Search

Background: In patients with schizophrenia, Diankuang Mengxing Decoction with antipsychotics is one of the treatments for it. However, little information is available regarding the difference between the therapeutic effect of Diankuang Mengxing Decoction with antipsychotics and other treatments. Systematic evaluation is conducted to assess the efficacy and safety of Diankuang Mengxing Decoction and other antipsychotics, which are used to treat schizophrenia., Methods: We performed a systematic review (PROSPERO ID: CRD42023414603). This entailed a computerized search of several research databases from their respective dates of establishment until April 11, 2023, which collected clinical randomized controlled trials of Diankuang Mengxing Decoction combined with antipsychotics. The databases that contributed to this study were PubMed, Web of Science, Embase, EBSCOhost, Cochrane, Scopus, and Google Scholar. Each publication was screened according to defined inclusion and exclusion criteria, and appropriate literature was extracted and evaluated for quality, for which meta-analysis was performed using RevMan 5.4., Results: A literature review of 456 publications resulted in the inclusion of 18 randomized controlled trials with data collected from a total of 1636 patients. Meta-analytical results showed combination with risperidone, olanzapine, chlorpromazine, clozapine, ziprasidone, or aripiprazole increased the overall effectiveness of Diankuang Mengxing Decoction when treating schizophrenia (P < . 00001), among whom olanzapine demonstrated the greatest enhancement (Z = 3.65, odds ratio = 4.26, 95% CI: 1.96-9.28, P = .0003). The 4-week/30-day treatment (P = .0003) and a dosage of 400 mL/d of Diankuang Mengxing Decoction (P = .0004) were more effective. Also, there were widespread reductions to the Positive And Negative Syndrome Scale (PANSS) total scores, PANSS-positive symptom scores, PANSS-negative symptom scores, general psychopathology scores (P < .05 for all), as well as the incidence of adverse effects (Z = 2.79, odds ratio = 0.34, 95% CI: 0.16-0.73, P = .005) in patients with schizophrenia., Conclusion: The combination of Diankuang Mengxing Decoction with different antipsychotics can improve the overall prognosis of patients with schizophrenia; Diankuang Mengxing Decoction combined olanzapine, a dosage of 400 mL/d and a duration of 4 weeks/30 days being the best in this regard, by alleviating the symptoms and diminishing the disorder's adverse effects. To build on this work, more large-sample, multi-center, and high-quality clinical studies in the future would help to further validate our findings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs., (© 2024. The Author(s).)

Background and Aims: We aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit., Methods: MEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA)., Results: Thirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158]., Conclusions: Carvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices., Competing Interests: MFY has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)

Background: Antibiotics may increase the risk of COVID-19 among non-vaccinated subjects via probable gut dysbiosis. We aimed to investigate whether antibiotics also affect the clinical outcomes of COVID-19 vaccine recipients. Methods: This was a territory-wide cohort study of 3,821,302 COVID-19 vaccine recipients (aged ≥ 18 years) with ≥2 doses of either BNT162b2 or CoronaVac. Exclusion criteria included prior COVID-19, prior gastrointestinal surgery, and immunocompromised status. The primary outcome was COVID-19 infection and secondary outcomes included COVID-19-related hospitalization and severe infection (composite of intensive care unit admission, ventilatory support, and/or death). Exposure was pre-vaccination antibiotic use (within 180 days of first vaccine dose). Covariates included age, sex, Charlson Comorbidity Index, and concomitant medication use. Subjects were followed from the index date (first dose vaccination) until outcome occurrence, death, an additional dose of vaccination, or 15 November 2022. Propensity score (PS) matching and a Poisson regression model were used to estimate the adjusted incidence rate ratio (aIRR) of outcomes with antibiotic use. Results : Among 342,338 PS matched three-dose vaccine recipients (mean age: 57.4 years; male: 45.1%) with a median follow-up of 13.6 months (IQR: 9.2-16.3), antibiotics were associated with a higher risk of COVID-19 infection (aIRR: 1.16;95% CI: 1.14-1.19), hospitalization (aIRR: 1.75;95% CI: 1.65-1.86), and severe infection (aIRR: 1.60; 95% CI: 1.21-2.11). Notably, antibiotic use was associated with a higher risk of severe infection and death among CoronaVac recipients (aIRR: 1.62 95% CI: 1.18-2.22 and aIRR: 2.70, 95% CI: 1.54-4.73 for the two secondary outcomes, respectively), but not BNT162b2 recipients. Conclusions: Pre-vaccination use of antibiotics was associated with a higher risk of COVID-19 infection, hospitalization, and severe disease outcomes.

