Elevated HbA1c Is an Independent Predictor of Aggressive Clinical Behavior in Patients with Colorectal Cancer: A Case-Control Study

AIM: The aim of this study was to seek an association between the control of type 2 diabetes mellitus (T2DM), as determined by hemoglobin A1c (HbA1c) levels, and the outcome of colorectal cancer (CRC). METHODS: We performed a retrospective review of patients with T2DM who had CRC diagnosed between 1997 and 2001. We defined well-controlled T2DM as HbA1c < 7.5% and poorly controlled T2DM as HbA1c > or = 7.5%. A group of age- and gender-matched patients who had CRC without T2DM were used as controls. Forty clinical factors were reviewed, and those associated with poor clinical outcome in each group were examined by univariate analysis (UA) and by the maximum likelihood analysis of logistic regression to determine the independent predictors of cancer outcome. RESULTS: We identified 155 patients with T2DM and CRC, and 114 control patients who had CRC without T2DM. We found no significant differences in any clinical factor by UA between the patients with well-controlled T2DM and the patients who had CRC without T2DM. Compared to both of those patients groups, in contrast, the patients with poorly controlled T2DM had more right-sided CRCs (P = 0.04, OR = 2, 95% CI = 1-4.1), more advanced CRCs (P = 0.02, OR = 2.1, 95% CI = 1-4.4), a younger age of presentation (P = 0.05), greater use of exogenous insulin (P = 0.002), and a poorer 5-year survival (P = 0.001) by UA. Logistic regression showed that poorly controlled T2DM independently predicted the early onset of CRC, a more advanced stage at the time of presentation, poorer 5-year survival, and an increased incidence of right-sided CRCs. CONCLUSIONS: In patients with T2DM who have CRC, poor glycemic control is associated with a clinically aggressive course for the cancer.     

Serial studies of protein C and its plasma inhibitor in patients with disseminated intravascular coagulation

This study was undertaken to determine the levels of protein C antigen and activity and protein C inhibitor in sequential plasma samples of disseminated intravascular coagulation (DIC) patients. Our normal range for both protein C antigen and activity is 70 to 130 U/dL, and protein C inhibitor is 65 to 135 U/dL. A decreased level of protein C activity was found in 96% of the plasma samples from individuals with DIC; the protein C antigen was decreased in 73%. The inhibitor of protein C was decreased in all samples. Analysis of serial samples from patients with DIC reveals that protein C activity and antigen and protein C inhibitor decrease progressively during the initial stages of DIC and remain at a low level for 24 to 48 hours before gradually returning toward normal in nonfatal cases. The protein C activity decreases in parallel with protein C inhibitor and is lower than protein C antigen. In a fatal case of DIC, protein C activity and protein C inhibitor rapidly decreased to undetectable levels; however, protein C antigen was gradually decreasing but still detectable at time of death. In DIC, a discrepancy initially occurs between the activity and antigen of protein C, suggesting a complex with the inhibitor or other inactive forms of protein C. Protein C appears to play a major role in the control of DIC.     

TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection

The TNF family member, transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), is a key molecule for plasma cell maintenance and is required in infections where protection depends on antibody response. Here, we report that compared with WT mouse, TACI KO Μϕs expressed lower levels of Toll-like receptors (TLRs), CD14, myeloid differentiation primary response protein 88, and adaptor protein Toll/IL-1 receptor domain-containing adapter-inducing IFN-β and responded poorly to TLR agonists. Analysis of Μϕ phenotype revealed that, in the absence of TACI, Μϕs adapt the alternatively activated (M2) phenotype. Steady-state expression levels for M2 markers IL-4Rα, CD206, CCL22, IL-10, Arg1, IL1RN, and FIZZ1 were significantly higher in TACI KO Μϕ than in WT cells. Confirming their M2 phenotype, TACI-KO Mϕs were unable to control Leishmania major infection in vitro, and intradermal inoculation of Leishmania resulted in a more severe manifestation of disease than in the resistant C57BL/6 strain. Transfer of WT Μϕs to TACI KO mice was sufficient to significantly reduce disease severity. TACI is likely to influence Mϕ phenotype by mediating B cell-activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL) signals because both these ligands down-regulated M2 markers in WT but not in TACI-deficient Μϕs. Moreover, treatment of Μϕs with BAFF or APRIL enhanced the clearance of Leishmania from cells only when TACI is expressed. These findings may have implications for understanding the shortcomings of host response in newborns where TACI expression is reduced and in combined variable immunodeficiency patients where TACI signaling is ablated.Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a member of the TNF family molecules (1). It is a receptor for B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). Although BAFF and APRIL share a second receptor, B-cell maturation antigen (BCMA), BAFF-R only binds to BAFF, and heparan sulfate proteoglycans only engage APRIL. TACI is primarily expressed on mature B cells and mediates signals for Ig isotype switch and secretion (2). Studies in TACI KO mice (3), combined variable immune deficient (CVID) patients with mutations in TACI gene tnfrsf13b (4), and newborns who express severely reduced B-cell TACI (5) all point to its pivotal role in determining antibody (Ab) development against T cell-independent type 2 (TI-2) antigens. In contrast to earlier publications (3), more recent reports showed diminished sustainment of plasma cells in response to T cell-dependent (TD) antigens in TACI KO mice (6). Interestingly, Tsuji et al. reported that despite impaired plasma cell survival and reduced Ab response to TD antigens, TACI KO mice manifest enhanced clearance of the enteric pathogen Citrobacter rodentium, presumably due to generation of higher avidity of Abs in the absence of TACI (7). Whereas TACI is well established as a B-cell receptor, its involvement in innate immune response is less clear. One study reported diminished B-cell responses to Toll-like receptor (TLR)7 and TLR9 agonists in CVID patients with TACI mutations (4). A second possible link between TACI and innate immune system was suggested by He and colleagues, who have shown that the TLR adaptor molecule myeloid differentiation primary response protein 88 (MyD88) is downstream of TACI in B cells (8). Other members of the innate immune system such as dendritic cells (DCs) and monocytes are known to be the main sources of circulating BAFF and APRIL, but TACI expression is limited to intracellular compartments in these cells (9, 10). Although BAFF and APRIL can induce inflammatory cytokine secretion in human DCs and monocytes, the significance of their activity remains to be understood (9, 10).Here, we investigated the role of TACI in innate immune response and showed that TACI deficient macrophages (Mϕs) respond poorly to TLR agonists, and this ablated response is likely due to reduced expression of TLRs, CD14, MyD88, and adaptor protein Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) in TACI KO cells. Furthermore, TACI KO Mϕs manifested alternatively activated Μϕ (M2) phenotype characterized by elevated levels of molecules associated with M2 phenotype and impaired resistance to in vitro Leishmania major infection. Moreover, intradermal inoculation with L. major resulted in a more severe manifestation of disease in TACI KO mouse than the Leishmania-resistant WT C57BL/6 strain, and adaptive transfer of Μϕs from the WT mouse was sufficient to reduce the severity of Leishmania induced cutaneous disease in the TACI KO mouse. Comparison of the response of WT and TACI-deficient Μϕs revealed that TACI mediates ligand induced down-regulation of molecules associated with M2 Mϕ phenotype and up-regulation of some of the markers representative of classically activated (M1) phenotype. Collectively, these findings extend the role of TACI from its well-defined involvement in B-cell homeostasis to Mϕ phenotype determination and resistance to intracellular pathogens.     

The effects of phosphanegold(I) thiolates on the biological properties of <Emphasis Type="Italic">Acanthamoeba castellanii</Emphasis> belonging to the T4 genotype

Background

Gold compounds have shown promise in the treatment of non-communicable diseases such as rheumatoid arthritis and cancer, and are considered of value as anti-microbial agents against Gram-negative and Gram-positive bacteria, and have anti-parasitic properties against Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, Leishmania infantinum, Giardia lamblia, and Entamoeba histolytica. They are known to affect enzymatic activities that are required for the cellular respiration processes.

Methods

Anti-amoebic effects of phosphanegold(I) thiolates were tested against clinical isolate of A. castellanii belonging to the T4 genotype by employing viability assays, growth inhibition assays, encystation assays, excystation assays, and zymographic assays.

Results

The treatment of A. castellanii with the phosphanegold(I) thiolates tested (i) had no effect on the viability of A. castellanii as determined by Trypan blue exclusion test, (ii) did not affect amoebae growth using PYG growth medium, (iii) did not inhibit cellular differentiation, and (iv) had no effect on the extracellular proteolytic activities of A. castellanii.

Conclusion

Being free-living amoeba, A. castellanii is a versatile respirator and possesses respiratory mechanisms that adapt to various aerobic and anaerobic environments to avoid toxic threats and adverse conditions. For the first time, our findings showed that A. castellanii exhibits resistance to the toxic effects of gold compounds and could prove to be an attractive model to study mechanisms of metal resistance in eukaryotic cells.

