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Ethnopharmacological Relevance: Cordyceps sinensis (CS) is a fungus parasitic on lepidopteran larvae which is often used to treat lung diseases and regulate immune function., Aim of the Study: This review aimed to evaluate the efficacy of CS in the adjuvant treatment of lung cancer., Materials and Methods: As of June 2022, the electronic database search was conducted in PubMed, EMBASE, Cochrane Library, China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Database and China Science Journal Database (VIP database). Randomized clinical trials (RCTs) that evaluated the efficacy of CS as an adjuvant treatment for lung cancer were included. After the quality evaluation, meta-analysis was performed with Stata 16.0 software., Results: A total of 12 RCTs with 928 patients were identified for this meta-analysis, which showed that as an adjuvant treatment, CS has the following advantages in the treatment of lung cancer: (1) Improved tumor response rate (TRR) (RR: 1.17， 95%CI: 1.05-1.29，P = 0.00); (2) improved immune function, including increased CD4 (MD: 4.98, 95%CI: 1.49-8.47, P = 0.01), CD8 (MD: 1.60, 95%CI: 0.40-2.81, P = 0.01, I 2  = 0.00%), NK (MD: 4.17, 95%CI: 2.26-6.08, P = 0.00), IgA (MD: 1.29, 95%CI: 0.35-2.24, P = 0.01), IgG (MD: 3.95, 95%CI: 0.98-6.92, P = 0.01) and IgM (MD: 6.44, 95%CI: 0.63-12.26, P = 0.03); (3) improved patients' quality of life based on the mean ± SD of Karnofsky Performance Status (KPS) (MD: 8.20, 95%CI: 6.87-9.53, P = 0.00); (4) reduced the incidence of adverse drug reactions (ADRs), including the incidence of myelosuppression (RR: 0.38, 95%CI: 0.19-0.75, P = 0.01), leukopenia (RR: 0.76, 95%CI: 0.63-0.92, P = 0.00), and thrombocytopenia (RR: 0.52, 95%CI: 0.31-0.86, P = 0.01) (5) reduced the incidence of radiation pneumonitis (RR: 0.74, 95%CI: 0.62-0.88, P = 0.00). However, the number of improved patients based on KPS (RR: 1.47, 95%CI: 0.98-2.20, P = 0.06) were similar between two groups, liver and renal damage (RR: 0.32, 95%CI: 0.09-1.10, P = 0.07) and gastrointestinal adverse reactions (RR: 0.80, 95%CI: 0.47-1.37, P = 0.42) as well. Subgroup analysis showed that CS could increase the TRR in the treatment with 6 g/d and 21 days/3-4 cycles., Conclusion: Compared with conventional treatment, adjuvant treatment with CS of lung cancer not only improve TRR, QOL and immune function, but also reduce the incidence of ADRs and radiation pneumonitis. The optimal usage may be 6 g/d and 21 days/3 to 4 cycles., Prospero Registration No: CRD42022333681., Competing Interests: Declaration of competing interest All authors disclosed no relevant relationships., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Leukopenia could be induced by chemotherapy, which leads to bone marrow suppression and even affects the therapeutic progression of cancer. Qijiao Shengbai Capsule (QSC) has been used for the treatment of leukopenia in clinic, but its bioactive components and mechanisms have not yet been elucidated clearly., Purpose: This study aimed to elucidate the molecular mechanisms of QSC in treating leukopenia., Study Design: Serum pharmacochemistry, multi-omics, network pharmacology, and validation experiment were combined to study the effect of QSC in murine leukopenia model., Methods: First, UPLC-QTOF-MS was used to clarify the absorbed components of QSC. Then, cyclophosphamide (CTX) was used to induce mice model with leukopenia, and the therapeutic efficacy of QSC was assessed by an integrative approach of multi-omics and network pharmacology strategy. Finally, molecular mechanisms and potential therapeutic targets were identified by validated experiments., Results: 121 compounds absorbed in vivo were identified. QSC significantly increase the count of white blood cells (WBCs) in peripheral blood of leukopenia mice with 15 days treatment. Multi-omics and network pharmacology revealed that leukotriene pathway and MAPK signaling pathway played crucial roles during the treatment of leukopenia with QSC. Six targets (ALOX5, LTB4R, CYSLTR1, FOS, JUN, IL-1β) and 13 prototype compounds were supposed to be the key targets and potential active components, respectively. The validation experiment further confirmed that QSC could effectively inhibit the inflammatory response induced by leukopenia. The inhibitors of ALOX5 activity can significantly increase the number of WBCs in leukopenia mice. Molecular docking of ALOX5 suggested that calycosin, daidzein, and medicarpin were the potentially active compounds of QSC., Conclusion: Leukotriene pathway was found for the first time to be a key role in the development of leukopenia, and ALOX5 was conformed as the potential target. QSC may inhibit the inflammatory response and interfere the leukotriene pathway, it is able to improve hematopoiesis and achieve therapeutic effects in the mice with leukopenia., Competing Interests: Declaration of competing interest All contributing authors are listed below: Chi Ma, Jing Zhao, Guangyong Zheng, Shiyu Wu, Ruijun Wu, Dianping Yu, Jingyu Liao, Hongwei Zhang, Li Liu, Lu Jiang, Fei Qian, Huawu Zeng, Gaosong Wu, Zhenhui Lu, Ji Ye, Weidong Zhang. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Leukopenia is the most common side effect of chemotherapy and radiotherapy. It potentially deteriorates into a life-threatening complication in cancer patients. Despite several agents being approved for clinical administration, there are still high incidences of pathogen-related disease due to a lack of functional immune cells. ADP-ribosyl cyclase of CD38 displays a regulatory effect on leukopoiesis and the immune system. To explore whether the ADP-ribosyl cyclase was a potential therapeutic target of leukopenia. We established a drug screening model based on an ADP-ribosyl cyclase-based pharmacophore generation algorithm and discovered three novel ADP-ribosyl cyclase agonists: ziyuglycoside II (ZGSII), brevifolincarboxylic acid (BA), and 3,4-dihydroxy-5-methoxybenzoic acid (DMA). Then, in vitro experiments demonstrated that these three natural compounds significantly promoted myeloid differentiation and antibacterial activity in NB4 cells. In vivo, experiments confirmed that the compounds also stimulated the recovery of leukocytes in irradiation-induced mice and zebrafish. The mechanism was investigated by network pharmacology, and the top 12 biological processes and the top 20 signaling pathways were obtained by intersecting target genes among ZGSII, BA, DMA, and leukopenia. The potential signaling molecules involved were further explored through experiments. Finally, the ADP-ribosyl cyclase agonists (ZGSII, BA, and DMA) has been found to regenerate microbicidal myeloid cells to effectively ameliorate leukopenia-associated infection by activating CD38/ADP-ribosyl cyclase-Ca 2+ -NFAT. In summary, this study constructs a drug screening model to discover active compounds against leukopenia, reveals the critical roles of ADP-ribosyl cyclase in promoting myeloid differentiation and the immune response, and provides a promising strategy for the treatment of radiation-induced leukopenia., Competing Interests: Declaration of Competing Interest All the authors declare no competing interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Chemotherapy-induced leukopenia is a common side effect of cytotoxic anticancer drugs. It can deprive patients of treatment opportunities, resulting in the delay, reduction, or discontinuation of chemotherapy or other anticancer drug administration. Two researchers searched English, Chinese, Japanese, and Korean electronic databases, without limiting the time period and language, using search terms such as "Bojungikgi," "WBC," "leuko," and "neutrop." Among the human randomized controlled studies in which Bojungikgi-tang was administered to patients who underwent chemotherapy, studies reporting leukopenia-related outcomes were selected, and data extraction, bias risk assessment, and meta-analysis were performed on the selected papers. Ten studies were selected, and a systematic review with meta-analysis was conducted. Nine papers were published in China and the total number of participants was 715. As a result of administering Bojungikgi-tang to these patients, the number of patients with chemotherapy-induced leukopenia significantly decreased (OR: 0.41, 95% CI: 0.27-0.61, P  = .0001, I 2  = 35%). Further, white blood cell counts were compared with that of the control group, and it showed an effect on prevention (MD: 0.64, 95% CI: 0.46-0.83, P  < .00001, I 2  = 90%). A pronounced effect was observed, especially when administered after a diagnosis based on the pattern identification, such as Qi deficiency. (OR: 0.32, 95% CI: 0.18-0.58, P  = .0002, I 2  = 0%). However, all studies had a high risk of bias due to non-blinding, and most studies had a high or uncertain risk of bias in creating random assignment orders and concealing them. Bojungikgi-tang has an effect on the prevention and treatment of chemotherapy-induced leukopenia. The effect rate can be increased when administered after proper diagnosis, and the possibility of adverse reactions and side effects is lower than that of Granulocyte-Colony Stimulating Factor (G-CSF) injection. Bojungikgi-tang appears to be useful in the treatment and prevention of leukopenia caused by cytotoxic anticancer drugs. However, it is necessary to conduct high-quality clinical studies in the future, considering the possibility of local and language bias, heterogeneity of carcinoma and intervention, and the risk of bias.Registration: PROSPERO CRD4202341054., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Adverse lamotrigine effects are more likely with concomitant use of antiepileptic drugs, rapid dose titration, and multiple drug use, highlighting the importance of measuring its concentration. Here, lamotrigine was administered the day after the third mRNA vaccination to a 20-year-old bipolar woman with these risk factors. Leukopenia occurred on day 12 without rapid concentration increase, but leukocytes gradually recovered after 22 weeks without discontinuation of lamotrigine. The second mRNA vaccination did not induce leukopenia. Possibly, a synergetic immune response to simultaneous vaccination and lamotrigine caused leukopenia, which recovered as the response weakened. Lamotrigine initiation immediately after mRNA vaccination may be a leukopenia risk factor.

