Production and persistence of specific antibodies in COVID-19 patients with hematologic malignancies: role of rituximab.

The ability of patients with hematologic malignancies (HM) to develop an effective humoral immune response after COVID-19 is unknown. A prospective study was performed to monitor the immune response to SARS-CoV-2 of patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), chronic lymphoproliferative disorders (CLD), multiple myeloma (MM), or myelodysplastic/myeloproliferative syndromes (MDS/MPN). Antibody (Ab) levels to the SARS-CoV-2 nucleocapsid (N) and spike (S) protein were measured at +1, +3, +6 months after nasal swabs became PCR-negative. Forty-five patients (9 FL, 8 DLBCL, 8 CLD, 10 MM, 10 MDS/MPS) and 18 controls were studied. Mean anti-N and anti-S-Ab levels were similar between HM patients and controls, and shared the same behavior, with anti-N Ab levels declining at +6 months and anti-S-Ab remaining stable. Seroconversion rates were lower in HM patients than in controls. In lymphoma patients mean Ab levels and seroconversion rates were lower than in other HM patients, primarily because all nine patients who had received rituximab within 6 months before COVID-19 failed to produce anti-N and anti-S-Ab. Only one patient requiring hematological treatment after COVID-19 lost seropositivity after 6 months. No reinfections were observed. These results may inform vaccination policies and clinical management of HM patients.

Ministry of Health clinical practice guidelines: depression.

The Ministry of Health (MOH) have updated the clinical practice guidelines on Depression to provide doctors and patients in Singapore with evidence-based treatment for depression. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH clinical practice guidelines on Depression, for the information of readers of the Singapore Medical Journal. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: http://www.moh.gov.sg/content/moh_web/home/Publications/guidelines/cpg/2012/depression.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Cytokine gene-modulated dendritic cells protect against allergic airway inflammation by inducing IL-10(+)IFN-gamma(+)CD4(+) T cells.

Asthma is characterized by allergen-induced airway inflammation orchestrated by Th2 cells. Dendritic cells (DCs) were found to efficiently prime naive T-helper cells. Thus, modification of DC function may be used as an ideal tool to treat allergic asthma by changing CD4(+) T-cell differentiation or suppressing Th2 development. In this study, we examined whether a DC-based vaccine can be applied to DCs modified with interleukin (IL)-10- and IL-12-expressing adenoviruses to prevent ovalbumin (OVA)-induced asthma in mice. Herein, we show that these modified DCs efficiently moderated the characteristics of asthma, including expressions of OVA-specific antibodies, airway hyperresponsiveness, eosinophilic airway inflammation, and Th2 cytokines production. Additionally, IL-10 and IL-12 gene-modified DCs enhanced the development of both T-helper type 1 (Th1) and IL-10(+)IFN-gamma(+) (interferon-gamma) double-positive T cells in vivo. In vitro-generated OVA-specific IL-10(+)IFN-gamma(+)CD4(+) T cells inhibited the proliferation of naive CD4(+) T cells, and this suppressive effect was a cell contact-dependent mechanism. Furthermore, we showed that combined cytokine-modulated DCs could alleviate established allergic airway inflammation. Taken together, these results suggest that IL-10 and IL-12 gene-modulated DCs are effective in suppressing asthmatic airway inflammation through both immune deviation and immune suppression and are a potential therapeutic approach for asthma.

Improving neural network prediction of effluent from biological wastewater treatment plant of industrial park using fuzzy learning approach.

Three types of adaptive network-based fuzzy inference system (ANFIS) in which the online monitoring parameters served as the input variable were employed to predict suspended solids (SS(eff)), chemical oxygen demand (COD(eff)), and pH(eff) in the effluent from a biological wastewater treatment plant in industrial park. Artificial neural network (ANN) was also used for comparison. The results indicated that ANFIS statistically outperforms ANN in terms of effluent prediction. When predicting, the minimum mean absolute percentage errors of 2.90, 2.54 and 0.36% for SS(eff), COD(eff) and pH(eff) could be achieved using ANFIS. The maximum values of correlation coefficient for SS(eff), COD(eff), and pH(eff) were 0.97, 0.95, and 0.98, respectively. The minimum mean square errors of 0.21, 1.41 and 0.00, and the minimum root mean square errors of 0.46, 1.19 and 0.04 for SS(eff), COD(eff), and pH(eff) could also be achieved.