Background: Ibrutinib is a Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment for several mature B-cell malignancies. Reactivation of hepatitis B virus (HBV) is a well-described complication in patients with chronic HBV infection or prior HBV exposure undergoing cytotoxic or immunosuppressive chemotherapy for hematologic malignancies. This phenomenon has been frequently reported with rituximab. However, published data on the risk of HBV reactivation induced by ibrutinib are scarce. Cases of HBV reactivation in hematologic patients receiving ibrutinib therapy have recently been described, but limited only to overt hepatitis B patients or seropositive occult hepatitis B patients., Case Presentation: We report the first case of HBV reactivation during ibrutinib treatment in an asymptomatic 82-year-old woman with seronegative occult hepatitis B patient (i.e., negative for HBsAg, anti-HBc and anti-HBs). Four months after ibrutinib treatment, her liver function test (LFT) was deranged, with seroconversion to HBsAg positivity. Serum hepatitis B virus DNA was quantified to be 1.92 × 10 8 IU/ml. Antiviral treatment was initiated, and viral load was gradually suppressed with improvement in LFT., Conclusions: Our case illustrated that in populations with a high incidence of HBV exposure, systematic screening for HBV exposure is essential prior to ibrutinib treatment, followed by serial monitoring of serologic and molecular markers of hepatitis B. There is a need for an international consensus to support the recommendation of antiviral prophylaxis against HBV reactivation in patients using ibrutinib., (© 2023. The Author(s).)

Background: We aimed to investigate the effect of non-alcoholic fatty liver disease (NAFLD) on BNT162b2 immunogenicity against wild-type SARS-CoV-2 and variants and infection outcome, as data are lacking., Methods: Recipients of two doses of BNT162b2 were prospectively recruited. Outcomes of interest were seroconversion of neutralizing antibody by live virus microneutralization (vMN) to SARS-CoV-2 strains (wild-type, delta and omicron variants) at day 21, 56 and 180 after first dose. Exposure of interest was moderate-to-severe NAFLD (controlled attenuation parameter ≥ 268 dB/M on transient elastography). We calculated adjusted odds ratio (aOR) of infection with NAFLD by adjusting for age, sex, overweight/obesity, diabetes and antibiotic use., Results: Of 259 BNT162b2 recipients (90 (34.7%) male; median age: 50.8 years (IQR: 43.6-57.8)), 68 (26.3%) had NAFLD. For wild type, there was no difference in seroconversion rate between NAFLD and control groups at day 21 (72.1% vs. 77.0%; p = 0.42), day 56 (100% vs. 100%) and day 180 (100% and 97.2%; p = 0.22), respectively. For the delta variant, there was no difference also at day 21 (25.0% vs. 29.5%; p = 0.70), day 56 (100% vs. 98.4%; p = 0.57) and day 180 (89.5% vs. 93.3%; p = 0.58), respectively. For the omicron variant, none achieved seroconversion at day 21 and 180. At day 56, there was no difference in seroconversion rate (15.0% vs. 18.0%; p = 0.76). NAFLD was not an independent risk factor of infection (aOR: 1.50; 95% CI: 0.68-3.24)., Conclusions: NAFLD patients receiving two doses of BNT162b2 had good immunogenicity to wild-type SARS-CoV-2 and the delta variant but not the omicron variant, and they were not at higher risk of infection compared with controls.