Background: This study's objective was to investigate the predictors for severe anemia, severe leukopenia, and severe thrombocytopenia when amphotericin B deoxycholate-based induction therapy is used in HIV-infected patients with talaromycosis., Methods: A total of 170 HIV-infected patients with talaromycosis were enrolled from January 1st, 2019, to September 30th, 2020., Results: Approximately 42.9%, 20.6%, and 10.6% of the enrolled patients developed severe anemia, severe leukopenia, and severe thrombocytopenia, respectively. Baseline hemoglobin level < 100 g/L (OR = 5.846, 95% CI: 2.765 ~ 12.363), serum creatinine level > 73.4 µmol/L (OR = 2.573, 95% CI: 1.157 ~ 5.723), AST/ALT ratio > 1.6 (OR = 2.479, 95% CI: 1.167 ~ 5.266), sodium level ≤ 136 mmol/liter (OR = 4.342, 95% CI: 1.747 ~ 10.789), and a dose of amphotericin B deoxycholate > 0.58 mg/kg/d (OR = 2.504, 95% CI:1.066 ~ 5.882) were observed to be independent risk factors associated with the development of severe anemia. Co-infection with tuberculosis (OR = 3.307, 95% CI: 1.050 ~ 10.420), and platelet level (per 10 × 109 /L) (OR = 0.952, 95% CI: 0.911 ~ 0.996) were shown to be independent risk factors associated with the development of severe leukopenia. Platelet level < 100 × 10 9 /L (OR = 2.935, 95% CI: 1.075 ~ 8.016) was identified as the independent risk factor associated with the development of severe thrombocytopenia. There was no difference in progression to severe anemia, severe leukopenia, and severe thrombocytopenia between the patients with or without fungal clearance at 2 weeks. 10 mg on the first day of amphotericin B deoxycholate was calculated to be independent risk factors associated with the development of severe anemia (OR = 2.621, 95% CI: 1.107 ~ 6.206). The group receiving a starting amphotericin B dose (10 mg, 20 mg, daily) exhibited the highest fungal clearance rate at 96.3%, which was significantly better than the group receiving a starting amphotericin B dose (5 mg, 10 mg, 20 mg, daily) (60.9%) and the group receiving a starting amphotericin B dose (5 mg, 15 mg, and 25 mg, daily) (62.9%)., Conclusion: The preceding findings reveal risk factors for severe anemia, severe leukopenia, and severe thrombocytopenia. After treatment with Amphotericin B, these severe adverse events are likely unrelated to fungal clearance at 2 weeks. Starting amphotericin B deoxycholate at a dose of 10 mg on the first day may increase the risk of severe anemia but can lead to earlier fungal clearance., Trial Registration: ChiCTR1900021195. Registered 1 February 2019., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients., Methods: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia., Results: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036)., Conclusion: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To outline the characteristics of Kikuchi-Fujimoto disease (KFD) in children and analyze factors associated with severe and recurring courses., Methods: Electronic medical records of children histopathologically diagnosed with KFD at Seoul National University Bundang Hospital from March 2015 to April 2021 were retrospectively reviewed., Results: A total of 114 cases (62 males) were identified. The mean patient age was 12.0 ± 3.5 years. Most patients came to medical attention with cervical lymph node enlargement (97.4%) and fever (85%); 62% had a high-grade fever (≥39°C). Prolonged fever (≥14 days) was seen in 44.3% and was associated with a high-grade fever (P = .004). Splenomegaly, oral ulcer, or rash was present in 10.5%, 9.6%, and 15.8%, respectively. Laboratory findings showed leukopenia, anemia, and thrombocytopenia in 74.1%, 49%, and 24%, respectively. Sixty percent of cases had a self-limited course. Antibiotics were initially prescribed in 20%. A corticosteroid was prescribed in 40% of patients and was associated with oral ulcer (P = .045) and anemia (P = .025). Twelve patients (10.5%) had a recurrence with a median interval of 19 months. No risk factor for recurrence was identified in multivariable analysis. Clinical characteristics of KFD were similar between our current and previous studies. However, antibiotics use decreased (P < .001); nonsteroidal anti-inflammatory drugs use increased (P < .001), and, although statistically not significant, corticosteroid treatment also increased., Conclusions: Over a span of 18 years, the clinical characteristics of KFD did not change. Patients presenting with high-grade fever, oral ulcer, or anemia may benefit from corticosteroid intervention. All patients should be monitored for recurrence., Competing Interests: Declaration of Competing Interest The data presented in this study are available on request from the corresponding author. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort., Methods: Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex., Results: In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ± 15.8 years vs. 35.1 ± 13.7 years, P  = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ± 1.13 vs. 0.34 ± 0.81, P  = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P  = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P  = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P  = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P  = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P  = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P  = 0.002), musculoskeletal damage (P  = 0.023), cardiovascular impairment (P  = 0.009), and CYC use (P  = 0.001); while leukopenia (P  = 0.017), arthritis (P  = 0.014), and mycophenolate usage (P  = 0.013) rates were lower., Conclusions: Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients., (Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

Fluoropyrimidine plus platinum (FP) and taxanes plus platinum (TP) are standard treatments for esophageal cancer (EC). This systematic review and meta-analysis aim to explore the difference in the therapeutic effect and toxicity of FP and TP regimens in EC patients. PubMed, Embase, and Cochrane were fully searched and analyzed to find relevant articles on EC patients treated with FP and TP regimens up to 22 March 2022. Thirty-one studies, with a total of 3432 participants, were included in this review. The primary outcomes showed that the prognosis and therapeutic efficacy of TP groups were better than those of FP groups for the EC patients treated with definitive chemoradiotherapy treatment (3-year OS: RR: 1.25, 95% CI: 1.08−1.44, p = 0.003; 3-year PFS: RR: 1.43, 95% CI: 1.17−1.75, p = 0.0006; ORR: RR: 1.17, 95% CI: 1.06−1.29, p = 0.001). However, TP therapy was significantly correlated with a higher incidence of leukopenia and thrombocytopenia (p < 0.05). In the preoperative neoadjuvant chemoradiotherapy group, these two groups had a similar survival time (p > 0.05). The FP regimen corresponded to a higher incidence of thrombocytopenia, while the TP regimen was associated with an increased incidence of febrile leukopenia (p < 0.05). Therefore, TP regimens could generate both superior clinical response and survival benefits when compared with FP regimens in EC patients undergoing definitive chemoradiotherapy.

