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author:("pahaa, S.")
1.  Management of gastric variceal bleeding: Role of endoscopy and endoscopic ultrasound 
World Journal of Hepatology  2014;6(3):130-136.
Gastric varices (GVs) are notorious to bleed massively and often difficult to manage with conventional techniques. This mini-review addresses endoscopic management principles for gastric variceal bleeding, including limitations of ligation and sclerotherapy and merits of endoscopic variceal obliteration. The article also discusses how emerging use of endoscopic ultrasound provides optimism of better diagnosis, improved classification, innovative management strategies and confirmatory tool for eradication of GVs.
doi:10.4254/wjh.v6.i3.130
PMCID: PMC3959113  PMID: 24672642
Gastric; Varices; Endoscopy; Ligation; Sclerotherapy; Management; Transjugular intrahepatic portosystemic shunt; Endoscopic ultrasound; Balloon-occluded retrograde transvenous obliteration; Endoscopic variceal obliteration
2.  Defining the Pros and Cons of Open, Conventional Laparoscopy, and Robot-Assisted Pyeloplasty in a Developing Nation 
Advances in Urology  2014;2014:850156.
Introduction. Congenital pelviureteric junction obstruction (PUJO) is one of the most common causes of hydronephrosis. Historically, open dismembered pyeloplasty has been considered the gold standard intervention for correcting PUJO. The aim of this study was to compare the surgical and functional outcomes of three different approaches, namely, open, conventional laparoscopy, and robotic pyeloplasty. Material and Methods. 60 patients underwent minimally invasive pyeloplasty (30 conventional laparoscopies and 30 robotics) for congenital PUJO at a tertiary health center in India. Demographic, perioperative, and postoperative data were prospectively collected and analyzed. The data of these patients were retrospectively compared with another cohort of 30 patients who had undergone open pyeloplasty. Results. There was significant difference in operative time, time to drain removal, hospital stay, pain score, and complications rate between open and minimally invasive pyeloplasty (P < 0.05). SFI was considerably lesser in robotic as compared to conventional laparoscopy. The success rate in OP, CLP, and RP was 93.33, 96.67, and 96.67%. Conclusion. Robotic pyeloplasty is safe, effective, and feasible. It is associated with significantly lesser operative time, lesser blood loss, less pain, shorter hospital stay, and fewer complications. It is also associated with considerably lesser surgeon fatigue as compared to conventional laparoscopy pyeloplasty.
doi:10.1155/2014/850156
PMCID: PMC3929287  PMID: 24624138
3.  A Comparative Study of Dorsal Buccal Mucosa Graft Substitution Urethroplasty by Dorsal Urethrotomy Approach versus Ventral Sagittal Urethrotomy Approach 
Advances in Urology  2013;2013:124836.
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.
doi:10.1155/2013/124836
PMCID: PMC3806324  PMID: 24194754
4.  Isolated Renal Mucormycosis in a Healthy Immunocompetent Patient: Atypical Presentation and Course 
Korean Journal of Urology  2013;54(9):641-643.
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.