Background: Taohong Siwu Decoction (THSWD) is a classic prescription of traditional Chinese medicine. Recent research has shown that the practical components of THSWD have specific curative effects on various cardiovascular diseases, including hypertension, suggesting THSWD could effectively lower blood pressure (BP) with fewer side effects. However, little information is available regarding the effectiveness of THSWD combined with antihypertensive medicine on hypertension., Objective: This meta-analysis aimed to study the efficacy and safety of THSWD in treating hypertension., Methods: According to the search strategy, 8 databases were searched, including China Knowledge Network (CNKI), Wanfang Database, VIP Database, Pubmed, China Biomedical Literature Database (CBM), web of science, EMBASE and Cochrane Library, for the randomized controlled trial of THSWD on hypertension. 9 RCTs were included and 827 patients were involved. This meta-analysis used RevMan 5.4 to evaluate the articles., Results: This review included 9 RCTs. All studies were THSWD with the antihypertensive drug compared with single antihypertensive western medicine. The total effective rate of THSWD combined with corresponding western medicine was significantly improved (Relative risk = 1.26; 95% CI: 1.16-1.37, P < .00001), which could effectively reduce the systolic BP (MD = -15.28 mm Hg; 95% CI: -20.17 to -10.40, P < .00001=, diastolic BP (MD = -9.70 mm Hg; 95% CI: -12.66 to -6.73, P < .00001), Triglycerides (MD = -1.48, 95%CI: -2.09 to -0.87, P < .00001), total cholesterol (MD = -1.43, 95% CI: -1.63 to -1.24, P < .00001) and low density lipoprotein cholesterol (MD = -0.93, 95% CI: -1.07 to -0.80, P < .00001). Compared with the single routine western medicine group, THSWD combined with the corresponding western medicine increased serum high-density lipoprotein (MD = 0.41, 95% CI: 0.35 to 0.46, P < .00001)., Conclusion: THSWD combined with antihypertensive drugs in treating hypertension was curative in lowering BP, improving blood lipid levels and reducing the incidence of adverse reactions compared to antihypertensive medications treatment. However, more high-quality studies are needed due to the biased results and the small number of studies for further verification of the effectiveness of THSWD, and providing a new treatment for clinical reference., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Gut microbiota can be associated with COVID-19 vaccine immunogenicity. We investigated whether recent antibiotic use influences BNT162b2 vaccine immunogenicity. Methods: BNT162b2 recipients from three centers were prospectively recruited. Outcomes of interest were seroconversion of neutralising antibody (NAb) at day 21, 56 and 180 after first dose. We calculated the adjusted odds ratio (aOR) of seroconversion with antibiotic usage (defined as ever use of any antibiotics within six months before first dose of vaccine) by adjusting for covariates including age, sex, smoking, alcohol, and comorbidities. Results: Of 316 BNT162b2 recipients (100 [31.6%] male; median age: 50.1 [IQR: 40.0-57.0] years) recruited, 29 (9.2%) were antibiotic users. There was a trend of lower seroconversion rates in antibiotic users than non-users at day 21 (82.8% vs. 91.3%; p = 0.14) and day 56 (96.6% vs. 99.3%; p = 0.15), but not at day 180 (93.3% vs. 94.1%). A multivariate analysis showed that recent antibiotic usage was associated with a lower seroconversion rate at day 21 (aOR 0.26;95% CI: 0.08-0.96). Other factors associated with a lower seroconversion rate after first dose of the BNT162b2 vaccine included age ≥ 60 years (aOR: 0.34;95% CI: 0.13-0.95) and male sex (aOR: 0.14, 95% CI: 0.05-0.34). There were no significant factors associated with seroconversion after two doses of BNT16b2, including antibiotic use (aOR: 0.03;95% CI: 0.001-1.15). Conclusions: Recent antibiotic use may be associated with a lower seroconversion rate at day 21 (but not day 56 or 180) among BNT162b2 recipients. Further long-term follow-up data with a larger sample size is needed to reach a definite conclusion on how antibiotics influence immunogenicity and the durability of the vaccine response.

Background/aims: Studies of hepatic steatosis (HS) effect on COVID-19 vaccine immunogenicity are lacking. We aimed to compare immunogenicity of BNT162b2 and CoronaVac among moderate/severe HS and control subjects., Methods: Two hundred ninety-five subjects who received BNT162b2 or CoronaVac vaccines from five vaccination centers were categorized into moderate/severe HS (controlled attenuation parameter ≥268 dB/m on transient elastography) (n=74) or control (n=221) groups. Primary outcomes were seroconversion rates of neutralising antibody by live virus Microneutralization (vMN) assay (titer ≥10) at day21 (BNT162b2) or day28 (CoronaVac) and day56 (both). Secondary outcome was highest-tier titer response (top 25% of vMN titer; cutoff: 160 [BNT162b2] and 20 [CoronaVac]) at day 56., Results: For BNT162b2 (n=228, 77.3%), there was no statistical differences in seroconversion rates (day21: 71.7% vs. 76.6%; day56: 100% vs. 100%) or vMN geometric mean titer (GMT) (day21: 13.2 vs. 13.3; day56: 91.9 vs. 101.4) among moderate/severe HS and control groups respectively. However, lower proportion of moderate/severe HS patients had highest-tier response (day56: 5.0% vs. 15.5%; P=0.037). For CoronaVac (n=67, 22.7%), there was no statistical differences in seroconversion rates (day21: 7.1% vs. 15.1%; day56: 64.3% vs. 83.0%) or vMN GMT (5.3 vs. 5.8,) at day28. However, moderate/severe HS patients had lower vMN GMT (9.1 vs. 14.8, P=0.021) at day 56 with lower proportion having highest-tier response (21.4% vs. 52.8%, P=0.036)., Conclusion: While there was no difference in seroconversion rate between moderate/severe HS and control groups after two doses of vaccine, a lower proportion of moderate/severe HS patients achieved highest-tier response for either BNT162b2 or CoronaVac.