Ethnopharmacological Relevance: Xihuang Pill is a traditional Chinese medicine prescription for the treatment of breast cancer. There are many randomized controlled trials (RCTs) of Xihuang Pill in the treatment of breast cancer that have been published. Hence, a comprehensive systematic review and meta-analysis is needed., Aim: To evaluate the safety of Xihuang pill/capsule and its effect on the improvement of tumor progression, quality of life, immunity and prognosis in adjuvant treatment of breast cancer., Methods: Chinese and English databases such as Sinomed, PubMed, Embase were searched to collect the RCTs of Xihuang pill/capsule in adjuvant treatment of breast cancer. Then the researchers extracted data from the RCTs that met the inclusion criteria, and used Cochrane standard risk bias to assess the quality of the data, and used Rev Man 5.3 statistical software for statistical analysis., Results: A total of 26 RCTs with 2272 participants were included. The primary outcomes showed that Xihuang pill combined with chemotherapy and with endocrine therapy may suppress of tumor progression {Chemotherapy: risk ratio (RR) = 0.59, 95%Confidence interval (CI) [0.48,0.73], P < 0.00001; Endocrine therapy: RR = 0.56, 95%CI [0.33,0.96], P = 0.04}. Xihuang pill combined with chemotherapy, with endocrine therapy and with radiotherapy may improve the quality of life (chemotherapy: RR = 1.73, 95%CI[1.11, 2.70], P = 0.02; Endocrine therapy: RR = 1.18, 95%CI [1.01,1.38], P = 0.03; radiotherapy:RR = 1.51, 95%CI [1.01,2.27], P = 0.05). Xihuang pill combined with TCM + chemotherapy may decrease the inefficiency rate for clinical symptom improvement (RR = 0.50, 95%CI [0.28, 0.88], P = 0.02). Xihuang pill combined with chemotherapy may increase the Karnofsky Performance Scale (KPS) {Weighted Mean Difference (WMD) = 15.40, 95%CI [8.18, 22.62], P < 0.0001}. For adverse events, Xihuang pill combined with chemotherapy may alleviate adverse digestive events and leukopenia; Xihuang pill combined with endocrine therapy will not increase adverse events; Xihuang pill combined with non-antitumor therapy may reduce the incidence of leukopenia and red blood cell or hemoglobin reduction., Conclusion: The addition of Xihuang pill/capsule to breast cancer in conventional anti-tumor therapy may inhibit tumor progression, improve patient quality of life, reduce toxic reactions, regulate immunity, and reduce tumor markers. However, due to the overall low quality of RCTs, the research results need more high-quality RCTs to further test the conclusions., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: To investigate the safety of COVID-19 vaccination in patients on clozapine as regards plasma clozapine concentration and haematological parameters., Methods: We conducted a multicentre observational cohort study from 22 February 2021 to 2 September 2021. Primary outcomes were clinically relevant increase in clozapine blood levels (>100 μg/L increase compared to baseline) and clozapine alert levels (>1000 μg/L). Secondary outcomes were granulocytopenia, leukocytopenia and lymphocytopenia. Outcomes were measured approximately 5 days after the first and (where applicable) second dose of COVID-19 vaccine., Results: This study included 139 patients. Compared to baseline, clozapine blood levels increased significantly (ES = 0.28, p = 0.003) after the second vaccination. Clinically relevant increases in clozapine blood levels occurred in 20/92 patients (22%) and in 16/56 patients (29%) during the first and second phases, respectively. Clozapine alert levels developed in one patient (1%) following the first dose and in three patients (5%) after the second dose. In both phases, changes in white blood cells (WBC) were limited to mild granulocytopenia (3% and 5%), moderate granulocytopenia (1% and 0%) and leukocytopenia (2% and 3%) without cause for extra monitoring according to the guideline., Conclusion: In general, as regards WBC counts COVID-19 vaccination seems to be safe in patients with SMI. Changes in WBC had no clinical implications. Psychoeducation on the symptoms of clozapine intoxication is recommended, especially in patients with clozapine blood levels approaching the upper limit of the therapeutic range. Increase in the C-reactive protein (CRP) level can signal inflammation rapidly and help to prevent clozapine intoxication following vaccination., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Leishmaniasis is a disease caused by a protozoan and transmitted by sandfly species in several emerging countries. Visceral leishmaniasis is a serious complication, especially in immunosuppressed patients, and is uncommon after liver transplantation. We report the case of a 48-year-old female patient who underwent liver transplantation owing to polycystic liver disease. Six months after the procedure, she was hospitalized with diarrhea, acute kidney failure, and leukopenia. She had been off steroids for 3 months and was taking mycophenolate and tacrolimus. She had already been treated for cytomegalovirus, which was negative on admission. During hospitalization, fever, splenomegaly, ascites, and pancytopenia appeared. Serology for Leishmania by indirect immunofluorescence was negative. Then, bone biopsy and molecular testing for Leishmania diagnosed it as visceral leishmaniasis. Amphotericin therapy was initiated with resolution of fever after 4 days of treatment and gradual recovery from pancytopenia. This case highlights the challenge of early diagnosis of visceral leishmaniasis in liver transplant recipients with diarrhea and leukopenia, which can be caused by immunosuppression or more prevalent viral diseases. Late onset of fever, splenomegaly, and a first negative serologic test also made early diagnosis difficult. The aim of the report is to emphasize the suspicion of visceral leishmaniasis in symptomatic patients from emerging countries and to question the benefit of including protozoan screening in liver transplant donors and recipients in endemic areas., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Although the relationship between NUDT15 and thiopurine-induced leukopenia has been proven in previous studies, no prominent factors explaining interindividual variations in its active metabolite, 6-thioguanine nucleotide (6-TGN), and clinical efficacy have been identified. In this study, the correlation between genotypes (thiopurine S-methyltransferase, NUDT15, and ITPA polymorphisms), 6-TGN concentrations, and clinical outcomes (efficacy and side effects) in patients with inflammatory bowel disease were investigated., Methods: In total, 160 patients with inflammatory bowel disease were included, and the 3 genotyped genes and 6-TGN levels were measured by high-performance liquid chromatography. Statistical analyses and calculations were performed to determine their relationships., Results: ITPA genotypes and 6-TGN concentration were both associated with the clinical effectiveness of azathioprine (P = 0.036 and P = 4.6 × 10-7), with a significant correlation also detected between them (P = 0.042). Patients with ITPA variant alleles exhibited higher 6-TGN levels than those with the wild-type allele. In addition, the relationship between NUDT15 and leukopenia and neutropenia was confirmed (P = 1.79 × 10-7 and 0.002)., Conclusions: In summary, it is recommended that both ITPA and NUDT15 genotyping should be performed before azathioprine initiation. Moreover, the 6-TGN concentration should be routinely monitored during the later period of treatment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Prostate-specific membrane antigen (PSMA), overexpressed in prostate cancer, has become a popular target for radionuclide-based theranostic applications in the advanced stages of prostate cancer. We conducted a meta-analysis of the therapeutic effects of PSMA-targeting α-therapy ( 225 Ac-PSMA radioligand therapy [RLT]) in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: A systematic search was performed using the keywords "mCRPC," " 225 Ac-PSMA," and "alpha therapy." Therapeutic responses were analyzed as the pooled proportions of patients with more than a 50% prostate-specific antigen (PSA) decline and any PSA decline. Survival outcomes were analyzed by estimating summary survival curves for progression-free survival and overall survival. Adverse events were analyzed as the pooled proportions of patients with xerostomia and severe hematotoxicity (anemia, leukocytopenia, and thrombocytopenia). Results: Nine studies with 263 patients were included in our meta-analysis. The pooled proportions of patients with more than a 50% PSA decline and any PSA decline were 60.99% (95% CI, 54.92%-66.83%) and 83.57% (95% CI, 78.62%-87.77%), respectively. The estimated mean progression-free survival and mean overall survival were 9.15 mo (95% CI, 6.69-11.03 mo) and 11.77 mo (95% CI, 9.51-13.49 mo), respectively. The pooled proportions of patients with adverse events were 62.81% (95% CI, 39.34%-83.46%) for xerostomia, 14.39% (95% CI, 7.76%-22.63%) for anemia, 4.12% (95% CI, 0.97%-9.31%) for leukocytopenia, and 7.18% (95% CI, 2.70%-13.57%) for thrombocytopenia. Conclusion: In our study, around 61% of patients had more than a 50% PSA decline and 84% of patients had any PSA decline after 225 Ac-PSMA RLT. The common adverse events in 225 Ac-PSMA RLT were xerostomia in 63% of patients and severe hematotoxicity in 4%-14% of patients., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To explore the trends of plasma drug concentration changes after high-dose methotrexate (MTX) treatment of osteosarcoma (OS), analyse the risk factors for leukopenia (LP) after MTX treatment, and establish a LP prediction nomogram., Methods: A total of 35 OS patients at Tianjin Medical University Cancer Institute and Hospital between 2017 and 2021 were collected (the construction cohort). Another 12 OS patients between 2019 and 2021 in P.A. Hertsen Moscow Oncology Research Center were involved (the external validation cohort). Peripheral venous blood MTX concentration (C MTX ) was monitored at 0h, 6h, 24h, 48h and 72h after MTX administration. The characteristics were collected: age, sex, body surface area, lesion site, pathological subtype, pathological fractures, American Joint Committee on Cancer (AJCC) clinical stage, MTX dose, tumour necrosis, Ki-67 index, erythrocyte count, haemoglobin count, white blood cell count, platelet count (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, albumin concentration, creatinine, alkaline phosphatase, and lactate dehydrogenase. Logistic regression analysis was used to determine the risk factors for LP occurrence. Significant factors were used to construct the prediction nomogram., Results: A total of 128 MTX chemotherapy cycles from 35 OS patients were included. Female, Ki-67>20%, C MTX >112μmol/L at 6h, PLT, and AST were risk factors for post-chemotherapy LP occurrence. The LP prediction nomogram was created and validated., Conclusions: Female, C MTX at 6h, Ki-67 index, AST and PLT before MTX treatment were risk factors for LP in OS patients who received MTX treatment. The established nomogram can guide personalized LP prediction in OS patients receiving MTX chemotherapy.

Objective: To examine serum C-reactive protein levels and the prevalence of leukopenia in patients with Crohn's disease or ulcerative colitis undergoing treatment with azathioprine and/or mesalazine., Methods: Retrospective observational study based on clinical and laboratory data collected from medical records of 76 adult patients with inflammatory bowel disease treated with azathioprine, mesalazine or both. Sex, age, diagnosis, number of blood samples and elevated serum C-reactive protein levels during the follow-up period were recorded. The following variables were analyzed in terms of C-reactive protein levels and leukopenia episodes: sex, age, diagnosis of inflammatory bowel disease and type of drug. Statistical analyses included multiple logistic regression and the Fisher's exact test for qualitative variables., Results: Leukopenia was observed in 18.4% of patients and was associated with older age and higher doses of medication. In 44% of patients, C-reactive protein levels were high. However, symptoms were not associated with abnormal levels of this marker., Conclusion: Regardless of symptoms, serum C-reactive protein levels were not a reliable indicator of controlled inflammatory bowel disease. Leukopenia was independently associated with older age and higher doses of medication and is a common side effect, which should be routinely monitored.

