Objectives. To compare the outcome of dorsal buccal mucosal graft (BMG) substitution urethroplasty by dorsal urethrotomy approach with ventral urethrotomy approach in management of stricture urethra. Methods and Materials. A total of 40 patients who underwent dorsal BMG substitution urethroplasty were randomized into two groups. 20 patients underwent dorsal onlay BMG urethroplasty as described by Barbagli, and the other 20 patients underwent dorsal BMG urethroplasty by ventral urethrotomy as described by Asopa. Operative time, success rate, satisfaction rate, and complications were compared between the two groups. Mean follow-up was 12 months (6–24 months). Results. Ventral urethrotomy group had considerably lesser operative time although the difference was not statistically significant. Patients in dorsal group had mean maximum flow rate of 19.6 mL/min and mean residual urine of 27 mL, whereas ventral group had a mean maximum flow rate of 18.8 and residual urine of 32 mL. Eighteen out of twenty patients voided well in each group, and postoperative imaging study in these patients showed a good lumen with no evidence of leak or extravasation. Conclusion. Though ventral sagittal urethrotomy preserves the blood supply of urethra and intraoperative time was less than dorsal urethrotomy technique, there was no statistically significant difference in final outcome using either technique.
Isolated renal mucormycosis is rarely identified and has been described in only a handful of cases. We hereby report a case of isolated renal mucormycosis with an atypical presentation in an immunocompetent patient with no identifiable risk factors. A 30-year-old nondiabetic male presented with a poorly functioning right kidney with minimal constitutional symptoms. The patient underwent a right simple nephrectomy. Histopathology revealed necrotizing xanthogranulomatous pyelonephritis with mucormycosis. The postoperative period was uneventful and the patient was managed without any antifungal administration. We hereby emphasize that renal mucormycosis can affect immunocompetent healthy adults without any previously known risk factors and that asymptomatic patients with no evidence of fungemia or disseminated disease can be managed without administration of intravenous amphotericin.
Amphotericin B; Immunocompetence; Mucormycosis; Urinary tract infection
We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined.
We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks.
The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands.
Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects.
Regulatory T cells are essential to maintain immune homeostasis and prevent autoimmunity. Therapy with in vitro expanded human nTRegs is being tested to prevent graft versus host disease, which is a major cause for morbidity and mortality associated with hematopoietic stem cell transplantation. Their usefulness in therapy will depend on their capacity to survive, migrate appropriately and retain suppressive activity when introduced into a transplant recipient. The lack of a suitable animal model for studying the in vivo reconstitutive capability of human nTRegs is a major impediment for investigating the behavior of adoptively transferred nTRegs
in vivo. We show that injection of a plasmid encoding human IL-2 is necessary and sufficient for long term engraftment of in vitro expanded nTRegs in NOD-SCID IL2rγcnull mice. We also demonstrate that these in vivo reconstituted TRegs traffic to different organs of the body and retain suppressive function. Finally, in an IL-2 accelerated GVHD model, we show that these in vivo reconstituted TRegs are capable of preventing severe xenogenic response of human PBMCs. Thus, this novel ‘hu-TReg mouse’ model offers a pre-clinical platform to study the in vivo function and stability of human nTRegs and their ability to modulate autoimmune diseases and GVHD.
Mechanisms underlying failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood.
To investigate innate immune factors regulating B cell function in HIV infected persons and to correlate them with serologic responses to H1N1/09 vaccine.
We evaluated immunologic characteristics of 17 HIV-infected patients and eight healthy controls (HC) at 0, 7 and 28 days (designated T0, T1 and T2) following a single 15 mcg dose of non-adjuvanted H1N1/09 influenza vaccine using Flow cytometry, ELISPOT and ELISA assays. All HC and nine patients (53%) seroconverted with >1:40 hemagglutination inhibition antibody titer at T2.
In vaccine responders (R) and HC, serum levels of BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand) increased from T0 to T2 in conjunction with increases in frequencies of memory B cells. Concurrently, receptors for these factors showed changes, with increases in expression of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) and decreases in BAFF receptor in memory B cells. IL-2 secreting cells and IgG antibody secreting cells increased at T2 in R and HC in ex-vivo H1N1 antigen stimulated cultures. These immunologic responses were not evident at T1 and were deficient in vaccine non-responder patients at T2. At T0, vaccine non-responders had lower frequencies of BAFF-R and TACI expressing memory B cells than responders.