Background: Recent studies suggested that use of antibiotics may interfere with treatment responses to immune checkpoint inhibitors (ICIs). We determined whether concurrent use of antibiotics during ICI therapy was associated with adverse outcomes in patients with advanced hepatocellular carcinoma (HCC)., Methods: This is a territory-wide retrospective cohort study including all advanced HCC patients who received ICIs (nivolumab, pembrolizumab, or ipilimumab) between January 2014 and December 2019. Exclusion criteria included prior liver transplantation and use of cabozantinib, regorafenib, or ramucirumab. The exposure of interest was concurrent antibiotic use within 30 days before or after the commencement of ICI. The adjusted hazard ratio (aHR) of cancer-related mortality and all-cause mortality with antibiotic use was derived by propensity score (PS) matching in 1:2 ratio of covariates including baseline characteristics, causes of cirrhosis, Child-Pugh status, prior HCC treatment, comorbidities, concurrent medications, and laboratory results including alpha fetoprotein., Results: A total of 395 HCC patients who had received ICIs were included. During a median follow-up of 16.5 months (interquartile range [IQR]: 5.6-44.3), there were 286 (72.4%) deaths including 231 cancer-related deaths. The median time from the first ICI to event was 7.7 months (IQR: 4.0-16.8). PS matching of 56 antibiotic users with 99 nonusers showed that concurrent antibiotic use with ICI was associated with higher cancer-related (aHR: 1.66; 95% CI: 1.08-2.54) and all-cause mortality (aHR: 1.63; 95% CI: 1.17-2.28)., Conclusions: Concurrent antibiotic use during immunotherapy was associated with higher mortality in patients with advanced HCC. Further studies should examine the role of gut dysbiosis on responses to ICI., Competing Interests: K.S.C. has received speaker fee from AstraZeneca. W.K.L. has received speaker fee from Eisai, Ipsen and honorarium for attending advisory board for Janssen and Pfizer., (Copyright © 2021 by S. Karger AG, Basel.)

Most previous studies of interferon-alpha/beta (IFN-α/β) response antagonism by alphaviruses have focused upon interruption of IFN-α/β induction and/or receptor signaling cascades. Infection of mice with Venezuelan equine encephalitis alphavirus (VEEV) or Sindbis virus (SINV) induces serum IFN-α/β, that elicits a systemic antiviral state in uninfected cells successfully controlling SINV but not VEEV replication. Furthermore, VEEV replication is more resistant than that of SINV to a pre-existing antiviral state in vitro. While host macromolecular shutoff is proposed as a major antagonist of IFN-α/β induction, the underlying mechanisms of alphavirus resistance to a pre-existing antiviral state are not fully defined, nor is the mechanism for the greater resistance of VEEV. Here, we have separated viral transcription and translation shutoff with multiple alphaviruses, identified the viral proteins that induce each activity, and demonstrated that VEEV nonstructural protein 2-induced translation shutoff is likely a critical factor in enhanced antiviral state resistance of this alphavirus., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A gold standard of antiviral vaccination has been the safe and effective live-attenuated 17D-based yellow fever virus (YFV) vaccines. Among more than 500 million vaccinees, only a handful of cases have been reported in which vaccinees developed a virulent wild type YFV infection. This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. However, the particular immune components required for protection against YFV have never been evaluated. An understanding of the immune mechanisms that underlie 17D-based vaccine efficacy is critical to the development of next-generation vaccines against flaviviruses and other pathogens. Here we have addressed this question for the first time using a murine model of disease. Similar to humans, vaccination elicited long-term protection against challenge, characterized by high neutralizing antibody titers and a robust T cell response that formed long-lived memory. Both CD4+ and CD8+ T cells were polyfunctional and cytolytic. Adoptive transfer of immune sera or CD4+ T cells provided partial protection against YFV, but complete protection was achieved by transfer of both immune sera and CD4+ T cells. Thus, robust CD4+ T cell activity may be a critical contributor to protective immunity elicited by highly effective live attenuated vaccines.

