Reduction of SARS-CoV-2 by biological nutrient removal and disinfection processes in full-scale wastewater treatment plants.

Detection of SARS-CoV-2 RNA in wastewater poses people's concerns regarding the potential risk in water bodies receiving wastewater treatment effluent, despite the infectious risk of SARS-CoV-2 in wastewater being speculated to be low. Unlike well-studied nonenveloped viruses, SARS-CoV-2 in wastewater is present abundantly in both solid and liquid fractions of wastewater. Reduction of SARS-CoV-2 in past studies were likely underestimated, as SARS-CoV-2 in influent wastewater were quantified in either solid or liquid fraction only. The objectives of this study were (i) to clarify the reduction in SARS-CoV-2 RNA during biological nutrient removal and disinfection processes in full-scale WWTPs, considering the SARS-CoV-2 present in both solid and liquid fractions of wastewater, and (ii) to evaluate applicability of pepper mild mottle virus (PMMoV) as a performance indicator for reduction of SARS-CoV-2 in WWTPs. Accordingly, large amount of SARS-CoV-2 RNA were partitioned in the solid fraction of influent wastewater for composite sampling than grab sampling. When SARS-CoV-2 RNA in the both solid and liquid fractions were considered, log reduction values (LRVs) of SARS-CoV-2 during step-feed multistage biological nitrogen removal (SM-BNR) and enhanced biological phosphorus removal (EBPR) processes ranged between>2.1-4.4 log and did not differ significantly from those in conventional activated sludge (CAS). The LRVs of SARS-CoV-2 RNA in disinfection processes by ozonation and chlorination did not differ significantly. PMMoV is a promising performance indicator to secure reduction of SARS-CoV-2 in WWTPs, because of its higher persistence in wastewater treatment processes and abundance at a detectable concentration even in the final effluent after disinfection.

Evaluation of the meropenem dosage and administration schedule in patients with bacteremia initial therapy.

BACKGROUND: The standard meropenem (MEPM) regimen allowed by insurance in Japan is 0.5 g two or three times a day. Differences in dosages and administration schedules in Japan were evaluated. METHODS: Patients with bacteremia for whom MEPM was used as the initial treatment at our institution between 2016 and 2021 were included. We retrospectively investigated patients classified into two groups: those treated according to severe infections (high-dose groupand others (low-dose group). After propensity score matching, we compared the probability of achieving free drug blood levels above the minimum inhibitory concentration (MIC) in 24 h (%fT > MIC) and outcomes. RESULTS: The probability of 100% fT > MIC was significantly higher in the high-dose group (96.4% vs 74.5%, odds ratio [OR] = 0.3, 95% confidence interval [CI] = 0.2-0.4, P = < 0.001). Regarding outcomes, the 30-day mortality rate was significantly lower in the high-dose group (1.4% vs. 11.4%, OR = 8.0, 95% CI = 1.5-43.7, P = 0.019). CONCLUSIONS: To improve outcomes in patients with bacteremia treated with MEPM, support for appropriate antimicrobial use is necessary for compliance with the dosage and administration schedule according to severe infections in initial treatment.

Clinical Significance of Expression of Immunoadjuvant Molecules (LAG-3, TIM-3, OX-40) in Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND/AIM: Various immunosuppressive factors that inhibit the immune response to cancer are present in cancer cells and the cancer microenvironment. Co-inhibitory and co-stimulatory receptors are dynamically expressed on T-cells as immunoadjuvant molecules that regulate the state of T-cell activity. In this report we focus on immunoadjuvant molecules such as LAG-3, TIM-3, and OX-40, for which there have been few published reports. We investigated the expression of LAG-3, TIM-3 and OX-40 in tumor-infiltrating lymphocytes (TILs), and clinically verified the significance of that expression in relation to neoadjuvant thermotherapy (NAC). PATIENTS AND METHODS: A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, LAG-3, TIM-3 and OX-40 status were assessed by immunohistochemistry. RESULTS: The group with low-LAG-3 expression was significantly smaller than the group with high expression in triple-negative breast cancer (TNBC) (p=0.038) and HER2-enriched breast cancer (HER2BC) (p=0.021), while the total number of pathological complete response (pCR) patients was greater (p<0.001). In TNBC and HER2BC, the pCR rate was significantly higher in the low-LAG-3 expression group than in the high-LAG-3 expression group (p<0.001 and p=0.02, respectively). Moreover, on multivariate analysis low-LAG-3 expression status was an independent predictor of favorable prognosis (TNBC: p=0.014, HR=8.124; HER2BC: p=0.048, HR=10.400). CONCLUSION: Our findings suggest that LAG-3 may become a biomarker in highly malignant breast cancers such as TNBC and HER2BC that can predict the therapeutic efficacy of NAC.