doi:10.4111/kju.2013.54.9.641
PMCID: PMC3773597  PMID: 24044101
Amphotericin B; Immunocompetence; Mucormycosis; Urinary tract infection
5.  Activity enhances dopaminergic long-duration response in Parkinson disease 
Jung Kang, Un | Auinger, Peggy | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Fahn, Stanley | Oakes, David | Shoulson, Ira | Kieburtz, Karl | Rudolph, Alice | Marek, Kenneth | Seibyl, John | Lang, Anthony | Olanow, C. Warren | Tanner, Caroline | Schifitto, Giovanni | Zhao, Hongwei | Reyes, Lydia | Shinaman, Aileen | Comella, Cynthia L. | Goetz, Christopher | Blasucci, Lucia M. | Samanta, Johan | Stacy, Mark | Williamson, Kelli | Harrigan, Mary | Greene, Paul | Ford, Blair | Moskowitz, Carol | Truong, Daniel D. | Pathak, Mayank | Jankovic, Joseph | Ondo, William | Atassi, Farah | Hunter, Christine | Jacques, Carol | Friedman, Joseph H. | Lannon, Margaret | Russell, David S. | Jennings, Danna | Fussell, Barbara | Standaert, David | Schwarzschild, Michael A. | Growdon, John H. | Tennis, Marsha | Gauthier, Serge | Panisset, Michel | Hall, Jean | Gancher, Stephen | Hammerstad, John P. | Stone, Claudia | Alexander-Brown, Barbara | Factor, Stewart A. | Molho, Eric | Brown, Diane | Evans, Sharon | Clark, Jeffrey | Manyam, Bala | Simpson, Patricia | Wulbrecht, Brian | Whetteckey, Jacqueline | Martin, Wayne | Roberts, Ted | King, Pamela | Hauser, Robert | Zesiewicz, Theresa | Gauger, Lisa | Trugman, Joel | Wooten, G. Frederick | Rost-Ruffner, Elke | Perlmutter, Joel | Racette, Brad A. | Suchowersky, Oksana | Ranawaya, Ranjit | Wood, Susan | Pantella, Carol | Kurlan, Roger | Richard, Irene | Pearson, Nancy | Caviness, John N. | Adler, Charles | Lind, Marlene | Simuni, Tanya | Siderowf, Andrew | Colcher, Amy | Lloyd, Mary | Weiner, William | Shulman, Lisa | Koller, William | Lyons, Kelly | Feldman, Robert G. | Saint-Hilaire, Marie H. | Ellias, Samuel | Thomas, Cathi-Ann | Juncos, Jorge | Watts, Ray | Partlow, Anna | Tetrud, James | Togasaki, Daniel M. | Stewart, Tracy | Mark, Margery H. | Sage, Jacob I. | Caputo, Debbie | Gould, Harry | Rao, Jayaraman | McKendrick, Ann | Brin, Mitchell | Danisi, Fabio | Benabou, Reina | Hubble, Jean | Paulson, George W. | Reider, Carson | Birnbaum, Alex | Miyasaki, Janis | Johnston, Lisa | So, Julie | Pahwa, Rajesh | Dubinsky, Richard M. | Wszolek, Zbigniew | Uitti, Ryan | Turk, Margaret | Tuite, Paul | Rottenberg, David | Hansen, Joy | Ramos, Serrano | Waters, Cheryl | Lew, Mark | Welsh, Mickie | Kawai, Connie | O'Brien, Christopher | Kumar, Rajeev | Seeberger, Lauren | Judd, Deborah | Barclay, C. Lynn | Grimes, David A. | Sutherland, Laura | Dawson, Ted | Reich, Stephen | Dunlop, Rebecca | Albin, Roger | Frey, Kirk | Wernette, Kristine | Mendis, Tilak
Neurology  2012;78(15):1146-1149.
Objective:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1212/WNL.0b013e31824f8056
PMCID: PMC3466780  PMID: 22459675
6.  Long-Term Engraftment of Human Natural T Regulatory Cells in NOD/SCID IL2rγcnull Mice by Expression of Human IL-2 
PLoS ONE  2012;7(12):e51832.
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.
doi:10.1371/journal.pone.0051832
PMCID: PMC3525660  PMID: 23272176
7.  Innate immune defects correlate with failure of antibody responses to H1N1/09 vaccine in HIV-infected patients 
Background
Mechanisms underlying failure of influenza vaccine-induced antibody responses in HIV-infected persons are poorly understood.
Objective
To investigate innate immune factors regulating B cell function in HIV infected persons and to correlate them with serologic responses to H1N1/09 vaccine.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2011.05.033
PMCID: PMC3229646  PMID: 21752440
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
8.  Interleukin-21 administration to Rhesus macaques chronically infected with Simian Immunodeficiency Virus increases cytotoxic effector molecules in T cells and NK cells and enhances B cell function without increasing immune activation or viral replication 
Vaccine  2011;29(49):9229-9238.
