Mixed allogeneic chimerism by combined use of nonlethal radiation and antilymphocyte serum in a rat small bowel transplantation model.
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Animals↗
Biomedical subjects
J Miller
Publications and source records attributed to J Miller.
Long-term functional end points following middle cerebral artery occlusion in the rat.
The purpose of the present study was to assess the magnitude and stability of a number of functional deficits in rats subjected to occlusion of the middle cerebral artery (MCAO). Three groups of rats, treated with 90-min, 120-min, or sham occlusion were used in functional studies for 22 weeks following surgery. The following tests were used: methamphetamine-induced rotation, the staircase test, acquisition of operant responding, running-wheel behavior, and performance of operant differential reinforcement of a low-rate responding (DRL) schedule of reinforcement. Histology performed at 23 weeks following infarct showed on average modest damage of a 19% reduction in hemispheric volume. Of the behavioral tests conducted, rotation, the staircase test, and the operant DRL were sensitive to ischemic damage, and were under some circumstances related to lesion size. These data show that long-term functional deficits following MCAO are demonstrable, and hence, assessment of long-term neuroprotection is feasible.
Animals↗
Bone marrow cells inhibit the generation of autologous EBV-specific CTL.
Recently, we reported that human bone marrow cells (BMC) inhibited the proliferative (recall) response of lymphocytes to Epstein-Barr virus (EBV) and cytomegalovirus (CMV) protein antigens [12]. To clarify further the effect of BMC on the immune response to viral antigens, we obtained PBL from EBV IgG antibody positive kidney transplant recipients (R) and their living-related donors (LRD) 1 year after renal transplantation and generated EBV-specific CTL in vitro in the presence or absence of autologous BMC. The addition of freshly aspirated autologous iliac crest BMC from either R or LRD caused a significant inhibitory effect on the generation of EBV-specific CTL from CTL precursors, in contrast to the addition of autologous PBL used as controls (62.29 +/- 10.85% inhibition using BMC from the kidney transplant recipients; 74.47 +/- 15.21% inhibition using BMC from the living-related donors). This inhibitory effect was only exerted during the CTL generation phase; but not in the effector CTL killing phase. The expression of CD94, a component of the killer inhibitory receptor (KIR) on CD3(+) cells was elevated in the cultures with BMC, in contrast to the cultures without BMC. The BMC inhibitory effect was partially abrogated by pre-incubation of the CTL effectors with anti-CD94 monoclonal antibody, in contrast with its isotype control. In addition, supernatants obtained from the CTL generating cultures with BMC contained high levels of prostaglandin E(2) (PGE(2)), and EBV-specific CTL activity was inhibited by the addition of exogenous PGE(2) in the absence of BMC. The induction of CD40L cell surface expression by anti-CD3 was also decreased on the effector T cell population when BMC were added. There was a concomitant reduction in protein kinase C (PKC) activity. These studies demonstrate that BMC exert an inhibitory effect on T cell-mediated immunity to viral antigens in humans by regulating autologous effector T cell generation and early T cell activation signaling pathways.
Antigens, CD↗
Bone marrow cells promote TH2 polarization and inhibit virus-specific CTL generation.
This laboratory recently reported that human bone marrow cells (BMC) inhibit the generation of virus-specific CTL in culture. The culture supernatants contained increased levels of prostaglandin E(2) (PGE(2)) (shown to favor TH2 cell development) and also inhibited EBV-CTL effector cell development. In this study, we obtained PBL from Epstein-Barr virus (EBV) IgG antibody positive kidney transplant recipients (R) and their living-related donors (LRD) one year after renal transplantation. EBV-specific CTL were then generated in vitro by stimulating PBL with autologous EBV-transformed B cells (EBV-B) in the presence or absence of autologous BMC. The addition of BMC to the EBV-CTL generation cultures increased the intracellular expression in CD3+ cells of IL-4,-5,-6,-10, and -13. These CD3+ cells also expressed increased levels of the TH2 associated receptor CCR3. Inhibition was even observed by preparing EBV-CTL generating cultures in trans-wells that separated the autologous BMC from the PBL + EBV-B. It was then observed that CD3+ cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV-CTL generation. Protein Kinase A (PKA), a cAMP kinase that is involved in the upregulation of TH2 cytokine activity, was increased in EBV-CTL cultures by the presence of BMC. Additionally, IL-4-mediated signal transduction and activation of transcription (STAT-6) phosphorylation was slightly increased. These results show that the BMC inhibition is mediated by soluble factors (cytokines) and that cell-cell contact in this autologous system is not required, so that BMC (at least partially, via cytokine production) promote TH2 polarization in culture. Moreover, TH2 cells induced by culturing with autologous BMC directly inhibit EBV-CTL generation, and TH2 associated PKA, CCR3, and STAT-6 phosphorylation are enhanced by BMC.
