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BACKGROUND: Plasma albumin has been considered as important for governing glomerular permselectivity as well as being tubulotoxic in proteinuric states. The purpose of this study was to examine glomerular permselectivity and protein clearance of plasma albumin-deficient Nagase analbuminaemic rats (NAR) in normal and proteinuric states associated with puromycin aminonucleoside nephrosis (PAN) and anti-glomerular basement membrane glomerulonephritis (anti-GBM GN) and to compare the results with those of previous studies using Sprague-Dawley rats. METHODS: Glomerular permselectivity was measured using tritium-labelled polydisperse Ficoll. In vivo fractional clearance (FC) of albumin, transferrin and immunoglobulin G was measured to include both intact and degraded forms of filtered material. Endogenous protein clearance was analysed using two-dimensional electrophoresis in combination with matrix-assisted laser desorption ionization (MALDI) mass spectrometry. RESULTS: FCs of proteins and Ficoll in control NAR were similar to those found in Sprague-Dawley rats. Despite the lack of serum albumin in NAR, proteinuria and morphological changes observed were also similar to those found in Sprague-Dawley rats, with total protein excretion increasing 6-fold in PAN rats and 4-fold in anti-GBM GN rats with respect to controls. Two-dimensional electrophoresis in combination with MALDI mass spectrometry identified the major proteins being excreted as transferrin and a group of mildly acidic proteins in the MW range 40-50 kDa, namely antithrombin III, kininogen, alpha-1-antiproteinase, haemopexin and vitamin D-binding protein. CONCLUSIONS: Both diseases exhibited similar effects to those observed in Sprague-Dawley rats despite the lack of serum albumin, including inhibition of renal protein degradation. The net changes in protein FC, particularly in the range of radii of 36-55 A, could not be accounted for by changes in size selectivity as Ficoll FC was little affected by the disease states. This emphasizes the need to reassess the relative importance of changes in renal tubular handling vs changes in glomerular capillary barrier in proteinuric states. These studies also demonstrate that albumin is not a critical factor in governing glomerular permselectivity or proteinuria.

Control of serum phosphate remains a difficult clinical issue in most hemodialysis (HD) patients. This study examines 2 nonpharmacological approaches to improving phosphate control in HD patients.First, 9 stable HD patients underwent dialysis in random fashion for either 4 hours 3 times weekly or 5 hours 3 times weekly. Adjustments were made to blood flow rates such that Kt/V was the same for all sessions, thus allowing independent assessment of the influence of time. The primary end point was weekly dialysate phosphate removal. In the second study, 12 different patients underwent an exercise program in which they pedaled a bicycle ergometer either immediately before or during dialysis. Again, weekly dialysate phosphate removal was measured.In the time study, urea reduction ratio (69% +/- 0.02% versus 68% +/- 0.07, 4 versus 5 hours) and weekly urea removal were no different between the 2 groups. However, weekly phosphate removal (3,007 +/- 641 versus 3,400 +/- 647 mg; P0.02) significantly improved with longer dialysis duration. Serum phosphate levels improved, but did not reach statistical significance in this short-term study. In the exercise study, weekly phosphate removal improved with exercise, but did not reach significance (2,741 +/- 715 [no exercise] versus 2,917 +/- 833 [exercise predialysis] versus 2,992 +/- 852 mg [exercise during dialysis]; P = 0.055), although comparing only exercise during dialysis with no exercise reached significance (P = 0.02). There was no significant difference in serum phosphate levels.Both increased dialysis time and exercise result in increased dialytic removal of phosphate and could be expected in the long term to improve phosphate control.

A randomized clinical trial compared the effects of traditional behavioral couple therapy (TBCT) and integrative behavioral couple therapy (IBCT) on 134 seriously and chronically distressed married couples, stratified into moderately and severely distressed groups. Couples in IBCT made steady improvements in satisfaction throughout the course of treatment, whereas TBCT couples improved more quickly than IBCT couples early in treatment but then, in contrast to the IBCT group, plateaued later in treatment. Both treatments produced similar levels of clinically significant improvement by the end of treatment (71% of IBCT couples and 59% of TBCT couples were reliably improved or recovered on the Dyadic Adjustment Scale; G. B. Spanier, 1976). Measures of communication also showed improvement for both groups. Measures of individual functioning improved as marital satisfaction improved.

Epidemiology of vascular access in the Australian hemodialysis population.BackgroundA number of demographic and comorbid factors have been demonstrated to be associated with the placement of arteriovenous grafts (AVG) and central venous catheters (CVC) as opposed to native arteriovenous fistulas (AVF). However, no data are available regarding these factors in a hemodialysis population where AVF utilization is high.MethodsAll adult patients on hemodialysis on September 30, 2001 in Australia were included in the study. Vascular access was recorded as AVF, AVG, or CVC. Patients were separated into incident (

Background: Plasma homocysteine is elevated in patients with end-stage renal disease (ESRD) and is a risk factor for cardiovascular disease. Folic acid has been shown to partially reduce homocysteine levels in dialysis patients. It is not known whether vitamin B12 reduces homocysteine independent of folic acid in patients who are not vitamin B12 deficient. Aim: To determine whether 1 mg vitamin B12 lowers homocysteine in stable, chronic, haemodialysis patients independent of folic acid. Methods: Twenty-eight haemodialysis patients were randomized to receive three doses of 1 mg vitamin B12 or 1 mL saline placebo in a double-blind fashion at 1-month intervals. Fasting plasma total homocysteine, folic acid, red-cell folate, vitamin B12 and haemoglobin levels were determined prior to each dose and 4 weeks after the final injection. The study was powered to detect a 30% reduction in homocysteine over the 3 months. Results: Both the two groups were well matched with respect to total homocysteine levels, folic acid, red-cell folate and vitamin B12 levels. Serum vitamin B12 levels were significantly higher in the treatment group compared to placebo (217.7 pmol/L; 95% confidence interval (CI) 103.0−332.5; P

Background. Macrophages constitute 38% to 60% of infiltrating cells during acute renal allograft rejection. Their contribution to tissue damage during acute rejection was examined by depleting macrophages in a rat model. Methods. Lewis rats underwent bilateral nephrectomy and then received a Dark Agouti renal allograft and liposomal-clodronate, control phosphate-buffered saline liposomes, or saline intravenously (n=7 per group) on days 1 and 3 postsurgery. Grafts were harvested on day 5. Results. Liposomal-clodronate treatment resulted in a 70% reduction in blood ED1 + monocytes and 60% reduction in intragraft ED1 + macrophages (both P

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory molecule involved in cell-mediated immunity and delayed-type hypersensitivity (DTH). We inhibited systemic and local MIF production to determine its contribution to acute rejection (AR). Skin DTH response and acute rejection of skin and kidney allografts were examined using MIF gene knockout (MIF -/-) and wild-type mice (MIF +/+) with anti-MIF or control antibody. MIF-Ab reduced skin DTH by 60% (p < 0.01), but absence of the MIF gene (MIF -/-) had no effect. Local absence of MIF had no effect on the survival of skin grafted onto BALB/c recipients. Similarly MIF +/+ and MIF -/- kidneys transplanted into BALB/c recipients showed a similar degree of histological rejection, graft dysfunction and cellular infiltrate suggesting that AR is not dependent on local MIF production. To investigate the influence of systemic MIF, BALB/c donor skin was grafted onto MIF +/+ and MIF -/- mice. The tempo of AR was not altered by systemic absence of MIF (MIF-Ab or MIF -/-). BALB/c kidneys transplanted into MIF +/+ (with or without MIF-Ab) and MIF -/- mice showed similar parameters of rejection. MIF blockade reduces the DTH response; however, neither local nor systemic MIF are required for the rejection of fully mismatched skin and renal allografts.