Impaired memory B cell responses, deficiencies in serum BAFF and APRIL and alterations in their receptors on B cells were associated with failure of H1N1/09 influenza vaccine responses among virologically controlled HIV-infected patients.
2009 H1N1 vaccination and HIV; B cell defect in HIV; BAFF-binding receptors and HIV; Innate immune defect and HIV; T-independent humoral immune factors
We have previously shown that Interleukin-21, a pleiotropic C γ-chain signaling cytokine, induces the expression of the cytotoxic molecules granzyme B (GrB) and perforin in vitro in CD8 T cells and NK cells of chronically HIV infected individuals. In this pilot study, four chronically SIV infected Rhesus macaques (RM) in late- stage disease were given two doses of recombinant MamuIL-21, 50μg/kg, intravenously 7 days apart, followed by one subcutaneous dose, 100μg/kg, 23 days after the second dose. Three animals served as controls. After each dose of IL-21, increases were noted in frequency and mean fluorescence intensity of GrB and perforin expression in memory and effector subsets of CD8 T cells in peripheral blood (PB), in peripheral and mesenteric lymph node (LN) cells, in PB memory and effector CD4 T cells and in NK cells. Frequencies of SIV-gag specific CD107a+IFNγ+ CD8 increased 3.8 fold in PB and 1.8 fold in LN. In addition, PB CD27+ memory B cells were 2 fold higher and serum SIV antibodies increased significantly after IL-21 administration. No changes were observed in markers of T cell activation, T cell proliferation or plasma virus load. Thus, administration of IL-21 to chronically SIV infected viremic animals was safe, well tolerated and could augment the cytotoxic potential of T cells and NK cells, promote B cell differentiation with increases in SIV antibody titers without discernable increase in cellular activation. Further studies are warranted to elucidate the effects and potential benefit of IL-21 administration in the context of SIV/HIV infection and in HIV/SIV vaccine design.
Interleukin-21; T cells; B cells; Natural Killer cells; Rhesus macaques; SIV
Mechanisms underlying failure of novel 2009 H1N1 influenza vaccine-induced Ab responses in HIV-infected persons are poorly understood. This study prospectively evaluated 16 HIV-infected patients on combination antiretroviral therapy and eight healthy controls (HC) who received a single 15 μg dose of nonadjuvanted novel 2009 H1N1 influenza vaccine during the 2009 H1N1 epidemic. Peripheral blood was collected at baseline (T0) and at 7 d (T1) and 28 d (T2) postvaccination for evaluation of immune responses. Prevaccination hemagglutination inhibition Ab titer was <1:20 in all except one study participant. At T2, all HC and 8 out of 16 patients (50%) developed a vaccine-induced Ab titer of ≥1:40. Vaccine responder (R) and vaccine nonresponder patients were comparable at T0 in age, CD4 counts, virus load, and B cell immunophenotypic characteristics. At T2, HC and R patients developed an expansion of phenotypic and functional memory B cells and ex vivo H1N1-stimulated IgG Ab-secreting cells in an ELISPOT assay. The memory B cell response was preceded by a significant expansion of plasmablasts and spontaneous H1N1-specific Ab-secreting cells at T1. At T2, HC and R patients also exhibited significant increases in serum IL-21 levels and in the frequency and mean fluorescence intensity of IL-21R–expressing B cells, which correlated with serum H1N1 Ab titers. Vaccine nonresponder patients failed to develop the above-described vaccine-induced immunologic responses. The novel association of novel 2009 H1N1 vaccine-induced Ab responses with IL-21/IL-21R upregulation and with development of memory B cells and plasmablasts has implications for future research in vaccine design.
Chronic HIV-1 infection is associated with excessive immune activation as well as immune exhaustion. We investigated the relationship of these two phenotypes and frequency of regulatory T cells (Tregs) in controlled and uncontrolled chronic HIV-1 infection.
Immune exhaustion marker PD-1, its ligand PD-L1, CD4+CD25brightFoxP3+ Tregs, HLA-DR and CD38 coexpression as activation markers were investigated in peripheral blood lymphocytes of 44 HIV-1 infected patients and 11 HIV-1 uninfected controls by multi-color flow cytometry.
