C-Type Lectin Receptor DCAR Recognizes Mycobacterial Phosphatidyl-Inositol Mannosides to Promote a Th1 Response during Infection.

Phosphatidyl-inositol mannosides (PIM) are glycolipids unique to mycobacteria and other related bacteria that stimulate host immune responses and are implicated in mycobacteria pathogenicity. Here, we found that the FcRγ-coupled C-type lectin receptor DCAR (dendritic cell immunoactivating receptor; gene symbol Clec4b1) is a direct receptor for PIM. Mycobacteria activated reporter cells expressing DCAR, and delipidation of mycobacteria abolished this activity. Acylated PIMs purified from mycobacteria were identified as ligands for DCAR. DCAR was predominantly expressed in small peritoneal macrophages and monocyte-derived inflammatory cells in lungs and spleen. These cells produced monocyte chemoattractant protein-1 (MCP-1) upon PIM treatment, and absence of DCAR or FcRγ abrogated MCP-1 production. Upon mycobacterial infection, Clec4b1-deficient mice showed reduced numbers of monocyte-derived inflammatory cells at the infection site, impaired IFNγ production by T cells, and an increased bacterial load. Thus, DCAR is a critical receptor for PIM that functions to promote T cell responses against mycobacteria.

Predictive Value of Vancomycin AUC24/MIC Ratio for 30-day Mortality in Patients with Severe or Complicated Methicillin-Resistant Staphylococcus aureus Infections: A Multicenter Retrospective Study.

BACKGROUND: Although vancomycin is typically employed against methicillin-resistant Staphylococcus aureus (MRSA) infections, the optimal ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) for severe or complicated infections lacks clear guideline recommendations. This study aimed to determine the target AUC24/MIC ratio associated with treatment outcomes of infections treated with vancomycin. METHODS: This retrospective multicenter cohort study included adult patients receiving ≥ 5 days of vancomycin for severe/complicated MRSA infections (e.g., osteoarticular, pulmonary, endocarditis, etc.) between January 2018 and December 2023. The primary outcome was 30-day mortality, with secondary outcomes including clinical success, microbiological eradication, and nephrotoxicity. Receiver operating characteristic (ROC) curve analysis was used to identify the AUC24/MIC cutoff for 30-day mortality. Multivariate regression analysis was used to determine association between AUC24/MIC and outcomes. RESULTS: This study included 82 patients. ROC identified a target AUC24/MIC of ≥ 505 for 30-day mortality. The overall 30-day mortality rate (22.0%) was significantly higher for below average AUC24/MIC cutoff (34.1%) than for above AUC24/MIC cutoff group (9.8%). Multivariate analysis confirmed AUC24/MIC of < 505 as an independent predictor (adjusted odds ratio, 5.001; 95% confidence interval, 1.335-18.75). The clinical success rate differed significantly between below- and above-cutoff groups, whereas microbiological eradication tended to favor the above-cutoff group. The nephrotoxicity rates were comparable between groups. CONCLUSIONS: In treating severe/complicated MRSA infections, vancomycin AUC24/MIC ratio ≥ 505 was independently associated with favorable 30-day mortality. Given the retrospective nature of this study, further prospective studies are essential to confirm the reliability of the target AUC24/MIC ratios.

Preliminary comparative study of lower extremity pressure measurements under the conditions using former models and new lithotomy stirrups in rectal cancer surgery.

BACKGROUND: This study aimed to investigate the effect of the use of new lithotomy stirrups-2 on the pressure dispersal on lower limbs, which may lead to the prevention of well-leg compartment syndrome (WLCS) and deep venous thrombosis (DVT), which are the most commonly associated adverse events with laparoscopic and robot-assisted rectal surgery. METHODS: A total of 30 healthy participants were included in this study. The pressure (mmHg) applied on various lower limb muscles when using conventional lithotomy stirrups-1 and new type stirrups-2 was recorded in various lithotomy positions; 1) neutral position, 2) Trendelenburg position (15°) with a 0° right inferior tilt, and 3) Trendelenburg position (15°) with a 10° right inferior tilt. Using a special sensor pad named Palm Q®, and the average values were compared between two types of stirrups. RESULTS: The use of new lithotomy stirrups-2 significantly reduced the pressure applied on the lower limb muscles in various lithotomy positions compared with the use of lithotomy stirrups-1. The most pressured lower limb muscle when using both lithotomy stirrups was the central soleus muscle, which is the most common site for the development of WLCS and DVT. In addition, when using the conventional lithotomy stirrups-1, the pressure was predominantly applied to the proximal soleus muscle; however, when using lithotomy stirrups-2, the pressure was shifted to the more distal soleus muscle. CONCLUSION: These results suggest that the new lithotomy stirrups-2 is useful in reducing the pressure load on leg muscles, especially on the proximal to central soleus, and may reduce the incidence of WLCS and DVT after rectal surgery performed in the lithotomy position. Further clinical studies are needed to determine whether the use of lithotomy stirrups-2 prevents these complications in various clinical settings.

