Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact.

Neurologic complications (NCs) may be a significant source of morbidity and mortality after hematopoietic cell transplantation (HCT). We performed a retrospective study of 263 consecutive patients undergoing allogeneic HCT for hematological malignancies to determine the incidence, risk factors and clinical impact of NCs in the first 5 years after HCT. We determined the incidence of central nervous system (CNS) infection, intracranial hemorrhage, ischemic stroke, metabolic encephalopathy, posterior reversal encephalopathy syndrome, seizure and peripheral neuropathy. In all, 50 patients experienced 63 NCs-37 early (⩽day +100), 21 late (day +101 to 2 years) and 5 very late (2 to 5 years). The 1- and 5-year cumulative incidences of all NCs were 15.6% and 19.2%, respectively, and of CNS complication (CNSC; all of the above complications except peripheral neuropathy) were 12.2 and 14.5%. Risk factors for CNSC were age (hazard ratio (HR)=1.06 per year, P=0.0034), development of acute GvHD grade III-IV (HR=2.78, P=0.041), transfusion-dependent thrombocytopenia (HR=3.07, P=0.025) and delayed platelet engraftment (>90th centile; HR=2.77, P=0.043). CNSCs negatively impacted progression-free survival (HR=2.29, P=0.0001), overall survival (HR=2.63, P<0.0001) and non-relapse mortality (HR=8.51, P<0.0001). NCs after HCT are associated with poor outcomes, and usually occur early after HCT.

Clinical value and safety of liver biopsies in patients transplanted for hepatitis C virus-related end-stage liver disease.

BACKGROUND: Hepatitis C is the leading indication for liver transplantation. Differentiation between recurrent graft hepatitis C (RGH-C) and graft rejection (GR) is challenging. Liver biopsy is standard to diagnose both conditions; however, little information is available regarding this procedure in hepatitis C virus (HCV)-infected liver transplant recipients. METHODS: Liver biopsies (n = 211) from all consecutive patients (n = 138) transplanted for hepatitis C at Hannover Medical School between January 2000 and October 2011 were screened, and a final cohort of 96 patients with 196 biopsies was included. Indications, histopathological findings, and biopsy-related complications were documented. Modifications in the treatment based on the biopsy result and the biochemical outcome were analyzed. RESULTS: Most biopsies (196/211, 93%) were representative. Five patients (2.5%) developed non-fatal biopsy-related complications. Biopsy results were GR (35%), RGH-C (31%), and other diagnoses (34%). GR was independently associated with lower albumin (P = 0.025) and higher bilirubin levels (P = 0.011). Treatment was modified based on the biopsy result in 25% of cases. Alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), and bilirubin levels improved in 41%, 25%, and 31% of cases 4 weeks post biopsy respectively. ALT improvements were more significant in patients with GR than in those with RGH-C. CONCLUSION: Liver biopsy in HCV-infected liver transplant recipients is safe and representative in >90% of cases. GR is independently associated with lower albumin and higher bilirubin levels.

Hepatitis C virus core antigen testing in liver and kidney transplant recipients.

HCV RNA levels correlate with the long-term outcome of hepatitis C in liver transplant recipients. Nucleic acid testing (NAT) is usually used to confirm HCV reinfection and to examine viral loads after liver transplantation. HCV core antigen (HCVcoreAg) testing could be an alternative to NAT with some potential advantages including very low intra- and interassay variabilities and lower costs. The performance of HCVcoreAg testing in organ transplant recipients is unknown. We prospectively studied 1011 sera for HCV RNA and HCVcoreAg in a routine real-world setting including 222 samples obtained from patients after liver or kidney transplantation. HCV RNA and HCVcoreAg test results showed a consistency of 98% with a very good correlation in transplanted patients (r > 0.85). The correlation between HCV RNA and HCVcoreAg was higher in sera with high viral loads and in samples from patients with low biochemical disease. Patients treated with tacrolimus showed a better correlation between both parameters than individuals receiving cyclosporine A. HCV RNA/HCVcoreAg ratios did not differ between transplanted and nontransplanted patients, and HCV RNA and HCVcoreAg kinetics were almost identical during the first days after liver transplantation. HCVcoreAg testing can be used to monitor HCV viral loads in patients after organ transplantation. However, the assay is not recommended to monitor antiviral therapies.

Enrichment of regulatory T cells in acutely rejected human liver allografts.