The reconstruction of defects in the head and neck region has remained a challenging problem for head and neck surgeons. The amount of tissue loss may be extensive or the tissue destruction may involve composite elements. It is important to consider both the functional and aesthetic aspects while planning the reconstruction. The application of microvascular free tissue transfer allows the selection of the most appropriate tissue for reconstruction of the defect created following tumour extirpation. As these free tissues bring in new blood supply, wound healing is usually not a problem even if the region had received previous radiotherapy. Despite all the benefits associated with microvascular free tissue transfer these procedures remain associated with a small chance of failure. The application of pedicle tissue for reconstruction for certain defects still has a role in reconstruction of the head and neck region. The selection of the appropriate method and suitable tissue for reconstruction depends on the experience of the surgeon. Contemporary head and neck surgeons should consider all the reconstructive options before deciding on the optimal reconstruction method after adequate tumour resection.

Background: Pharyngolaryngoesophagectomy (PLE) for hypopharyngeal cancers and tumors of the cervical esophagus is a procedure of significant morbidity and mortality. Conventional esophageal mobilization is performed with the transhiatal dissection technique. Thoracoscopic esophageal mobilization is tested as an alternative to determine whether surgical outcome can be improved., Methods: From 1994 to 1998, thoracoscopic mobilization was carried out in 30 consecutive patients who underwent PLE (PLE-TS). This was compared to a historical cohort of 30 patients who had PLE with transhiatal mobilization (PLE-TH)., Results: In PLE-TS, thoracoscopic esophageal mobilization was successful in 28 patients (93%). Median blood loss was 700 mL (range, 164 to 3,000 mL) compared to 1,000 mL (range, 400 to 2,200 mL) in group PLE-TH, p = 0.21. Thoracoscopy time was 90 minutes (range, 60 to 180 minutes). Total operating time were 392 minutes (range, 180 to 570 minutes) and 300 minutes (range, 150 to 550 minutes) in PLE-TS and PLE-TH, respectively (p = 0.03). Major pulmonary complications occurred in 7 (23%) and 8 (27%) patients in PLE-TS and PLE-TH, respectively (p = 0.77). Cardiac complications occurred in 7 (23%) and 5 (17%) patients in PLE-TS and PLE-TH, respectively (p = 0.52). Thirty-day mortality rates were 3.3% and 10% (p = 0.6) and hospital mortality rates were 13% and 17%, (p = 1.0)., Conclusions: Thoracoscopy was safe and feasible. Morbidity and mortality after PLE was not significantly reduced. The theoretical advantage offered by thoracoscopy may be offset by the lengthened time of one-lung anesthesia.

Patients with facial trauma may have associated injuries requiring immediate or specialised attention. This paper reports the incidence and nature of significant associated neurosurgical, ocular, spinal, torso and extremity injuries in facial fracture patients treated by the Department of Plastic and Reconstructive Surgery from June 1989 to June 1992. Of 839 patients treated during the period, 95 patients (11.3%) sustained significant concomitant injuries outside the facial skeleton. There were 45 (5.4%) patients with associated neurosurgical injuries, 33 (3.9%) with ocular injuries, 8 (0.9%) with spinal injuries, 16 (1.9%) with injuries of the torso, and 62 (7.4%) with injuries of the extremities. The spectrum of the injuries is presented. Most neurosurgical injuries are a result of focal impact and the intervention required is related mainly to local fracture management and the repair of dural tears. The risk of significant ocular injury is highest when the fracture involves the orbit. Injuries of the spine, torso (chest, abdomen, pelvis), and limbs were seen mainly in road trauma patients.