[A Case of Hyperammonemic Encephalopathy following mFOLFOX6 plus Panitumumab Therapy for Rectal Cancer].

An 80-year-old man underwent laparoscopic rectal high anterior resection with perineal dissemination for the management of RS rectal cancer. Following the diagnosis of RS rectal cancer with muc, pT4a, N3(14/15), M1c, P1, pStage Ⅳc, RAS/BRAF: wild type, treatment was initiated with mFOLFOX6 plus panitumumab(Pmab). Laboratory examination on admission revealed mild renal dysfunction(Cr 1.45 mg/dL). The patient became confused on day 3 of chemotherapy(JCS Ⅲ-200). Furthermore, laboratory findings revealed a serum ammonia level of 338µg/dL. He was diagnosed with 5-FU- induced hyperammonemic encephalopathy. Discontinuation of high-dose 5-FU and branched-chain amino acid solutions improved his mental status and decreased serum ammonia levels. We switched his chemotherapy regime to CPT-11 plus Pmab, but it was discontinued after 1 course on his request.

Discovery and structure-activity relationships study of positive allosteric modulators of the M3 muscarinic acetylcholine receptor.

The M3 muscarinic acetylcholine receptor (mAChR) is a member of the family of mAChRs, which are associated with a variety of physiological functions including the contraction of various smooth muscle tissues, stimulation of glandular secretion, and regulation of a range of cholinergic processes in the central nerve system. We report here the discovery and a comprehensive structure--activity relationships (SARs) study of novel positive allosteric modulators (PAMs) of the M3 mAChR through a high throughput screening (HTS) campaign. Compound 9 exhibited potent in vitro PAM activity towards the M3 mAChR and significant enhancement of muscle contraction in a concentration-dependent manner when applied to isolated smooth muscle strips of rat bladder. Compound 9 also showed excellent subtype selectivity over other subtypes of mAChRs including M1, M2, and M4 mAChRs, and moderate selectivity over the M5 mAChR, indicating that compound 9 is an M3-preferring M3/M5 dual PAM. Moreover, compound 9 displayed acceptable pharmacokinetics profiles after oral dosing to rats. These results suggest that compound 9 may be a promising chemical probe for the M3 mAChR for further investigation of its pharmacological function both in vitro and in vivo.

Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase.

Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.

Therapeutic impact of dietary vitamin D supplementation for preventing right ventricular remodeling and improving survival in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension (PH), caused by elevated pulmonary vascular resistance, leads to right heart failure and ultimately death. Vitamin D deficiency can predispose individuals to hypertension and left ventricular dysfunction; however, it remains unknown how serum vitamin D level is related to PH and right ventricular (RV) dysfunction. METHODS: Serum 25-hydroxyvitamin D [25(OH)D] levels were assessed in PH patients for an association with disease severity. To examine whether vitamin D supplementation could prevent the development of pulmonary vascular remodeling and RV dysfunction in PH, a rat model of PH was fed either normal chow or a high vitamin D diet. RESULTS: The majority (95.1%) of PH patients had 25(OH)D levels in the insufficiency range, which is associated with increased mean pulmonary artery pressure, increased pulmonary vascular resistance, and decreased cardiac output in PH patients. Vitamin D supplementation significantly increased serum 25(OH)D levels and improved survival in PH rats. Interestingly, while the supplemented rats retained the typical increases in medial thickness of the muscular pulmonary arteries and RV systolic pressure, RV cardiomyocyte hypertrophy and B-type natriuretic peptide expression was significantly attenuated. CONCLUSIONS: Vitamin D deficiency is frequently seen in patients diagnosed with PH and low serum levels of 25(OH)D are associated with severity of PH and RV dysfunction. Vitamin D supplementation in PH rats improved survival via ameliorating pathological RV hypertrophy. These findings suggest an insufficient intake of vitamin D might potentially accelerate RV dysfunction, leading to a crucial clinical impact of vitamin D supplementation in PH.