Acute cellular rejection (ACR) occurs frequently after liver transplantation and can usually be controlled. Triggering of allospecific immune responses and lack of immunoregulation are currently suggested as a cause of ACR, but there are no investigations of intrahepatic immune responses during ACR. Therefore we prospectively analyzed the intrahepatic T cell infiltration pattern in correlation to the severity of ACR in a cohort of patients with graft hepatitis (n = 151). While CD4(+) cells dominated the portal infiltrates in mild-moderate ACR, CD8(+) cells prevailed in severe ACR. Furthermore portal CD8(+) and not CD4(+) infiltration correlated with serum transaminases and with the likelihood of subsequent ACRs. Surprisingly, the rise of portal effector T cells density during ACR was surpassed by the increase in portal infiltration of regulatory T cells by a factor of two. Thus ACRs rather showed an increase and not a lack of regulation, as was suggested by analysis of peripheral blood mononuclear cells. Despite the pattern of enhanced immunoregulation, patients with severe ACR had a higher risk for subsequent rejections and showed a trend to a reduced survival. Thus, patients with severe rejections might need a modification of their immunosuppression to improve prognosis.

Fulminant hepatic failure due to chemotherapy-induced hepatitis B reactivation: role of rituximab.

Hepatitis B virus reactivation during immunosuppressive therapies can lead to liver failure with very limited treatment options available. We report here on two cases of severe hepatitis B reactivation during chemotherapy including rituximab for B cell lymphoma which were treated with liver or liver-cell transplantation. Liver function was normal and HBV infection was unknown in both patients before chemotherapy was started. Impaired liver function became apparent after 4 and 6 courses of chemotherapy, respectively, and both patients experienced fulminant hepatic failure despite antiviral treatment with lamivudine or entecavir. Patient A underwent liver transplantation after documentation of complete remission of the lymphoma and survived without any evidence for hepatitis B recurrence. Patient B received 4 courses of hepatocyte transplantation but did not survive. These cases underline the importance of anti-HBc screening in patients receiving immunosuppressive treatments in particular when rituximab is given. Pre-emptive antiviral treatments should be administered since delayed antiviral treatment is frequently unable to prevent liver failure.

[CMV-enterocolitis as a cause for repeated intestinal intussusceptions in an adult patient after liver transplantation?]. / CMV-Enterokolitis bei einer erwachsenen lebertransplantierten Patientin als Ursache rezidivierender Invaginationen?

Intestinal intussusception in the adult is often idiopathic but also known to be associated with chronic inflammatory bowel disease, coeliac disease, tumours or previous abdominal operations. A 22-year-old women after liver transplantation due to Crigler Najar Syndrome suffered from repeated episodes of abdominal pain. The diagnosis of repeated self-limited intestinal intussusceptions was made by computed tomography and ultrasonography. A laparoscopy revealed no cause for the intussusceptions. During a new episode of abdominal pain caused again by an intussusception a colonoscopy was performed that showed aspects of a discreet colitis. In the biopsies CMV was detected by qualitative PCR, while blood tests for CMV pp65 antigen were negative. A therapy with gancyclovir was initiated which lead to remission of the patient's symptoms. A colonoscopy six weeks later showed a completely normal colon, while in the biopsies CMV was not detectable. After a follow-up of one year the patient has not suffered from any further episodes. This case demonstrates the role of chronic intestinal CMV infection as a possible causative factor for repeated intussusceptions in immunosuppressed patients. Whenever possible a PCR for CMV in colon biopsies should be carried out to detect an intestinal CMV infection because as shown in our case results for immunohistopathology and CMV pp65 can be negative despite a chronic infection.

Comparison of outcomes of peritoneal dialysis catheters placed by the fluoroscopically guided percutaneous method versus directly visualized surgical method.

PURPOSE: To compare complications in catheters placed by the fluoroscopically guided percutaneous method versus directly visualized surgery. MATERIALS AND METHODS: A retrospective cohort analysis was performed. Mechanical complication rate data, including catheter leakage, malfunction, malposition, and bleeding, were compared between the two groups over a 1-year follow-up period. Additionally, exit site infection rates, tunnel infection rates, and peritonitis episodes were evaluated based on the incidence within 30 days of insertion and 30 days to 1 year after insertion. RESULTS: A total of 101 patients were analyzed (52 in the fluoroscopic guidance group, 49 in the direct visualization group). Prevalence of diabetes was similar: 56% in the directly visualized surgery group and 47% in the fluoroscopically guided treatment group (P = .37). Although the difference was not significant, complication rates tended to be higher in the directly visualized surgery group compared with the percutaneous placement group. These included catheter leakage (13% vs 4%; P = .093), malfunction (11% vs 9%; P = .73), malposition (13% vs 6%; P = .20), and bleeding (8% vs 2%; P = .21). There were no differences in early and late exit site infections and tunnel infections. Late peritonitis rates were lower in the percutaneous placement group (20%) than in the direct visualization group (42%) (P = .018). Diabetic patients had approximately six times greater risk of catheter malfunction than nondiabetic patients regardless of method of catheter insertion. CONCLUSIONS: Placement of peritoneal dialysis catheters percutaneously with fluoroscopic guidance is as safe as placement with direct visualization techniques.