Objective To measure the prevalence of untreated hypertension in Australian adults, and examine the associations with clinical and lifestyle factors. Design AusDiab, a cross-sectional survey conducted between May 1999 and December 2000, involved participants from 42 randomly selected census districts throughout Australia. Participants Of 20 347 eligible people aged >or= 25 years who completed a household interview, 11 247 attended a physical examination (response rate, 55%). Main outcome measures The prevalence of hypertension (blood pressure >or= 140/90 mmHg or self-reported use of antihypertensive drugs) and its treatment; associations of clinical and lifestyle factors with the treatment of hypertension; and adequacy of treatment for primary and secondary prevention of cardiovascular disease. Results The prevalence of hypertension was 28.6 per 100 (95% CI, 25.0-32.3), and the prevalence of untreated hypertension was 15.2 per 100 (95% CI, 13.2-17.2). Of those with untreated hypertension, 80.8% (95% CI, 74.7%-85.0%) had had a blood pressure check within the preceding 12 months. At least one modifiable lifestyle factor was present in 71.7% (95% CI, 68.5%-74.8%) of participants with untreated hypertension. Although lower risk clinical characteristics of younger age and lack of hyperlipidaemia were independently associated with untreated hypertension, 53.5% warranted treatment based on current cardiovascular disease prevention guidelines and multivariable absolute risk assessment. Conclusions Considerable scope remains for reducing the burden of cardiovascular disease through lifestyle modification and rational treatment of hypertension.

The incidence of ESRD is increasing dramatically. Progression to end-stage may be halted or slowed when kidney damage is detected at an early stage. Kidney damage is frequently asymptomatic but is indicated by the presence of proteinuria, hematuria, or reduced GFR. Population-based studies relating to the prevalence of kidney damage in the community are limited, particularly outside of the United States. Therefore, the prevalence of proteinuria, hematuria, and reduced GFR in the Australian adult population was determined using a cross-sectional study of 11,247 noninstitutionalized Australians aged 25 yr or over, randomly selected using a stratified, cluster method. Subjects were interviewed and tested for proteinuria-spot urine protein to creatinine ratio (abnormal: >/=0.20 mg/mg); hematuria-spot urine dipstick (abnormal: 1+ or greater) confirmed by urine microscopy (abnormal: >10,000 red blood cells per milliliter) or dipstick (abnormal: 1+ or greater) on midstream urine sample; and reduced GFR-Cockcroft-Gault estimated GFR (abnormal

Macrophage migration inhibitory factor (MIF) promotes macrophage accumulation and leucocyte activation during inflammation. Macrophage migration inhibitory factor is upregulated in intrinsic renal cells in many types of kidney diseases, and has a pathogenic role in rat crescentic nephritis. However, little is known about the factors that regulate the production and secretion of MIF in kidney cells. In this study, we evaluated whether interferon-gamma (IFN-gamma), a cytokine implicated in the development of kidney disease and a potent inducer of MIF production in macrophages, could promote MIF synthesis and secretion from renal tubular epithelial cells. Northern blot analysis detected constitutive expression of MIF mRNA in rat tubular epithelial cells (NRK52E), which increased twofold after a 6-h stimulation with IFN-gamma. Macrophage migration inhibitory factor protein was found only in the cytoplasm of NRK52E cells. Following IFN-gamma stimulation, intracellular MIF in NRK52E cells was rapidly secreted with a maximal reduction of 50% after 20 min, which returned to normal levels after 2-4 h. Rapid secretion of MIF in response to IFN-gamma was also seen in rat mesangial cells. These findings indicate that IFN-gamma induces rapid secretion of MIF by tubular epithelial cells, and suggest that this may be an important mechanism leading to inflammatory cell accumulation and activation during kidney disease.

Background Advances in immunosuppression have made renal transplantation an effective therapy for end stage renal failure; with low rejection rates and long graft survival times. However, the major adverse consequences, infection and malignancy have not diminished. To predict this risk a score of immune competence has been developed from the simultaneous laboratory assessment of multiple parameters of immune function. Methods The immune status of 152 transplant recipients (138 renal and 14 pancreas/renal) was assessed by measurement of lymphocyte subsets, mitogen-induced T-cell proliferative responses, neutrophil phagocytic capacity and reactive oxygen species (ROS) generation. A scoring system was devised based on the average number of these parameters below 10th percentile of normal. Results The most common abnormality was B-cell lymphopenia (85%) followed by reduced neutrophil ROS production (63% of patients), NK cell lymphopenia (50%), lymphocyte mitogen response (49%) and CD4 number (23%). The abnormalities were unrelated to the duration of immunosuppression (up to 15 years), and variable combinations of cyclosporine A, azathioprine, prednisolone and mycophenolate mofetil (MMF) (except for a consistent reduction in lymphocyte mitogen response in MMF treated patients). Retrospective comparison of infective episodes showed a significantly greater index of infections in patients with the worst score compared with a normal score. Conclusions The data suggests that this quantification of immune function may allow assessment of the level of host immune defence reflecting the level of drug-induced immunosuppression and thus risks of immunosuppressive complications.

Macrophages have been implicated in causing renal injury in both human and experimental kidney disease. The aim of the current study was to determine whether modulating the state of macrophage activation directly affects the capacity of these cells to cause renal injury. This was investigated using an adoptive transfer model in which macrophage activation can be manipulated in vitro, using interferon-gamma (IFN-gamma) or dexamethasone (Dex), and then macrophage-mediated renal injury determined in vivo. In this model, rats were made leukopenic by administration of cyclophosphamide (CyPh). Two days later (day 0), animals were injected with sheep anti-GBM serum followed by a single injection of rat NR8383 macrophages on day 1 and then killed 3 or 24 h after cell transfer. NR8383 macrophages were incubated IFN-gamma and/or Dex before adoptive transfer into animals. Induction of proteinuria and glomerular cell proliferation (PCNA+ cells) in this model was dependent on transfer of NR8383 macrophages. Exposure of macrophages to IFN-gamma for 18 h (but not 3 h) before transfer caused a twofold increase in the degree of proteinuria and glomerular cell proliferation compared with unstimulated cells (Nil versus IFN-gamma; P0.001). This was due to an increase in the number of transferred macrophages within the glomerulus and a significant increase in degree of renal injury per transferred glomerular macrophage. IFN-gamma increased iNOS and PDGF-B gene expression and upregulated adhesion molecule expression in NR8383 macrophages. In contrast, exposure of NR8383 cells to Dex for 18 h (but not 1 h) abrogated renal injury due to a failure of transferred macrophages to accumulate within the glomerulus. In addition, Dex abrogated renal injury caused by IFN-gamma-stimulated macrophages. In conclusion, activation of macrophages by IFN-gamma, independent of any effect on other leukocytes or renal cells, can substantially augment macrophage-mediated renal injury. This IFN-gamma augmentation of renal injury is sensitive to the action of glucocorticoids, which act directly on macrophages to prevent their recruitment to the inflamed glomerulus. This study provides the first evidence that it is possible to directly modulate macrophage-mediated renal injury.