Cervical chylous leakage following esophagectomy that was successfully treated by intranodal lipiodol lymphangiography: a case report.

BACKGROUND: Chylous leakage is a well-known complication after esophagectomy, but cervical chylous leakage is relatively rare, and considerable controversy remains regarding the appropriate management strategies. We herein report a case of cervical chylous leakage treated successfully by lipiodol lymphangiography. CASE PRESENTATION: The patient, a 70-year-old man with middle thoracic esophageal cancer, underwent radical esophagectomy with 3-field lymph node dissection and subsequently developed cervical chylous leakage. From the second postoperative day (POD2), the amount of fluid in the cervical drainage tube increased by 200-300 ml/day. We started octreotide (300 µg/day) on POD5 and etilefrine (120 mg/day) on the POD6. However, the amount of cervical discharge did not decrease. We performed lipiodol lymphangiography on POD8. Thereafter, the amount of cervical discharge finally began to decrease. We removed the drainage tube on POD13, and the patient was discharged from the hospital on POD23. CONCLUSIONS: Our case suggests the clinical efficacy of lipiodol lymphangiography for cervical chylous leakage after esophagectomy.

Branched-Chain Amino Acid-Rich Supplements Containing Microelements Have Antioxidant Effects on Nonalcoholic Steatohepatitis in Mice.

BACKGROUND: The aim of the present study was to elucidate whether the administration of antioxidant-rich nutrients, including branched-chain amino acids (BCAAs), microelements, and vitamins, both alone and in combination, has a positive impact on liver function in a nonalcoholic steatohepatitis (NASH) mouse model and identify the mechanisms underlying these effects. METHODS: Seven-week-old male KKAy mice fed a methionine- and choline-deficient diet (MCD) for 4 weeks were divided into 7 groups and fed the following planned diets for another 4 weeks: group A (normal diet), group B (MCD; control), group C (MCD with rich microelements), group D (MCD with rich BCAAs), group E (MCD with rich microelements and BCAAs), and group F (MCD with rich microelements, BCAAs, and vitamins). We then conducted biochemical assays, histological analyses, immunohistochemistry for 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2'-nonenal (4-HNE), and Western blotting for insulin glucose signaling, lipid metabolism, and endoplasmic reticulum (ER) stress-related signaling in liver specimens obtained from mice in each group. RESULTS: The morphometric grades of all NASH-related findings and the mean degree of 8-OHdG immunolocalization in groups D-F were significantly lower than those observed in group B. The expression levels of insulin receptor ß subunit (IRß) and p-elF in groups E and F and those of phosphatidyl-inositol 3 kinase (PI3K85), p-AcelCoA, and PERK in group F were similar to those noted in group A. CONCLUSIONS: The administration of a combination of antioxidant-rich nutrients, including BCAAs and microelements, is likely to suppress the progression of NASH by reducing oxidative stress, primarily via the downregulation of the ER stress pathway.

[A Patient with Recurrent Ulcerative Colitis-Associated Rectal Cancer Attaining a Complete Response with FOLFIRI plus Bevacizumab].