Bone Marrow Cells↗
De novo ANCA-associated vasculitis occurring 14 years after kidney transplantation.
A cadaveric kidney transplant recipient, with no history of a connective tissue disease, was admitted with malaise, arthralgias, diplopia, mild headache, and a painful left eye. The patient was on maintenance immunosuppression for 14 years with cyclosporine and methylprednisolone. Initial laboratory data indicated an elevated serum creatinine from baseline, 2+ proteinuria, and 50 to 100 red blood cells (RBCs)/high-power field (HPF) in the urine. Renal biopsy was consistent with necrotizing vasculitis involving glomerular capillaries, with crescent formation and an absence of immune complexes. Perinuclear antineutrophil cytoplasmic autoantibodies (P-ANCA) and anti-myeloperoxidase (MPO) were found to be elevated. To the best of our knowledge, this is the first reported case of an ANCA-associated small vessel vasculitis (SVV) developing in a renal transplant recipient without history of connective tissue disease.
Antibodies, Antineutrophil Cytoplasmic↗
Sex differences and phases of the estrous cycle alter the response of spinal cord dynorphin neurons to peripheral inflammation and hyperalgesia.
The neuromodulatory interactions of sex steroids with the opioid system may result in sex differences in pain and analgesia. Dynorphin is an endogenous kappa-opioid peptide that is upregulated in an animal model of peripheral inflammation and hyperalgesia and is possibly regulated by circulating levels of sex steroids. The present study compared behavioral responses of male, cycling female, and gonadectomized Sprague-Dawley rats in a model of persistent pain. Cycling female rats were behaviorally tested over a 14-day period, and their estrous cycles were monitored by daily vaginal smears. Thermal hyperalgesia was measured by paw withdrawal latencies taken prior to and 24-72 h after rats received a unilateral hindpaw injection of complete Freund's adjuvant (CFA). Prior to CFA administration, there was no significant difference in paw withdrawal latencies between male rats, cycling female rats, and ovariectomized female rats. Following CFA administration, female rats in proestrus exhibited significantly increased hyperalgesia compared with male rats, ovariectomized female rats, and female rats in other estrous stages (P</=0.05). Levels of spinal preprodynorphin (PPD) mRNA induction in the L4-L5 segments were assessed by Northern blot analysis. PPD mRNA expression ipsilateral to the injected paw was significantly higher in female rats in diestrus (P</=0.05) and proestrus (P</=0.01) compared with rats in estrus and intact male rats. Ovariectomized rats had significantly higher levels of PPD mRNA expression compared with intact male rats (P</=0.05). However, castrated male rats had significantly lower levels of PPD mRNA expression than intact male rats (P</=0.05). PPD mRNA expression was not altered on the contralateral side of the spinal cord in any group. These results suggest a hormonal regulatory influence on the response of spinal cord dynorphin neurons to chronic inflammation and furthermore, that the association of the endocrine and opioid systems have the ability to influence an animal's sensitivity to pain.
Animals↗
Health literacy and health-related knowledge among persons living with HIV/AIDS.