Despite its demonstrated efficacy, marital therapy's impact has been limited by couples' general reluctance to seek help until their problems become severe. To understand this delay, 147 married couples (294 individuals) in the process of seeking marital therapy were surveyed. Using multilevel confirmatory factor analysis, three relatively independent steps (problem recognition, treatment consideration, and treatment seeking) were identified. On average, wives were rated as completing all three steps before their husbands. Gender-role orientation, demographics, relationship satisfaction, and specific relationship problems (especially husbands' dissatisfaction with sex) were also predictive of the steps toward therapy. Implications for marital therapy are discussed.

Adoptive transfer studies demonstrate that macrophages can induce proteinuria and mesangial cell proliferation.BackgroundGlomerular macrophage accumulation is a feature of proliferative human and experimental glomerulonephritis. However, our understanding of the role of macrophages in the induction of renal injury is based upon indirect evidence from depletion studies, most of which lack specificity for this cell type. Therefore, an adoptive transfer approach was used to directly assess the potential of macrophages to induce renal injury.MethodsAccelerated anti-glomerular basement membrane (anti-GBM) disease was induced in rats by immunization with sheep IgG (day -5), followed by administration of sheep anti-rat GBM serum (day 0), with animals killed on day 2. To facilitate the adoptive transfer studies, immunized animals were made leukopenic by cyclophosphamide (CyPh) given on day -2. Bone marrow-derived (BM) or NR8383 macrophages were transferred by tail vein injection 24 hours after injection of anti-GBM serum, with animals killed 3 or 24 hours after transfer.ResultsPretreatment with CyPh prevented glomerular leukocyte accumulation and completely inhibited proteinuria, glomerular cell proliferation and hypercellularity in accelerated anti-GBM disease. Adoptive transfer led to significant glomerular accumulation of BM or NR8383 macrophages within 3 hours of injection, and this was still evident 24 hours later. Adoptive transfer of BM or NR8383 macrophages induced proteinuria (63 ± 16 BM vs. 5 ± 2 mg/24 h CyPh control; P < 0.001), glomerular cell proliferation (5.1 ± 1.2 BM vs. 0.5 ± 0.1 PCNA+ cells/gcs CyPh; P < 0.001) and glomerular hypercellularity (51.2 ± 2.0 BM vs. 41.9 ± 0.9 nuclei/gcs CyPh; P < 0.001). The degree of renal injury correlated with the number of transferred glomerular macrophages. Two-color immunostaining demonstrated that most glomerular proliferative cell nuclear antigen+ (PCNA+) proliferating cells were OX-7+ mesangial cells. CyPh treatment did not prevent up-regulation of glomerular intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) expression or an increase in urinary monocyte chemoattractant protein-1 (MCP-1) excretion.ConclusionThis study provides the first direct evidence that macrophages can induce renal injury in terms of proteinuria and mesangial cell proliferation.

Background: Measurement of vascular access flow (Qa) has been proposed as the ideal method for surveillance of native fistulae. However, debate exists about the influence of blood pressure (mean arterial pressure [MAP]) on Qa during dialysis. Methods: During three consecutive dialysis treatments, 10 patients had paired measurements of Qa and MAP performed at 30, 60, 120, 180, 210, and 240 minutes. Access resistance (AR; in peripheral resistance units, PRUs) was calculated from MAP and Qa values. Results: Overall pooled coefficients of variation (CVs) for MAP, Qa, and AR were 8.4%, 12.3%, and 12.9%, respectively. A significant reduction in Qa and MAP occurred throughout the dialysis treatment (Qa, 104 mL/min; P = 0.008; MAP, 10.4 mm Hg; P = 0.007). Mean percentages of change in Qa for the first third compared with the middle and last thirds of the session were −4.6% ± 11.15% (SD) and −9.6% ± 10.5%, respectively. Thus, Qa varied between 11.4% and −30.6% from baseline during the last hour of dialysis treatments. A stronger correlation between MAP and Qa was seen in radiocephalic ( r 2 = 0.55; P r 2 = 0.06; P = 0.023). Mean AR was unchanged during the dialysis session (0.23 PRU; P = 0.358). AR for radiocephalic fistulae was significantly greater compared with brachiocephalic fistulae (6.03 ± 3.90 versus 3.00 ± 1.11 PRU; P Conclusion: Qa could decrease up to 30% from baseline, potentially impairing the ability of Qa to predict impending vascular access failure. AR remained stable during the treatment and may be a more useful measure of vascular access performance as part of an access surveillance program. Am J Kidney Dis 41:132-139. © 2003 by the National Kidney Foundation, Inc.

Production of macrophage-colony stimulating factor (M-CSF), the major macrophage growth factor, is increased in tissues during inflammation. Therefore, w determined whether M-CSF, acting through its receptor c-fms, contributes to macrophage accumulation at a site of tissue injury. Daily treatment with anti-c-fms or control antibody was given to mice with renal inflammation resulting from unilateral ureteric obstruction (UUO). Following UUO, kidney M-CSF mRNA increased in association with macrophage accumulation (days 1, 5, and 10) and local macrophage proliferation (days 5 and 10). Anti-c-fms treatment caused a minor inhibition of monocyte recruitment at day 1, reduced macrophage accumulation by 75% at day 10, but did not affect blood monocyte counts or the CD4 and CD8 lymphocytic infiltrate. Prevention of macrophage accumulation by anti-c-fms treatment was associated with a 90% reduction in local macrophage proliferation at days 5 and 10 without evidence of increased macrophage apoptosis. Therefore, M-CSF/c-fms signaling plays a key role in macrophage accumulation during tissue injury.

Recurrent glomerulonephritis is a known cause of renal allograft loss; however, the incidence of this complication is poorly defined. We determined the incidence, timing, and relative importance of allograft loss due to the recurrence of glomerulonephritis.A total of 1505 patients with biopsy-proved glomerulonephritis received a primary renal transplant in Australia from 1988 through 1997. Recurrence was confirmed by renal biopsy. The Kaplan-Meier method was used to estimate the 10-year incidence of allograft failure due to recurrent glomerulonephritis, and this incidence was compared with the incidence of acute rejection, chronic rejection, and death with a functioning allograft. Characteristics of the recipients and donors were examined as potential predictors of recurrence.Allograft loss due to the recurrence of glomerulonephritis occurred in 52 recipients, with a 10-year incidence of 8.4 percent (95 percent confidence interval, 5.9 to 12.0). The type of glomerulonephritis, the sex of the recipient, and the peak level of panel-reactive antibodies were independent predictors of the risk of recurrence. Recurrence was the third most frequent cause of allograft loss at 10 years, after chronic rejection and death with a functioning allograft. Despite the effect of recurrence, the overall 10-year incidence of allograft loss was similar among transplant recipients with biopsy-proved glomerulonephritis and among those with other causes of renal failure (45.4 percent [95 percent confidence interval, 40.9 to 50.2] vs. 45.8 percent [95 percent confidence interval, 42.3 to 49.3], P=0.09).Recurrence is an important cause of allograft loss for those with renal failure due to glomerulonephritis. No risk factors for recurrence were identified that warrant altering the approach to transplantation. However, accurate estimates of risk can now be provided to potential recipients of renal allografts.