Efficacy of minimally invasive proximal gastrectomy followed by valvuloplastic esophagogastrostomy using the double flap technique in preventing reflux oesophagitis.

BACKGROUND: Valvuloplastic esophagogastrostomy (VEG) using the double flap technique (DFT) after proximal gastrectomy (PG) represents a promising procedure for the prevention of reflux oesophagitis. We aimed to retrospectively investigate the efficacy of minimally invasive PG followed by VEG-DFT in preventing reflux oesophagitis among patients who require intra-mediastinal anastomosis. METHODS: A total of 80 patients who underwent reconstruction with DFT after LPG from November 2013 to January 2021 were enrolled in the present study. Data were obtained through a review of our prospectively maintained database. At 1 year after surgery, multivariate analyses were performed to identify risk factors for gastroesophageal reflux disease of Los Angeles (LA) classification grade B or higher. RESULTS: The incidence of LA grade B or higher reflux oesophagitis 1 year after surgery was 10%. Multivariate analyses revealed that the longitudinal length of the resected oesophagus of > 20 mm was the only significant risk factor for reflux oesophagitis. Patients with a longitudinal length of the resected oesophagus > 20 mm (group-L, n = 35) had a significantly longer total operative time and a higher rate of complications within 30 days of surgery than those with a length of ≤ 20 mm (group-S, n = 45). LA grade B or higher reflux oesophagitis was significantly higher in group-L than in group-S (20% vs. 2.2%; P = 0.011). CONCLUSIONS: There is a need for surgical procedures with improved efficacy for the prevention of reflux oesophagitis in patients requiring oesophageal resection of > 20-mm.

Optimal timing for therapeutic drug monitoring of voriconazole to prevent adverse effects in Japanese patients.

BACKGROUND: The optimal timing for therapeutic drug monitoring (TDM) of voriconazole in Asians, who have higher rates of poor metabolisers than non-Asians, is unclear. This can cause unexpectedly high concentrations and delays in reaching steady-state levels. OBJECTIVES: To determine the appropriate timing of TDM in Japanese patients receiving voriconazole. PATIENTS/METHODS: Trough levels (Cmin ) were measured on days 3-5 (recommended timing, RT) and days 6-14 (delayed timing, DT) after starting voriconazole in patients receiving an appropriate dosage. Considering bioavailability, Cmin was only compared in patients receiving oral voriconazole. RESULTS: A total of 289 and 186 patients were included in the safety and pharmacokinetic analyses, respectively. There was a significant difference in Cmin measured no later than and after day 5 (3.59 ± 2.12 [RT] vs. 4.77 ± 3.88 µg/mL [DT], p = .023), whereas no significant difference was observed on cutoff day 6 (3.91 ± 2.60 vs. 4.40 ± 3.94 µg/mL, p = .465), suggesting that Cmin close to the steady-state was achieved after day 5. DT causes a delay in achieving the therapeutic range. The hepatotoxicity rates were 21.5% and 36.8% in the RT and DT groups, respectively (p = .004); DT was an independent risk factor for hepatotoxicity. CONCLUSION: Although steady-state concentrations may not be achieved by day 5, early dose optimisation using RT can prevent hepatotoxicity in Japanese patients. TDM should be performed on days 3-5 to ensure safety. However, subsequent TDM may be necessary due to a possible further increase in Cmin .

Vancomycin Hydrochloride as a Risk Factor for Acute Kidney Injury: A Retrospective Study.