Comparisons of grey and neural network prediction of industrial park wastewater effluent using influent quality and online monitoring parameters.

In this study, Grey model (GM) and artificial neural network (ANN) were employed to predict suspended solids (SSeff) and chemical oxygen demand (CODeff) in the effluent from a wastewater treatment plant in industrial park of Taiwan. When constructing model or predicting, the influent quality or online monitoring parameters were adopted as the input variables. ANN was also adopted for comparison. The results indicated that the minimum MAPEs of 16.13 and 9.85% for SSeff and CODeff could be achieved using GMs when online monitoring parameters were taken as the input variables. Although a good fitness could be achieved using ANN, they required a large quantity of data. Contrarily, GM only required a small amount of data (at least four data) and the prediction results were even better than those of ANN. Therefore, GM could be applied successfully in predicting effluent when the information was not sufficient. The results also indicated that these simple online monitoring parameters could be applied on prediction of effluent quality well.

Metformin-like effects of Quei Fu Di Huang Wan, a Chinese herbal mixture, on streptozotocin-induced diabetic rat.

Effect on plasma glucose concentration of Quei Fu Di Huang Wan (Quei Fu DHW), the herbal mixture widely used to treat diabetic disorder in Chinese traditional medicine, was investigated in diabetic rats deficient in insulin. Changes of plasma glucose in streptozotocin-induced diabetic rats (STZ-diabetic rats) receiving repeated oral administration of Quei Fu DHW were determined. Also, the mRNA level (by Northern blotting) and protein level (by Western blotting) of phosphoenolpyruvate carboxykinase (PEPCK) in liver from STZ-diabetic rats were measured to compare differences between groups receiving repeated oral administration of Quei Fu DHW, metformin, and two active herbs (Zou Guei or Fuzei) at effective dosages. In STZ-diabetic rats, acute oral administration of Quei Fu DHW decreased the plasma glucose level significantly in a dose-dependent manner from 5 mg/kg to 26.0 mg/kg. Similar treatment with Quei Fu DHW also brought on a plasma glucose-lowering effect in normal rats, although the effectiveness was not as significant as in STZ-diabetic rats. Repeated oral treatment of Quei Fu DHW at 26 mg/kg every 8 h, three times daily for 3 days, produced a plasma glucose-lowering activity similar to that of metformin-treatment in STZ-diabetic rats. Oral administration of Zou Guei (Cinnamomi Cortex) or Fuzei (Aconiti Tuber), the individual constituent of Quei Fu DHW, at the dose of 50 mg/kg into STZ-diabetic rats for 3 days normalized hyperglycemia. Similar to the repeated treatment with Quei Fu DHW, Fuzei at the effective dose reversed the elevated mRNA and protein levels of PEPCK in liver from STZ-diabetic rats. This is consistent with findings that metformin restored the increased gene expression of PEPCK in liver from STZ-diabetic rats. However, the gene expression of PEPCK in STZ-diabetic rats was not influenced by similar treatment with Zou Guei. The present study found that oral administration of Quei Fu DHW could decrease hepatic gluconeogenesis in a way similar to metformin in lowering plasma glucose in diabetic rats lacking insulin. Thus, this preparation may be a helpful adjuvant for the treatment of diabetic disorders in clinical practice.

NK cell functions restrain T cell responses during viral infections.