SUMMARY: Current experimental models of glomerulonephritis focus on the acute phases of renal injury. Models replicating the features of human glomerulonephritis, including hypertension, protein-uria, hyperlipidaemia, renal fibrosis and renal failure, are lacking. the aim of this experiment was to define a rat model of glomerulonephritis that replicates the features of progressive glomerulonephritis in humans. Passive accelerated antiglomerular basement membrane disease was induced in inbred Sprague-Dawley rats. Age-matched control rats received pre-immunisation, but were given saline rather than nephrotoxic serum. Groups of diseased rats (n=4–6) were killed at 4, 6 and 7 weeks, and tissues were extracted for histological assessment. Diseased rats developed renal failure over 7 weeks (91% reduction in creatinine clearance vs controls at week 7, P< 0.001). Proteinuria reached a plateau from week 2 to week 7 (269.1 ± 107.9 mg/24h vs 1.00 ± 0.18 mg/mL for controls at week 7, P< 0.001). Diseased rats became hyperlipidaemic (108% increase in cholesterol vs control, P

SUMMARY: Tubular expression of the cell-surface adhesion molecule CD44 is upregulated in both human and experimental glomerulonephritis, and this is associated with interstitial leucocytic infiltration. However, we know little of the mechanisms by which renal CD44 expression is upregulated in disease. This study focuses on the potential role of the proinflammatory cytokine interleukin 1 (IL-1) and the IL-1-inducible transcription factor early growth response factor-1 (Egr-1) on tubular CD44 expression in vivo and in vitro. Immunostaining identified constitutive CD44 expression by occasional glomerular cells and a small number of cortical tubules in normal rat kidney. Glomerular and tubular CD44 expression was markedly upregulated in rat crescentic anti-glomerular basement membrane glomerulonephritis. Blocking IL-1 activity by administration of the IL-1 receptor antagonist significantly reduced glomerular and tubular CD44 expression in this disease model. In vitro studies found that the NRK52E rat tubular epithelial cell line constitutively expresses CD44 mRNA and protein. Stimulation with 10U/mL IL-1 caused upregulation in both CD44 mRNA and protein expression. A role for the transcription factor Egr-1 in this process was suggested by a time course study in which IL-1 stimulation of NRK52E cells caused a rapid and transient increase in Egr-1 mRNA, peaking at 30–60 min, which preceded the increase in CD44 mRNA that was evident at 3–6h. A direct link between Egr-1 and CD44 expression was provided by the ability of an Egr-1 antisense oligonu-cleotide, but not sense or scrambled control oligonucleotides, to inhibit IL-1-induced upregulation of CD44 protein in NRK52E cells. These data demonstrate that IL-1 is an important stimulus for upregulation of tubular CD44 expression in vivo and in vitro. Furthermore, in vitro studies have shown that IL-1-induced upregulation of CD44 expression operates, at least in part, via the transcription factor Egr-1.

OBJECTIVE—To determine the population-based prevalence of diabetes and other categories of glucose intolerance (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) in Australia and to compare the prevalence with previous Australian data. RESEARCH DESIGN AND METHODS—A national sample involving 11,247 participants aged ≥25 years living in 42 randomly selected areas from the six states and the Northern Territory were examined in a cross-sectional survey using the 75-g oral glucose tolerance test to assess fasting and 2-h plasma glucose concentrations. The World Health Organization diagnostic criteria were used to determine the prevalence of abnormal glucose tolerance. RESULTS—The prevalence of diabetes in Australia was 8.0% in men and 6.8% in women, and an additional 17.4% of men and 15.4% of women had IGT or IFG. Even in the youngest age group (25–34 years), 5.7% of subjects had abnormal glucose tolerance. The overall diabetes prevalence in Australia was 7.4%, and an additional 16.4% had IGT or IFG. Diabetes prevalence has more than doubled since 1981, and this is only partially explained by changes in age profile and obesity. CONCLUSIONS—Australia has a rapidly rising prevalence of diabetes and other categories of abnormal glucose tolerance. The prevalence of abnormal glucose tolerance in Australia is one of the highest yet reported from a developed nation with a predominantly Europid background.

SUMMARY: The importance of various inflammatory cytokines in mediating renal disease is now recognized, and the potential for the use of cytokine blockade as a therapeutic intervention is under active investigation. Studies in rat anti-glomerular basement membrane (GBM) disease model showed that antagonism of the proinflammatory cytokine IL-1 inhibited induction of glomerulonephritis, and prevented progression of established disease. A second cytokine Tumour Necrosis Factor-alpha (TNF-α) had similar proinflammatory effects to IL-1 in this model. Blocking the actions of both cytokines together, however, had no added benefit. Another cytokine Macrophage Migration Inhibitory Factor (MIF) has been shown to override the anti-inflammatory effects of corticosteriods. Renal MIF is markedly up-regulated in rat anti-GBM disease and blocking studies have demonstrated MIF plays a pathological role in mediating renal injury in this model. the importance of MIF in glomerulonephritis has been demonstrated by the fact that MIF is produced locally within the kidney, that it reflects the severity of the cellular immune response, and can be measured in the urine. Macrophage Migration Inhibitory Factor is up-regulated in human glomerular disease and correlates with loss of renal function and is thus a potential target for therapy for human glomerulonephritis. Thus, the inflammatory cytokines, IL 1, TNF-α and MIF each play a role in the immune/inflammatory process in glomerulonephritis. Blocking their action reduces disease and cytokine blocking agents have therapeutic potential.

BACKGROUND : Studies of infiltrating cells from acutely rejecting renal allografts show that a high proportion of these cells are macrophages, and early macrophage infiltration is a poor prognostic sign for transplant survival. Macrophage colony-stimulating factor (M-CSF), produced by tubular and mesangial cells, has been associated with macrophage infiltration and proliferation in experimental and human kidney diseases. We investigated the expression of M-CSF in a model of acute rejection. METHODS : Lewis rats underwent bilateral nephrectomies and received an orthotopic Dark Agouti allograft or Lewis isograft. Animals received cyclosporine (10 mg/kg/day) from day 0 to day 3 and were killed at days 4, 8, or 14 after transplantation. Macrophages (ED1+) and T cells (W3-13+) were identified by immunohistochemistry, and M-CSF expression was identified by Northern blotting and in situ hybridization. RESULTS : Isografts had normal renal function without histological evidence of rejection. Allografts exhibited a moderate infiltrate at day 4 but progressed to severe rejection at day 14, with elevated serum creatinine level and severe tubulointerstitial damage. Macrophages and T cells were present in equal proportion in the infiltrate at day 4. At day 14, the number of macrophages increased fivefold (2580/mm2), although T cells were unchanged (380/mm2). Proliferating macrophages (ED1+, BrdU+) increased from day 4 (4%) to day 14 (10%). M-CSF mRNA expression was strongly up-regulated in allografts compared with isografts and normal rat. In situ hybridization demonstrated M-CSF expression by resident and infiltrating cells. Renal tubular expression was minimally increased at day 4 but strongly up-regulated at day 14 (more than 50% of tubules positive), particularly in areas of tubular damage. Tubular M-CSF expression colocalized with areas of intense macrophage infiltration and proliferation. Serial sections with double labeling demonstrated that T cells were the dominant source of M-CSF at day 4, yet later in the rejection (day 14) the predominant sites of production were both renal tubular cells and interstitial macrophages. CONCLUSIONS : Renal production of M-CSF by graft-infiltrating (macrophages and T lymphocytes) and resident (tubular) cells was up-regulated during acute rejection. M-CSF promotes macrophage recruitment and proliferation and may thereby play a pathogenic role in acute rejection. The kinetics of M-CSF production during acute rejection suggest that local macrophage proliferation may be initiated by T cells and perpetuated by both renal tubular and autocrine release.