BACKGROUND: Functional health literacy is associated with illness-related knowledge, understanding, and treatment perceptions for several chronic illnesses. This study examined health literacy in relation to knowledge and understanding of HIV/AIDS. METHODS: Persons living with HIV/AIDS recruited from AIDS service organizations and HIV clinics completed the Test of Functional Health Literacy for Adults (TOFHLA) reading comprehension scale and measures of health status, knowledge and understanding of health status, perceptions of primary care givers, and perceptions of anti-HIV treatments. RESULTS: Eighteen percent of the sample scored below the cutoff for marginal functional health literacy on the TOFHLA. Controlling for years of education, persons of lower health literacy were significantly less likely to have an undetectable HIV viral load, somewhat less likely to know their CD4 cell count and viral load, and lower health-literacy persons who knew their CD4 count and viral load were less likely to understand their meaning. Lower health literacy was also related to misperceptions that anti-HIV treatments reduce risks for sexually transmitting HIV and beliefs that anti-HIV treatments can relax safer-sex practices. CONCLUSIONS: Poor health literacy creates barriers to fully understanding one's health, illness, and treatments. Misperceptions of treatment in the case of HIV infection creates danger for potentially transmitting treatment-resistant strains of HIV. These results have implications for patient education and treatment programming for people who have poor health-literacy skills and are living with HIV/AIDS.
Acquired Immunodeficiency Syndrome↗
Differences in young adult psychopathology among drug abstainers, experimenters, and frequent users.
Shedler and Block offered the provocative proposal that individuals who experiment with drugs are psychologically healthier than either those who abstain completely or those who are frequent users. Not all studies have come to such conclusions, however. In an effort to specify under what conditions Shedler and Block's conclusions might hold, the present study examined three groups of drug users (abstainers, experimenters, frequent users) classified according to three different criteria: (a) marijuana use at age 20; (b) alcohol use during 10th grade; and (c) alcohol use at age 20. The three groups were compared at age 20 in terms of personality, deviant behavior, and psychopathology. The results revealed that abstainers were never more psychologically impaired, and were occasionally healthier, than experimenters. Frequent users of marijuana were consistently more imparied than both the abstainers and experimenters, in terms of both internalizing and externalizing disorders. Classification according to marijuana use appeared to be more related to psychopathology than did classification according to alcohol use.
Adolescent↗
Levels of mycophenolic acid and its glucuronide derivative in the plasma of liver, small bowel and kidney transplant patients receiving tacrolimus and cellcept combination therapy.
In order to help assess the usefulness of mycophenolate mofetil (MMF) as an immunosuppressive agent in recipients of organs other than kidneys, we measured the trough levels of the active metabolite of MMF, mycophenolic acid (MPA), and its inactive glucuronide derivative (MPAG), in the plasma of liver (n = 83) and small bowel transplant patients (n = 15) receiving MMF in combination with tacrolimus. These levels were compared with a group of renal transplant patients (n = 25) receiving the same drug regimen. All patient groups were otherwise comparable except the small bowel patient group which contained more pediatric patients (average age 18.7 +/- 3.9 years), and, therefore, received a higher average drug dose (in mg/kg). Despite this, these patients displayed the lowest levels of MPA of any group (0.39 +/- 0.08 microg/ml, P < 0.001 vs. 1.10 +/- 0.17 microg/ml for liver transplant patients, P < 0.001 or 2.46 +/- 0.37 microg/ml for renal transplant patients, P < 0.001). There were no statistically significant differences in MPAG levels between any of the groups. Although preliminary, these data demonstrate significant transplanted organ-specific differences in MMF pharmacology and/or bioavailability, and suggest the need for separate evaluation of MMF dosing for each transplant type.
Adolescent↗
Navigating the technology maze.
'Pharmaceutical companies face difficult, complex decisions when identifying, evaluating and selecting new technologies.'
Journal Article↗
Opening of the active site of Clostridium perfringens alpha-toxin may be triggered by membrane binding.
On the basis of amino acid sequence homologies with other phospholipases C, the alpha-toxin of Clostridium perfringens was predicted to be a two-domain protein. Using truncated forms of alpha-toxin the phospholipase C active site was shown to be located in the amino-terminal domain. Crystallographic studies have confirmed this organisation and have also revealed that the carboxy-terminal domain is structurally similar to the phospholipid-binding domains in eukaryotic proteins. This information has been used to devise a model predicting how alpha-toxin interacts with membranes via calcium-mediated recognition of phospholipid head groups and the interaction of hydrophobic amino acids with the phospholipid tail group. The binding of alpha-toxin to membranes appears to result in the opening of the active site allowing hydrolysis of membrane phospholipids.