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.
doi:10.1016/j.vaccine.2011.09.118
PMCID: PMC3260006  PMID: 21996099
Interleukin-21; T cells; B cells; Natural Killer cells; Rhesus macaques; SIV
10.  Upregulation of IL-21 Receptor on B Cells and IL-21 Secretion Distinguishes Novel 2009 H1N1 Vaccine Responders from Nonresponders among HIV-Infected Persons on Combination Antiretroviral Therapy 
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.
doi:10.4049/jimmunol.1100264
PMCID: PMC3170914  PMID: 21531891
11.  Immune Exhaustion Occurs Concomitantly with Immune Activation and Decrease in Regulatory T Cells in Viremic Chronically HIV-1 Infected Patients 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1097/QAI.0b013e3181e0c7d0
PMCID: PMC3095513  PMID: 20463584
HIV-1; ART; immune exhaustion; immune activation; CD8+ T cells
12.  Alterations in T-Cell Receptor Vβ Repertoire of CD4 and CD8 T Lymphocytes in Human Immunodeficiency Virus-Infected Children 
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.
doi:10.1128/CDLI.10.1.53-58.2003
PMCID: PMC145262  PMID: 12522039
13.  Decreased in vitro humoral immune responses in aged humans. 
Journal of Clinical Investigation  1981;67(4):1094-1102.
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.
PMCID: PMC370669  PMID: 7009651
14.  Heterogeneity of b lymphocyte differentiation in severe combined immunodeficiency disease. 
Journal of Clinical Investigation  1980;66(3):543-550.
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.
PMCID: PMC371683  PMID: 6447166
15.  T-lymphocyte differentiation in vitro in severe combined immunodeficiency. Defects of stem cells. 
Journal of Clinical Investigation  1979;64(6):1632-1641.
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.
PMCID: PMC371317  PMID: 315416
16.  Excessive daytime sleepiness among rural residents in Saskatchewan 
Obstructive sleep apnea and its sequelae are emerging public health issues in North America, and symptoms are often under-recognized or under-reported. Although several patient factors have been identified, limited data regarding the prevalence of and predictors for excessive daytime sleepiness in rural or remote populations area available. Accordingly, this study used Epworth Sleepiness Scale scores to evaluate daytime sleepiness in a large rural population participating in the Saskatchewan Rural Health Study.
BACKGROUND:
Obstructive sleep apnea (OSA) is a common diagnosis in clinical practice. Excessive daytime sleepiness may be a warning for possible OSA.
OBJECTIVES:
To assess the prevalence of excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) in a rural community population; potential risk factors for OSA were also assessed.
METHODS:
In 2010, a baseline respiratory health questionnaire within the Saskatchewan Rural Health Study was mailed to 11,982 households in Saskatchewan. A total of 7597 adults within the 4624 (42%) respondent households completed the ESS questionnaire. Participants were categorized according to normal or high (>10) ESS scores. Data obtained included respiratory symptoms, doctor-diagnosed sleep apnea, snoring, hypertension, smoking and demographics. Body mass index was calculated. Multivariable logistic regression analysis examined associations between high ESS scores and possible risk factors. Generalized estimating equations accounted for the two-tiered sampling procedure of the study design.
RESULTS:
The mean age of respondents was 55.0 years and 49.2% were male. The prevalence of ESS>10 and ‘doctor diagnosed’ OSA were 15.9% and 6.0%, respectively. Approximately 23% of respondents reported loud snoring and 30% had a body mass index >30 kg/m2. Of those with ‘doctor-diagnosed’ OSA, 37.7% reported ESS>10 (P<0.0001) and 47.7% reported loud snoring (P<0.0001). Risk of having an ESS>10 score increased with age, male sex, obesity, lower socioeconomic status, marriage, loud snoring and doctor-diagnosed sinus trouble.
CONCLUSIONS:
High levels of excessive daytime sleepiness in this particular rural population are common and men >55 years of age are at highest risk. Examination of reasons for residual sleepiness and snoring in persons with and without sleep apnea is warranted.
PMCID: PMC4173890  PMID: 24791255
Epworth Sleepiness Scale; Farm; Nonfarm; Obesity; Rural; Sleep apnea; Snoring; Socioeconomic
17.  CD4/CD8 T-cell ratio predicts HIV infection in infants: The National Heart, Lung, and Blood Institute P2C2 Study 
Background
In resource-poor regions of the world, HIV virologic testing is not available.