Background: Unlike other cancers, breast cancer does not occur at increased frequency in renal transplant patients but fibroadenomata may be more common as a result of exposure to cyclosporin. In order to determine the incidence of benign breast disease in renal transplant patients at Monash Medical Centre, current female patients were studied. Methods: The study was divided into two parts: (i) a retrospective review of those who presented with clinically detectable breast lumps; and (ii) mammographic screening of current female transplant patients who had been transplanted for more than 1 year. Results: In the retrospective study there were 11 patients with 16 breast lumps among a total of 85 patients. All were confirmed by biopsy. The mean age at diagnosis of breast lumps was 41.5 years (range 25–70 years). The mean time to presentation was 3.5 years after transplantation. Nine out of 11 patients had benign breast disease including fibroadenoma (six patients), fibrocystic disease (two patients) and intraductal papillomatosis (one patient). Two patients had breast cancer. Five of the patients with fibroadenoma had multiple lumps and a recurrent course. All patients with fibroadenomata had received cyclosporin. In the second part, 54 patients were further screened. The mean duration of transplantation was 6.4 years (range 1.25–18.5 years). Eighty-seven per cent of the patients had received cyclosporin, and 80% had a negative (normal) study. Seven of 54 had abnormalities including cysts and calcification, of whom two patients had fibroadenomata. Four patients had ‘dense mammograms’, all of whom received cyclosporin as a part of their immunosuppression. No breast cancer was detected during the study. Conclusion: The incidence of benign breast disease in the female transplant patients studied was far greater then the general population. The increase in fibroadenomata, in particular, may relate to the use of cyclosporin.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pathogenic role in experimental crescentic glomerulonephritis (GN). Renal expression of MIF is also upregulated in human GN and correlates with leukocytic infiltration, histologic damage, and renal dysfunction. The study presented here examined whether MIF can be measured in urine and if so, whether the urine MIF concentration reflects the degree of renal injury. Urine and serum MIF was measured by enzyme-linked immunosorbent assay in 10 normal healthy volunteers and in a cohort of 63 patients with GN (2 thin basement membrane disease [TBM], 15 membranous GN, 10 focal segmental glomerular sclerosis, 20 IgA glomerularnephritis, 11 crescentic GN, 10 systemic lupus erythematosis World Health Organization class IV). Renal MIF expression was assessed by immunostaining of biopsy tissue. MIF was detected in urine from normal volunteers (mean +/- SD; 191 +/- 132 pg MIF/micromol creatinine). The urine MIF concentration was unchanged in patients with nonproliferative nephropathies (343 +/- 397 pg MIF/micromol Cr) but was increased 3.4-fold in proliferative nephropathies (645 +/- 527 pg MIF/micromol Cr; P < 0.05 versus normal and nonproliferative). Stratified analysis showed the greatest increase in urine MIF in crescentic GN (4.5-fold). In contrast, serum MIF levels were not different between normal patients and any patient group. Immunostaining demonstrated a significant increase in renal MIF expression in proliferative glomerulonephritides that was associated with macrophage and T cell infiltration. There was a significant correlation between the urine MIF concentration and renal MIF expression, but not with serum MIF, indicating a renal origin for the excreted urine MIF. The urine MIF concentration also correlated with the degree of renal dysfunction, histologic damage, and leukocytic infiltration, but not with the amount of proteinuria. In conclusion, this study shows that the urine MIF concentration is significantly increased in proliferative forms of GN and correlates with the degree of renal injury. Urine MIF levels reflect MIF expression within the kidney and may be a useful noninvasive tool for monitoring patients with crescentic GN, particularly in disease exacerbation.

Clinical significance refers to changes that are clinically meaningful for individuals as they progress through a course of treatment. Since the first method of assessing clinical significance was proposed, a number of alternatives have been suggested, each purporting to increase sensitivity for detecting meaningful change. However, few comparisons have been conducted on these methods, and there is little evidence for any method's predictive validity. This study compares classification rates of five clinical significance methods with participants treated for major depressive disorder (N = 128). It also compares the methods' accuracy in predicting relapse of depression 2 years posttreatment. Although all methods successfully predicted relapse from chance discrimination, no significant differences emerged between methods. Implications for future research are discussed.

Background: The dispassionate ability of smartphones to stream real-time, personalized data from an array of onboard sensors can inform assessment and treatment of a range of medical conditions, including mental health issues. This technology can potentially address some of the known access barriers, including cost, time, stigma, shortage of mental health professionals, language barriers and other factors that prevent people from seeking help in a timely fashion. While this technology holds much promise in healthcare, its utility in describing patient phenotype from passive sensor data is unclear and an important area for research. Objective: We will summarize the key learnings from two large-scale (>2,000 enrolled people) fully mobile clinical trials targeting depressed individuals. Both studies were designed to assess the feasibility of running a remote, randomized controlled trial via custom applications. While BRIGHTEN v1 was open to the general US population, BRIGHTEN v2 was designed to enroll both English-speaking and an underserved Latino/Hispanic population. Here we will highlight the noticeable differences in user recruitment, engagement, and daily mood prediction observed across these studies, and explore the possible differences for each. Methods: Both studies recruited participants through ads on Craigslist, targeted social media campaigns and other online classified-like resources. In total, 7,433 people responded and were screened for eligibility. Adults (18 years and older) with mild to severe depression as determined by a Patient Health Questionnaire [PHQ-9] score ≥5 were eligible to join the study. There were 3,310 eligible participants, of which 2,176 were enrolled. Sensor-based data were collected passively, from typical smartphone usage (aggregated call logs and messaging history for people with Android-based phones, and GPS data for both iOS and Android devices). The main outcomes of the study were depressive symptomatology, quantified by the PHQ-9. Daily mood fluctuations were measured using a two-item depression questionnaire (PHQ-2). Results: The overall compliance (the number of unique days an individual participates—i.e. completes active tasks) was drastically lower for V2 study with

Urinary albumin levels are important in diagnosing kidney disease and predicting risk of nonrenal morbidity and premature mortality. In many studies, urine samples are assayed after variable periods of cold storage, and sample stability is important for accurate results. The reproducibility of levels after freezing at −20°C has varied in different reports. Good preservation of albumin levels was found after 160 days of storage at −70°C, and Brinkman et al found good stability of immunonephelometry measurements after 12 months at −80°C. Our study investigates the effect of storage at −70°C for a much longer period on assays of albumin and creatinine. We conclude that with cautious interpretation of results, urine samples stored at −70°C for long periods might reasonably be used to measure urine albumin by immunonephelometry, whether to establish levels de novo, confirm previous levels, compare techniques, evaluate new assays or associations, inform prognosis, and guide treatment.

Collaboration between policy, research, and clinical partners is crucial to achieving proven quality care. The Veterans Health Administration has expended great efforts towards fostering such collaborations. Through this, we have learned that an ideal collaboration involves partnership from the very beginning of a new clinical program, so that the program is designed in a way that ensures quality, validity, and puts into place the infrastructure necessary for a reliable evaluation. This paper will give an example of one such project, the Lung Cancer Screening Demonstration Project (LCSDP). We will outline the ways that clinical, policy, and research partners collaborated in design, planning, and implementation in order to create a sustainable model that could be rigorously evaluated for efficacy and fidelity. We will describe the use of the Donabedian quality matrix to determine the necessary characteristics of a quality program and the importance of the linkage with engineering, information technology, and clinical paradigms to connect the development of an on-the-ground clinical program with the evaluation goal of a learning healthcare organization. While the LCSDP is the example given here, these partnerships and suggestions are salient to any healthcare organization seeking to implement new scientifically proven care in a useful and reliable way.