Activated and PD-1 expressing T cells were increased and Tregs were decreased in HIV-1 infected patients as compared to controls, and alterations were greatest in viremic patients. The proportion of activated CD8+ T cells exceeded activated CD4+ T cells. Tregs had an inverse correlation with activated T cells and PD-1 expressing T cells. PD-L1 was highly expressed on monocytes and to a lesser extent on T lymphocytes of patients. These abnormalities partially reversed with virologic control following potent antiretroviral therapy (ART).
Immune exhaustion is a component of aberrant immune activation in chronic HIV-1 infection and is associated with loss of Tregs and ongoing virus replication. These defects are corrected partially with effective virologic control by potent ART.
HIV-1; ART; immune exhaustion; immune activation; CD8+ T cells
Perturbations in the T-cell receptor (TCR) Vβ repertoire were assessed in the CD4 and CD8 T lymphocytes of human immunodeficiency virus (HIV)-infected children who were receiving therapy during the chronic phase of infection by flow cytometry (FC) and PCR analysis. By FC, representation of 21 TCR Vβ subfamilies was assessed for an increased or decreased percentage in CD4 and CD8 T cells, and by PCR, 22 TCR Vβ subfamilies of CD4 and CD8 T cells were analyzed by CDR3 spectratyping for perturbations and reduction in the number of peaks, loss of Gaussian distribution, or clonal dominance. The majority of the TCR Vβ subfamilies were examined by both methods and assessed for deviation from the norm by comparison with cord blood samples. The CD8-T-lymphocyte population exhibited more perturbations than the CD4 subset, and clonal dominance was present exclusively in CD8 T cells. Of the 55 total CD8-TCR Vβ families classified with clonal dominance by CDR3 spectratyping, only 18 of these exhibited increased expression by FC. Patients with high numbers of CD8-TCR Vβ families with decreased percentages had reduced percentages of total CD4 T cells. Increases in the number of CD4-TCR Vβ families with increased percentages showed a positive correlation with skewing. Overall, changes from normal were often discordant between the two methods. This study suggests that the assessment of HIV-induced alterations in TCR Vβ families at cellular and molecular levels yields different information and that our understanding of the immune response to HIV is still evolving.
Induction of antigen-specific and non-specific (polyclonal) humoral immune responses in vitro was investigated in peripheral blood mononuclear cells of aged (65-85 yr) and young (20-30 yr) volunteers. In vitro immunization of lymphocytes with antigen (sheep erythrocytes) was performed in a recently described microculture system, and anti-sheep erythrocyte plaque forming cells were quantitated in a direct hemolytic plaque assay. Immunoglobulin secreting cells, induced polyclonally with pokeweed mitogen, were quantitated in a reverse hemolytic plaque assay. Significant depressions of antigen-specific as well as polyclonal responses were noted in relation to advancing age. Antigen-specific responses were more frequently depressed than polyclonal responses. T cell mitogen concanavalin A (Con A) was used to amplify functions of autologous immunoregulatory T cells. Addition of 10 microgram/ml Con A to lymphocytes of young donors at culture initiation resulted in activation of suppressor cells and abrogated antigen-specific responses. Delayed addition of Con A, on the other hand, enhanced responses, presumably because of activation of helper T cells. Similar manipulations of lymphocyte cultures from aged donors showed failure of Con A to suppress antigen-specific responses in approximately half of the responders. In many nonresponders, responses within normal range were elicited by the delayed addition of Con A to their lymphocyte cultures. Deviations beyond the range of expected responses were noted in 32.5% of the co-cultures between pokeweed mitogen stimulated young and aged cells. Our findings suggest that age-related deficiencies of B cell function are frequently associated with dysfunction of immunoregulatory T cells and are only occasionally due to intrinsic defects of B cells.
Pokeweed mitogen-induced B lymphocyte differentiation in vitro into antibody secreting plaque-forming cells (PFC) was investigated in nine patients with severe combined immunodeficiency having variable proportions of circulating B lymphocytes. When cultured by themselves, the peripheral blood mononuclear cells did not respond to stimulation with pokeweed mitogen in any patient. In the presence of irradiated allogeneic T cells as helpers, however, PFC responses were elicited in lymphocyte cultures from peripheral blood and/or bone marrow in some patients. In one of these patients, results of allogeneic co-culture experiments were suggestive of genetically restricted suppressor cells. In a single patient with deficiency of the enzyme adenosine deaminase, PFC were generated in bone marrow lymphocyte cultures only when they were supplemented with exogenous adenosine deaminase and allogeneic helper cells. A parallel study of T lymphocyte differentiation in vitro performed in fractionated bone marrow cells was suggestive of arrested differentiation at different steps along the differentiation pathway. In two patients with evidence of functional B cell precursors, deficiencies of helper T cell function could be attributed to differentiation defects at the level of the stem cells in one and the thymus in the other. The findings reported here further substantiate the heterogeneity of the severe combined immunodeficiency disease syndromes.