Methods: Two-hundred patients were assessed for the presence of genetic allelic variants using PCR amplification and direct sequencing., Results: In 19 patients, we detected genetic allelic variants affecting TPMT activity; in 1 case, it was an unpublished heterozygous variant c.85T>C (p.W29R); of those, 15 patients were switched from AZA to a different medication, and 1 patient was prescribed a reduced dose of AZA., Conclusions: Our findings show the importance of testing for variants of the TPMT gene before the administration of AZA in clinical rheumatology practice. Patients with documented episodes of leukopenia or elevated liver biochemical tests while on AZA should undergo TPMT genotype testing and/or TPMT enzyme activity testing., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cytomegalovirus (CMV) infection remains a major challenge in solid organ transplantation. Ganciclovir has changed the prognosis, but with the expense of possible viral resistance. New antiviral drugs, such as letermovir, have not been studied sufficiently in kidney and pancreas transplant recipients. We reviewed abdominal organ transplants recipients with CMV infection from the national transplant registry and identified patients treated with letermovir from electronic medical records. We report on letermovir treatment in one kidney and three simultaneous pancreas and kidney (SPK) transplant patients with refractory or ganciclovir-resistant CMV infection (UL54/ UL97 mutation). In SPK patients, persistent leukopenia undermined immunosuppressive and antiviral treatment, favoring life-threatening bacterial infections or ganciclovir resistance. All patients achieved viral clearance after letermovir monotherapy of 1.5-6 months. Letermovir was well tolerated and leukopenia resolved. Adjustments of calcineurin inhibitor doses were challenging. One acute rejection occurred because of under immunosuppression. After the end of treatment, recurrent low-grade CMV-DNAemia was common requiring reinitiating antiviral therapy to achieve viral clearance. To conclude, letermovir was a well-tolerated valuable option for the treatment of refractory or resistant CMV infection in kidney and pancreas transplantation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: In the adjuvant setting for cervical cancer, classical risk factors for postoperative radiochemotherapy have been established. However, data on laboratory changes during therapy and the prognostic value of serological markers are limited and further knowledge is needed to optimize the toxic trimodal regimen. Methods: We retrospectively identified 69 women who underwent weekly postoperative radiochemotherapy with 40 mg/m 2 of cisplatin for cervical cancer between 2010 and 2021 at a single center. Laboratory parameters were recorded before, at each cycle and after radiochemotherapy. Kaplan-Meier and log-rank analyses were used to calculate and compare survival, groups were compared using the Mann-Whitney U , χ 2 , and variance tests. Results: With a median follow-up of 17.7 months, the 1- and 5-year local control rates were 94.0% and 73.7%, respectively, with significantly better rates for more chemotherapy cycles and negative resection margins. Only 68.1% of patients completed all cycles. The most common reasons for early discontinuation were persistent asymptomatic leukopenia in women aged ≤ 50 years, and limiting infections in women aged > 50 years. Leukopenia was more likely to occur after the third cycle. Significantly worse survival was observed for post-radiochemotherapy elevated C-reactive-protein and lactate dehydrogenase levels, low pre-radiochemotherapy nutritional index, and raised C-reactive-protein-levels; the latter were also predictable for local control. The Glasgow prognostic score did not reliably predict survival. Conclusion: Incomplete application of simultaneous chemotherapy leads to inferior local control, and age-dependent limiting factors should be identified at an early stage. In addition to classical risk factors, serological markers (C-reactive-protein, lactate dehydrogenase, nutritional index) show prognostic significance.

Leukopenia is a common manifestation of many diseases, including global outbreak SAS-CoV-2 infection. Granulocyte-macrophage colony-stimulating factor (GM -CSF) has been proved to be effective in promoting lymphocyte regeneration, but adverse immunological effects have also emerged. This study aim to investigate the effect of GM -CSF on BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration. Cyclophosphamide (CTX) and GM -CSF were used to inhibit and stimulate bone marrow hematopoiesis, respectively. High throughput sequencing was applied to detect the characteristics of BCR CDR3 repertoire in controls, CTX group and GM -CSF group. The white blood cells (WBCs) were quickly reduced (P < 0.05) with lymphocytes decreasing causing by CTX, and the WBCs and lymphocytes returned to the level of controls after GM -CSF treatment. The diversity of BCR heavy chain CDR3 repertoire was also significantly decreased in CTX group. Although there is still a big gap from the controls, the diversity was picked up after GM -CSF treatment. The expression of IGHD01-01, IGHD02-14 and IGHJ04-01 with high-frequency usage regularly and significantly changed in three groups, and many genes with low-frequency usage lost in CTX group and did not reappear in GM -CSF group. Moreover, two shared sequences and accounted for the highest proportion in GM -CSF group have been detected in animal model of chronic lymphocytic leukemia. These results revealed that GM -CSF can partially restore changes in the BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration, but it may also lead to rearrangement, proliferation and activation of abnormal B cells, which can provide a basis for further study on the adverse immunological effects and mechanism of GM -CSF treatment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: In Japan, docetaxel, a cytotoxic monotherapy, is the standard drug administered to older patients with advanced non-small-cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel has shown a high objective response rate in patients with squamous histology and was suggested to improve overall survival in patients aged 70 years and older. The CAPITAL trial aimed to assess the safety and efficacy of carboplatin plus nab-paclitaxel versus docetaxel as first-line therapy for patients aged 70 years and older with advanced squamous NSCLC., Methods: This multicentre, open-label, randomised, phase 3 trial was carried out at 92 medical institutions in Japan. Eligible patients were aged 70 years and older, had advanced squamous NSCLC with no previous systemic chemotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Using an electronic data capture system, patients were randomly assigned (1:1) to intravenous carboplatin (area under the concentration-time curve of 6 mg/mL per min for 30 min) on day 1 of a 21-day cycle and intravenous nab-paclitaxel (100 mg/m 2 for 60 min) on days 1, 8, and 15 every 3 weeks or intravenous docetaxel (60 mg/m 2 for 60 min) on day 1 every 3 weeks. Randomisation was computer-generated per participant and stratified by ECOG performance status, clinical stage, sex, age, and institution. The primary endpoint was overall survival, measured in the full analysis set and defined as the time from registration to the date of death due to any cause. Safety was assessed in all patients who received at least one dose of the trial treatment. This trial is registered with the UMIN Clinical Trials Registry, UMIN000019843, and the Japan Registry of Clinical Trials, jRCTs041180110. After the planned interim analysis in Aug 3, 2020, the independent data monitoring committee recommended that the trial be stopped early. This report represents the final analysis., Findings: Between Feb 24, 2016, and Aug 11, 2020, 196 patients were enrolled and were randomly assigned to the carboplatin plus nab-paclitaxel group (n=98) or the docetaxel group (n=98). Of these patients, four (carboplatin plus nab-paclitaxel group, n=3; docetaxel group, n=1) did not receive any treatment and two patients in the docetaxel group were excluded from the full analysis set. Median overall survival in the full analysis set was 16·9 months (95% CI 12·6-25·4) in the carboplatin plus nab-paclitaxel group and 10·9 months (8·5-12·4) in the docetaxel group (hazard ratio 0·52 [90% CI 0·38-0·70]; p=0·0003). Grade 3-4 adverse events occurred in 79 (83%) patients in the carboplatin plus nab-paclitaxel group and 77 (79%) patients in the docetaxel group (p=0·63). The most common grade 3-4 adverse events in the carboplatin plus nab-paclitaxel group and the docetaxel group were leukopenia (44 [46%] vs 55 [57%]; p=0·20), neutropenia (60 [63%] vs 75 [77%]; p=0·046), febrile neutropenia (nine [10%] vs 19 [20%]; p=0·073), and anaemia (37 [39%] vs two [2%]; p<0·0001). Serious treatment-related adverse events of all grades occurred in 13 (14%) patients in the carboplatin plus nab-paclitaxel group and 11 (11%) patients in the docetaxel group. Treatment-related deaths occurred in two (2%; respiratory failure n=1, visceral arterial ischaemia n=1) patients in the carboplatin plus nab-paclitaxel group and one (1%; sepsis) patient in the docetaxel group., Interpretation: Our study showed that overall survival was longer with carboplatin plus nab-paclitaxel than with docetaxel, suggesting that carboplatin plus nab-paclitaxel can be used as standard first-line treatment for patients aged 70 years and older with advanced squamous NSCLC., Funding: Taiho Pharmaceutical., Competing Interests: Declaration of interests YK reports grants from Taiho Pharmaceutical, during the conduct of the study; and grants and personal fees from MSD, personal fees from AstraZeneca, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Boehringer Ingelheim, and Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical; and personal fees from Chugai Pharmaceutical, AstraZeneca, MSD, Bristol Myers Squibb, Taiho Pharmaceutical, and Daiichi Sankyo, outside the submitted work. HS reports grants from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, MSD, Ono Pharmaceutical; and personal fees from Boehringer Ingelheim, Chugai Pharma, and Kyorin, outside the submitted work. AK reports grants from Taiho Pharmaceutical, during the conduct of the study; and personal fees from Bayer Yakuhin, outside the submitted work. SA reports grants from the National Cancer Center Research and Development Fund (26-A-22, 29-A-15, 2020-A-13) and Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from AstraZeneca, Ono Pharmaceutical, Taiho, Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, MSD, Eli Lilly, Chugai, and Merck; grants and non-financial support from F Hoffmann-La Roche; and personal fees from Hisamitsu, Kyowa Hakko Kirin, Novartis Pharma, and Thermo Fisher Scientific, outside the submitted work. YT reports grants and personal fees from Taiho Pharmaceutical, during the conduct of the study; grants and personal fees from Eli Lilly, Ono Pharmaceutical, Chugai Pharmaceutical, MSD, and Takeda; grants from Daiichi Sankyo and Kyowa-Hakko Kirin; and personal fees from Novartis, Boehringer Ingelheim, and AstraZeneca, outside the submitted work. AI reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Pfizer, Chugai Pharmaceutical, MSD, and Daiichi Sankyo, outside the submitted work. TK reports personal fees from AstraZeneca, MSD, Eli Lilly, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Boehringer Ingelheim; grants from AstraZeneca, MSD, Ono Pharmaceuticals, Eli Lilly, and Takeda, outside the submitted work. IO reports grants from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, MSD Oncology, Eli Lilly, Bristol Myers Squibb, and Chugai Pharma; grants from Astellas Pharma, Novartis, and AbbVie; and personal fees from Pfizer, outside the submitted work. MY reports grants and personal fees from Chugai Pharmaceutical; and grants from Daiichi Sankyo, MSD, and Pfizer Japan, outside the submitted work. MS reports grants and personal fees from Taiho Pharmaceutical, Chugai Pharmaceutical, MSD, Boehringer Ingelheim, and Eli Lilly Japan; and personal fees from AstraZeneca, outside the submitted work. MA reports grants from Kyowa Kirin, outside the submitted work. KK reports grants and personal fees from Ono Pharmaceutical and Boehringer Ingelheim; and personal fees from Chugai, MSD, AstraZeneca, Eli Lilly, Daiichi Sankyo, Bristol Myers Squibb, Kyowa Hakko Kirin, and Taiho, outside the submitted work. MT reports grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Nippon Boehringer Ingelheim, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, and Taiho Pharmaceutical; personal fees from Bristol Myers Squibb, Johnson & Johnson, and Nippon Kayaku; and grants from KM Biologics, outside the submitted work. TS reports grants and personal fees from Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, MSD, Novartis Pharma, Pfizer Japan, and Takeda Pharmaceutical; grants from AbbVie, Kissei Pharmaceutical, LOXO Oncology, and Merck Biopharma; and personal fees from AstraZeneca, Bristol Myers Squibb, Covidien Japan, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Thermo Fisher Scientific, and Precision Medicine Asia, outside the submitted work. NY reports grants and personal fees from MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Takeda Pharmaceutical, Eli Lilly Japan, Boehringer Ingelheim, Novartis, Pfizer, and AstraZeneca; and personal fees from Thermo Fisher Scientific, Bristol Myers Squibb, Life Technologies, Nippon Kayaku, and Merk Biopharma; grants from Astellas Pharma, Tsumura & Co, Shionogi, AbbVie, Amgen, Kyorin Pharmaceutical, Eisai, Terumo, Toppan Printing, and TOSOH, outside the submitted work. AG reports personal fees from Taiho, Nihon Kayaku, AstraZeneca, Chugai, Ono Pharmaceutical, and Boehringer Ingelheim, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Lithium carbonate is used to increase white blood cell counts as a means of counteracting leukopenia caused by the administration of antipsychotic drugs. To evaluate the effect of antipsychotics on the leukocyte-enhancing effect of lithium, we compared white blood cell counts, serum lithium levels, and lithium dosage in patients receiving antipsychotics and lithium in combination and patients receiving lithium alone. Chlorpromazine equivalent values were used as an indicator of the antipsychotic dose. Lithium serum levels were measured in 41 hospitalized patients. The lithium dose in the combination group (median, 800 mg) was significantly higher than that in group receiving only lithium (median, 400 mg) (P = 0.03). The lithium doses in the combination group receiving ≥1000 mg chlorpromazine equivalents (overdosing; median lithium dose 800 mg) and the combination group treated with 600-999 mg chlorpromazine equivalents (high dosing; median lithium dose 800 mg) were significantly higher than the group that was not treated with antipsychotic medication, with median lithium dose 400 mg (P < 0.05).There were no significant differences in the white blood cell counts and serum lithium levels. Because of the large variety of antipsychotic drugs used in combination with lithium and the various doses used, it was difficult to evaluate the effects of lithium, with or without antipsychotic administration, on leukocyte count enhancement. We are planning to study a larger number of patients and, since renal function could not be assessed in this study, we will also focus on renal function, including urine output., (© 2021 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Background: Adjuvant chemotherapy with CapeOX regimen is widely used in resected rectal cancer, which brings benefits to patients. But drug-related toxicities are severe during this process; thus, survival outcomes may potentially be affected. This study explored the efficacy of two Chinese herbal injections, Aidi injection (ADI) and Brucea javanica oil emulsion injection (BJOEI), as adjuvant drugs in CapeOX adjuvant chemotherapy on rectal cancer patients., Methods: A total of 240 cases were enrolled in this retrospective study. 80 cases received CapeOX with ADI (the ADI group), 80 cases received CapeOX with BJOEI (the BJOEI group), and the rest 80 cases received CapeOX alone (the control group). After four cycles' chemotherapy, adverse reactions (ADRs) and quality of life (QOL) were analyzed. Then, patients received follow-up for at least one year, and the endpoint was disease-free survival (DFS)., Results: All patients completed at least four cycles' adjuvant chemotherapy. The incidence of leukopenia and thrombocytopenia was significantly lower in the ADI group; the incidence of nausea was significantly lower in the BJOEI group; the incidence of hand-foot syndrome was significantly lower in both the ADI group and BJOEI group. Significant difference was found in the control group regarding the Karnofsky Performance Status (KPS) scores prior and posttreatment. No difference was found among three groups regarding one-year DFS., Conclusion: As adjuvant drugs for rectal cancer during CapeOX chemotherapy, ADI shows advantages in decreasing leukopenia and thrombocytopenia, while BJOEI results better in remitting nausea. Both two CHIs had positive impacts on decreasing hand-foot syndrome and the maintenance of patients' QOL. It is worthy of further study and promotion for CHIs., Competing Interests: The authors declares that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Wenjun Meng et al.)