OBJECTIVE Building on earlier work examining predictors of short- and moderate-term treatment response, demographic, intrapersonal, communication, and interpersonal variables were examined as predictors of clinically significant outcomes 5 years after couples completed 1 of 2 behaviorally based couple therapies. METHOD One hundred and thirty-four couples were randomly assigned to Integrative Behavioral Couple Therapy (IBCT; Jacobson & Christensen, 1998) or Traditional Behavioral Couple Therapy (TBCT; Jacobson & Margolin, 1979) and followed for 5 years after treatment. Outcomes include clinically significant change categories of relationship satisfaction and marital status at 5-year follow-up. Optimal subsets of predictors were selected using an automated, bootstrapped selection procedure based on Bayesian information criterion. RESULTS Higher levels of commitment and being married for a longer period of time were associated with decreased likelihood of divorce or separation (odds ratio [OR] = 1.39, p = .004; OR = 0.91, p = .015). Being married for a longer period of time was also associated with increased likelihood of positive, clinically significant change (OR = 1.12, p = .029). Finally, higher levels of wife-desired closeness were associated with increased odds of positive, clinically significant change and decreased odds of divorce for moderately distressed, IBCT couples (OR = 1.16, p = .002; OR = 0.85, p = .007, respectively), whereas the opposite was true for moderately distressed, TBCT couples (OR = 0.77, p < .001; OR = 1.17, p = .002, respectively). CONCLUSIONS Commitment-related variables are associated with clinically significant outcomes at 5-year follow-up as well as at termination and moderate-term follow-up.

Empathy measures the capacity of the therapist to experience the same cognitive and emotional dispositions as the patient, and is a key quality factor in counseling. In this work we build computational models to infer the empathy of therapist using prosodic cues. We extract pitch, energy, jitter, shimmer and utterance duration from the speech signal, and normalize and quantize these features in order to estimate the distribution of certain prosodic patterns during each interaction. We find significant correlation between empathy and the distribution of prosodic patterns, and achieve 75% accuracy in classifying therapist empathy levels using this distribution. Experiment results suggest high pitch and energy of the therapist are negatively correlated with empathy. These observations agree with domain literature and human intuition.

In this issue, Kansagara and colleagues' review finds that evidence of a mortality benefit of screening high-risk patients for HCC remains insufficient to support a strong recommendation for or aga...

In psychotherapy, the patient-provider interaction contains the treatment’s active ingredients. However, the technology for analyzing the content of this interaction has not fundamentally changed in decades, limiting both the scale and specificity of psychotherapy research. New methods are required in order to “scale up” to larger evaluation tasks and “drill down” into the raw linguistic data of patient-therapist interactions. In the current paper we demonstrate the utility of statistical text analysis models called topic models for discovering the underlying linguistic structure in psychotherapy. Topic models identify semantic themes (or topics) in a collection of documents (here, transcripts). We used topic models to summarize and visualize 1,553 psychotherapy and drug therapy (i.e., medication management) transcripts. Results showed that topic models identified clinically relevant content, including affective, content, and intervention related topics. In addition, topic models learned to identify specific types of therapist statements associated with treatment related codes (e.g., different treatment approaches, patient-therapist discussions about the therapeutic relationship). Visualizations of semantic similarity across sessions indicate that topic models identify content that discriminates between broad classes of therapy (e.g., cognitive behavioral therapy vs. psychodynamic therapy). Finally, predictive modeling demonstrated that topic model derived features can classify therapy type with a high degree of accuracy. Computational psychotherapy research has the potential to scale up the study of psychotherapy to thousands of sessions at a time, and we conclude by discussing the implications of computational methods such as topic models for the future of psychotherapy research and practice.

Brief motivational interventions (BMIs) that aim to reduce alcohol use and related problems have been widely implemented in college settings. BMIs share common principles, but vary in specific content. Thus far, the variation in content has not been thoroughly understood in relation to intervention outcomes. The present study addressed this gap by examining variation in breadth of BMI content (i.e., total number of components covered), the extent to which content was personalized to participants, and the interaction between breadth and personalization in relation to treatment outcomes. Data (N = 6,047 participants across 31 separate BMI conditions) came from an integrative data analysis (IDA) study featuring individual-level data from a broad sample of 24 BMI studies of college students. Participants were assessed at baseline and at least 1 follow-up point, conducted up to 12 months postbaseline. Structural equation modeling revealed a significant interaction effect between breadth and personalization of BMI content on alcohol use and related problems at the long-term follow-up (6-12 months) but not at the short-term follow-up (1-3 months). Results indicated that "more is better" for reducing both alcohol use and related problems when BMIs were highly personalized to participants. For less personalized BMIs, coverage of more components was associated with increases in both alcohol use and problems. Findings point to the importance of strategically designing BMIs to maximize their impact on drinking outcomes in college students.

Empathy is a basic psychological process that involves the development of synchrony in dyads. It is also a foundational ingredient in specific, evidence-based behavioral treatments like motivational interviewing (MI). Ratings of therapist empathy typically rely on a gestalt, “felt sense” of therapist understanding and the presence of specific verbal behaviors like reflective listening. These ratings do not provide a direct test of psychological processes like behavioral synchrony that are theorized to be an important component of empathy in psychotherapy. To explore a new objective indicator of empathy, we hypothesized that synchrony in language style (i.e., matching how statements are phrased) between client and therapists would predict gestalt ratings of empathy over and above the contribution of reflections. We analyzed 122 MI transcripts with high and low empathy ratings based on the Motivational Interviewing Treatment Integrity (MITI) global rating scale. Linguistic inquiry and word count was used to estimate language style synchrony (LSS) of adjacent client and therapist talk turns. High empathy sessions showed greater LSS across 11 language style categories compared to low empathy sessions (p < .01), and overall, average LSS was notably higher in high empathy vs. low empathy sessions (d = 0.62). Regression analyses showed that LSS was predictive of empathy ratings over and above reflection counts; a 1 SD increase in LSS is associated with 2.4 times increase in the odds of a high empathy rating, controlling for therapist reflections (odds ratio = 2.4, 95% CI: 1.36, 4.24, p < .01). These findings suggest empathy ratings are related to synchrony in language style, over and above synchrony of content as measured by therapist reflections. Novel indicators of therapist empathy may have implications for the study of MI process as well as the training of therapists.

This quasi experimental study compared the motivational interviewing (MI) integrity in two prevalent brief intervention (BI) service delivery models for drug abuse. Routine primary care providers (RCPs) and non-routine care providers (NRCPs) performed BIs using an MI style within the same medical setting, patient population, and Screening, Brief Intervention, and Referral for Treatment (SBIRT) protocol. Interventionists (9 RCPs and 6 NRCPs) underwent similar MI training and performed a total of 423 audiorecorded BIs. We compared the MI integrity scores for all audio recorded sessions from these two SBIRT models for up to 40months post MI training. Both groups met the lower standard (beginning proficiency in MI) on 4 of 5 MI integrity scores, but NRCPs met more of the higher standards (competency in MI) than RCPs. There may be limitations with regards to MI fidelity when using RCPs to conduct BIs in some primary care settings. Further experimental investigation is warranted to replicate this finding and identify casual factors of observed differences in MI fidelity.