D- and L-aminooxysuccinate were synthesized and evaluated as inhibitors of cytoplasmic aspartate aminotransferase (EC 2.6.1.1) from porcine heart. L-Aminooxysuccinate was shown to be a slow binding inhibitor of the pyridoxal phosphate form of the enzyme with a Ki of 160 nM and a half-life of the inhibited complex of 8 min. Kinetic analysis revealed that inhibition followed a two-step mechanism in which the last step was rate-limiting. D-Aminooxysuccinate was not inhibitory up to a concentration of 0.1 mM. These compounds were compared to D- and L-hydrazinosuccinate, which are potent slow binding inhibitors of aspartate aminotransferase with Ki values of 1.5 and 0.5 nM, respectively. Models of all four analogs were built into the active site of the closed form of the enzyme. The energy-minimized conformations of both L-isomers bound to aspartate aminotransferase show better geometry for hydrogen bond and ion pair formation than do the corresponding D-isomers. The aldimine double bond formed by the L-isomers is not coplanar with the pyridoxal phosphate ring in accordance with the spectral properties of the inhibitor complexes that are characterized by broad absorbance bands. This lack of planarity was not evident for the models of D-hydrazinosuccinate and D-aminooxysuccinate.

The inhibitory effects of 18 synthetic phenolic compounds added to the diet on benzo(a)pyrene-induced neoplasia of the forestomach of female ICR/Ha mice have been determined. Seven of the compounds showed suppression of neoplasia. The most potent inhibitors were p-methoxyphenol, 2-tert-butyl-4-hydroxyanisole [the minor isomer of 2(3)-tert-butyl-4-hydroxyanisole] and 3,5-di-tert-butylcatechol. A second group of compounds with a weaker inhibitory activity consisted of 3,5-di-tert-butylphenol, 3-tert-butyl-4-hydroxyanisole [the major isomer of 2(3)-tert-butyl-4-hydroxyanisole], 2-tert-butylhydroquinone, and 2-tert-butylphenol. In additional experiments, three naturally occurring phenolic derivatives of cinnamic acid, i.e., o-hydroxycinnamic acid, 3,4-dihydroxycinnamic acid (caffeic acid), and 4-hydroxy-3-methyoxycinnamic acid (ferulic acid), were investigated. All three suppressed benzo(a)pyrene-induced neoplasia of the forestomach. Humans ingest a variety of phenols. Data as to the inhibitory capacities of members of this group of compounds are of importance for evaluating the role that they play in determining the reaction to exposure to chemical carcinogens.

Both synthetic and natural estrogens have been studied for their ability to induce renal carcinomas in castrated male hamsters after 9.0 months of treatment. Tumor foci were detected in frozen serial sections stained histochemically for estrase activity. Both diethylstilbestrol (DES) and 17 beta-estradiol had equal ability (100%) to induce renal tumors [approximately 20.5 +/- 3 (S.E.) tumor foci] in these animals. Hexestrol induced the same incidence and number of renal carcinoma foci as DES or 17 beta-estradiol. However, alpha -dienestrol and DES 3,4-oxide showed an 86 to 88% incidence of renal tumors in hamsters (approximately 10.8 +/- 3). When equilin and d-equilenin, components of therapeutic conjugated estrogens, were tested, only equilin had a 76% incidence of renal tumor foci (5.5 +/- 0.9). The ability of these stilbene and steroidal estrogens to compete for renal tumor estrogen receptor generally correlated well with their ability to cause renal tumorigenesis in the hamster with one notable exception. Although ethinyl estradiol competed as well as did DES or 17 beta-estradiol for estrogen receptor, had similar ability to induce renal progesterone receptor, and led to similar high serum prolactin levels as either DES or 17 beta-estradiol, it had only weak carcinogenic activity (21%) in the hamster kidney (0.6 +/- 0.5 foci). These data represent the first detailed analysis of the relative carcinogenic activity of different estrogens within a given tumor-inducing system, and based on the carcinogenicity data of hexestrol and alpha-dienestrol presented herein, they suggest that epoxidation of the olefinic double bond and the p-quinone metabolite of DES probably are not involved significantly in its carcinogenic activity. Moreover, the poor carcinogenic activity of ethinyl estradiol in this system, despite strong estrogenicity, suggests that estronic activity alone may not be sufficient to effect renal tumorigenesis in the hamster.