A study of T-lymphocyte differentiation was made on fractionated bone marrow cells from normal volunteers and from 11 patients with severe combined immunodeficiency (SCID) using normal thymic epithelial monolayers and their culture supernates as inducing agents. Normal marrow cells could regularly be induced to bear the human T-lymphocyte antigen (HTLA), to form rosettes with sheep erythrocytes (E rosettes), and to respond to the mitogen concanavalin A (Con A) after coculture with the thymic epithelial monolayers or their culture supernates. In contrast, studies of T-cell differentiation on the marrow cells of patients with SCID revealed varying defects, ranging from a complete "absence" of definable T-cell precursors to partial differentiation resulting in acquisition of one (HTLA) or two (HTLA and E rosettes) markers for T lymphocytes. Only in one patient was there induction of all three T-cell markers, namely, HTLA, E rosettes, and responsiveness to Con A. These observations indicate that SCID is a heterogeneous disorder in which defects of differentiation can occur at one or more multiple sites of differentiation leading the the clinical expression of T- and B-cell dysfunction. Further, our studies indicate that in T-cell differentiation, HTLA probably appears before the capacity to form E-rosettes, and development of the latter capacity is followed by a state of responsiveness to mitogens. A scheme of normal differentiation along with the defects of precursor T cells seen in SCID is presented.
Background. Immune reconstitution inflammatory syndrome (IRIS) reflects an aberrant immune response that can develop in human immunodeficiency virus–infected patients initiating antiretroviral therapy (ART). Its pathogenesis remains unclear.
Methods. We performed a nested case-control study using specimens from ACTG A5164. We compared plasma biomarkers and T-cell subsets in 19 IRIS and 39 control participants at study entry, ART initiation, and IRIS and used conditional logistic regression to develop IRIS predictive models. We evaluated the effect of corticosteroids on biomarker levels.
Results. Eleven and 8 participants developed paradoxical and unmasking IRIS, respectively, none while still receiving corticosteroids. Compared to controls, cases displayed elevations at study entry in interleukin (IL) 8, T-helper (Th) 1 (IL-2, interferon [IFN]-γ, tumor necrosis factor [TNF]) and Th17 (IL-17) cytokine levels that persisted through ART initiation and IRIS. In logistic regression, baseline higher IFN-γ and TNF were strong predictors of IRIS. Participants who received corticosteroids and later developed IRIS had marked increases in IL-6, IL-8, and IFN-γ at the time of IRIS. T-cell activation markers did not differ in cases and controls prior to ART but were increased in cases at the time of IRIS.
Conclusions. Increased IL-8, Th1, and Th17 cytokine levels in IRIS patients precede ART initiation and could help identify patient populations at higher risk for IRIS.
Background. The CD14 gene has an important role in the detection of inflammatory provoking pathogens and in the ensuing signaling of the innate immune response. We assessed the role of CD14 C-159T, G-1359T in the expression of asthma, croup, and allergy in Canadian school children of ages 6 to 14 years. Methods. Children attending schools in a rural community participated in a cross-sectional survey of respiratory health. Following consent, we conducted clinical assessments to collect buccal swabs for genotyping and perform skin prick testing (SPT) to determine atopic status. Genotyping and SPT results were available for 533 and 499 children, respectively. Separate multivariable analyses that included both polymorphisms were conducted for each phenotype. Results. The prevalence of asthma, allergy, and croup was 18.6%, 22.4%, and 6.6%, respectively. Children with the T/T variant of CD14 G-1359T were more likely to have physician diagnosed asthma (26.8%). Children with C/C variant of CD14 C-159T had a significantly lower prevalence of croup (2.6%). Haplotype analyses of the two CD14 polymorphisms showed that individuals with the T|T haplotype combination were significantly more likely to have asthma (P = 0.014). Conclusions. In this study, CD14 variants are important for the expression of croup and asthma but not atopy.
Community integration is recognized as a crucial component of recovery from serious mental illness. Although the construct of community integration can be measured with structured instruments, little is known about the subjective and experiential meaning of community and community involvement for persons with serious mental illness.