Objective
We sought to evaluate the diagnostic usefulness of the CD4/CD8 T-cell ratio in predicting HIV infection in infants.
Methods
Data from the 3- and 9-month visits for non–breastfed infants born to HIV-infected mothers enrolled (1990–1994) in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study (mother-to-child transmission of HIV, 17%) were analyzed. Data from the 3-month visit for infants enrolled (1985–1996) in the Perinatal AIDS Collaborative Transmission Study (mother-to-child transmission of HIV, 18%) were used for validation.
Results
At 3 months of age, data were available on 79 HIV-infected and 409 uninfected non–breast-fed infants in the Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study. The area under the curve (AUC) of the receiver operating characteristic curve at 3 months was higher for the CD4/CD8 ratio compared with the CD4+ T-cell count (AUC, 0.83 and 0.75; P = .03). The mean CD4/CD8 ratio at the 3-month visit was 1.7 for HIV-infected infants and 3.0 for uninfected infants. A CD4/CD8 ratio of 2.4 at 3 months of age was almost 2.5 times more likely to occur in an HIV-infected infant compared with an uninfected infant (test sensitivity, 81%; posttest probability of HIV, 33%). Model performance in the Centers for Disease Control and Prevention Perinatal AIDS Collaborative Transmission Study validation test (224 HIV-infected and 1015 uninfected 3-month-old infants) was equally good (AUC, 0.78 for CD4/CD8 ratio).
Conclusion
The CD4/CD8 T-cell ratio is a more sensitive predictor of HIV infection in infants than the CD4+ T-cell count.
Clinical implications
The CD4/CD8 T-cell ratio can be used with caution to predict HIV infection in children.
doi:10.1016/j.jaci.2007.08.037
PMCID: PMC4271194  PMID: 17920669
CD4/CD8 T-cell ratio; mother-to-child transmission of HIV; HIV infection
18.  Defective dendritic cell response to toll like receptor 7/8 agonists in perinatally HIV infected children 
Pathogens and disease  2013;69(3):10.1111/2049-632X.12067.
Understanding the defects in innate immunity associated with perinatal HIV infection is prerequisite for the effective antiretroviral treatment. We therefore compared the innate immune response (Dendritic cell (DC) phenotype and function in peripheral blood by flow cytometry at baseline and 12 months in HIV infected children in order to determine the defect associated with perinatal HIV infection. As compared to controls patients had decreased numbers of total DC including plasmacytoid (p)DC and myeloid (m)DC and impaired function based on induction of maturation markers (CD83, CD80, CCR7) and cytokines TNF-α and IFN-α (exclusive to pDC) upon stimulation with TLR7/8 agonist Resiquimod. These abnormalities were evident in all three CD4 immune categories and persisted over 12 months; pDC function worsened in HIV+ children without treatment and improved slightly in those on HAART. In conclusion, a majority of perinatally HIV-infected older children without HAART remain clinically stable in the short term, but have demonstrable immunologic abnormalities indicative of defects in the innate immune system. Children initiated on HAART showed improvement in CD4 counts but didn’t show improvement in DC function over the short term.
doi:10.1111/2049-632X.12067
PMCID: PMC3838506  PMID: 23873734
Dendritic cells; innate immunity; pediatric HIV
19.  Combination Antiretroviral Therapy With Raltegravir Leads to Rapid Immunologic Reconstitution in Treatment-Naive Patients With Chronic HIV Infection 
The Journal of Infectious Diseases  2013;208(10):1613-1623.
Background. In treatment-naive, human immunodeficiency virus (HIV)–infected persons, combination antiretroviral therapy (cART) incorporating raltegravir (RAL) is highly effective for virologic suppression, but characteristics of immunologic recovery have not been described.
Methods. We performed a 48-week substudy of 15 patients, median age 40 years, within a phase 2 randomized trial of RAL-cART in treatment-naive patients with chronic HIV infection.