Butylated hydroxyanisole, a food additive, has been found to inhibit the neoplastic effects of a wide variety of chemical carcinogens. The commercially available preparations of butylated hydroxyanisole contain two isomers, 2-tert-butyl-4-hydroxyanisole (2-BHA) and 3-tert-butyl-4-hydroxyanisole (3-BHA). Both isomers induce increased activities of glutathione (GSH) S-transferase and epoxide hydrolase and increase acid-soluble sulfhydryl concentration in hepatic and forestomach tissues of A/HeJ mice. The inductions were assayed after 2 weeks of feeding diets containing the two isomers. 3-BHA induced an increase in the activity of hepatic microsomal epoxide hydrolase by 1.4 times that of the control. The activity of cytosolic GSH S-transferase was enhanced by both isomers. In the liver, the 3-BHA induction was more than 3 times higher than that of 2-BHA. In the forestomach, however, the induction effect of the two isomers was reversed. The overall magnitude of the induction was much lower in the forestomach than in the liver. Synergistic effects on the induction of GSH-S-transferase activity were observed in the forestomach cytosol when mixtures of different proportions of the two isomers were added to the diet. Maximum enzyme activity was obtained at a ratio of 75% 2-BHA and 25% 3-BHA. No synergistic effect was observed with the corresponding hepatic cytosolic enzyme. The relative inductive effects of 2- and 3-BHA on the acid-soluble sulfhydryl level of liver and forestomach tissues followed closely those on GSH S-transferase activity. The results of the present study show that the two isomers of butylated hydroxyanisole differ in the magnitude of their effects on carcinogen-metabolizing systems of the liver and forestomach.

The effect of bumetanide in infants with congenital heart disease presenting with cardiac failure was studied. The study was divided into acute (3 days) and long-term (mean 10.5 weeks) cases. A total of 12 male infants was included in the acute study and 13 cases were evaluated in the long-term study. The dose used in the acute study (0.015 mg/kg) was suboptimal; notwithstanding it was found to cause significant natriuresis and chloruresis. Bumetanide in doses varying in different infants from as little as 0.015 mg/kg on alternate days to as much as 0.10 mg/kg daily was shown to be an effective diuretic for long-term use. No side effects were observed in either study.

Analogs 1-8 of diaminopimelic acid (DAP) were synthesized and tested for inhibition of purified meso-DAP D-dehydrogenase from Bacillus sphaericus and of LL-DAP epimerase from Escherichia coli. The dehydrogenase was assayed by monitoring NADPH formation spectrophotometrically at 340 nm. N-Hydroxy DAP 4, N-amino DAP 5, and 4-methylene DAP 6 are substrates of the dehydrogenase with relative rates exceeding those of the meso isomers of the thia analogs 1ab, 2ab, and 3ab. DAP epimerase was assayed by coupling the epimerization of LL-DAP to DL-DAP (Km = 0.26 mM) with the dehydrogenase-catalyzed oxidation of DL-DAP by NADP. Lanthionine isomers 1ab and 1c were stronger inhibitors of the epimerase (Ki = 0.18 mM, Ki' = 0.67 mM, and Ki = 0.42 mM, respectively) than the corresponding meso-sulfoxide 2ab or the meso-sulfone 3ab. Other isomers of 2 and 3, as well as compounds 7 and 8, showed no epimerase inhibition. N-Hydroxy DAP 4 was the most potent competitive inhibitor (Ki = 0.0056 mM) of the epimerase, whereas N-amino DAP 5 is weaker (Ki = 2.9 mM) and 4-methylene DAP 6 is a noncompetitive inhibitor (Ki' = 0.95 mM). Although none of the analogs tested showed time-dependent inactivation of either enzyme, compounds 4, 5, 6, and 7 display substantial antibacterial activities. Possible mechanisms of epimerase inhibition and significance of the DAP pathway as a target for antibiotics are discussed.

Glutathione (GSH) S-transferase is a major detoxification enzyme system that catalyzes the binding of a variety of electrophiles, including reactive forms of chemical carcinogens, to GSH. Green coffee beans fed in the diet induced increased GSH S-transferase activity in the mucosa of the small intestine and in the liver of mice. A potent compound that induces increased GSH S-transferase activity was isolated from green coffee beans and identified as kahweol palmitate. The corresponding free alcohol, kahweol, and its synthetic monoacetate are also potent inducers of the activity of GSH S-transferase. A similar diterpene ester, cafestol palmitate, isolated from green coffee beans was active but less so than was kahweol palmitate. Likewise, the corresponding alcohol, cafestol, and its monoacetate showed moderate potency as inducers of increased GSH S-transferase activity. Kahweol palmitate and cafestol palmitate were extracted from green coffee beans into petroleum ether. The petroleum ether extract was fractionated by preparative normal-phase and reverse-phase liquid chromatographies successively. Final purification with silver nitrate-impregnated thin-layer chromatography yielded the pure palmitates of cafestol and kahweol. The structures were determined by examination of the spectroscopic data of the esters and their parent alcohols and by derivative comparison.