In 2010, 30 individuals with serious mental illness treated in two public mental health clinics completed semistructured interviews that elicited the places and people that they associate with the experience of community and the larger meaning of community in their lives.
Participants described four experiences as integral to their concepts of community: receiving help, minimizing risk, avoiding stigma, and giving back. Participants looked for communities that provide reliable support, and they described the need to manage community contact in order to protect themselves and others from their symptoms and from discrimination. Most participants experienced communities centered on mental health treatment or mentally ill peers as providing opportunities for positive engagement.
The experience of having a serious mental illness shapes preferences for and perceptions of community in pervasive ways. Participants describe community involvement not as a means to move away from illness experiences and identities but as a process that is substantially influenced by them. Mental health communities may help individuals with serious mental illness to both manage their illness and recognize and enjoy a sense of community. The findings indicate the need for further research on the relationship between community integration and outcome in serious mental illness.
Aging and HIV infection are independently associated with excessive immune activation and impaired immune responses to vaccines, but their relationships have not been examined.
For selecting an aging population we enrolled 28 post-menopausal women including 12 healthy volunteers and 16 HIV-infected women on antiretroviral treatment with <100 HIV RNA copies/ml. Antibody titers to trivalent influenza vaccination given during the 2011-2012 season were determined before and 4 weeks after vaccination.
Seroprotective influenza antibody titers (≥1:40) were observed in 31% HIV+ and 58% HIV-uninfected women pre-vaccination. Following vaccination, magnitude of antibody responses and frequency of seroprotection were lower in HIV+ (75%) than in HIV– (91%) women. Plasma IL-21, the signature cytokine of T follicular helper cells (Tfh), and CD4 T cell IL-21R were upregulated with seroconversion (≥4 fold increase in antibody titer). Post-vaccine antibody responses were inversely correlated with pre-vaccination plasma TNFα levels and with activated CD4 T cells, including activated peripheral (p)Tfh. Plasma TNFα levels were correlated with activated pTfh cells (r=0.48, p=0.02), and inversely with the post-vaccination levels of plasma IL-21 (r=-0.53, p=0.02). In vitro TNFα blockade improved the ability of CD4 T cells to produce IL-21 and of B cells to secrete immunoglobulins, and addition of exogenous IL-21 to cell cultures enhanced B cell function. Higher frequencies of activated and exhausted CD8 T and B cells were noted in HIV+ women, but these markers did not show a correlation with antibody responses.
In aging HIV-infected and uninfected women, activated CD4 and pTfh cells may compromise influenza vaccine-induced antibody response, for which a mechanism of TNFα-mediated impairment of pTfh-induced IL-21 secretion is postulated. Interventions aimed at reducing chronic inflammation and immune activation in aging, HIV-infected patients may improve their response to vaccines.
There is limited knowledge concerning chronic bronchitis (CB) in Canadian Aboriginal peoples.
To determine the prevalence (crude and adjusted) of CB and its associated risk factors in Canadian Aboriginal children and youth six to 14 years of age.
Data from the cross-sectional Aboriginal Peoples Survey were analyzed in the present study. Logistic regression analysis was used to determine risk factors influencing the prevalence of CB among Aboriginal children and youth. The balanced repeated replication method was used to compute standard errors of regression coefficients to account for clustering inherent in the study design. The outcome of interest was based on the question: “Have you been told by a doctor, nurse or other health professional that you have chronic bronchitis?” Demographics, environment and population characteristics (predisposing and enabling resources) were tested for an association with CB.
The prevalence of CB was 3.1% for boys and 2.8% for girls. Other significant risk factors of CB were age (OR 1.38 [95% CI 1.24 to 1.52] for 12 to 14 year olds versus six to eight year olds), income (OR 2.28 [95% CI 2.02 to 2.59] for income category <$25,000/year versus ≥$85,000/year), allergies (OR 1.96 [95% CI 1.78 to 2.16] for having allergies versus no allergies), asthma (OR 7.61 [ 95% CI 6.91 to 8.37] for having asthma versus no asthma) and location of residence (rural/urban and geographical location). A significant two-way interaction between sex and body mass index indicated that the relationship between the prevalence of CB and body mass index was modified by sex.
The prevalence of CB was related to well-known risk factors among adults, including older age and lower annual income.