A 60-year-old man underwent laparoscopic total proctocolectomy with ileostomy for advanced ulcerative colitis-associated rectal cancer. The final diagnosis was advanced cancer pT3, pN2 and M0 (pStage Ⅲb). Adjuvant therapy with XELOX was performed. However, abdominal CT revealed a liver metastasis and lymph node metastases in the pelvis 6 months after surgery. The patient was treated with FOLFIRI plus bevacizumab. After 20 courses of chemotherapy, the patient was considered to have experienced a clinical CR, which has been maintained for 3 years 5 months.

Intravital imaging of IL-1beta production in skin.

IL-1 is a prototypic inflammatory cytokine that has pathogenic roles in various skin disorders. Although Langerhans cells (LCs) have been reported to express IL-1beta mRNA upon application of contact sensitizers, it remains unclear whether other cell types produce IL-1beta in skin. Thus, we sought to directly identify IL-1beta-producing cells in living animals by construction of transgenic mice expressing DsRed fluorescence protein gene under the control of IL-1beta promoter. Little DsRed fluorescence signal was detected in skin under steady-state conditions. Striking increases in DsRed signal were observed after topical application of a contact sensitizer, oxazolone, which also induced markedly elevated IL-1beta mRNA and protein expression. DsRed signal was expressed primarily by CD45(+)/CD11b(+) myeloid leukocytes in both epidermal and dermal compartments and was detected only in small fractions of epidermal LCs. Interestingly, DsRed(+) cells emerged preferentially as clusters around hair follicles. Intravital confocal imaging experiments revealed highly motile potentials of DsRed(+) cells-they constantly crawled around hair follicles via amoeba-like movements with a mean velocity of 1.0+/-0.4 microm min(-1) (epidermis) or 2.7+/-1.4 microm min(-1) (dermis). The newly developed in vivo imaging system represents a useful tool for studying spatial regulation of IL-1beta production in skin.

The herbal medicine daikenchuto ameliorates an impaired anorectal motor activity in postoperative pediatric patients with an anorectal malformation--a pilot study.

Fecoflowmetry (FFM) has been introduced to simulate natural anorectal evacuation. So far, few reports have described the effect of the herbal medicine Daikenchuto (DKT) on impaired anorectal motor function. The aim of this pilot study was to assess anorectal motor function by FFM in postoperatively impaired patients with an anorectal malformation (ARM) before and after administration of DKT. Six postoperative patients with ARM (mean age, 7.8 years) who complained of intractable constipation with soiling in spite of administration of magnesia as a laxative were assessed over an extended period. These patients received 0.3 g/kg/d of DKT for an average of 128 days. Evacuative rate and maximum fecal stream flow were seen to increase significantly after administration of DKT when compared with values before administration of DKT. In conclusion, DKT had a favorable clinical effect on anorectal motor function in postoperative patients with ARM.

[A case report of advanced rectal cancer showing a pathological complete response by neo-adjuvant FOLFOX chemotherapy].

A 72-year-old man was admitted with melena. Colonoscopy detected an advanced rectal cancer. CT scan revealed the prostate was invaded. We decided to start a systemic chemotherapy (mFOLFOX6). The chemotherapy (mFOLFOX6) was performed six times. After the treatment with chemotherapy, the tumor shrunk. Abdominoperineal resection of rectum was done, and a final pathological examination revealed a complete response of the main tumor.

[The outcome of chemotherapy by sorafenib in advanced hepatocellular carcinoma].

We analyzed the treatment outcome and effect of sorafenib in advanced hepatocellular carcinoma. Nine patients were received the therapy of sorafenib between June 2009 and October 2009. The overall incidence of treatment-related adverse events was 87.5%. Grade 3 drug-related adverse events included a hand-foot skin reaction (two patients) and fatigue (one patient). Grade 2 hypertension (three patients), grade 1 diarrhea (two patients) and anorexia (four patients) occurred at this study. The response rate was 0% (CR/PR 0, SD 2, PD 6) and median overall survival length was 101 days. Now there are two patients undergoing the therapy of sorafenib. Effect of sorafenib in advanced hepatocellular carcinoma was not good in this study, and drug-related adverse events had a high rate. However, the continuous treatment was possible with dose modified chemotherapy.