     

Cortical Activation Through Passive-Motion Functional MRI

BACKGROUND AND PURPOSE:Functional brain mapping is an important technique for neurosurgical planning, particularly for patients with tumors or epilepsy; however, mapping has traditionally involved invasive techniques. Existing noninvasive techniques require patient compliance and may not be suitable for young children. We performed a retrospective review of our experience with passive-motion functional MR imaging in anesthetized patients to determine the diagnostic yield of this technique.MATERIALS AND METHODS:A retrospective review of patients undergoing passive-motion fMRI under general anesthesia at a single institution over a 2.5-year period was performed. Clinical records were evaluated to determine the indication for fMRI, the ability to detect cortical activation, and, if present, the location of cortical activation.RESULTS:We identified 62 studies in 56 patients in this time period. The most common indication for fMRI was epilepsy/seizures. Passive-motion fMRI identified upper-extremity cortical activation in 105 of 119 (88%) limbs evaluated, of which 90 (86%) activations were in an orthotopic location. Lower-extremity cortical activation was identified in 86 of 118 (73%) limbs evaluated, of which 73 (85%) activations were in an orthotopic location.CONCLUSIONS:Passive-motion fMRI was successful in identifying cortical activation in most of the patients. This tool can be implemented easily and can aid in surgical planning for children with tumors or candidates for epilepsy surgery, particularly those who may be too young to comply with existing noninvasive functional measures.

The criterion standard for presurgical brain mapping has typically been intraoperative cortical stimulation mapping and the Wada test.^1–4 Both methods are invasive procedures, and their efficacy and superiority over other mapping procedures have become less clear with advances in noninvasive brain-mapping techniques,^4–12 with some studies showing that these alternative methods are comparable to stand-alone and/or adjunct techniques.^9–18 Blood oxygen level–dependent functional MR imaging is an increasingly used imaging technique in the clinical setting. Since the early 1990s, it has been used to study brain function in healthy individuals and particularly for surgical planning in patients with brain tumors or epilepsy.^{2,4,17,19–22} This imaging technique maps areas of cortical activation via changes in blood flow to metabolically active brain regions during cortical activation, typically secondary to specific motor, language, and visual tasks. fMRI provides a number of benefits: it is noninvasive, it is a useful tool for presurgical evaluation for invasive procedures that involve high risk,^{2,4,17,19,20,23,24} and it can also assess the current function of patients with brain lesions or previous brain surgery.^20,25 Clinically, it is performed as a task-based technique that requires the patient to cooperate and keep all other body movements to a minimum. Incomplete compliance limits the utility of this technology and introduces risk for spurious results. Compliance with the tasks and remaining still is a particular concern in young children and patients with developmental or acquired cognitive deficits.^26,27 Even children who can perform the task during training sessions may not be able to comply in the MR imaging scanner.²⁷A strategy that allows this information to be obtained from subjects who are unable to cooperate is to perform a similar fMRI task under sedation. fMRI of sedated patients performed with passive motion of the extremities has been successful in some reports.^{15,23,24,28,29} The goal is to map the motor cortex while removing the need for task compliance and reducing or eliminating concerns for patient motion.^23,24,28 We performed a retrospective review of our institution''s 2.5-year experience with passive-motion fMRI to assess the feasibility and reliability of this imaging technique.     

Impact of physical distancing measures against COVID-19 on contacts and mixing patterns: repeated cross-sectional surveys,the Netherlands, 2016–17, April 2020 and June 2020

BackgroundDuring the COVID-19 pandemic, many countries have implemented physical distancing measures to reduce transmission of SARS-CoV-2.AimTo measure the actual reduction of contacts when physical distancing measures are implemented.MethodsA cross-sectional survey was carried out in the Netherlands in 2016–17, in which participants reported the number and age of their contacts the previous day. The survey was repeated among a subsample of the participants in April 2020, after strict physical distancing measures were implemented, and in an extended sample in June 2020, after some measures were relaxed.ResultsThe average number of community contacts per day was reduced from 14.9 (interquartile range (IQR): 4–20) in the 2016–17 survey to 3.5 (IQR: 0–4) after strict physical distancing measures were implemented, and rebounded to 8.8 (IQR: 1–10) after some measures were relaxed. All age groups restricted their community contacts to at most 5, on average, after strict physical distancing measures were implemented. In children, the number of community contacts reverted to baseline levels after measures were eased, while individuals aged 70 years and older had less than half their baseline levels.ConclusionStrict physical distancing measures greatly reduced overall contact numbers, which likely contributed to curbing the first wave of the COVID-19 epidemic in the Netherlands. However, age groups reacted differently when measures were relaxed, with children reverting to normal contact numbers and elderly individuals maintaining restricted contact numbers. These findings offer guidance for age-targeted measures in future waves of the pandemic.