Aboriginal children and youth; BRR; Chronic bronchitis; Complex survey
Dopamine agonist therapy and deep brain stimulation (DBS) of the subthalamic nucleus (STN) are antiparkinsonian treatments that act on a different part of the basal ganglia-thalamocortical motor circuitry, yet produce similar symptomatic improvements.
The purpose of this study was to identify common and unique brain network features of these standard treatments.
We analyzed images produced by H215O positron emission tomography (PET) of patients with Parkinson’s disease (PD) at rest. Nine patients were scanned before and after injection of apomorphine, and eleven patients were scanned while bilateral stimulators were off and while they were on.
Both treatments produced common deactivations of the neocortical sensorimotor areas, including the supplementary motor area, precentral gyrus, and postcentral gyrus, and in subcortical structures, including the putamen and cerebellum. We observed concomitant activations of the superior parietal lobule and the midbrain in the region of the substantia nigra/STN. We also detected unique, treatment-specific changes with possible motor-related consequences in the basal ganglia, thalamus, neocortical sensorimotor cortex, and posterolateral cerebellum. Unique changes in non-motor regions may reflect treatment-specific effects on verbal fluency and limbic functions.
Many of the common effects of these treatments are consistent with the standard pathophysiological model of PD. However, the common effects in the cerebellum are not readily explained by the model. Consistent deactivation of the cerebellum is interesting in light of recent reports of synaptic pathways directly connecting the cerebellum and basal ganglia, and may warrant further consideration for incorporation into the model.
Parkinson’s disease; deep brain stimulation; apomorphine; positron emission tomography
Surgical resection of the primary tumour in patients with advanced colorectal cancer (crc) remains controversial. This review compares survival in patients with advanced crc who underwent surgical resection of the primary tumour with that in patients not undergoing resection, and determines rates of post-operative mortality and nonfatal complications, the primary tumour complication rate, the non-resection surgical procedures rate, and quality of life (qol).
Reports in the central, medline, and embase databases were searched for relevant studies, which were selected using pre-specified eligibility criteria. The search was also restricted to publication dates from 1980 onward, the English language, and studies involving human subjects. Screening, evaluation of relevant articles, and data abstraction were performed in duplicate, and agreement between the abstractors was assessed. Articles that met the inclusion criteria were assessed for quality using the Newcastle–Ottawa Scale. Data were collected and synthesized per protocol.
From among the 3379 reports located, fifteen retrospective observational studies were selected. Of the 12,416 patients in the selected studies, 8620 (69%) underwent surgery. Median survival was 15.2 months (range: 10–30.7 months) in the resection group and 11.4 months (range: 3–22 months) in the non-resection group. Hazard ratio for survival was 0.69 [95% confidence interval (ci): 0.61 to 0.79] favouring surgical resection. Mean rates of postoperative mortality and nonfatal complications were 4.9% (95% ci: 0% to 9.7%) and 25.9% (95%ci: 20.1% to 31.6%) respectively. The mean primary tumour complication rate was 29.7% (95% ci: 18.5% to 41.0%), and the non-resection surgical procedures rate in the non-resection group was 27.6% (95 ci: 15.4% to 39.9%). No study provided qol data.
Although this review supports primary tumour resection in advanced crc, the results have significant biases. Randomized trials are warranted to confirm the findings.
Primary tumour resection; stage iv colorectal cancer; palliative surgery; survival
Interleukin (IL)-21 is one of a group of cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15 whose receptor complexes share the common γ chain (γc). Secretion of IL-21 is restricted mainly to T follicular helper (TFH) CD4 T cell subset with contributions from Th17, Natural Killer (NK) T cells, but the effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. The role of IL-21 in sustaining and regulating T cell, B cell and NK cell responses during chronic viral infections has recently come into focus. This chapter reviews current knowledge about the biology of IL-21 in the context of HIV infection.