What Is Known and the Objective: Our previous studies have shown that saponins of Sanguisorba parviflora (Maxim) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in mice with leukopenia. The hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in Sp. T to alleviate leukopenia., Methods: HAX-1 expression was examined in the peripheral blood neutrophils using real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemical staining. Neutrophil apoptosis was measured by flow cytometry. Mitochondrial function was evaluated via reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity., Results and Discussion: Our study indicated that the expression of the HAX-1 gene was significantly decreased in the peripheral blood neutrophils of leukopenia patients compared with healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability, while overexpression of HAX-1 reduced the production of reactive oxygen species (ROS) and maintained the integrity of the mitochondrial membrane potential. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or the addition of metformin., What Is New and Our Conclusion: Our data support a mechanism where Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner., (© 2021 John Wiley & Sons Ltd.)

Introduction: Leukocytes are found in organizing thrombi and are associated with thrombus growth. However, their role in the initial stage of thrombus formation is not well known. We investigated the role of leukocytes in the early stage of arterial thrombosis by inducing leukopenia., Methods: In this double-blind, randomized, placebo-controlled study, 72 Institute of Cancer Research mice were randomly treated with intraperitoneal 100 mg/kg cyclophosphamide or normal saline. The primary outcome was time to occlusion after FeCl 3 treatment. We also compared thrombus size, histological composition, and association with peripheral blood cell counts between cyclophosphamide and control groups., Results: Cyclophosphamide treatment significantly decreased leukocyte counts by 82.8% compared to placebo (P < 0.001). The time to occlusion was significantly longer in the cyclophosphamide group (3.31 ± 1.59 min) than in the control group (2.30 ± 1.14 min; P = 0.003). The immunoreactivity for Ly6G-positive cells, intracellular histone H3, and released histone H3 in thrombi was significantly reduced in the cyclophosphamide group by 92.8%, 50.2%, and 34.3%, respectively. Time to occlusion had a moderate negative correlation with leukocyte count in peripheral blood (r = -0.326, P = 0.022) in the entire group., Conclusions: Cyclophosphamide-induced leukopenia attenuated thrombus formation during the early stage of arterial thrombosis. Our findings suggest the potential role of leukocytes in the initial stage of arterial thrombosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

What Is Known and Objective: We have previously shown that the saponins of Sanguisorba parviflora (Maxim.) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in leukopenic mice. Haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. The aim of the present study was to comprehensively identify the role of HAX-1 in the mechanism of leukopenia alleviation by Sp. T., Methods: HAX-1 gene and protein expression levels in peripheral blood neutrophils were examined using real-time quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemical assays. Neutrophil apoptosis was measured using flow cytometry. Mitochondrial function was determined via assessments of the reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity levels., Results and Discussion: The HAX-1 gene expression level in the peripheral blood neutrophils was significantly lower in patients with leukopenia than in healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability. HAX-1 overexpression reduced the production of ROS and maintained ΔΨm integrity. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or metformin., What Is New and Conclusion: Our data suggest a mechanism through which Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner., (© 2021 John Wiley & Sons Ltd.)