Animals↗
Partial venous thrombosis of the pancreatic allografts after simultaneous pancreas-kidney transplantation.
Despite new advances in transplantation, complete venous thrombosis (VT) of the pancreas after simultaneous pancreas kidney (SPK) transplantation usually results in graft loss. Data are limited regarding the outcome and treatment of partial VT of the pancreas allograft. From July 1994 to December 1999, 126 patients with IDDM/end-stage renal disease underwent SPK with systemic bladder drainage at the University of Miami. We retrospectively reviewed our experience regarding the outcome and treatment options of partial VT of the pancreas allografts. From July 1994 to April 1997, partial VT was not seen in the first 66 SPK patients induced with anti-CD3 rnAb and oral or intravenous (i.v.) tacrolimus (TAC) in the operating room. From May 1997 to June 1999, 14 (29%) out of 48 patients had VT. These cases were identified following the i.v. use of TAC with anti-IL-2R antibody-induction therapy (7/15) or without (7/33). Partial thrombosis of the splenic vein (PTSV) was documented in 10 patients, 2 had complete thrombosis of the splenic vein (CTSV), 1 had partial thrombosis of the superior mesenteric vein (PTSMV), and 1 patient had PTSV and PTSMV. These were identified incidentally during routine color Doppler ultrasonography (CDU). None of these SPK recipients demonstrates a change in clinical parameters. The first 8 patients were systemically heparinized, followed by oral anticoagulation, except 1 patient with CTSV. He progressed to complete thrombosis of the pancreas allograft and was treated with percutaneous thrombectomy and urokinase infusion, followed by heparinization and oral anticoagulation. One patient required exploration for bleeding. In an attempt to reduce the morbidity of heparinization, we treated the next 6 patients with PTSV with aspirin followed by serial CDU. All 14 patients had preservation of the endocrine and exocrine pancreatic functions. CDU showed resolution with recanalization of the thrombosed vein(s). From July 1999 to December 1999, 12 SPK recipients were administered TAC orally with or without induction therapy with anti-IL-2R antibody. So far, in this group, VT has not been identified. In summary, a total of 14 out of 126 patients (11%) had isolated VT with a mean follow-up of 36.4 months. Based on our experience, we suggest that extensive VT after pancreas transplantation, including splenic and superior mesenteric VT, be treated with heparin and subsequent oral anticoagulation for 3 months. For more limited, partial splenic VT, aspirin may be sufficient. Follow-up CDU is critical for a successful outcome. The i.v. use of TAC appears to be a risk factor for the increased incidence of VT. Currently, using IL-2rmAb as induction, TAC is started orally on postoperative days 3 or 4 and aspirin on postoperative day 2.
Adult↗
Measurement error in subliminal perception experiments: simulation analyses of two regression methods.
A. G. Greenwald, M. R. Klinger, and E. S. Schuh (1995) investigated subliminal perception using a regression-based test for a dissociation between direct and indirect measures of perceptual ability. Direct and indirect measures were obtained for each observer, and a regression analysis was used to predict the amount of indirect perception at the point where the direct measure showed zero sensitivity. A significant positive intercept, obtained with both standard regression and a modified regression developed by K. C. Klauer, S. C. Draine, and A. G. Greenwald (1998), was used to argue for the key dissociation. When the assumptions of these methods are not met, however, simulations indicate that significant positive intercepts can often be obtained even if there is no dissociation. Moreover, the assumptions are theoretically implausible and inconsistent with some aspects of the results. Thus, the significant positive intercept is not strong evidence of the key dissociation.
Computer Simulation↗
Poor outcome in children with refractory/relapsed leukemia undergoing bone marrow transplantation with mismatched family member donors.