Management of patients with chronic kidney disease at Kaiser Permanente.

In the Southern California Kaiser Permanente health plan, all patients having serum creatinine measured will automatically have their GFR reported. Those with reduced GFR are identified and classified into one of the five CKD stages. The PCPs are encouraged to be involved in the care of patients in CKD stages 1-3. Education, guidelines, and algorithms are provided to the PCPs, and nephrology consultation is encouraged. Patients in CKD stage 3 with significant risk factors for developing ESRD and those in CKD stages 4 and 5 are referred to nephrologists. Patients are encouraged to participate [table: see text] in their own care by attending the educational classes provided.

Impact of predialysis care on clinical outcomes.

INTRODUCTION: A structured predialysis multidisciplinary team program is beneficial in improving quality of life in patients with end-stage renal disease (ESRD). Educating pre-ESRD patients about their disease is vital in their care. Patients who can identify signs and symptoms of impending problems can seek help and avoid complications that may lead to hospital admissions. Our dialysis center offers two predialysis classes in a structured format. The first class is for those patients with mild to moderate renal disease, whereas the second class is for those with advanced renal disease who are expected to need dialysis in 3 to 6 months. The patients are followed by a multidisciplinary team once they are enrolled in our chronic kidney disease program. METHODS: We retrospectively reviewed all the charts of patients who started dialysis at our center between 1997 and 2000. We identified 68 patients who participated in the predialysis education program and 35 patients who did not because of late referral or refusal to participate. We compared these two groups over a 100-day period (10 days before initial dialysis and 90 days after), for hospitalizations, emergency room (ER) visits, and dialysis access placement. Patients' comorbid conditions, complications, and length of hospitalizations were extracted from the medical records. RESULTS: The 68 patients who completed the predialysis program had an average age of 60.3 years, a total of 96 hospital days, and 39 ER visits. Average length of hospital stay for these patients was 1.4 days. Three patients (4.4%) required placement of temporary catheters for the initial dialysis. Fifty-one percent of these patients had diabetes mellitus. The 35 patients of average age of 54.9 years who did not go through the program had 347 total hospital days and 39 ER visits. Average length of hospitalization was 9.9 days. Thirteen patients (37%) required temporary catheters for initial dialysis. This group included 16 patients (45.7%) with diabetes. CONCLUSION: Patients who participated in a multidisciplinary predialysis education program had fewer complications, ER visits, and hospitalizations. They also had fewer temporary catheter placements, shorter hospital stays, and reduced costs associated with initial dialysis.

Differential activation solution to the motion correspondence problem.

The correspondence problem arises in motion perception when more than one motion path is possible for discontinuously presented visual elements. Ullman's (1979) "minimal mapping" solution to the correspondence problem, for which costs are assigned to competing motion paths on the basis of element affinities (e.g., greater affinity for elements that are closer together), is distinguished from a solution based on the differential activation of directionally selective motion detectors. The differential activation account was supported by evidence that path length affects detector activation in a paradignm for which motion correspondence is not a factor. Effects on detector activation in this paradigm also were the basis for the successful prediction of path luminance effects on solutions to the motion correspondence problem. Finally, the differential activation account was distinguished from minimal mapping theory by an experiment showing that the perception of an element moving simultaneously in two directions does not depend on whether the two motions are matched in path-length determined affinity; it is sufficient that the activation of detectors responding to each of the two motion directions is above the threshold level required for the motions to be perceived. Implications of the differential activation solution are discussed for the stability of perceived motions once they are established, and the adaptation of perceived and unperceived motions.

Bistability in the perception of motion and stationarity: effects of temporal asymmetry.

Evidence for bistability in the perception of motion and stationarity was obtained for a displaced dot-figure embedded in a background of randomly moving noise dots. In the temporal symmetry condition, the figure was presented for the same duration in its two locations; either figure motion or random motion was perceived, depending on the number of noise dots. In the temporal asymmetry condition, the figure was presented for different durations in its two locations; figure motion, a single, stationary figure in a fixed position, or random noise was perceived, again depending on the number of noise dots. Competition between these percepts was established by an analysis of switching rates and by an experiment demonstrating the presence of hysteresis as noise levels were gradually increased and decreased across the figure-motion and figure-stationarity boundaries. This evidence for bistability in the perception of figure motion and figure stationarity (one or the other, but not both, was perceived for the same stimulus) suggested the presence of strong inhibitory competition between motion- and position-detecting mechanisms.