INTRODUCTION: The incidence of acute kidney injury (AKI) caused by vancomycin hydrochloride (VCM) was reported to be 5-43%. VCM-induced AKI was reported to be more likely to occur 4-17 days after initiating VCM treatment; however, it may occur earlier. The aim of this study was therefore to investigate risk factors for the development of AKI within two (AKI2days) and seven (AKI7days) days of VCM administration. METHODS: This was a single-center, retrospective study including patients who underwent VCM therapy between April 1, 2013, and December 31, 2019. AKI was evaluated based on the Kidney Disease: Improving Global Outcomes criteria. RESULTS: In total, 287 patients were enrolled. The incidence of VCM-induced AKI within 7 days was 10.8% (31/286 cases), and the incidence of AKI within 2 days was 5.9% (15/252 cases). Serum VCM trough concentrations and tazobactam-piperacillin (TZP) were shown to be a risk factor for VCM-induced AKI. The serum VCM trough concentration was 12.67 µg/mL within the 48 h threshold (AKI2days) and 19.03 µg/mL within the 7-day threshold (AKI7days). CONCLUSION: Our study demonstrated that high serum VCM trough concentrations and the combination of VCM and TZP were independent risk factors for VCM-induced AKI. Avoiding the concomitant use of TZP, or thorough monitoring of renal function with the concomitant use of TZP, may be helpful in reducing the occurrence of AKI. Furthermore, monitoring serum VCM trough concentrations within 2 days may effectively reduce the incidence of AKI.

Risk Factors for Lenvatinib-Induced High-Grade Hypothyroidism in Patients with Hepatocellular Carcinoma: A Retrospective Study.

INTRODUCTION: Lenvatinib mesylate (LEN) is an orally administered tyrosine kinase inhibitor used for the treatment of various cancers, including hepatocellular carcinoma (HCC). HCC treatment with LEN is associated with a very high incidence of adverse events, especially hypothyroidism. This study investigated the incidence of hypothyroidism due to LEN and the relationships between hypothyroidism incidence and patient demographics by analyzing clinical laboratory data from HCC patients treated with LEN. METHODS: This was a single-center, retrospective study of HCC patients who received LEN between April 19, 2018, and September 30, 2020. The observation period was from 1 week before the start of LEN administration to 1 month after the end of administration. RESULTS: In total, 61 patients with HCC were enrolled. High-grade hypothyroidism (CTCAE Grade 2-3) was found in 36.1% (22/61 patients). In high-grade hypothyroidism, eosinophil (EOSINO) count was significantly low (p = 0.029). The cutoff value of EOSINO count was estimated to be approximately 150/µL. The adjusted odds ratios of high-grade hypothyroidism for current smoking and EOSINO count <150/µL were 0.237 (95% confidence interval: 0.063-0.893) and 4.219 (95% confidence interval: 1.119-15.92), respectively. CONCLUSION: The results showed that noncurrent smoking and EOSINO count <150/µL are risk factors for LEN-induced high-grade hypothyroidism.

The Induction of Antigen 85B-Specific CD8+ T Cells by Recombinant BCG Protects against Mycobacterial Infection in Mice.

Mycobacterium tuberculosis (Mtb) infection remains a major health problem worldwide. Although the Bacillus Calmette-Guérin (BCG) vaccine is the most widely used vaccination for preventing tuberculosis (TB), its efficacy is limited. We previously developed a new recombinant BCG (rBCG)-based vaccine encoding the Ag85B protein of M. kansasii (Mkan85B), termed rBCG-Mkan85B, and its administration is followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). Previously, we identified MHC-I (H2-Kd)-restricted epitopes that highly cross-react with those of Mtb in BALB/c (H2d) and CB6F1 (H2b/d) mice. We also reported that the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol protected CB6F1 mice against M. kansasii infection. In this study, to investigate the protective effect of our novel rBCG against Mtb infection, CB6F1 mice were either left unimmunized or immunized with the BCG, rBCG-Mkan85B, or rBCG-Mkan85B/DNA-Mkan85B vaccine for 10 weeks prior to inhalation exposure to the virulent Mtb Erdman strain for another 6 weeks. Compared with the BCG and rBCG-Mkan85B vaccinations, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination protocol significantly reduced the numbers of pulmonary colony-forming units (CFUs). Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime-boost vaccination induced antigen-specific polyfunctional CD4+ and CD8+ T cells. These results suggest that CD8+ T-cell immunity to immunodominant epitopes of Mtb is enhanced by rBCG vector-based immunization. Thus, rBCG vector-based vaccinations may overcome the limited ability of the current BCG vaccine to elicit TB immunity.