[Results of neo-adjuvant chemotherapy by FOLFOX and FOLFIRI for colorectal liver metastasis].

We analyzed a treatment outcome and the effect of FOLFOX and FOLFIRI neo-adjuvant chemotherapy (NAC) for patient with liver metastasis of colorectal cancer. Eleven patients undergoing hepatectomy after NAC were investigated. FOLFOX was performed for 8 patients, and FOLFIRI was for 3 patients. The response rate was 45.5% (PR 5, SD 6), and the reduction rate was 37.7%. The average ICG R15 value before hepatectomy was 13.7%. A complication during and after operations was not recognized. The average observation period was 19.8 months (8-45 months). Now, 9 patients are alive with no recurrence. NAC by FOLFOX for liver metastasis of colorectal cancer showed a high reduction rate, and there was a little influence to hepatectomy indicating that FOLFOX could be an effective therapy.

[A case of stage IV advanced esophageal cancer with a long term survival by radiation therapy combined with nedaplatin and 5-FU chemotherapy].

The patient was a 73-year-old man who complained of dysphagea. Various examinations revealed an esophageal cancer with direct invasion to the left main bronchus (cT4, N2 (104R, 106recR), M0, Stage IVa) and gastric cancer (cT2, N0, M0, Stage IB). The patient was given preoperative chemoradiotherapy (40 Gy/20 fr with CDGP 10 mg/body day 1-5, 8- 12, 15-19 and 5-FU 250 mg/body day 1-5, 8-12, 15-19). After the chemoradiotherapy, we estimated that the esophageal cancer was down stage (cT4-->T3), and that a curative operation was possible. Therefore, subtotal esophagectomy and partial gastrectomy were performed without a complication. Pathological therapeutic evaluation of the esophageal cancer was complete response (CR) and the gastric cancer was T2, N0. Adjuvant chemotherapy was undergone with S-1. However, two years after the first operation, we found a recurrence of gastric duct. Therefore a surgical resection for recurrence of gastric duct was performed. The patient is still alive without recurrence 5 years and 2 months after the first treatment. Radiation therapy combined with nedaplatin and 5-FU is a safe and effective method for treating cT4 advanced esophageal cancer.

Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells.

By screening 720 natural compounds in a standard 2-way allogeneic mixed leukocyte reaction assay, we identified a potent immunosuppressive capacity of crassin acetate (CRA), a coral-derived cembrane diterpenoid. CRA efficiently inhibited allogeneic mixed leukocyte reaction as well as antigen-specific activation of CD4 T cells by bone marrow-derived dendritic cells (DCs). With regard to cellular targets, CRA suppressed not only mitogen-triggered T-cell activation, but also lipopolysaccharide-induced DC maturation, indicating dual functionality. Treatment with CRA at nontoxic doses induced heme oxygenase-1 (HO-1) mRNA/protein expression and HO-1 enzymatic activity in DCs, suggesting a unique mechanism of action. In fact, lipopolysaccharide-induced DC maturation was also inhibited by structurally unrelated compounds known to induce HO-1 expression or carbon monoxide (CO) release. Allergic contact hypersensitivity response to oxazolone and oxazolone-induced Langerhans cell migration from epidermis were both prevented almost completely by systemic administration of CRA. Not only do our results support the recent concept that HO-1/CO system negatively regulates immune responses, they also form both conceptual and technical frameworks for a more systematic, large-scale drug discovery effort to identify HO-1/CO-targeted immunosuppressants with dual target specificity.

Prediction of seizure outcome following epilepsy surgery: asymmetry of thalamic glucose metabolism and cerebral neural activity in temporal lobe epilepsy.