[Quality assurance and teamwork in social medicine expert assessment exemplified by the expert assessment aid "corrective breast surgery" of the North Rhine Health Insurance Medical Service]. / Qualitätssicherung und Mitarbeiterpartizipation in der Sozialmedizinischen Begutachtung am Beispiel der Begutachtungshilfe "korrektive Mamma-Chirurgie" des MDK Nordrhein.

To standardise sociomedical expertising procedures in surgery of the breast a project team of medical advisors of the Medical Advisory and Expertising Service North Rhine worked out a manual. A form was created for sociomedical pre-advice occasions. Detail parameters for examination (time needed and advisor selection) were fixed in consent. Checklists were worked out, which may be admitted to quality assurance procedures. The manual "Medical opinion for surgery of the breast" has been implemented and is applied in the Medical Advisory and Expertising Service North Rhine since January 1999. In the sense of teamwork participation those who were involved as team-workers became participants in decision-making. The manual "Medical opinion for surgery of the breast" may be seen as an example of quality assurance and participation in socio-medical opinion procedures. The influence of this manual on the formal quality of medical opinion will be checked.

Temporal organization in children's strategy formation.

It is well established that children use study behaviors such as card sorting, category naming, and item-by-item rehearsal to assist subsequent word recall. In this article, we provide evidence that these behaviors are organized into coherent temporal patterns. Fourier analyses of individual behaviors over a sequence of five consecutive study/recall trials indicated that sorting was synchronized with the start of each trial, whereas rehearsal tended to occur later in each trial. Fourier analyses of pairs of behaviors indicated that sorting and category naming, both concerned with categorization of the to-be-remembered words, co-occurred early in each trial at a greater rate than expected based on their individual frequencies of occurrence (i.e., they were used cooperatively). In contrast, verbal rehearsal of individual words co-occurred with both sorting and category naming at a lesser rate than would be expected based on their individual frequencies of occurrence. The results thus point to a global strategy in which children learn the items' categories before they learn them individually. There was little apparent qualitative difference in temporal organization for second- and fourth-grade children. However, sorting early in each trial was more pronounced for children with better word recall (regardless of grade), and the suppressed co-occurrence of rehearsal with sorting and category naming (i.e., keeping category learning temporally separate from item learning) was more pronounced for the fourth-grade children.

Attentional control of spatial scale: effects on self-organized motion patterns.

Prior to the presentation of a test stimulus, subjects' attentional state was either narrowly focused on a particular location or broadly spread over a large spatial region. In previous studies, it was found that broadly spread attention enhances the sensitivity of relatively large spatial filters (increasing the perceiver's spatial scale), thereby diminishing spatial resolution and enhancing sensitivity to global stimulus structure. In this study it is shown that attentional spread also affects the self-organization of unidirectional versus oscillatory motion patterns for the directionally ambiguous, counterphase presentation of rows of evenly-spaced visual elements (lines segments; dots); i.e. qualitatively different motion patterns can be formed for the same stimulus at different spatial scales. Although the degree to which attention is spread along a spatial axis can be controlled by the perceiver, the effects of spread attention are not limited to a single axis. These results, as well as previously observed effects of attentional spread on spatial resolution, are accounted for by a neural model involving large, foveally-centered receptive fields with co-operatively interacting subunits (probably at the level of MST or higher).

Dynamic, state-dependent thresholds for the perception of single-element apparent motion: bistability from local cooperativity.

Previous studies have indicated that the formation of coherent patterns for multielement motion displays depends on global cooperative interactions among large ensembles of spatially distributed motion detectors. These interactions enhance certain motion directions and suppress others. It is reported here that perceiving one element moving between two nearby locations likewise is subject to cooperative influences (possibly facilitating and inhibiting interactions within a local ensemble of overlapping detectors). Thresholds depending on luminance contrast were measured for a generalized single-element apparent-motion stimulus, and evidence for spontaneous switching and hysteresis effects indicated that motion perception near the 50% threshold was bistable. That is, for conditions in which motion and nonmotion were perceived half the time, the two percepts were distinct; when one was perceived, it clearly was discriminable from the other. These results indicated that (1) single-element apparent-motion thresholds depended on the immediately preceding state of the ensemble of motion detectors responding to the stimulus, and (2) the stimulus activation of individual motion detectors always might be influenced by recurrent, cooperative interactions resulting from the detectors' being embedded within interconnected ensembles.