Background: Leukopenia is a common complication after kidney transplantation. The etiology is multifactorial, with medication adverse effects and cytomegalovirus infection as main causes. Optimal strategies to prevent or treat posttransplant leukopenia remain unknown. We aimed to identify risk factors for leukopenia and to investigate the benefit of switching the immunosuppressive therapy to hydrocortisone as a continuous infusion., Methods: We retrospectively evaluated all patients with leukopenia after kidney transplantation between 2007 and 2017 at our center relative to age- and sex-matched controls., Results: Leukopenia was associated with the degree of rejection therapy before leukopenia, the immunosuppressive therapy before transplantation, and an induction therapy with rabbit antithymocyte globulin. Patients with leukopenia exhibited increased mortality, an increased incidence of bacterial and viral infections, and more acute rejections. Switching to hydrocortisone as a continuous infusion in patients with severe leukopenia decreased the duration of leukopenia and the incidence of subsequent viral infections, especially with cytomegalovirus., Conclusion: Leukopenia is a risk factor for infectious complications and mortality, and it is associated with acute rejection. Switching immunosuppressive therapy to hydrocortisone as a continuous infusion is a safe approach to reduce the duration of leukopenia and the incidence of viral infections., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To investigate the therapeutic effect of spleen low molecular weight extracts on epileptics hydrochloride-induced leukopenia in mice and explore its mechanism., Methods: The model of leukopenia in mice was established by the injection of epirubicin hydrochloride (10 mg/kg). After the injection of chemotherapeutic drugs, leukocytopenia mice were treated with different doses of spleen low molecular weight extract, Ganoderma oral solution and recombinant granulocyte colony stimulating factor (rhG-CSF). The general survival status indicators such as body weight, coat color and athletic ability of mice in each group were recorded; the tail vein blood of mice in each group was collected and the white blood cell count in them was calculated; bone marrow of mice was taken and bone marrow smears were observed., Results: In the model group, the weight of the mice gradually decreased in the later period, their coat became dark and rough, and the ability to exercise decreased, while the mice in the treatment groups showed different degrees of improvement in their survival status except for the mice treated by rhG-CSF. There was no significant fluctuation in the white blood cell count of the blank control mice. After injection of epirubicin, the white blood cell count of peripheral blood in the model mice and treated mice were decreased. The white blood cell count was lower in the mice treated with high-dose low molecular weight extract and rhG-CSF than that in other experimental groups. Bone marrow smear showed that the proportion of bone marrow nucleated cells in the mice treated with the low molecular weight extract of the spleen was significantly higher than that of model mice (P<0.05)., Conclusion: The low molecular weight spleen extracts can significantly improve the hematopoietic state of mouse bone marrow, promote the proliferation of inhibited bone marrow cells, and thus has the effect of treating leukopenia in mice.

Background: Heterozygous mutations in the transcription factor GATA2 result in a wide spectrum of clinical phenotypes, including monocytopenia and Mycobacterium avium complex (MAC) infection (MonoMAC) syndrome. Patients with MonoMAC syndrome typically are infected by disseminated nontuberculous mycobacteria, fungi, and human papillomavirus, exhibit pulmonary alveolar proteinosis during late adolescence or early adulthood, and manifest with decreased content of dendritic cells (DCs), monocytes, and B and natural killer (NK) cells., Case Presentation: A 39-year-old woman was diagnosed with MonoMAC syndrome postmortem. Although she was followed up based on the symptoms associated with leukocytopenia that was disguised as sarcoidosis with bone marrow involvement, she developed disseminated nontuberculous mycobacterial infection, fungemia, and MonoMAC syndrome after childbirth. Genetic testing revealed a heterozygous missense mutation in GATA2 (c.1114G > A, p.A372T). Immunohistochemistry and flow cytometry showed the disappearance of DCs and decreased frequency of NK cells in the bone marrow, respectively, after childbirth., Conclusions: To the best of our knowledge, this is the first study reporting that MonoMAC syndrome can be exacerbated after childbirth, and that immunohistochemistry of bone marrow sections to detect decreased DC content is useful to suspect MonoMAC syndrome.

Fucoidans from brown seaweed shows various bioactive properties and promising prospects in biomedical field. Here, a novel fucoidan (F-4) was extracted and purified from Durvillaea antarctica. The structure of F-4 was characterized by HPLC, HPGPC, GC-MS, together with IR and NMR spectral analysis. F-4 is a sulfated polysaccharide mainly composed of fucose (Fuc), galactose (Gal), and glucose (Glc) in a molar ratio of 26.4: 7.1: 1.0. The backbone of F-4 is composed of (1→3) and (1→4)-linked-α-L-Fucp residues, which sulfated at C-4 or C-2 positions and branched with α-L-Fuc, β-D-Gal, and β-D-Glc residues. Furthermore, F-4 can effectively promote the growth of leukocyte in a mouse model induced by cyclophosphamide, possibly by activating hematopoietic progenitor cells and regulating the hematopoietic microenvironment of bone marrow. Our data provide useful information for further investigation of fucoidan in the treatment of chemotherapy-induced leukopenia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Malaria is a global public health burden due to large number of annual infections and casualties caused by its hematological complications. The bark of Annickia polycarpa is an effective anti-malaria agent in African traditional medicine. However, there is no standardization parameters for A. polycarpa. The anti-malaria properties of its leaf are also not known., Aim of the Study: To standardize the ethanol leaf extract of A. polycarpa (APLE) and investigate its anti-malaria properties and the effect of its treatment on hematological indices in Plasmodium berghei infected mice in the Rane's test., Materials and Methods: Malaria was induced by inoculating female ICR mice with 1.0 × 10 7 P. berghei-infected RBCs in 0.2 mL (i.p.) of blood. Treatment was commenced 3 days later with APLE 50, 200, 400 mg/kg p.o., Quinine 30 mg/kg i.m. (Standard drug) or sterile water (Negative control) once daily per group for 4 successive days. Anti-malarial activity and gross malaria indices such as hyperparasitemia, mean change in body weight and mean survival time (MST) were determined for each group. Changes in white blood cells (WBCs), red blood cells (RBCs), platelets (PLT) counts, hemoglobin (HGB) concentration, hematocrit (HCT) and mean corpuscular volume (MCV) were also measured in the healthy mice before infection as baseline and on day 3 and 8 after inoculation using complete blood count. Standardization was achieved by UHPLC-MS chemical fingerprint analysis and quantitative phytochemical tests., Results: APLE, standardized to its total alkaloids, phenolics and saponin contents, produced significant (P < 0.05) dose-dependent clearance of mean hyperparasitemia of 22.78 ± 0.93% with the minimum parasitemia level of 2.01 ± 0.25% achieved at 400 mg/kg p.o. on day 8. Quinine 30 mg/kg i.m. achieved a minimum parasitemia level of 6.15 ± 0.92%. Moreover, APLE (50-400 mg/kg p.o.) evoked very significant anti-malaria activity of 89.22-95.50%. Anti-malaria activity of Quinine 30 mg/kg i.m. was 86.22%. APLE also inverse dose-dependently promotes weight gain with the effect being significant (P < 0.05) at 50 mg/kg p.o. Moreover, APLE dose-dependently increased the MST of malaria infested mice with 100% survival at 400 mg/kg p.o. Quinine 30 mg/kg i.m. also produce 100% survival rate but did not promote (P > 0.05) weight gain. Hematological studies revealed the development of leukocytopenia, erythrocytosis, microcytic anemia and thrombocytopenia in the malaria infected mice which were reverted with the treatment of APLE 50-400 mg/kg p.o. or Quinine 30 mg/kg i.m. but persisted in the negative control. The UHPLC-MS fingerprint analysis of APLE led to identification of one oxoaporphine and two aporphine alkaloids (1-3). Alkaloids 1 and 3 are being reported in this plant for the first time., Conclusion: These results indicate that APLE possessed significant anti-malaria, immunomodulatory, erythropoietic and hematinic actions against malaria infection. APLE also has the ability to revoke deleterious physiological alteration produced by malaria and hence, promote clinical cure. These properties of APLE are due to its constituents especially, aporphine and oxoaporphine alkaloids., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this study, we investigated the therapeutic efficacy of a combination of liposomal amphotericin B (Lip-Amp B) and Methylglyoxal (Lip-MG) against Candida albicans in the leukopoenic mice. The antifungal efficacy of Lip-Amp B or Lip-MG or a combination of Lip-Amp B and Lip-MG was evaluated by the analysis of the survival rate and the fungal load in the treated mice. The immune-stimulatory effect of Lip-MG on macrophages was evaluated by analysing the secretion of proinflammatory cytokines. C. albicans infected mice treated at the doses of 1 and 2 mg/kg of Lip-Amp B showed 20% and 50% survival rates, respectively. Whereas the mice treated with free Amp B at the same doses died within 40 days of treatment. Interestingly, C. albicans infected mice treated with a combination of Lip-Amp B and Lip-MG had 70% survival rate on day 40 postinfection. Moreover, treatment of macrophages with Lip-MG increased their fungicidal activity and the secretion of proinflammatory cytokines, including TNF-α and IL-1β. These findings suggested that co-treatment with Lip-Amp B and Lip-MG had a synergistic effect and could be effective against C. albicans in immunocompromised subjects.

Clozapine is an antipsychotic with clozapine-induced agranulocytosis (CIA) as a rare, but potentially life-threatening side-effect, for which the white blood cell count and absolute neutrophil count are routinely monitored. Observed leukopenia may lead to more frequent monitoring, or even acute discontinuation of clozapine treatment. COVID-19 may cause deviating blood parameters such as leukopenia, and more exceptionally even granulocytopenia, just as clozapine does. In case of a SARS-CoV-2 infection and leukopenia, it is important to differentiate whether the reduced white blood cell count is caused by clozapine - in which case it needs to be stopped immediately - or as a consequence of infection with the coronavirus. In case of a mild leukopenia, based on a lymphopenia, clozapine can be safely continued with more frequent blood monitoring. Additionally, the dosage of clozapine should be reduced by half, due to the risk of a sudden increase of clozapine serum levels.