CD8 T Cells Show Protection against Highly Pathogenic Simian Immunodeficiency Virus (SIV) after Vaccination with SIV Gene-Expressing BCG Prime and Vaccinia Virus/Sendai Virus Vector Boosts.

Toward development of a dual vaccine for human immunodeficiency virus type 1 (HIV-1) and tuberculosis infections, we developed a urease-deficient bacillus Calmette-Guérin (BCG) strain Tokyo172 (BCGΔurease) to enhance its immunogenicity. BCGΔurease expressing a simian immunodeficiency virus (SIV) Gag induced BCG antigen-specific CD4+ and CD8+ T cells more efficiently and more Gag-specific CD8+ T cells. We evaluated its protective efficacy against SIV infection in cynomolgus monkeys of Asian origin, shown to be as susceptible to infection with SIVmac251 as Indian rhesus macaques. Priming with recombinant BCG (rBCG) expressing SIV genes was followed by a boost with SIV gene-expressing LC16m8Δ vaccinia virus and a second boost with SIV Env-expressing Sendai virus. Eight weeks after the second boost, monkeys were repeatedly challenged with a low dose of SIVmac251 intrarectally. Two animals out of 6 vaccinees were protected, whereas all 7 control animals were infected without any early viral controls. In one vaccinated animal, which had the most potent CD8+ T cells in an in vitro suppression activity (ISA) assay of SIVmac239 replication, plasma viremia was undetectable throughout the follow-up period. Protection was confirmed by the lack of anamnestic antibody responses and detectable cell-associated provirus in various organs. Another monkey with a high ISA acquired a small amount of SIV, but it later became suppressed below the detection limit. Moreover, the ISA score correlated with SIV acquisition. On the other hand, any parameter relating anti-Env antibody was not correlated with the protection.IMPORTANCE Because both AIDS and tuberculosis are serious health threats in middle/low-income countries, development of a dual vaccine against them would be highly beneficial. To approach the goal, here we first assessed a urease-deficient bacillus Calmette-Guérin (BCG) for improvement of immunogenicity against both Mycobacterium tuberculosis and SIV. Second, we demonstrated the usefulness of Asian-origin cynomolgus monkeys for development of a preclinical AIDS vaccine by direct comparison with Indian rhesus macaques as the only validated hosts that identically mirror the outcomes of clinical trials, since the availability of Indian rhesus macaques is limited in countries other than the United States. Finally, we report the protective effect of a vaccination regimen comprising BCG, the highly attenuated vaccinia virus LC16m8Δ strain, and nontransmissible Sendai virus as safe vectors expressing SIV genes using repeated mucosal challenge with highly pathogenic SIVmac251. Identification of CD8+ T cells as a protective immunity suggests a future direction of AIDS vaccine development.

Vaccination with Intradermal Bacillus Calmette-Guérin Provides Robust Protection against Extrapulmonary Tuberculosis but Not Pulmonary Infection in Cynomolgus Macaques.

Recently, the efficacy of Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination is being reassessed in accordance with the achievements of clinical tuberculosis (TB) vaccine research. However, the mechanisms ultimately determining the success or failure of BCG vaccination to prevent pulmonary TB remain poorly understood. In this study, we analyzed the protective effects of intradermal BCG vaccination by using specific pathogen-free cynomolgus macaques of Asian origin that were intradermally vaccinated with BCG (Tokyo strain) followed by Mycobacterium tuberculosis (Erdman strain) infection. Intradermal BCG administration generated TB Ag-specific multifunctional CD4 T cell responses in peripheral blood and bronchoalveolar lavage and almost completely protected against the development of TB pathogenesis with aggravation of clinical parameters and high levels of bacterial burdens in extrapulmonary organs. However, interestingly, there were no differences in bacterial quantitation and pathology of extensive granulomas in the lungs between BCG-vaccinated monkeys and control animals. These results indicated that the changes in clinical parameters, immunological responses, and quantitative gross pathology that are used routinely to determine the efficacy of TB vaccines in nonhuman primate models might not correlate with the bacterial burden and histopathological score in the lung as measured in this study.

