns who met the inclusion criteria and hospitalized in the Affiliated Hospital of Jiangnan University were recruited in this prospectively randomized control study. According to the random number table, silver sulfadiazine group and VSD group were both allocated with 30 patients, aged (36±8) and (35±10) years respectively; with total burn area of (7.2±2.0) % and (8.5±3.0) % total body surface area respectively. After admission, patients in silver sulfadiazine group were treated with conventional silver sulfadiazine dressing change once a day after debridement; patients in VSD group were given continuous VSD treatment after debridement, with the negative pressure setting at -10.67 kPa, and the negative pressure materials were replaced every 6 to 8 days. On treatment day 1, 4, and 7, the exudate from the wounds of patients in silver sulfadiazine group and the wound drainage fluid of patients in VSD group were collected, the pH value was measured by a portable pH meter, and the volume of exudate/drainage fluid was measured. After 7, 14, and 21 days of treatment, the wound healing rates of patients were calculated in the two groups. Before treatment and 7 days after treatment, venous blood was collected from the patients in the two groups to detect the serum level of tumor necrosis factor α (TNF-α) and interleukin 8 (IL-8). Within treatment day 14, Visual Analogue Scale was used to assess the pain score of patients in the two groups during each time of dressing change. The medical costs and discharge satisfaction scores of patients in the two groups were recorded. Data were statistically analyzed with analysis of variance for repeated measurement, t test, and Bonferroni correction. Results: (1) On treatment day 1, 4, and 7, the pH values of the drainage fluid of patients in VSD group were 9.75±0.59, 9.01±0.46, and 8.13±0.28, respectively, which were significantly higher than 9.35±0.62, 8.18±0.18, and 7.58±0.09 of exudate of patients in silver sulfadiazine group (t=2.03, 6.80, 7.56, P<0.05 or P<0.01). On treatment day 1 and 4, the volumes of drainage fluid of patients in VSD group were (553±83) and (239±65) mL respectively, which were significantly higher than (440±77) and (175±49) mL of exudate of patients in silver sulfadiazine group (t=3.44, 2.24, P<0.05). On treatment day 7, the volume of drainage fluid of patients in VSD group was (21±8) mL, which was significantly lower than (149±44) mL of exudate of patients in silver sulfadiazine group (t=-12.61, P<0.01). (2) After 7, 14, and 21 days of treatment, the wound healing rates of patients in VSD group were (39±6) %, (74±10) %, and (92±3) %, respectively, which were significantly higher than (25±3) %, (59±6) %, and (77±6) % in silver sulfadiazine group (t=7.07, 5.59, 7.09, P<0.01). (3) Before treatment, the serum levels of TNF-α and IL-8 of patients in the two groups were similar. After 7 days of treatment, the serum levels of TNF-α and IL-8 of patients in VSD group were significantly lower than those in silver sulfadiazine group (t=-8.75, -8.04, P<0.01). (4) The pain score during dressing change and medical cost of patients in VSD group were significantly lower than those in silver sulfadiazine group (t=-4.28, -7.56, P<0.01), while the discharge satisfaction score of patients in VSD group was significantly higher than that in silver sulfadiazine group (t=10.91, P<0.05). Conclusions: The application of VSD technology in clinical alkali burn wounds can effectively promote the removal of residual lye, alleviate the further damage of lye to skin tissue, shorten the wound healing time, effectively remove inflammatory mediators, reduce the pain of dressing change, decrease the total cost of treatment, and enhance satisfaction of patient.

Management of postoperative chyloretroperitoneum in adults.