Background For over 2 decades, brief motivational interventions (BMIs) have been implemented on college campuses to reduce heavy drinking and related negative consequences. Such interventions include in-person motivational interviews (MIs), often incorporating personalized feedback (PF), and stand-alone PF interventions delivered via mail, computer, or the Web. Both narrative and meta-analytic reviews using aggregate data from published studies suggest at least short-term efficacy of BMIs, although overall effect sizes have been small. Methods This study was an individual participant-level data (IPD) meta-analysis of 17 randomized clinical trials evaluating BMIs. Unlike typical meta-analysis based on summary data, IPD meta-analysis allows for an analysis that correctly accommodates the sampling, sample characteristics, and distributions of the pooled data. In particular, highly skewed distributions with many zeroes are typical for drinking outcomes, but have not been adequately accounted for in existing studies. Data are from Project INTEGRATE, one of the largest IPD meta-analysis projects to date in alcohol intervention research, representing 6,713 individuals each with 2 to 5 repeated measures up to 12 months postbaseline. Results We used Bayesian multilevel over dispersed Poisson hurdle models to estimate intervention effects on drinks per week and peak drinking, and Gaussian models for alcohol problems. Estimates of overall intervention effects were very small and not statistically significant for any of the outcomes. We further conducted post hoc comparisons of 3 intervention types (individual MI with PF, PF only, and group MI) versus control. There was a small, statistically significant reduction in alcohol problems among participants who received an individual MI with PF. Short-term and long-term results were similar. Conclusions This study questions the efficacy and magnitude of effects of BMIs for college drinking prevention and intervention and suggests a need for the development of more effective intervention strategies.

The goal of measuring therapist adherence is to determine whether a therapist can perform a given treatment. Yet, the evaluation of therapist behaviors in most clinical trials is limited. Typically, randomized trials have few therapists and minimize therapist variability through training and supervision. Furthermore, therapist adherence is confounded with uncontrolled differences in patients across therapists. Consequently, the extent to which adherence measures capture differences in actual therapist adherence versus other sources of variance is unclear.We estimated intra-class correlations (ICCs) for therapist adherence in sessions with real and standardized patients (RPs and SPs), using ratings from a motivational interviewing (MI) dissemination trial (Baer et al., 2009) in which 189 therapists recorded 826 sessions with both patient types. We also examined the correlations of therapist adherence between SP and RP sessions, and the reliability of therapist level adherence scores with generalizability coefficients (GCs).ICCs for therapist adherence were generally large (average ICC for SPs = .44; average ICC for RPs = .40), meaning that a given therapist's adherence scores were quite similar across sessions. Both ICCs and GCs were larger for SP sessions compared to RPs on global measures of MI adherence, such as Empathy and MI Spirit. Correlations between therapist adherence with real and standardized patients were moderate to large on 3 of 5 adherence measures.Differences in therapist-level adherence ratings were substantial, and standardized patients have promise as tools to evaluate therapist behavior.

Although recent studies have documented high-risk drinking occurring during Spring Break (SB), particularly on SB trips with friends, published intervention studies are few. In the present study, we evaluated the efficacy of event specific prevention strategies for reducing SB drinking among college students, compared to general prevention strategies and an assessment-only control group, as well as evaluated inclusion of peers in interventions and mode of intervention delivery (in-person vs. web).Participants included 783 undergraduates (56.1% women; average age = 20.5 years) intending to go on a SB trip with friends as well as to drink heavily on at least 1 day of SB. Participants completed assessments prior to SB and were randomized to 1 of 5 intervention conditions: SB in-person Brief Alcohol Screening and Intervention for College Students (BASICS; Dimeff, Baer, Kivlahan,Marlatt, 1999), SB web BASICS, SB in-person BASICS with friend, SB web BASICS with friend, general BASICS, or an attention control condition. Follow-up assessment was completed 1 week after SB.Although the SB web BASICS (with and without friends) and general BASICS interventions were not effective at reducing SB drinking, results indicated significant intervention effects for SB in-person BASICS in reducing SB drinking, particularly on trip days. Follow-up analyses indicated that change in descriptive norms mediated treatment effect and reductions in drinking, whereas SB drinking intentions and positive expectancies did not.Overall, results suggest that an in-person SB-specific intervention is effective at reducing SB drinking, especially during trips. In contrast, interventions that contain non-SB-related content, are web-based, or seek to involve friends may be less effective at reducing SB drinking.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of personalized normative feedback (PNF) on college student alcohol-related risky sexual behavior (RSB). METHOD: In a randomized controlled trial, 480 (57.6% female) sexually active college students were stratified by gender and level of drinking and randomly assigned to an alcohol-only intervention, an alcohol-related RSB-only intervention, a combined alcohol and alcohol-related RSB intervention, or control. All assessment and intervention procedures were Web-based. RESULTS: Results indicated a significant reduction in drinking outcomes for the alcohol only and the combined alcohol and alcohol-related RSB interventions relative to control. Findings further demonstrated a significant reduction in alcohol-related RSB outcomes for the alcohol-related RSB only and the combined alcohol and alcohol-related RSB interventions relative to control. There were no significant intervention effects on alcohol-related negative consequences. These findings demonstrate that the combined alcohol and alcohol-related RSB intervention was the only intervention successful at reducing both drinking and alcohol-related RSB outcomes relative to control. There were no significant differences when comparing the combined alcohol and alcohol-related RSB intervention to the alcohol-only intervention or the alcohol-related RSB-only intervention. Finally, results suggested that the intervention effects on high-risk behaviors were mediated by reductions in descriptive normative perceptions. CONCLUSIONS: These findings demonstrate that PNF specific to drinking in sexual situations was needed to reduce alcohol-related RSB. Furthermore, this study highlights the potential utility of a brief intervention that can be delivered via the Internet to reduce high-risk drinking and alcohol-related RSB among college students. (PsycINFO Database Record (c) 2014 APA, all rights reserved). Language: en

Standardized rating systems are often used to evaluate the proficiency of Motivational Interviewing (MI) counselors. The published inter-rater reliability (degree of coder agreement) in many studies using these instruments has varied a great deal; some studies report MI proficiency scores that have only fair inter-rater reliability, and others report scores with excellent reliability. How much can we to trust the scores with fair versus excellent reliability? Using a Monte Carlo statistical simulation, we compared the impact of fair (0.50) versus excellent (0.90) reliability on the error rates of falsely judging a given counselor as MI proficient or not proficient. We found that improving the inter-rater reliability of any given score from 0.5 to 0.9 would cause a marked reduction in proficiency judgment errors, a reduction that in some MI evaluation situations would be critical. We discuss some practical tradeoffs inherent in various MI evaluation situations, and offer suggestions for applying findings from formal MI research to problems faced by real-world MI evaluators, to help them minimize the MI proficiency judgment errors bearing the greatest cost.

SUMMARY: Studies in experimental models have established that blockade of either interleukin 1 (IL-1) or tumour necrosis factor α (TNF-α) is effective in suppressing crescentic glomerulonephritis. However, it is not known whether simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We have addressed this question in a study of accelerated crescentic anti-glomerular basement membrane (GBM) glomerulonephritis in the rat. Groups of six animals were treated with an IL-1 receptor antagonist (IL-1ra), TNF-α-binding protein (TNFbp), IL-1ra + TNFbp (combined) or saline (control) from the time of anti-GBM serum injection until being killed, 10 days later. Saline-treated animals developed crescentic glomerulonephritis with tubulointerstitial damage, heavy proteinuria and renal impairment. Compared with saline, treatment with either IL-1ra or TNFbp alone resulted in significant suppression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; both P < 0.001 vs. control), tubulointerstitial leucocytic infiltration (262 ± 31 and 282 ± 32 cells/mm2 vs. 481 ± 71 cells/mm2; both P < 0.001 vs. control) and proteinuria (167 ± 44 and 164 ± 23 mg/24 h vs. 279 ± 36 mg/24 h; both P < 0.001 vs. control) and prevented the loss of renal function. Combined IL-1ra and TNFbp treatment resulted in a virtually identical degree of disease suppression as individual cytokine blockade in terms of crescent formation (2.7%), interstitial leucocytic infiltration (274 ± 45 cells/mm2), proteinuria (190 ± 18 mg/24 h) and renal function preservation. In conclusion, this study has demonstrated that blockade of either IL-1 or TNF-α alone substantial suppresses experimental crescentic glomerulonephritis to a similar extent to that achieved by simultaneous blockade of both cytokines. These findings provide a rationale for the use of cytokine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.