Background: The relationship between chemotherapy-induced leukopenia (CIL) and survival has not been investigated in patients undergoing preoperative chemotherapy for esophageal squamous cell carcinoma (ESCC). We analyzed the association of CIL with survival outcomes using data from JCOG9907 on the efficacy of preoperative chemotherapy for stage II/III ESCC., Methods: Preoperative chemotherapy consisted of two courses of 5-FU (800 mg/m 2 days 1-5) and cisplatin (80 mg/m 2 day 1) repeated every 3 weeks. Patients in the preoperative chemotherapy arm receiving at least one course of chemotherapy and undergoing subsequent surgery in JCOG9907 were divided into two subgroups: CIL ( +), those with grade 2-4 leukopenia at least once during preoperative chemotherapy; and CIL (-), those with grades 0-1. The association of CIL with overall survival (OS) and progression-free survival (PFS) was analyzed., Results: Among 164 patients enrolled in JCOG9907, 152 patients were included in this analysis, 52 in CIL ( +) and 100 patients in CIL (-) subgroups. The 3-year OS for CIL ( +) was inferior to that for CIL (-) (48.1% vs. 73.9%); hazard ratio (HR) = 1.94 (95% CI 1.18-3.16, P < .01). For 3-year PFS, a similar tendency was observed (44.2% vs. 55.8%; HR = 1.38 (95% CI 0.88-2.17, P = .16). Multivariable analysis revealed that CIL was not an independent factor for OS (HR = 1.14, 95% CI 0.63-2.07, P = .67)., Conclusion: We showed that CIL during preoperative chemotherapy might not be a prognostic factor in patients with ESCC.

Background: Rheumatic diseases have many hematological manifestations. Blood dyscrasias and other hematological abnormalities are sometimes the first sign of rheumatic disease. In addition, novel antirheumatic biological agents may cause cytopenias., Summary: The aim of this review was to discuss cytopenias caused by systemic lupus erythematosus and antirheumatic drugs, Felty's syndrome in rheumatoid arthritis, and autoimmune hemolytic anemia, thrombosis, and thrombotic microangiopathies related to rheumatological conditions such as catastrophic antiphospholipid syndrome and scleroderma renal crisis. Key Message: The differential diagnosis of various hematological disorders should include rheumatic autoimmune diseases among other causes of blood cell and hemostasis abnormalities. It is crucial that hematologists be aware of these presentations so that they are diagnosed and treated in a timely manner., (© 2020 S. Karger AG, Basel.)

Leukopenia is the most common hallmark of hematopoietic diseases in clinic. Sanguisorba Officinalis L., a traditional Chinese medicine, has long been used for alleviating leukopenia. However, its associated mechanism still remains unknown. In this study, a network pharmacology approach was used to elucidate the underlying mechanisms of Sanguisorba Officinalis L. against leukopenia. Firstly, 12 active compounds of Sanguisorba Officinalis L. were identified through TCMSP database with absorption, distribution, metabolism, excretion (ADME) screening, and UHPLC-MS analysis. Then, 258 leukopenia related targets of the identified active compounds were predicted via the Swiss Target Prediction database, GeneCards database and DisGeNET database, respectively. After taking the intersection of two related targets, 72 common targets were selected. Among them, 8 core targets (VEGFA, HSP90AA1, EGFR, PTGS2, MTOR, ESR1, ERBB2, MDM2) of Sanguisorba Officinalis L. against leukopenia were obtained through the topological analysis. Meanwhile, both the GO and KEGG pathway analysis reveal that the core targets are mainly enriched in PI3K-Akt, HIF-1, VEGF and estrogen signaling pathways. In addition, molecular docking simulation was performed to explore the binding ability between the 12 active compounds of Sanguisorba Officinalis L. with 8 core targets. Furthermore, a myelosuppressive mice model was established to evaluate the protective effect of Sanguisorba Officinalis L. against leukopenia. The results showed that the ethanol extract of Sanguisorba Officinalis L. significantly raised the number of peripheral white blood cells. Overall, this study provides an insight into the underlying mechanisms of Sanguisorba Officinalis L. against leukopenia, which lays a theoretical foundation for the further experimental verification and clinical application., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A selective, accurate, and efficient liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of 13 phenolic acids. Additionally, for more comprehensively determining the chemical constituents in Sanguisorba officinalis L. extract, a previously developed method was employed for the simultaneous determination of six triterpenes. Thus, two methods were used to ensure the comprehensiveness and reliability of this study. Based on these methods, the pharmacokinetic profiles of the 13 phenolic acids and 6 triterpenes in normal and leukopenia rats after oral administration of S. officinalis L. extract were compared for the first time in the present study. Quantitative detection of the 13 phenolic acids and 6 triterpenes was performed using the multiple reaction monitoring mode with the electrospray ion source in negative and positive electrospray ionization, respectively. Chromatographic separation was performed on an Agilent Eclipse Plus C18 RRHD column (50 × 2.1 mm, 1.8 µm) using gradient elution with a mobile phase composed of methanol-0.1% aqueous formic acid. The pharmacokinetic results demonstrated that the pharmacokinetic characteristics of the 19 analytes in leukopenia rats differed significantly from those determined in normal rats, which could provide a helpful reference for the clinical application of S. officinalis L. in the prevention and treatment of leucopenia., (© 2020 Wiley-VCH GmbH.)

Ziyuglycoside I (ZgI), one of the main active ingredients in the popular Diyushengbai tablet made from Sanguisorba officinalis L., has been proven to relieve leukopenia clinically. However, to our knowledge, no studies have investigated the pharmacokinetics of either Diyushengbai tablet or ZgI in leukopenic vs. healthy individuals. In the present study, a rapid and sensitive UHPLC-MS/MS method was developed for detecting ZgI. On using this method on a novel cyclophosphamide-induced leukopenia model, we investigated differences in the pharmacokinetic characteristics of ZgI between leukopenic and normal rats. Chromatographic separation of ZgI and glycyrrhetinic acid (IS) was achieved via gradient elution in 0.5 min, and the total run time lasted for 5 min. Methodological validation results presented a good accuracy (102.6 %-110.8 %) and precision (% RSD ≤ 13.8) with a limit of quantitation of 0.5 ng/mL. Pharmacokinetic results showed a significantly shortened peak time (T max ) (0.93 vs. 0.33 h) while a remarkably decreased maximum concentration (C max ) (7.96 vs. 3.40 ng/L) in the 20 mg/kg leukopenia group in comparison with those in the 20 mg/kg normal group. In addition, a prolonged elimination half-life (t 1/2β ) was observed in the 20 mg/kg leukopenia group (5.02 vs. 18.51 h). We observed similar trends in the 5 mg/kg oral dosing treatment and control groups, except for C max , which did not differ between the groups. We did not find pharmacokinetic differences in ZgI between the two leukopenia groups. Thus, the pharmacokinetic parameters of ZgI (e.g., T max , C max, and T 1/2β ) changed based on the presence of a leukopenic state. This study may provide guidance for the development of ZgI as an agent for the treatment of leukopenia., (Copyright © 2019 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: To investigate the antioxidant mechanism of diallyl sulfide (DAS) in antagonizing the reduction in peripheral blood white blood cells (WBC) induced by benzene in rats. Methods: A total of 60 specific pathogen-free adult male Sprague-Dawley rats, with a body weight of 180-220 g, were selected, and after 5 days of adaptive feeding, they were randomly divided into blank control group, DAS control group, benzene model group, benzene+low-dose DAS group, benzene+middle-dose DAS group, and benzene+high-dose DAS group, with 10 rats in each group. The rats in the benzene+low-dose DAS group, the benzene+middle-dose DAS group, the benzene+high-dose DAS group, and the DAS control group were given DAS by gavage at a dose of 40, 80, 160, and 160 mg/kg·bw, respectively, and those in the blank control group and the benzene model group were given an equal volume of corn oil; 2 hours later, the rats in the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group were given a mixture of benzene (1.3 g/kg·bw) and corn oil (with a volume fraction of 50%), and those in the blank control group and the DAS control group were given an equal volume of corn oil. The above treatment was given once a day for 4 consecutive weeks. At 1 day before treatment, anticoagulated blood was collected from the jugular vein for peripheral blood cell counting. After anesthesia with intraperitoneally injected pentobarbital (50 mg/kg·bw), blood samples were collected from the abdominal aorta, serum was isolated, and the thymus, the spleen, and the femur were freed at a low temperature to measure oxidative and antioxidant indices. The femur at one side was freed for WBC counting in bone marrow. Results: Compared with the blank control group, the benzene model group had significant reductions in the volume, weight, and organ coefficient of the spleen and the thymus ( P <0.05) ; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had significant increases in the volume of the spleen and the thymus and the weight and organ coefficient of the spleen ( P <0.05), and the benzene+middle-dose DAS group and the benzene+high-dose DAS group had significant increases in the weight and organ coefficient of the thymus ( P <0.05). Compared with the blank control group, the benzene model group had a significant reduction in WBC count in peripheral blood and bone marrow ( P <0.05), and compared with the benzene model group, the benzene+middle-dose DAS group and the benzene+high-dose DAS group had a significant increase in WBC count in peripheral blood and bone marrow ( P <0.05). Compared with the blank control group, the benzene model group had a significant increase in the serum level of malondialdehyde (MDA) ( P <0.05) and significant reductions in total superoxide dismutase (T-SOD) activity, reduced glutathione (GSH) level, GSH/oxidized glutathione (GSSG) ratio, total antioxidant capacity (T-AOC) ( P <0.05) ; compared with the benzene model group, the benzene+high-dose DAS group had a significant reduction in the serum level of MDA and significant increases in T-SOD activity, GSH level, GSH/GSSG ratio, and T-AOC ( P <0.05). Compared with the blank control group, the benzene model group had a significant increase in the level of MDA ( P <0.05) and significant reductions in GSH level, GSH/GSSG ratio, and T-AOC ( P <0.05) in the spleen; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had a significant reduction in MDA level ( P <0.05) and significant increases in GSH level and T-AOC ( P <0.05), and the benzene+high-dose DAS group had significant increases in T-SOD activity and GSH/GSSG ratio ( P <0.05). Compared with the blank control group, the benzene model group had a significant increase in the level of MDA in bone marrow cells (BMCs) and peripheral blood mononucleated cells (PBMCs) ( P <0.05) and a significant reduction in T-AOC in PBMCs ( P <0.05) ; compared with the benzene model group, the benzene+low-dose DAS group, the benzene+middle-dose DAS group, and the benzene+high-dose DAS group had a significant reduction in the level of MDA in BMCs and PBMCs ( P <0.05), and the benzene+high-dose DAS group had significant increases in GSH level and GSH/GSSG ratio ( P <0.05) . Conclusion: DAS can antagonize the benzene-induced reduction in peripheral blood WBC, possibly by exerting an anti-oxidative stress effect.