Retroperitoneal chylous effusion after urological surgery is a rare and serious complication. Failure in treatment may result in cachexia, threatening the life of the patient. We present the treatment of two cases of postoperative chyloretroperitoneum with the use of somatostatin, octreotide and total parenteral nutrition. In Case 1, an 87-year-old man, a retroperitoneal lymphatic fistula occurred four days after the resection of the left kidney due to carcinoma, whereas in Case 2, a 56-year-old man, a continuous lymph fistula from the renal fossa occurred one month after resection of the right adrenal pheochromocytoma. Case 1 was treated with intravenous administration of somatostatin, and in Case 2, treatment consisted of subcutaneous administration of octreotide, in combination with total parenteral nutrition and other symptomatic therapies. In both cases, lymph exudation was terminated in about two weeks, and the patients recovered. Somatostatin therapy and total parenteral nutrition can effectively treat chyloretroperitoneum.

P2-achiral, P'-extended alpha-ketoamide inhibitors of calpain I.

A series of potent P2-achiral, P'-extended alpha-ketoamide inhibitors of calpain I is described.

The mechanical-chemical attachment between the artificial articular cartilage (PVA-hydrogel) and metal substrate (or underlying bone).

PVA-hydrogel has excellent biocompatibility as well as preferable tribological characteristics as an artificial articular cartilage. One of the most difficult problems is the attachment of PVA-hydrogel to the underlying bone (or metal substrate). In the present study, the micro-mechanical attachment between the PVA-hydrogel and metal fibre mesh was at first accomplished to obtain a composite artificial cartilage device (CACD), then the surface of fibre mesh is chemically bonded to the metal substrate (or underlying bone) by adhesive (PMMA). This method can be used to accomplish mechanical-chemical attachment between composite artificial cartilage device and underlying bone (or metal substrate). Microstructure analysis and mechanical tests indicate that the CACD can be firmly bonded to the metal substrate (or underlying bone).

The development of artificial articular cartilage--PVA-hydrogel.

Aqueous poly(vinyl alcohol) solutions were frozen at -20 degrees C for 6-12 h, and subsequently thawed for 1-2 h. The above mentioned process repeated for 1-3 times. After the specimen was dehydrated in vacuum, a kind of artificial articular cartilage--PVA-hydrogel--was developed. The micromorphology of PVA-hydrogel has been observed by means of optical microscopy and SEM. DSC and mechanical tests have been employed to investigate the influence of freezing, thawing, dehydrating and irradiating upon the crystallinity and the mechanical properties of PVA-hydrogel.

P2-proline-derived inhibitors of calpain I.

The syntheses and biological activities of a series of calpain I inhibitors, derived from D- and L-Pro, are described.

(2S,4R)-4-methylglutamic acid (SYM 2081): a selective, high-affinity ligand for kainate receptors.

Glutamic acid activates ionotropic glutamate receptors that mediate excitatory transmission in the central nervous system. The introduction of a methyl group at position 4 of glutamic acid imparts selectivity for kainate receptors, relative to other (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ionotropic glutamate receptors. Among the stereoisomers of 4-methylglutamic acid, the potency of the (2S,4R)-isomer (SYM 2081) to inhibit [3H]kainic acid binding to both wild-type (rat forebrain) and recombinant (GluR6) kainate receptors (IC50 values of approximately 32 and 19 nM, respectively) was comparable to that of kainic acid (IC50 values of approximately 13 and 28 nM, respectively). SYM 2081 was approximately 800- and 200-fold less potent as an inhibitor of radioligand binding to wild-type (rat forebrain) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate receptors, respectively. Preexposure of human embryonic kidney 293 cells stably expressing GluR6 receptors to low concentrations of SYM 2081 (30-300 nM) resulted in a reversible blockade of the rapidly desensitizing currents produced by kainate application. At higher concentrations, SYM 2081 (EC50 of approximately 1 microM) elicited kainate-like, rapidly desensitizing, inward currents. Pretreatment of recombinant GluR6 receptors with concanavalin A both abolished the effect of SYM 2081 to block kainate-induced currents and revealed nondesensitizing currents induced by SYM 2081 alone. The latter observations provide strong support for the hypothesis that SYM 2081 blocks kainate-induced currents through a process of agonist-induced desensitization. SYM 2081 also activated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents in primary cultures of cerebral cortex and, consistent with data obtained by radioligand binding, was approximately 5-fold less potent than kainate (EC50 values of 325 and 70 microM, respectively) in this measure. SYM 2081 is a high-affinity, selective, kainate agonist that may prove useful both as a probe to examine the physiological functions of kainate receptors and as the prototype of a novel class of therapeutic agents.