Background. Macrophage accumulation is a prominent feature in many forms of glomerulonephritis. Local proliferation of macrophages within the kidney has been described in human and experimental glomerulonephritis and may have an important role in augmenting the inflammatory response. The current study examined the relationship between local macrophage proliferation and renal expression of macrophage colony-stimulating factor (M-CSF). Methods. A total of 118 renal biopsies of patients with a wide range of glomerulonephridities were examined for M-CSF protein and macrophage proliferation (KP1 + PCNA + cells) by single and double immunohistochemistry staining, respectively. Results. Biopsies of thin membrane disease (TMD) with histologically normal kidney showed M-CSF protein expression by 33% of cortical tubules, while glomerular M-CSF expression was limited to resident macrophages and some podocytes. Glomerular M-CSF expression increased significantly in proliferative forms of glomerulonephritis, with M-CSF staining of infiltrating macrophages, podocytes and some mesangial cells. Segmental areas of strong M-CSF expression, particularly in crescents, co-localized with KP1 + PCNA + proliferating macrophages. There was also an increase in tubular M-CSF expression in most types of glomerulonephritis. Tubular M-CSF staining was strongest in areas of tubular damage and co-localized with KP1 + macrophages, including KP1 + PCNA + proliferating macrophages. Many interstitial macrophages and α-smooth muscle actin-positive myofibroblasts showed strong M-CSF staining. Statistical analysis showed a highly significant correlation between M-CSF expression and local macrophage proliferation in both the glomerulus and tubulointerstitium. Glomerular and tubular M-CSF expression gave a significant correlation with renal dysfunction. Conclusions. Glomerular and tubulointerstitial M-CSF expression is up-regulated in human glomerulonephritis, being most prominent in proliferative forms of disease. This correlated with local macrophage proliferation, suggesting that increased renal M-CSF production plays an important role in regulating local macrophage proliferation in human glomerulonephritis.

This article reviews the research literature on the effectiveness of paraprofessional counsellors and the impact of psychotherapy training on client outcome. Methodological and conceptual difficulties that have hampered previous research in this area are noted, and several well-designed individual studies are highlighted. The existing evidence supports the efficacy of paraprofessional counsellors, although professional training may lead to better outcome in specific areas, such as greater client retention, briefer therapy, and better overall wellbeing for clients. However, methodological limitations of the research prohibit definitive conclusions. Guidelines for future research are offered.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is a potent activator of macrophages and T cells. Previous studies have shown that local MIF production is increased in acute renal allograft rejection, suggesting that it may play an important role in the rejection process. AIMS: To determine if urine and serum MIF concentrations: (1) are increased in acute rejection, and (2) can be used as noninvasive tools to discriminate between acute rejection (AR) and cyclosporine nephrotoxicity (CyA toxicity). METHODS: In a prospective study of nine renal allograft patients (five acute rejection and four stable), serial urine MIF concentrations were measured by ELISA in the first 14 days after transplantation. In a retrospective study, MIF concentrations in urine and serum were measured in 24 patients who were biopsied for acute renal transplant dysfunction (11 AR, 13 CyA toxicity). Urine and serum MIF were also measured in 23 stable renal transplant patients and 10 normals. RESULTS: MIF was readily detected in the urine of normal healthy controls (106+/-61 pg/micromol creatinine). In the prospective study, the urinary MIF concentration was increased substantially on day 1 posttransplantation and subsequently fell in parallel with the serum creatinine. However, urine MIF increased before episodes of biopsy proven acute rejection. The retrospective study showed that urine MIF concentrations in patients with AR were increased 5-fold compared to normal controls (439+/-313 pg/micromol Cr; P

Interleukin-1 (IL-1) has been shown to exert profibrotic activity in a number of disease models, including crescentic glomerulonephritis and pulmonary fibrosis, but the mechanisms by which this operates are poorly understood. Recent studies have identified a novel mechanism promoting renal fibrosis: tubular epithelial-myofibroblast transdifferentiation (TEMT). The present study examined whether IL-1 can stimulate TEMT in vitro. Cells of the normal rat kidney tubular epithelial cell line (NRK52E) were grown to confluence on collagen-coated plates and cultured for 5 days in the presence 1 to 20 ng/mL of IL-1alpha. Doses of 10 to 20 ng/mL of IL-1 caused transdifferentiation of NRK52E cells into myofibroblast-like cells. Scanning electron microscopy identified IL-1-induced morphological changes as a loss of apical-basal polarity and microvilli, cell hypertrophy, and the development of an elongated and invasive appearance. Phenotypically, IL-1-induced TEMT was characterized by de novo messenger RNA and protein expression of the mesenchymal marker alpha-smooth muscle actin, shown by Northern blotting, immunohistochemistry, and Western blotting. This was accompanied by loss of the epithelial marker E-cadherin. The addition of an excess of IL-1-receptor antagonist completely inhibited IL-1-induced TEMT. IL-1 was shown to stimulate the secretion of active transforming growth factor-beta1 (TGF-beta1) by NRK52E cells. Furthermore, the addition of a neutralizing anti-TGF-beta1 antibody inhibited IL-1-induced TEMT. In conclusion, IL-1 is a profibrogenic cytokine capable of inducing TEMT through a TGF-beta1-dependent mechanism. This may represent a novel mechanism by which IL-1 induces renal fibrosis in vivo.

Diabetes and hypertension are major contributors to the increasing incidence of progressive renal disease. In addition to more potent antihypertensive agents that block the renin-angiotensin system, drugs that modulate other pathogenetic pathways are also in development. Recent preclinical studies indicate that compounds that interfere with the formation and action of advanced glycation end products may have a role in the treatment and prevention of diabetic nephropathy, as may agents targeting the activity of protein kinase C.

Between 34 and 15 million years (Myr) ago, when planetary temperatures were 3–4 °C warmer than at present and atmospheric CO2 concentrations were twice as high as today1, the Antarctic ice sheets may have been unstable2, 3, 4, 5, 6, 7. Oxygen isotope records from deep-sea sediment cores suggest that during this time fluctuations in global temperatures and high-latitude continental ice volumes were influenced by orbital cycles8, 9, 10. But it has hitherto not been possible to calibrate the inferred changes in ice volume with direct evidence for oscillations of the Antarctic ice sheets11. Here we present sediment data from shallow marine cores in the western Ross Sea that exhibit well dated cyclic variations, and which link the extent of the East Antarctic ice sheet directly to orbital cycles during the Oligocene/Miocene transition (24.1–23.7 Myr ago). Three rapidly deposited glacimarine sequences are constrained to a period of less than 450 kyr by our age model, suggesting that orbital influences at the frequencies of obliquity (40 kyr) and eccentricity (125 kyr) controlled the oscillations of the ice margin at that time. An erosional hiatus covering 250 kyr provides direct evidence for a major episode of global cooling and ice-sheet expansion about 23.7 Myr ago, which had previously been inferred from oxygen isotope data (Mi1 event5).