The effect of attentional spread on spatial resolution.

The effects of attentional spread were studied by having subjects detect a luminance increment along a row of evenly spaced dots. The increment could occur for the central, fixated dot (Narrow Attention) or for either the fixation dot or one of the four dots to its left or right (Broad Attention). Narrow Attention enhanced the detection of luminance increments for the fixated dot, and also enhanced spatial resolution near the fixation dot for judgments of vernier alignment and separation. This indicated that the sensitivity of small spatial filters in the fovea was increased more by narrowly focused than broadly spread attention. Effects of attentional spread on spatial resolution were not obtained for judgments of the separation between two peripherally located targets, perhaps because of their dependence on eccentricity (position) rather than separation.

The influence of adaptation and stochastic fluctuations on spontaneous perceptual changes for bistable stimuli.

Spontaneous perceptual change was studied by measuring the probabilities of the first two spontaneous pattern switches as a function of time following the onset of a bistable apparent quartet for which either horizontal or vertical motion is perceived. Contrary to the classical satiation hypothesis (Köhler & Wallach, 1944), differential time-dependent adaptation of the perceived compared with the unperceived motion directions was not necessary to account for the first spontaneous switch. In addition, adaptation of the perceived motion accompanied by recovery from adaptation of the unperceived motion was not necessary to account for the increased probability of the second spontaneous switch. It was concluded that regardless of possible adaptation effects, stochastic fluctuations are necessary for the actual reversal of activation levels that produces the spontaneous switch. When the difference in detector activation is reduced by differential adaptation of competing motion detectors (or by the occurrence of a prior spontaneous pattern change), smaller stochastic fluctuations are sufficient to reverse the relative activation of competing detectors. Thus, adaptation can increase the probability of spontaneous switches without directly causing them.

Perceptual stability and the selective adaptation of perceived and unperceived motion directions.

Adaptation was studied in a paradigm in which the adapting stimulus was a variably biased version of a bistable apparent motion stimulus, a motion quartet, and the post-adaptation test stimulus was a "neutral" motion quartet. Either horizontal or vertical motion was perceived, never both at the same time. When only one of these was perceived during the entire adaptation phase of a trial, and the perceived motion was highly stable, adaptation effects were greater for the perceived than the unperceived motion directions (i.e., adaptation was selective to the perceived motion). However, when the perceived motion during adaptation was relatively unstable (i.e., when the perceived motion was more likely to spontaneously change directions), similar levels of adaptation were obtained for perceived as well as unperceived, but possible motion directions. Thus, adaptation occurs prior to the determination of which of the competing motion directions will be perceived. The relationship between the stability of the adapting percept and the selectivity of adaptation is explained in terms of differences in the activation of mutually inhibitory horizontal and vertical motion detectors.

Cooperative interactions and the perception of motion and stationarity for directionally ambiguous apparent-motion stimuli.

Evidence is reported that stationarity rather than motion can be perceived for displaced stimuli, not because of insufficient motion energy for the stimulus to activate individual motion detectors, but because of cooperative interactions that actively suppress the perception of motion. A long row of evenly spaced dots was presented in counterphase; the dots presented during each 180 ms frame were located midway between the dots presented during the previous frame. When either a blank interval as brief as 15 ms was inserted between successive frames or the luminance polarity of the dots was reversed on successive frames, the unidirectional motion pattern perceived for small interdot distances (small displacements) was replaced by the perception of stationarity. However, when under the same conditions a single dot was displaced over the same small distances, motion rather than stationarity was perceived. The contrasting results for the long row of displaced dots and the single displaced dot indicated that when the activation of motion detectors is weakened (by nonzero interframe intervals and/or the reversal of luminance polarity), the perception of motion can be actively suppressed by the collective effects of inhibitory interactions among the large ensemble of detectors that is activated by the long row of dots.

Context effects on perceived position: sustained and transient temporal influences on spatial interactions.

The effects of sustained and transient responses to inducing lines on the perceived position of nearby test lines were measured as constant errors in the vernier alignment of the test lines. The sustained response to the continued presence of the inducing lines had no effect on the perceived position of the test lines for very small inducing/test-line distances, and a repulsive effect for larger distances. Transient responses to the onset of the inducing lines had attractive effects for small distances, whereas transient responses to the offset of the inducing lines had repulsive effects for all distances tested. Attraction and repulsion effects on perceived position are accounted for by facilitating and inhibiting interactions that influence the relative sensitivities of an ensemble of position-selective detecting units.