SOCS1 Antagonist-Expressing Recombinant Bacillus Calmette-Guérin Enhances Antituberculosis Protection in a Mouse Model.

Suppressor of cytokine signaling 1 (SOCS1) plays a key role in the negative regulation of JAK/STAT signaling, which is involved in innate immunity and subsequent adaptive immunity. Bacillus Calmette-Guérin (BCG) induces upregulation of SOCS1 expression in host cells, which may lead to the suppression of immune responses by BCG via inhibition of the JAK/STAT signaling pathway. This might cause A reduction in the protective effect of a BCG vaccine. In the current study, we assessed the immune responses to and the protective efficacy of a recombinant BCG secreting a dominant negative mutant of the SOCS1 molecule (rBCG-SOCS1DN). C57BL/6 mice were immunized with rBCG-SOCS1DN or parental BCG Tokyo vaccine strain harboring an empty plasmid vector (rBCG-pSO). rBCG-SOCS1DN enhanced the activation of bone marrow-derived dendritic cells and the activation of T cells compared with those with rBCG-pSO. The amounts of IFN-γ, TNF-α, and IL-6 produced by splenocytes of rBCG-SOCS1DN-immunized mice were larger than those produced by splenocytes of rBCG-pSO-immunized mice. Moreover, the rBCG-SOCS1DN-immunized mice showed a substantial reduction in the number of CFU of Mycobacterium tuberculosis in the lungs and spleens compared with that in control BCG-immunized mice when the immunized mice were infected with a highly pathogenic M. tuberculosis strain by inhalation. These findings provide evidence for the possibility of rBCG-SOCS1DN being an effective M. tuberculosis vaccine with a novel concept of rBCG as a tool for immunomodulation in host cells.

Inhibitory Effects of Antipsychotics on the Contractile Response to Acetylcholine in Rat Urinary Bladder Smooth Muscles.

The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10-5 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.

Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis.

INTRODUCTION: Multiple sclerosis (MS) is an autoimmune disease mediated by a pro-inflammatory immune response. Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with a myelin oligodendrocyte glycoprotein (MOG) peptide emulsified in killed Mycobacterium tuberculosis-containing complete Freund's adjuvant (CFA-EAE) is used as a model of MS. Mycobacterium bovis BCG has been reported to ameliorate clinical symptoms of CFA-EAE, although the precise mechanism has not yet been documented. Since CFA-EAE uses adjuvant with mycobacterial antigens, mycobacterial antigen-specific T cells induced by CFA may cross-react with BCG and modulate EAE. METHODS: To exclude the influence of cross-reactivity, a modified murine EAE model (cell wall skeleton (CWS)-EAE) that does not induce mycobacterial antigen-specific T cells was established and used to reevaluate the therapeutic effects of BCG on EAE. RESULTS: Inoculation with BCG 6 d after CWS-EAE induction successfully ameliorated EAE symptoms, suggesting that the therapeutic effects of BCG are independent of the mycobacterial antigen-specific T cells induced by the CFA-EAE protocol. BCG inoculation into the CWS-EAE mice resulted in reduced levels of MOG-specific Th17 in the central nervous system (CNS) with reduced demyelinated lesions of the spinal cord. In the draining lymph nodes of the MOG-immunized sites, BCG inoculation resulted in an increase in MOG-specific Th17 and Th1 cells at an early stage of immune response. CONCLUSION: The results suggest that BCG inoculation suppresses the Th17 response in the CNS of EAE mice via a mechanism that may involve the suppression of egress of encephalitogenic T cells from lymphoid organs.

A New Mouse Model of Chronic Myocarditis Induced by Recombinant Bacille Calmette-Guèrin Expressing a T-Cell Epitope of Cardiac Myosin Heavy Chain-α.

Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology remains unclear. Here, we report a novel mouse model of chronic myocarditis induced by recombinant bacille Calmette-Guérin (rBCG) expressing a CD4+ T-cell epitope of cardiac myosin heavy chain-α (rBCG-MyHCα). Mice immunized with rBCG-MyHCα developed chronic myocarditis, and echocardiography revealed dilation and impaired contraction of ventricles, similar to those observed in human DCM. In the heart, CD62L-CD4+ T cells were increased and produced significant amounts of IFN-γ and IL-17 in response to cardiac myosin. Adoptive transfer of CD62L-CD4+ T cells induced myocarditis in the recipient mice, which indicated that CD62L-CD4+ T cells were the effector cells in this model. rBCG-MyHCα-infected dendritic cells produced proinflammatory cytokines and induced MyHCα-specific T-cell proliferation and Th1 and Th17 polarization. This novel chronic myocarditis mouse model may allow the identification of the central pathophysiological and immunological processes involved in the progression to DCM.

Occurrence of Infusion-Related Reactions due to Obinutuzumab Therapy for Follicular Lymphoma.

BACKGROUND: Obinutuzumab is used to treat follicular lymphoma in Japan. Its characteristic adverse event is infusion- related reactions(IRRs). Although interruption of administration improves many IRRs, serious symptoms can occur; thus, timing the interruption to correspond with the onset of these symptoms is necessary. However, the specific symptoms and timing of IRRs caused by obinutuzumab remain unclear. Therefore, the purpose of this study was to clarify the specific symptoms and timing of the onset of IRRs with obinutuzumab treatment. METHODS: Thirty patients were administered obinutuzumab for one year from October 2018 to September 2019. The frequency of IRRs, expression time, severity, symptoms, and correspondence were investigated. RESULTS: IRRs occurred in 13 patients(43.3%), and all occurred after the first dosing. In 9 of 13 cases(69.2%), IRRs occurred within 90 min of the first dosage. Grade 3 symptoms were expressed in 1 of 13 cases (7.7%). The symptoms of IRRs were throat discomfort, breathing difficulty, skin rash, chills, and fever. CONCLUSIONS: Most IRRs due to obinutuzumab occurred within 90 min of the first dosage. They were mostly Grade 2 or lower, and the frequency of serious IRRs was low. Thus, careful observation of symptoms during treatment with obinutuzumab is necessary.

MHC-restricted Ag85B-specific CD8+ T cells are enhanced by recombinant BCG prime and DNA boost immunization in mice.

Despite efforts to develop effective treatments and vaccines, Mycobacterium tuberculosis (Mtb), particularly pulmonary Mtb, continues to provide major health challenges worldwide. To improve immunization against the persistent health challenge of Mtb infection, we have studied the CD8+ T cell response to Bacillus Calmette-Guérin (BCG) and recombinant BCG (rBCG) in mice. Here, we generated CD8+ T cells with an rBCG-based vaccine encoding the Ag85B protein of M. kansasii, termed rBCG-Mkan85B, followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). We identified two MHC-I (H2-Kd )-restricted epitopes that induce cross-reactive responses to Mtb and other related mycobacteria in both BALB/c (H2d ) and CB6F1 (H2b/d ) mice. The H2-Kd -restricted peptide epitopes elicited polyfunctional CD8+ T cell responses that were also highly cross-reactive with those of other proteins of the Ag85 complex. Tetramer staining indicated that the two H2-Kd -restricted epitopes elicit distinct CD8+ T cell populations, a result explained by the X-ray structure of the two peptide/H2-Kd complexes. These results suggest that rBCG-Mkan85B vector-based immunization and DNA-Mkan85B boost may enhance CD8+ T cell response to Mtb, and might help to overcome the limited effectiveness of the current BCG in eliciting tuberculosis immunity.

Pharmacological Characteristics of Anxiolytics on Acetylcholine-Induced Contractions in Rat Detrusor Smooth Muscle.