NK cell functions for regulation of T cell responses were evaluated during acute viral infections. In vivo depletion studies established that the presence of NK cells in murine cytomegalovirus (MCMV)-infected immunocompetent mice negatively affected CD4 and CD8 T cell IFN-gamma expression, bromodeoxyuridine (BrdU) incorporation, and expansion. To evaluate NK cell effects, under conditions when NK cells do not control viral replication, experiments were performed using lymphocytic choriomeningitis virus (LCMV). Depletion of NK cells did not affect LCMV-elicited T cell responses in immunocompetent mice; however, the presence of NK cells did inhibit CD4 T cell IFN-gamma production, BrdU incorporation, and expansion in infected MHC class I- and CD8 T cell-deficient beta2M-/- mice. Together, the results reveal a previously unappreciated immunoregulatory role of NK cells for downstream T cell responses.

Case study: how to apply data mining techniques in a healthcare data warehouse.

Healthcare provider organizations are faced with a rising number of financial pressures. Both administrators and physicians need help analyzing large numbers of clinical and financial data when making decisions. To assist them, Rush-Presbyterian-St. Luke's Medical Center and Hitachi America, Ltd. (HAL), Inc., have partnered to build an enterprise data warehouse and perform a series of case study analyses. This article focuses on one analysis, which was performed by a team of physicians and computer science researchers, using a commercially available on-line analytical processing (OLAP) tool in conjunction with proprietary data mining techniques developed by HAL researchers. The initial objective of the analysis was to discover how to use data mining techniques to make business decisions that can influence cost, revenue, and operational efficiency while maintaining a high level of care. Another objective was to understand how to apply these techniques appropriately and to find a repeatable method for analyzing data and finding business insights. The process used to identify opportunities and effect changes is described.

Stimulation of insulin release in rats by Die-Huang-Wan, a herbal mixture used in Chinese traditional medicine.

Die-Huang-Wan is a herbal mixture widely used in Chinese traditional medicine to treat diabetic disorders. We have investigated the effect of Die-Huang-Wan on plasma glucose concentration in-vivo. Die-Huang-Wan was administered orally (5.0, 15.0 or 26.0 mg kg(-1)) to three rat models. Wistar rats were used as the normal animal model, rats with insulin-resistance (induced by the repeated thrice daily injection of human long-acting insulin) were used as the non-insulin-dependent diabetic model, and streptozotocin-induced diabetic rats were used as the insulin-dependent diabetic model. In normal rats, approximately 1 h after oral administration of Die-Huang-Wan the plasma glucose concentration decreased significantly in a dose-dependent manner, from 5 to 26.0 mg kg(-1). A similar effect was observed in rats with insulin-resistance. However, this effect was not observed in streptozotocin-induced diabetic rats, even at an oral dose of 26.0 mg kg(-1). These results suggested an insulin-dependent action, a view supported by the increase of plasma insulin-like immunoreactivity in normal rats receiving Die-Huang-Wan. The results indicated that Die-Huang-Wan had an ability to stimulate the secretion of insulin and this preparation seemed helpful in improving the diabetic condition, especially hyperglycaemia in type-II diabetes.

Effect of mitomycin C for combined trabeculectomy and phacoemulsification.

BACKGROUND: To evaluate the efficacy and safety of intraoperative mitomycin C (MMC) for trabeculectomy combined with phacoemulsification (phacotrab) in patients with coexisting glaucoma and cataract. METHODS: We retrospectively reviewed the charts of consecutive patients who underwent phacotrab from July, 1996, to March, 1998. The pre- and postoperative intraocular pressure (IOP), number of glaucoma medications, visual acuity (VA), and postoperative complications were compared among 22 patients (22 eyes) who received intraoperative MMC and 18 patients (18 eyes) who did not receive MMC, served as the control group. Data of age, gender, type of glaucoma, number of glaucoma medications, cup-to-disc ratio of the optic nerve and the extent of visual field defects were also evaluated. Kaplan-Meier survival analysis was used to compare the surgical success rates between two groups. RESULTS: The mean IOP decreased from 16.1 +/- 4.2 mmHg to 10.94 +/- 3.6 mmHg in the MMC group, and from 18.7 +/- 6.9 mmHg to 14.6 +/- 1.9 mmHg in the control group at one year of follow-up. The mean postoperative IOPs were significantly lower in the MMC group than in the control group at one week, two weeks, and one, two, nine and 12 months. Postoperative mean VA log10 minimum angle of resolution (MAR) improved significantly in both groups. The mean number of medications decreased from 1.91 +/- 0.75 to 0.18 +/- 0.50 in the MMC group, and from 1.89 +/- 0.47 to 0.72 +/- 0.75 in the control group (p < 0.001 for both). The one-year complete success rate was significantly higher in the MMC group (p = 0.0038) than in the control group. No major complication was found throughout the study. CONCLUSIONS: Intraoperative MMC in phacotrab may improve postoperative filtration with less dependence on glaucoma medication. No significant adverse effects were associated with MMC application.