Results. Plasma viral load decreased from 5.2 ± 5.3 log10 HIV RNA copies/mL to 2.2 ± 2.4 log10 copies/mL at week 4, reaching <50 copies/mL at week 8 in 13 of 15 patients. Total CD4 T cells increased at week 4, as did central memory CD4 T cells in association with reduction of the immune activation markers HLA-DR and CD38 and immune exhaustion marker PD1 in CD4 and CD8 T cells. Naive CD4 T cells increased at week 24 with appearance of HIV gag–specific interleukin 2, interferon-γ, and CD107a responses in CD4 and CD8 T cells at week 48. Plasma lipopolysaccharide and soluble CD14 decreased, but at week 48 were elevated as compared to healthy volunteers. Altogether, the week 48 immune profile was more favorable in patients taking RAL-cART than in patients treated with non–RAL-cART.
Conclusions. RAL in first-line treatment regimens results in rapid immune reconstitution with residual low-level microbial translocation.
doi:10.1093/infdis/jit387
PMCID: PMC3805240  PMID: 23922374
HIV; raltegravir; immune reconstitution; immune activation; immune exhaustion; RAL-cART
20.  CD4 Depletion in SIV-Infected Macaques Results in Macrophage and Microglia Infection with Rapid Turnover of Infected Cells 
PLoS Pathogens  2014;10(10):e1004467.
In rhesus macaques (RMs), experimental depletion of CD4+ T-cells prior to SIV infection results in higher viremia and emergence of CD4-independent SIV-envelopes. In this study we used the rhesus recombinant anti-CD4 antibody CD4R1 to deplete RM CD4+ T-cells prior to SIVmac251 infection and investigate the sources of the increased viral burden and the lifespan of productively infected cells. CD4-depleted animals showed (i) set-point viral load two-logs higher than controls; (ii) macrophages constituting 80% of all SIV vRNA+ cells in lymph node and mucosal tissues; (iii) substantial expansion of pro-inflammatory monocytes; (iv) aberrant activation and infection of microglial cells; and (v) lifespan of productively infected cells significantly longer in comparison to controls, but markedly shorter than previously estimated for macrophages. The net effect of CD4+ T-cell depletion is an inability to control SIV replication and a shift in the tropism of infected cells to macrophages, microglia, and, potentially, other CD4-low cells which all appear to have a shortened in vivo lifespan. We believe these findings have important implications for HIV eradication studies.
Author Summary
CD4+ T-cells are both mediators of antiviral immune response and critical targets for HIV replication. We have previously shown that experimental depletion of CD4+ T-cells prior to SIV infection in rhesus macaques results in higher viremia and the emergence of CD4-independent SIV-envelopes. The findings reported in this new study of CD4 depletion address key unanswered questions about the phenotype, location, and lifespan of the sources of the increased viral replication in the absence of CD4+ T-cells. Altogether, our new data indicate that depletion of CD4+ T-cells prior to SIV infection results in activation of monocyte and massive infection of tissue-resident macrophages, which appear to be the predominant population of productively infected cells. Furthermore, our analysis of the slope of viremia decline after initiation of antiretroviral therapy suggests that the lifespan of these virus targets is markedly shorter than those previously estimated for macrophages. In summary, in the context of CD4+ T-cell depletion macrophages can be highly infectable, exhibit rapid turnover, and short in vivo lifespan. These finding raises a suggestive hypothesis that eradication of HIV from this reservoir could be enhanced by therapeutics able to modulate monocyte/macrophage turnover.
doi:10.1371/journal.ppat.1004467
PMCID: PMC4214815  PMID: 25356757
21.  The Role of Resting State Networks in Focal Neocortical Seizures 
PLoS ONE  2014;9(9):e107401.
Objective
The role of resting state functional networks in epilepsy is incompletely understood. While some pathologic diagnoses have been shown to have maintained but altered resting state connectivity, others have implicated resting state connectivity in disease progression. However little is known about how these resting state networks influence the behavior of a focal neocortical seizure.
Methods
Using data taken from invasively monitored patients with intractable focal neocortical epilepsy, we evaluated network connectivity (as determined by oscillatory covariance of the slow cortical potential (<0.5 Hz)) as it relates to neocortical seizure foci both in the interictal and ictal states.