Contribution of "diazepam-insensitive" GABAA receptors to the alcohol antagonist properties of Ro 15-4513 and related imidazobenzodiazepines.

Both in vivo and in vitro studies have shown that Ro 15-4513 can antagonize many of the pharmacologic actions of ethanol. In contrast to many benzodiazepine receptor (BzR) ligands, Ro 15-4513 binds with high affinity to a novel GABAA receptor subtype, referred to as "diazepam-insensitive" (DI). This study examined the contribution of DI GABAA receptors to the modulation of ethanol-induced sleep time by Ro 15-4513 and related imidazobenzodiazepines [e.g., Ro 19-4603, Ro 16-6028, and ZG-63 (t-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-imidazo[1,5,a] [1,4]benzodiazepine-3-carboxylate)] that possess high affinities for this GABAA receptor subtype. Ro 15-4513 (0.6-5 mg/kg) significantly reduced ethanol (3.5 g/kg, i.p.) sleep time in mice (p < 0.001, analysis of variance). This effect was not blocked by BzR antagonists ZK 93426 (5 mg/kg) and Ro 14-7437 (5 mg/kg), which possess low affinities for DI but bind with high affinities to other "diazepam-sensitive" (DS) GABAA receptor isoforms. Although Ro 19-4603 (2.5 mg/kg) also reduced ethanol sleep time (p < 0.01), this effect was attenuated by coadministration of ZK 93426 (2.5 mg/kg). Ro 16-6028 (2.5 mg/kg) prolonged (p < 0.01) ethanol sleep time. However, in the presence of either Ro 19-7437 (5 mg/kg) or ZK 93426 (2.5 mg/kg) ethanol-induced sleep time was reduced to values approaching those obtained with ethanol in the presence of Ro 15-4513. A low dose (2.5 mg/kg) of ZG-63 did not significantly affect alcohol sleep time. However, in the presence of ZK 93426, ZG-63 increased sleep time (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Computer-aided molecular modeling, synthesis, and biological evaluation of 8-(benzyloxy)-2-phenylpyrazolo[4,3-c]quinoline as a novel benzodiazepine receptor agonist ligand.

Using computer-aided conformational analysis, based on molecular dynamics simulation, cluster analysis, and Monte Carlo techniques, we have designed and synthesized compounds in which a benzyloxy substituent has been incorporated into a series of pyrazoloquinoline benzodiazepine receptor (BZR) ligands. Earlier studies had shown that the benzyloxy group could act as part of the agonist pharmacophoric determinant in the beta-carboline ring system. Furthermore, the agonist beta-carboline had been correlated with a binding site orientation and volume fit for an agonist 6-phenylimidazobenzodiazepine carboxylate. The present study was undertaken to determine whether the benzyloxy substituent could be used as an agonist pharmacophoric descriptor for the phenylpyrazolo[4,3-c]quinolin-3-one BZR ligands. The results of a determination of GABA shift ratios for the synthetic ligands indicate that 8-(benzyloxy)-2-phenylpyrazolo[4,3-c]quinolin-3-one can be predicted to be an agonist at the BZR.

Relationship between plasma benzodiazepine receptor ligand concentrations and severity of hepatic encephalopathy.