Primary neuroendocrine differentiated mucinous adenocarcinoma of the vulva: case report and review of the literature.

Only a few cases on mucinous adenocarcinomas of the vulva have been reported. In this study, we present a case of a 75-year-old woman with a tumor in the left major labium. Because biopsy had shown formations of squamous cell carcinoma, radical vulvectomy with bilateral inguinal and femoral lymph node dissection were performed. At that time, histology was interpreted as small-cell, anaplastic carcinoma, with focal epidermoid differentiation. Postoperative radiation therapy was performed. Sixteen months after surgery, the patient presented with bilateral breast carcinomas. Histology showed a scirrhous carcinoma of the left and a medullary carcinoma of the right breast, but no lymph node metastases. Histochemical and immunohistochemical re-examination of the vulvar carcinoma now revealed a mucinous adenocarcinoma with neuroendocrine differentiation. The tumor expressed neuroendocrine markers such as chromogranin A and protein gene-product (PGP) 9.5, as well as peptides of the vasoactive intestinal polypeptide (VIP) family, and serotonin. Histochemical silver stains demonstrated Grimelius argyrophilia and Masson argentaffinity. Because of positive estrogen and progesterone receptor status of both breast cancers, postoperative Tamoxifen therapy was performed. The patient is still alive four years after vulvectomy.

CD4+ and CD8+ T cell interactions in IFN-gamma and IL-4 responses to viral infections: requirements for IL-2.

Cytokine responses to lymphocytic choriomeningitis virus infections were evaluated, and CD8+ T cell, CD4+ T cell, and IL-2 contributions delineated. In immunocompetent mice, lymphocytic choriomeningitis virus induced both IFN-gamma and IL-4 as well as IL-2. Experiments in mice either beta2-microglobulin-deficient, lacking MHC class I molecules and CD8+ T cells, or A beta(b)-deficient, lacking MHC class II molecules and CD4+ T cells, demonstrated that mixtures of T cell responses were required for optimal ex vivo cytokine productions. Intracellular cytokine expression analyses of cells from immunocompetent and immunodeficient mice showed that CD8+ T cells were predominant IFN-gamma producers, and that expansion of CD8+ T cells primed to make IFN-gamma was independent of CD4+ T cells in vivo. Studies in IL-2-deficient mice demonstrated that this cytokine promoted IFN-gamma and IL-4 responses, and ex vivo experiments showed that exogenous IL-2 was required to maintain high-level IFN-gamma production by in vivo-primed CD8+ T cells. Conditions associated with cytokine decreases were accompanied by reduced detectable plasma Ab responses. The results indicate that, although IL-2-dependent CD8+ T cell proliferation does not require endogenous CD4+ T cells, IL-2 production by the CD4+ T cells may promote continued cytokine release from activated CD8+ T cells. By defining these critical steps in cellular and cytokine interactions for shaping endogenous immune responses, the studies advance understanding of the unique conditions regulating CD8+ T cell responses to viral challenges.

Quantitative analysis of calcitonin gene-related peptide- and neuropeptide Y-immunoreactive nerve fibers in mesenteric blood vessels of rats irradiated with cobalt-60 gamma rays.