The utility of bone marrow transplantation for childhood leukemia in patients unable to achieve a remission prior to transplant is controversial. To address this issue, we analyzed a subset of patients with advanced leukemia entered on prospective transplant trials at our hospital. Fifty-eight patients with ALL or AML (age 1-19) were identified. They had failed standard chemotherapy and were in relapse (22 in 1st, 27 in 2nd, three in 3rd, and three in 4th) or had never achieved an initial remission (three) at the time of transplant. Fifty-two patients received marrow from mismatched family members (haplo or DR-identical), while six received marrow from matched siblings. Most patients received myeloablative therapy consisting of total body irradiation, etoposide, cyclophosphamide, and cytosine arabinoside. Marrow from mismatched donors was T cell depleted. Only one of 52 patients transplanted with a mismatched donor survived long-term while three of six patients transplanted in relapse with a fully matched sibling donor are alive 6-10 years post BMT. The major causes of death were infection (39%) and relapse (28%). Acute GVHD grade III-IV was noted in 7% of patients. A comparable group of patients with leukemia transplanted at our center in remission using similarly mismatched family member donors (haplo or DR-identical) had an event-free survival of 28%. In conclusion, our data suggest that BMT utilizing mismatched family member donors is a poor option for patients in relapse at the time of transplant. New treatment strategies need to be developed to effectively manage these patients.
Adolescent↗
Gender disparity in living renal transplant donation.
Numerous studies document that women constitute the majority of living kidney donors, but the reasons behind the disparity in donation rates between men and women remain obscure. We studied this issue by gathering data on family members of living donor allograft recipients at a single large center over a 5-year period (n = 144). By considering all potential donors (spouses and first-degree relatives) within each recipient's immediate family, we determined that men and women are excluded as donors at approximately similar rates on the basis of medical condition or known blood group type A, type B, type O incompatibility, and that a greater percentage of acceptable female donors (28.3%) compared with men (20.3%) go on to donate a kidney (P: = 0.027). However, when only first-degree relatives are considered, the difference in donation rate between men and women becomes nonsignificant (26.9% of women versus 22.2% of men; P = 0.229). Among spouses, the gender disparity in donation rate is greater (36% of wives versus 6.5% of husbands who are acceptable donors go on to donate a kidney; P = 0.003). Evidence that economic factors may contribute to the overall gender disparity is also presented. In conclusion, the gender disparity among living kidney donors observed in our population can be largely attributed to an overwhelming predominance of wives among spousal donors. Possible explanations and potential interventions to address underrepresentation of male donors are discussed.
Adult↗
Scaphocapitate syndrome in an adolescent.
Scaphocapitate syndrome is a rare injury and its incidence in immature skeleton is not well documented. We describe our experience of scaphocapitate syndrome in a 12-year-old boy and report the results after a 3-year follow-up period. Treatment involved open reduction internal fixation using K-wires. The 3-year follow-up evaluation revealed no evidence of avascular necrosis. The wrist was completely asymptomatic and the patient used it normally. The difficulty in examining an injured child and the presence of open physes on radiographs can make diagnosis difficult. Awareness among orthopedic surgeons about this injury in children is needed to avoid misdiagnosis and to initiate timely treatment.
Accidents, Traffic↗
B vitamins, homocysteine, and neurocognitive function in the elderly.
Evidence of the importance of the B vitamins folic acid, vitamin B-12, and vitamin B-6 for the well-being and normal function of the brain derives from data showing neurologic and psychologic dysfunction in vitamin deficiency states and in cases of congenital defects of one-carbon metabolism. The status of these vitamins is frequently inadequate in the elderly and recent studies have shown associations between loss of cognitive function or Alzheimer disease and inadequate B vitamin status. The question that arises is whether these B vitamin inadequacies contribute to such brain malfunctions or result from aging and disease. From a theoretical standpoint, these inadequacies could give rise to impairment of methylation reactions that are crucial to the health of brain tissue. In addition or perhaps instead, these inadequacies could result in hyperhomocysteinemia, a recently identified risk factor for occlusive vascular disease, stroke, and thrombosis, any of which may result in brain ischemia. Advances in the understanding of this putative relation between inadequate vitamin status and loss of cognitive function in the elderly are likely to be slow and may depend on the outcomes of both prospective studies and longitudinal studies in which nutritional intervention is provided before cognitive decline occurs.
Aging↗