Results
Similar to what has been shown in the past for sleep and anesthesia, electophysiologic resting state networks that are defined by this slow cortical potential covariance maintain their topographic correlation structure throughout an ictal event. Moreover, in the context of focal epilepsy in which the seizure has a specific site of onset, seizure propagation is not chaotic or random. Rather, the seizure (reflected by an elevation of high frequency power) preferentially propagates along the network that contains the seizure onset zone.
Significance
Taken together, these findings further undergird the fundamental role of resting state networks, provide novel insights into the network-influenced behavior of seizures, and potentially identify additional targets for surgical disconnection including informing the location for the completion of multiple subpial transections (MSPTs).
doi:10.1371/journal.pone.0107401
PMCID: PMC4172478  PMID: 25247680
22.  Reliability of a new scale for essential tremor 
Objective
To determine the reliability of a new scale for the clinical assessment of essential tremor.
Background
The Essential Tremor Rating Assessment Scale contains nine performance items that rate action tremor in the head, face, voice, limbs and trunk 0–4 in half-point intervals. Head and limb tremor ratings are defined by specific amplitude ranges in centimeters.
Design/Methods
Videos of 44 patients and 6 controls were rated by 10 specialists on two occasions, 1–2 months apart. Inter- and intra-rater reliabilities were assessed with a two-way random effects intraclass correlation, using an absolute agreement definition.
Results
The inter- and intra-rater intraclass correlations for head and upper limb tremor ranged from 0.86 to 0.96, and the intraclass correlations for the total score were 0.94 and 0.96. The intraclass correlations for voice, face, trunk and leg were less robust.
Conclusions
This scale is an exceptionally reliable tool for the clinical assessment of essential tremor.
doi:10.1002/mds.25162
PMCID: PMC4157921  PMID: 23032792
essential tremor; rating scale; reliability
23.  Cigarette smoking and risk of Hodgkin lymphoma and its subtypes: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph) 
Annals of Oncology  2013;24(9):2245-2255.
Summary
Background
The etiology of Hodgkin lymphoma (HL) remains incompletely characterized. Studies of the association between smoking and HL have yielded ambiguous results, possibly due to differences between HL subtypes.
Patients and methods
Through the InterLymph Consortium, 12 case–control studies regarding cigarette smoking and HL were identified. Pooled analyses on the association between smoking and HL stratified by tumor histology and Epstein–Barr virus (EBV) status were conducted using random effects models adjusted for confounders. Analyses included 3335 HL cases and 14 278 controls.
Results
Overall, 54.5% of cases and 57.4% of controls were ever cigarette smokers. Compared with never smokers, ever smokers had an odds ratio (OR) of HL of 1.10 [95% confidence interval (CI) 1.01–1.21]. This increased risk reflected associations with mixed cellularity cHL (OR = 1.60, 95% CI 1.29–1.99) and EBV-positive cHL (OR = 1.81, 95% CI 1.27–2.56) among current smokers, whereas risk of nodular sclerosis (OR = 1.09, 95% CI 0.90–1.32) and EBV-negative HL (OR = 1.02, 95% CI 0.72–1.44) was not increased.
Conclusion
These results support the notion of etiologic heterogeneity between HL subtypes, highlighting the need for HL stratification in future studies. Even if not relevant to all subtypes, our study emphasizes that cigarette smoking should be added to the few modifiable HL risk factors identified.
doi:10.1093/annonc/mdt218
PMCID: PMC3755332  PMID: 23788758
Hodgkin lymphoma; case–control; cigarette smoking; epidemiology; Epstein–Barr virus; individual patient data meta-analysis
25.  Physical activity level, waist circumference, and mortality 
This study predicted all-cause mortality based on physical activity level (active or inactive) and waist circumference (WC) in 8208 Canadian adults in Alberta, Manitoba, Nova Scotia, and Saskatchewan, surveyed between 1986–1995 and followed through 2004. Physically inactive adults had higher mortality risk than active adults overall (hazard ratio, 95% confidence interval = 1.20, 1.05–1.37) and within the low WC category (1.51, 1.19–1.92). Detrimental effects of physical inactivity and high WC demonstrate the need for physical activity promotion.
doi:10.1139/h2012-058
PMCID: PMC4120100  PMID: 22703160
physical activity; inactivity; waist circumference; obesity; mortality

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