The effects of 60Co gamma rays on calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers and neuropeptide Y (NPY)-immunoreactive nerve fibers were examined in mesenteric blood vessels of rats. Using a free-floating immunostaining streptavidin-biotin peroxidase complex method combined with a nickel-enhancement technique, we found that the distribution pattern of these two peptidergic nerve fibers in superior mesenteric arteries and superior mesenteric veins did not change, while the densities of CGRP-immunoreactive nerve fibers and NPY-immunoreactive nerve fibers in superior mesenteric arteries and veins varied with the time after irradiation. The results suggested that CGRP and NPY may be important in the development and elimination of radiation-induced injury.

A developmental study of novH gene expression in human central nervous system.

The expression pattern of the human nephroblastoma overexpressed (novH) gene in the fetal human central nervous system was examined by in situ hybridization using digoxigenin-labeled novH-specific riboprobes. In the spinal cord, the nov-expressing neurons were first detected both in the ventral region at 16 weeks of gestation (G16W) and in the dorsal region at G38W. In the medulla, nov-expressing neurons were detected in the principal nucleus of the inferior olive, the hypoglossal nucleus and the dorsal motor nucleus of vagus at G16W. Nov-positive neurons were detected at G28W in the nucleus of the spinal tract of the trigeminal and cuneate nucleus, and at G38W in the abducens nucleus of pons, the red nucleus and the substantia nigra of the midbrain, the ventral posterolateral and the mediodorsal thalamic nucleus. A strong labeling was also detected in the striatum of the cerebrum and the cerebral cortex of the parietal lobe. These data established that novH is mainly expressed in somato-motor neurons in the lower central nervous system at early developmental stages and in the higher central nervous system at later stages, suggesting that nov may play an important role in neuronal differentiation.

Mapping of a major genetic modifier of embryonic lethality in TGF beta 1 knockout mice.

The transforming growth factor beta 1 (TGF beta 1) signalling pathway is important in embryogenesis and has been implicated in hereditary haemorrhagic telangiectasia (HHT), atherosclerosis, tumorigenesis and immunomodulation. Therefore, identification of factors which modulate TGF beta 1 bioactivity in vivo is important. On a mixed genetic background, approximately 50% Tgfb1-/- conceptuses die midgestation from defective yolk sac vasculogenesis. The other half are developmentally normal but die three weeks postpartum. Intriguingly, the vascular defects of Tgfb1-/- mice share histological similarities to lesions seen in HHT patients. It has been suggested that dichotomy in Tgfb1-/- lethal phenotypes is due to maternal TGF beta 1 rescue of some, but not all, Tgfb1-/- embryos12. Here we show that the Tgfb1-/- phenotype depends on the genetic background of the conceptus. In NIH/Ola, C57BL/6J/Ola and F1 conceptuses, Tgfb1-/- lethality can be categorized into three developmental classes. A major codominant modifier gene of embryo lethality was mapped to proximal mouse chromosome 5, using a genome scan for non-mendelian distribution of alleles in Tgfb1-/- neonatal animals which survive prenatal lethality. This gene accounts for around three quarters of the genetic effect between mouse strains and can, in part, explain the distribution of the three lethal phenotypes. This approach, using neonatal DNA samples, is generally applicable to identification of loci that influence the effect of early embryonic lethal mutations, thus furthering knowledge of genetic interactions that occur during early mammalian development in vivo.

Interferon-alpha/beta inhibition of interleukin 12 and interferon-gamma production in vitro and endogenously during viral infection.