OBJECTIVE: The objective of this retrospective study is to analyze whether preoperative functional imaging studies using FDG-PET and MEG enable prediction of postoperative seizure outcomes. METHODS: Thirty-six patients with intractable temporal lobe epilepsy were studied. Asymmetry index of tCMRgluc (PET-AI) and the equivalent current dipole intensity of first response of SEF (SEF-AI) were determined preoperatively using (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and magnetoencephalography (MEG), respectively. Seizure outcomes were evaluated according to the classification proposed by the International League Against Epilepsy (ILAE) at least 24 months after resection of epileptic focuses. Twelve healthy volunteers were included in this study to determine the normal value. RESULTS: Quantitative analysis revealed mean PET-AI in the patients was 5.4+/-5.2% (significantly different from normal controls); mean SEF-AI was 25.2+/-20.6% (not significantly different). PET-AI was positive (indicative of epileptic focus) in 29 of 36 patients (80.6%), while SEF-AI was positive in 17 of 36 patients (47.2%). Although no significant correlation between PET-AI and SEF-AI was noted (r=0.43), concordant asymmetry in both PET-AI and SEF-AI was significantly associated with better seizure outcome than discordant or paradoxical asymmetry of both factors (p<0.01). CONCLUSIONS: The results suggest that quantitative analysis of tCMRgluc with SEF may be helpful in characterizing the preoperative epileptogenic condition and predicting postoperative seizure outcome in patients with temporal lobe epilepsy, although a constellation of developmental brain abnormalities and environmental factors that together produce epilepsy need to be further explored.

Probable interaction between warfarin and antitumor agents used in R-ESHAP chemotherapy.

BACKGROUND: The pharmacologic effects of warfarin might be altered by various factors, including drug-drug interaction. CASE SUMMARY: A 49-year-old Japanese man (height, 174 cm; weight, 68 kg) presented with a 20-month history of malignant lymphoma (diffuse large B cell lymphoma, clinical stage IV). He was treated with a combination of rituximab chemotherapy and etoposide, cisplatin, high-dose cytarabine, and methyl-prednisolone (R-ESHAP). He had been receiving warfarin for the secondary prevention of pulmonary embolism with deep venous thrombosis. When R-ESHAP was started, international normalized ratio (INR) increased from 1 to 5. This phenomenon was observed again in the second R-ESHAP. The INR was increased from 2.44 to 4.71 during chemotherapy but was returned to within the normal range (1.05; normal range: 0.81-1.009) 5 days after chemotherapy was completed. CONCLUSION: In this patient, R-ESHAP chemotherapy might have affected warfarin anticoagulation sensitivity; thus, careful monitoring of INR is essential, particularly in patients receiving warfarin who undergo R-ESHAP chemotherapy.

[Infection treatment caused by multiple-drug-resistant Pseudomonas aeruginosa in a patient undergoing allogeneic hematopoietic stem cell transplantation].

Infections caused by multiple-drug-resistant Pseudomonas aeruginosa (MDRP) are a clinically significant problem. We reported here the effective use of combination therapy in a patient with infection caused by MDRP according to an interventional treatment strategy suggested by a pharmacist. The patient was a 70-year-old male who underwent allogeneic hematopoietic stem cell transplantation. On day 45 after transplant, MDRP was newly isolated from urine, but the diagnosis at that time was colonization. On day 61, the patient developed a fever (> or =38.0 degrees C). In addition, laboratory data showed that C-reactive protein (CRP) was also increased. At the medical team conference, the pharmacist proposed the following treatment strategy for this infection. Aztreonam and amikacin were intravenously administered at doses of 2 g/day and 800 mg/day, respectively. The subsequent clinical course was well controlled, but the infection recurred and was aggravated. Aztreonam and ciprofloxacin were then intravenously administered at doses of 4 g/day and 600 mg/day, respectively, resulting in the alleviation of fever in the patient as well as a decrease in CRP and disappearance of MDRP isolates from urine on day 67; that is, MDRP infection was consequently well controlled. In conclusion, the combination therapy between aztreonam and amikacin, or ciprofloxacin may be clinically useful for severe infections of MDRP in compromised hosts.