Levels of benzodiazepine receptor ligands were measured in plasma samples from 25 patients in various stages of hepatic encephalopathy due to fulminant liver failure who were not exposed to pharmaceutical benzodiazepines immediately before or during hospitalization. Chromatographic analysis of extracted plasma samples revealed one to nine fractions containing material that competitively inhibited [3H]flumazenil binding to benzodiazepine receptors with the pharmacological properties of benzodiazepine receptor agonists. Two of these peaks were positively identified as the 1,4-benzodiazepines diazepam and N-desmethyldiazepam on the basis of chromatographic, ultraviolet and mass spectral evidence. The plasma levels of diazepam and N-desmethyldiazepam were significantly increased above control values in stage 4 hepatic encephalopathy, whereas total benzodiazepine receptor ligand concentrations were increased above control in stages 1 through 4. A significant but weak linear correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor ligands and the severity of hepatic encephalopathy. Thus increased concentrations of benzodiazepine receptor ligands appear to contribute to the enhancement of GABAergic neurotransmission in hepatic encephalopathy, particularly in stage 4. These results constitute further support for a role for benzodiazepine receptor ligands in the pathogenesis of hepatic encephalopathy associated with acute liver failure.

Labelling of diazepam-sensitive and -insensitive benzodiazepine receptors with [3H]tert-butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine 3-carboxylate (ZG-63).

A diazepam-insensitive subtype of benzodiazepine receptor has been identified in the cerebella of several species, including man. t-Butyl-8-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4] benzodiazepine 3-carboxylate (ZG-63) was recently described as a selective, high affinity ligand at diazepam-insensitive benzodiazepine receptors. This compound was tritiated, and its properties as a radioligand evaluated in rat brain membranes. Consistent with the high affinity and selectivity described for the non-radioactive form of this compound, saturation analyses of [3H]ZG-63 binding to cerebellar diazepam-insensitive and other, diazepam-sensitive benzodiazepine receptors revealed Kd values of 2.6 +/- 0.2 nM and 10.6 +/- 1.4 nM, respectively. The density (Bmax) of cerebellar diazepam-insensitive receptors labelled with [3H]ZG-63 was not significantly different from values obtained with the prototypical diazepam-insensitive receptor ligand [3H]Ro 15-4513, representing approximately 30% of total cerebellar benzodiazepine receptors. [3H]ZG-63 also labelled cortical diazepam-sensitive benzodiazepine receptors, with Bmax values that were not significantly different from those obtained with [3H]flunitrazepam. Diazepam-insensitive benzodiazepine receptors in rat cerebral cortex could be detected with [3H]ZG-63, but the densities of these sites are a very minor component (< or = 5%) of total benzodiazepine receptors. In the presence of GABA, [3H]ZG-63 behaved as a 'gamma-aminobutyric acid (GABA) -positive', 'GABA-negative', and 'GABA-neutral' ligand at cortical diazepam-sensitive receptors, cerebellar diazepam-sensitive receptors, and cerebellar diazepam-insensitive benzodiazepine receptors, respectively. This profile differs from the prototype diazepam-insensitive receptor ligand, [3H]Ro 15-4513. Competition studies demonstrated a very high correlation (r2 = 0.98; P < 0.002) between the potencies of a series of benzodiazepine receptor ligands to inhibit [3H]ZG-63 and [3H]Ro 15-4513 binding to cerebellar diazepam-insensitive receptors. The high affinity and selectivity of [3H]ZG-63 for diazepam-insensitive receptors (diazepam-insensitive/diazepam-sensitive ratio of approximately 0.25) together with a GABA-shift profile which differs from Ro 15-4513 suggests that this compound may be useful in elucidating the function(s) of this benzodiazepine receptor subtype.

Synthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at sigma receptors. 2. Piperazines, bicyclic amines, bridged bicyclic amines, and miscellaneous compounds.

As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4343) we conformationally restricted the sigma-receptor ligand 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. sigma-Receptor binding affinities were obtained using [3H](+)-pentazocine in guinea pig brain membrane sigma 1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding interaction. Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 [ as in 4-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[3.2.2]nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substituted homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The synthesis of 6,7-dichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding interaction at sigma-receptors. sigma-Receptor Ki's ranged from 0.55 nM for 1-[2-(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine (7) to 654 nM for 16. Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the sigma receptor is not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.