INTRODUCTION: Benzodiazepine anxiolytics are believed to cause urination disorders due to their anticholinergic effects. OBJECTIVE: This study was carried out to investigate the potential inhibitory effects of 15 clinically available anxiolytics in Japan on acetylcholine (ACh)-induced contractions in rat detrusor smooth muscle (DSM) to predict whether these anxiolytics could induce urination disorders. METHODS: -Effects of anxiolytics on contractions induced by ACh and 80 mmol/L KCl solution in rat DSM and effects of anxiolytics on specific binding of [N-methyl-3H]scopolamine ([3H]NMS) in mouse cerebral cortex were investigated. RESULTS AND CONCLUSIONS: ACh-induced contractions in rat DSM were inhibited by clotiazepam and diazepam (benzodiazepine anxiolytics) at concentrations that were clinically relevant. These contractions were also significantly inhibited by paroxetine, escitalopram (selective serotonin reuptake inhibitors -[SSRIs]), and hydroxyzine (a histamine H1 receptor antagonist), albeit at concentrations that substantially exceeded clinically achievable blood levels. At a concentration of 10-5 mol/L, paroxetine, escitalopram, and hydroxyzine inhibited 80 mmol/L high-KCl solution-induced rat DSM contractions but not clotiazepam and diazepam. Paroxetine, escitalopram, and hydroxyzine also inhibited specific binding of [3H]NMS in mouse cerebral cortex but clotiazepam and diazepam did not. In contrast to the effects of the abovementioned anxiolytics, ACh-induced contractions were not significantly affected by tofisopam, alprazolam, lorazepam, bromazepam, oxazolam, chlordiazepoxide, clonazepam, ethyl loflazepate (benzodiazepine anxiolytics), fluvoxamine (an SSRI), or tandospirone (a serotonin 5-HT1A receptor agonist). These findings suggest that most clinically used anxiolytics are not likely to result in anticholinergic-induced urination disorders within their clinically achievable blood concentration ranges. However, clotiazepam and diazepam may induce urination disorders within their clinical dose ranges via nonanticholinergic inhibition of DSM contractility.

[Preoperative Imatinib Therapy Followed by Laparoscopic Local Gastrectomy for a Giant Gastric Gastrointestinal Stromal Tumor-A Case Report].

A 55-year-old man complained of abdominal distention. Gastroscopy showed a submucosal tumor in the upper-third portion of the stomach, with a biopsy diagnosis of gastrointestinal stromal tumor(GIST). Because abdominal contrast- enhanced CT findings suspected the invasion of the tumor into the pancreatic tail, preoperative imatinib therapy was performed. After 2 weeks of treatment, the tumor had shrunk to 44% of its starting volume. Six months later, CT findings suggestive of the tumor invasion had disappeared. Therefore, the laparoscopic local resection of the stomach was performed. The postoperative course was uneventful. A pathological diagnosis was c-kit-positive GIST, with less than 5/50 HPF of mitotic counts. Imatinib was restarted 2 weeks after the operation. The patient is alive 8 months after the operation, with no obvious recurrence. Preoperative imatinib therapy can be a useful option for large GIST tumors.

[Laparoscopic Local Resection for Duodenal Gastrointestinal Stromal Tumor Located in the Third Portion Using Kocher's Maneuver-A Case Report].

Duodenal gastrointestinal stromal tumor(GIST)are relatively rare. Here, we report a case of a duodenal GIST located in the third portion that was successfully treated via laparoscopic local resection using the Kocher maneuver. A 49-year-old woman with a high BMI of 43.4 kg/m2 was diagnosed with a 20 mm duodenal submucosal tumor in the third portion that was suspected to be a GIST; subsequently, she underwent laparoscopic local resection. After mobilization from the first to third portion of the duodenum using the Kocher maneuver, local resection using a linear stapler was completed. The surgery time was 152 minutes, and the estimated blood loss was approximately zero. The postoperative course was uneventful, and she was discharged on the 7th postoperative day. The pathological diagnosis was ultra-low-grade GIST. This procedure can be a useful option for obese patients with good operative field of view.

Characterization of binding of antipsychotics to muscarinic receptors using mouse cerebral cortex.

Antipsychotics are often the first-line treatment for behavioral and psychological symptoms of dementia. However, the potential anticholinergic effects of antipsychotics could counteract the therapeutic effects of cholinesterase inhibitors used to treat dementia. We investigated the inhibitory effects of 26 antipsychotics on [N-Methyl-3H]scopolamine specific binding in mouse cerebral cortex. At 10-5 M, chlorpromazine, levomepromazine, prochlorperazine, timiperone, zotepine, pimozide, blonanserin, olanzapine, quetiapine, and clozapine inhibited [N-Methyl-3H]scopolamine binding by > 45%. Furthermore, the pKi values of chlorpromazine, levomepromazine, zotepine, olanzapine, and clozapine overlapped with their clinically achievable blood concentrations. Therefore, the anticholinergic properties of these antipsychotics could attenuate the effects of cholinesterase inhibitors.