IL-21 and T cells; IL-21 and B cells; HIV and IL-21; immunomodulation by IL-21; IL-21 and immunity
Despite the notion that increases in functioning should be associated with increases in life satisfaction in schizophrenia, research has often found no association between the two. Dual change models of global and domain-specific life satisfaction and functioning were examined in 145 individuals with schizophrenia receiving community-based services over 12 months. Functioning and satisfaction were measured using the Role Functioning Scale and Satisfaction with Life Scale. Data were analyzed using latent growth curve modeling. Improvement in global life satisfaction was associated with improvement in overall functioning over time. Satisfaction with living situation also improved as independent functioning improved. Work satisfaction did not improve as work functioning improved. Although social functioning improved, satisfaction with social relationships did not. The link between overall functioning and global life satisfaction provides support for a recovery-based orientation to community based psychosocial rehabilitation services. When examining sub-domains, the link between outcomes and subjective experience suggests a more complex picture than previously found. These findings are crucial to interventions and programs aimed at improving functioning and the subjective experiences of consumers recovering from mental illness. Interventions that show improvements in functional outcomes can assume that they will show concurrent improvements in global life satisfaction as well and in satisfaction with independent living. Interventions geared toward improving social functioning will need to consider the complexity of social relationships and how they affect satisfaction associated with personal relationships. Interventions geared towards improving work functioning will need to consider how the quality and level of work affect satisfaction with employment.
Severe mental illness; Schizophrenia; Functioning; Life satisfaction
Continuous-time Markov processes are often used to model the complex natural phenomenon of sequence evolution. To make the process of sequence evolution tractable, simplifying assumptions are often made about the sequence properties and the underlying process. The validity of one such assumption, time-homogeneity, has never been explored. Violations of this assumption can be found by identifying non-embeddability. A process is non-embeddable if it can not be embedded in a continuous time-homogeneous Markov process. In this study, non-embeddability was demonstrated to exist when modelling sequence evolution with Markov models. Evidence of non-embeddability was found primarily at the third codon position, possibly resulting from changes in mutation rate over time. Outgroup edges and those with a deeper time depth were found to have an increased probability of the underlying process being non-embeddable. Overall, low levels of non-embeddability were detected when examining individual edges of triads across a diverse set of alignments. Subsequent phylogenetic reconstruction analyses demonstrated that non-embeddability could impact on the correct prediction of phylogenies, but at extremely low levels. Despite the existence of non-embeddability, there is minimal evidence of violations of the local time homogeneity assumption and consequently the impact is likely to be minor.
In pathogenic HIV and SIV infections of humans and rhesus macaques (RMs), preferential depletion of CD4+ Th17 cells correlates with mucosal immune dysfunction and disease progression. Interleukin (IL)-21 promotes differentiation of Th17 cells, long-term maintenance of functional CD8+ T cells, and differentiation of memory B cells and antibody-secreting plasma cells. We hypothesized that administration of IL-21 will improve mucosal function in the context of pathogenic HIV/SIV infections. To test this hypothesis, we infected 12 RMs with SIVmac239 and at day 14 post-infection treated six of them with rhesus rIL-21-IgFc. IL-21-treatment was safe and did not increase plasma viral load or systemic immune activation. Compared to untreated animals, IL-21-treated RMs showed (i) higher expression of perforin and granzyme B in total and SIV-specific CD8+ T cells and (ii) higher levels of intestinal Th17 cells. Remarkably, increased levels of Th17 cells were associated with reduced levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation in the chronic infection. In conclusion, IL-21-treatment in SIV-infected RMs improved mucosal immune function through enhanced preservation of Th17 cells. Further preclinical studies of IL-21 may be warranted to test its potential use during chronic infection in conjunction with antiretroviral therapy.
In the gastrointestinal tract, preferential depletion of CD4+ Th17 cells occurs during the early stage of pathogenic HIV/SIV infections and correlates with loss of mucosal integrity, microbial translocation, immune activation and disease progression. As such, therapeutic intervention aimed at preserving intestinal Th17 cells may be of critical importance. IL-21 plays an important role in promoting the differentiation and survival of Th17 cells, as well as in stimulating CD8+ T cell cytolytic function. Here, we treated SIV-infected rhesus macaques with IL-21-IgFc in the early stage of infection. Consistent with the main functions of IL-21, we found that IL-21 treated animals had higher expression of perforin and granzyme B in total and SIV-specific CD8+ T cells and higher frequencies of intestinal Th17 cells as compared to untreated controls. Remarkably, the increased proportions of Th17 cells during early infection was associated with significantly lower levels of intestinal T cell proliferation, microbial translocation and systemic activation/inflammation during chronic infection. Thus, our results suggest that IL-21 treatment in SIV-infected RMs is effective in preserving intestinal Th17 cells and results in an improvement of mucosal immune function. Further preclinical studies may be warranted to test IL-21 during chronic infection and in conjunction with antiretroviral therapy.