Problem: Quercetin has been shown to display intensive antioxidant activity against ROS-mediated damage in chilled semen, and the effects and molecular mechanisms of Quercetin on sperm function in the infertile patients with leukocytospermia remain largely unknown., Methods: Semen samples were collected from the infertile men with leukocytospermia (n = 56) and fertile men (n = 44). Computer-assisted semen analysis (CASA) was used to determine sperm motility before and after Quercetin incubation (10 μmol/L). Changes in H 2 O 2 , sperm mitochondrial DNA (mtDNA), cytochrome B (Cty B), and NADH dehydrogenase 5 (NADH5) contents were measured. Furthermore, hyperactivated motility (HA) and acrosome reaction rates were detected after the stimulation by progesterone with or without Quercetin, respectively., Results: Quercetin could significantly improve sperm motility from the leukocytospermic patients. The level of H 2 O 2 was significantly decreased in the supernatant of leukocytospermic patients after Quercetin treatment. The content of mtDNA in sperm was significantly decreased, whereas the contents of Cyt B and NADH 5 in sperm were significantly increased. Sperm hyperactivated motility and acrosome reaction induced by progesterone were enhanced by Quercetin in sperm from the infertile men with leukocytospermia., Conclusion: These data indicate Quercetin could display protective effects against oxidative damage on sperm from the infertile men with leukocytospermia., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Leukopenia is a frequent complication following kidney transplantation. Granulocyte colony-stimulating factor (G-CSF) has been used to accelerate white blood cell (WBC) count recovery; however, published experience in kidney transplantation is limited., Methods: We retrospectively reviewed our kidney transplant recipients from January 2012 to September 2016 with a G-CSF order to evaluate leukopenia management (defined as WBC <3000 cells/μL)., Results: Thirty-six recipients were included. On average, G-CSF treatment began at 98 ± 38 days. At G-CSF initiation, mean WBC count was 1240 ± 420 cells/μL and absolute neutrophil count (ANC) was 653 ± 368 cells/μL. Mean G-CSF dose was 4.6 ± 1.2 mcg/kg/dose (total 11.8 ± 9.0 mcg/kg), 77.8% of recipients were prescribed G-CSF as outpatients, and overall, median time to WBC count recovery was 9 (IQR 4-14) days. Changes in immunosuppression and prophylaxis regimens for leukopenia were also common. Within 1 month following leukopenia onset, no patients experienced acute rejection and 5 (14%) developed infection requiring hospitalization or opportunistic infection., Conclusion: In kidney recipients with leukopenia, G-CSF may be helpful to achieve WBC count recovery in addition to changes in immunosuppression and prophylaxis medications. Prospective, randomized data are still needed to determine optimal G-CSF dosing in this population., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To study the protective effects of diallyl sulfide (DAS) on leukopenia induced by benzene. Methods: 90 Healthy male ICR mice, adaptive feeding 5 days later, 15 were randomly divided into blank control group、model group、low、middle、high dose DAS intervention groups and DAS control group. Mice in intervention groups and DAS control group were orally given DAS at 40, 80, 160, 160 mg/kg·bw, while mice in the other two groups received an equal volume of corn oil. After 2 hours, model group and the other three intervention groups were given benzene, corn oil suspension (1.3 g/kg·bw) , the two control groups treated with the same volume of corn oil, Benzene and DAS are dissolved in corn oil. one time for each day. 4 weeks later, Anesthesia at 14/29, make blood routine examination and count organ index and observe pathological examinations of spleen and thymus. Results: On day 14, the counts of peripheral blood white blood cells (WBC) , lymphocytes, monocytes in the model group decreased to 68.99%, 71.72%, 53.19% ( P <0.05) ; On day 29, the counts of peripheral blood lymphocytes, monocytes, neutrophils in the model group decreased to 83.00%, 81.03%, 89.37%, 20.84%, 19.25% ( P <0.05) ; spleen weight, spleen index, white pulp area ratio of spleen, thymus weight, thymus index, thymic cortex area ratio of mice in the model group decreased ( P <0.05) . On day 14, the counts of peripheral blood monocytes and lymphocytes in the DAS high dose intervention group increased by 136.36%, 260.00% ( P <0.05) ; On day 29, the counts of White blood cells, lymphocytes, red blood cells, platelets, hemoglobin in the DAS low, middle and high dose intervention groups increased ( P <0.05) ; spleen weight, spleen index, white pulp area ratio of spleen, thymus weight, thymus index, thymic cortex area ratio of mice in the DAS high dose intervention groups increased ( P <0.05) . Conclusion: DAS can effectively suppress benzene-induced leucopenia in mice.

Objective: We aimed to find the incidence and risk factors of hematologic adverse effects of piperacillin-tazobactam (TZP)., Materials and Methods: Adult patients who used TZP for more than 10 days were included in the study., Results: The incidence of leukopenia, neutropenia, and eosinophilia in 110 TZP therapy episodes was found to be 16.3%, 10%, and 10%, respectively. Lower Charlson Comorbidity Index score, lower initial leukocyte count, combination of TZP with another antibiotic, and total duration of TZP therapy were found to be independent risk factors for leukopenia, while initial higher eosinophil count (IHEC) and usage of TZP for >20 days were independent risk factors for neutropenia and IHEC and total duration of TZP therapy were independent risk factors for eosinophilia., Conclusion: Longer duration of therapy, combination with other antibiotics, younger age with fewer comorbidities, and IHEC could result in hematologic adverse effects in patients treated with TZP. Patients with IHEC may be more prone to allergic reactions, so immunological mechanisms may facilitate the development of hematological adverse effects of TZP.

Introduction:  The analysis of the periodic table of elements by Jan Scholten opened the way for a new kind of classification and repertorisation of homeopathic remedies. Thereby, group analysis (resorting to series and stages) makes precise prescriptions possible. This approach appears to yield striking results, even in severe cases. Whereas Hahnemann stressed the emotional state ('Gemüthssymptome', Organon § 210) when choosing a remedy, Scholten 200 years later investigated the mental picture that represents a life conflict or even a life theme that may maintain the disease process. The person's environment, emotional traumas or a conflict drives him or her to suppress and dissect painful emotions. Such compensations can become subconscious and so strong that they can no longer be controlled; they then influence the patient with a highly destructive energy., Methods:  We present five case reports, each dealing with an unusual clinical course of severe cancer associated with homeopathic treatment using the Scholten method., Results:  By presenting these cases, we consider how the constitution (lifelong signs and symptoms of the patient) and the mental state are interwoven and, as a complex mechanism, might provoke disease., Conclusion:  The appropriate homeopathic remedy, reflecting the Scholten approach, seemed to have beneficial impact on the disease process of the five individuals presented., Competing Interests: None., (The Faculty of Homeopathy.)

Objective: To observe the duration for normalization of the Total Leucocyte Count (TLC) with adjuvant Granulocyte-Colony Stimulating Factor (G-CSF) treatment in leukopenic neonatal sepsis, and to compare the neutrophilic response to G-CSF in neutropenic vs non-neutropenic subgroups., Methods: This prospective cohort study was carried out at the Neonatal Intensive Care Unit at Military Hospital Rawalpindi (NICU) from 1st August 2015 to 25th January 2017. Fifty one newborns with sepsis and leucopenia were sampled judgmentally from a population of 5666 admitted to NICU during the study period. The sample was then divided into neutropenic (exposed) and non-neutropenic (non-exposed) subgroups on basis of the absolute neutrophil count (ANC). Adjuvant G-CSF was given to all subjects and stopped once TLC normalized. SPSS v22 was used to calculate mean G-CSF treatment duration and rise in ANC. A Pearson correlation coefficient and simple linear regression were computed to assess the relationship between pre-GCSF ANC and the duration of treatment with GCSF. Comparison of subgroups with respect to rise in ANC was done using independent samples T-test., Results: The mean duration of G-CSF treatment was 1.82±0.81 days (1.0 - 4.0). Neutropenic neonates constituted 49% (n=25). The Pearson correlation coefficient showed a positive but negligible and non-significant correlation between the two variables, r = 0.070, n = 51, p = 0.625. A non-significant regression equation was found (F(1,49) = 0.242,p=0.625) with an R2 of 0.005. There was a 7.06±4.5 fold rise in ANC in the neutropenic subgroup compared to the 4.5±3.1 fold rise in the non-neutropenic subgroup (p=0.04)., Conclusions: The mean duration for recovery from leukopenia with G-CSF treatment in neonatal sepsis was less than 2 days and had no significant relationship with pre-GCSF absolute neutrophil count. The neutrophilic response was significantly higher in neutropenic compared to non-neutropenic neonates. As GCSF made no difference to the outcome in terms of mortality, its routine use is not recommended in leukopenic neonatal sepsis. .