Interferon (IFN)-alpha/beta-mediated negative regulation of interleukin 12 (IL-12) and IFN-gamma proteins is reported here. Both IFN-alpha and IFN-beta inhibited fixed Staphylococcus aureus Cowan strain induction of IL-12 and IFN-gamma production by mouse splenic leukocytes in culture. Extended studies with IFN-alpha demonstrated that inhibition was at the level of biologically active IL-12 p70. Effects were selective, as induction of tumor necrosis factor was unaffected and induction of IL-6 was enhanced. Neutralization of IFN-alpha/beta expressed endogenously during infections with murine cytomegalovirus (MCMV) enhanced early IL-12 and IFN-gamma protein production. Furthermore, during infections of mice with lymphocytic choriomeningitis virus (LCMV), this treatment revealed a previously undetected early IL-12 and IFN-gamma protein expression, and mice deficient in IFN-alpha/beta receptor function, but not control mice, also expressed endogenous LCMV-induced IL-12. The effects of IFN-alpha/beta neutralization on production of IL-12 and IFN-gamma during the viral infections were detected in both serum samples and medium conditioned with splenic leukocytes isolated from infected animals. In vitro studies demonstrated that splenic leukocytes isolated from LCMV-infected mice were primed to produce IL-12 in response to stimulation with Staphylococcus aureus Cowan strain, but that this responsiveness was sensitive to added IFN-alpha. Moreover, endogenous IFN-alpha/beta induced by LCMV inhibited in vivo lipopolysaccharide stimulation of IL-12 production. These results demonstrate a new pathway for regulating cytokine responses, and suggest a mechanism for inhibition of IL-12-dependent immune responses during viral infections.

Genistein suppresses EGF-induced prostaglandin biosynthesis by a mechanism independent of EGF receptor tyrosine kinase inhibition.

This study demonstrated that genistein, a selective tyrosine kinase inhibitor, blocked PGE2 production in human A431 and WISH cells and murine 3T3 cells in response to epidermal growth factor and platelet-derived growth factor. Blockade of growth factor-induced PGE2 production was dose-dependent (IC50 approximately equal to 7-8 microM). Genistein also abolished PGE2 formation in response to calcium ionophores, A23187 and ionomycin, and the phorbol ester, phorbol myristate acetate. Moreover, genistein-treated A431 and WISH cells incorporated significantly less [3H]arachidonic acid into membrane phospholipids than control cells. Finally, genistein decreased the specific activity of prostaglandin H2 synthase prepared from A431 cells, WISH cells, and ram seminal vesicle. The IC50 of genistein for inhibition of prostaglandin H2 synthase specific activity extracted from A431 and WISH cells approximated that half-maximal inhibitory concentration in the whole cell assay. These data indicate that genistein may interfere with arachidonic acid metabolism at several key points by a mechanism(s) that is independent of its inhibitory action on receptor tyrosine protein kinases. Taken together, these results also suggest that caution should be exercised when drawing conclusions about the putative role of tyrosine kinases in signal transduction events using genistein as a pharmacological blocker.

Serotypes, biotypes and antibiotic susceptibility of 126 clinical isolates of Haemophilus influenzae.

Serotypes, biotypes, and antibiotic susceptibility of 126 Haemophilus influenzae isolates were determined. Five of the 126 isolates were from blood and were encapsulated type b strains; those taken from other sites were not typable. There were 13% biotype I, 36% biotype II, 38% biotype III, 5% biotype IV, 4% biotype V, and 4% biotype VI isolates. Antibiotic susceptibility tests using the standard disk diffusion method showed the following resistance: ampicillin 51%, cefamandole 10%, cefuroxime 3%, chloramphenicol 28%, tetracycline 37% and sulfamethoxazole-trimethoprim 49%. None of the five type b isolates were resistant to cefotaxime, a third generation cephalosporin. The second generation cephalosporins, cefamandole and cefuroxime, showed a superior activity against H. influenzae isolates, compared to other antibiotics. Multiple drug resistance was found in 64 (51%) isolates. Four of the five type b isolates were resistant to multiple drugs. The multiple-resistance pattern most frequently observed was to ampicillin, chloramphenicol, tetracycline and sulfamethoxazole-trimethoprim. Most clinical isolates did not contain plasmids; therefore, the antibiotic resistance of these H. influenzae strains was probably chromosome-mediated.