Association of Volume and Outcomes in 234 556 Patients Undergoing Surgical Aortic Valve Replacement.

BACKGROUND: The relationship between institutional volume and operative mortality after surgical aortic valve replacement (SAVR) remains unclear. METHODS: From January 2013 to June 2018, 234 556 patients underwent isolated SAVR (n = 144 177) or SAVR with coronary artery bypass grafting (CABG) (n = 90 379) within the Society of Thoracic Surgeons Adult Cardiac Surgery Database. The association between annualized SAVR volume (group 1 [1-25 SAVRs], group 2 [26-50 SAVRs], group 3 [51-100 SAVRs], and group 4 [>100 SAVRs]) and operative mortality and composite major morbidity or mortality was assessed. Random effects models were used to evaluate whether historical (2013-2015) SAVR volume or risk-adjusted outcomes explained future (2016-2018) risk-adjusted outcomes. RESULTS: The annualized median number of SAVRs per site was 35 (interquartile range, 22-59; isolated aortic valve replacement [AVR], 20; AVR with CABG, 13). Among isolated SAVR cases, the mean operative mortality and composite morbidity or mortality were 1.5% and 9.7%, respectively, at the highest-volume sites (group 4), with significantly higher rates among progressively lower-volume groups (P trend < .001). After adjustment, lower-volume centers had increased odds of operative mortality (group 1 vs group 4 [reference]: adjusted odds ratio [AOR] for SAVR, 2.24 [95% CI, 1.91-2.64]; AOR for SAVR with CABG, 1.96 [95% CI, 1.67-2.30]) and major morbidity or mortality (AOR for SAVR, 1.53 [95% CI, 1.39-1.69]; AOR for SAVR with CABG, 1.46 [95% CI, 1.32-1.61]) compared with the highest-volume institutions. Substantial variation in outcomes was observed across hospitals within each volume category, and prior outcomes explained a greater proportion of hospital operative outcomes than did prior volume. CONCLUSIONS: Operative outcomes after SAVR with or without CABG is inversely associated with institutional procedure volumes; however, prior outcomes are more predictive of future outcomes than is prior volume. Given the excellent outcomes observed at many lower-volume hospitals, procedural outcomes may be preferable to procedural volumes as a quality metric.

Harnessing 64Cu/67Cu for a theranostic approach to pretargeted radioimmunotherapy.

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels-Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

The relationship between minority stress and biological outcomes: A systematic review.

Sexual minority (non-heterosexual) individuals experience higher rates of physical health problems. Minority stress has been the primary explanatory model to account for this disparity. The purpose of this study was to identify in published research empirically established relationships between minority stress processes and biological outcomes and identify avenues for future research. The PubMed database was queried with search terms relevant to minority stress and a comprehensive list of physical and biological outcomes. To be included in the analysis, studies had to examine the relationship between minority stress and a biological outcome among sexual minority individuals. Those meeting inclusion criteria were coded for key variables including methodology used, positive and null results, participant characteristics, and specific minority stress processes and biological outcomes considered. In total, 26 studies met inclusion criteria. Studies tested relationships between specific minority stress processes including prejudice, expectations of prejudice, concealment of sexual orientation, and internalized stigma and multiple biological outcomes, such as overall physical health, immune response, HIV specific outcomes, cardiovascular outcomes, metabolic outcomes, cancer related outcomes, and hormonal outcomes. Studies included both analyses that detected this relationship (42% of analyses) and analyses that did not detect this relationship (58%). There is substantial evidence to support the relationship between minority stress and biological outcomes, yet additional research is needed to identify the measurements and outcomes that have the most rigorous and replicable results.

Dual Radionuclide Theranostic Pretargeting.

Recent years have played witness to the advent of nuclear theranostics: the synergistic use of "matched pair" radiopharmaceuticals for diagnostic imaging and targeted radiotherapy. In this investigation, we report the extension of this concept to in vivo pretargeting based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between tetrazine (Tz) and trans-cyclooctene (TCO). We demonstrate that a single injection of a TCO-modified immunoconjugate can be used as a platform for pretargeted PET imaging and radiotherapy via the sequential administration of a pair of Tz-bearing radioligands labeled with the positron-emitting radiometal copper-64 (t1/2 ≈ 12.7 h) and the beta-emitting radiometal lutetium-177 (t1/2 ≈ 6.7 days). More specifically, a mouse model of human colorectal carcinoma received a dose of the A33 antigen-targeting immunoconjugate huA33-TCO, followed 24 and 48 h later by injections of [64Cu]Cu-SarAr-Tz and [177Lu]Lu-DOTA-PEG7-Tz, respectively. This approach produces high activity concentrations of both radioligands in tumor tissue (16.4 ± 2.7 %ID/g for [64Cu]Cu-SarAr-Tz at 48 h post-injection and 18.1 ± 2.1 %ID/g for [177Lu]Lu-DOTA-PEG7-Tz at 120 h post-injection) as well as promising tumor-to-healthy organ activity concentration ratios. Ultimately, we believe that this work could not only have important implications in nuclear theranostics-most excitingly with isotopologue-based radioligand pairs such as [64Cu]Cu-SarAr-Tz and [67Cu]Cu-SarAr-Tz-but also in the delivery of fractionated doses during pretargeted radioimmunotherapy.

Ipilimumab cystic hypophysitis mimicking metastatic melanoma.

Ipilimumab is an immunotherapeutic agent used in the treatment of metastatic melanoma, and is known to cause hypophysitis in some patients. Magnetic resonance imaging of ipilimumab-induced hypophysitis typically shows diffuse enlargement of the pituitary gland with variable enhancement or enlargement of the infundibulum. This often produces a diagnostic dilemma as melanoma not uncommonly metastasizes to the pituitary gland due to the rich vascular plexus of the hypophyseal portal system, and has a similar imaging appearance to autoimmune hypophysitis. We present a case of a 49-year-old man with a Clark level 4 melanoma of the left calf with inguinal nodal metastases that was treated with resection and 2 cycles of ipilimumab, and subsequently developed a "cystic" pituitary mass. To our knowledge, all of the described cases of ipilimumab-induced hypophysitis to date have shown solid enhancement on imaging. Because metastatic melanoma to the pituitary gland often has internal hemorrhage that produces a "cystic" appearance, and ipilimumab-induced hypophysitis is typically a solidly enhancing abnormality, this presented a significant diagnostic and therapeutic dilemma. Our patient's symptoms, although significant, did not necessitate immediate surgical intervention, and a conservative approach of withholding the ipilimumab and administering therapeutic corticosteroids was pursued. The patient's symptoms abated and follow-up magnetic resonance imaging 1 month later showed near complete resolution of the pituitary abnormalities. As such, this is a unique case of ipilimumab-induced hypophysitis presenting as a "cystic" pituitary mass.

Infrared radiative properties and thermal modeling of ceramic-embedded textile fabrics.

The infrared optical properties of textiles are of great importance in numerous applications, including infrared therapy and body thermoregulation. Tuning the spectral response of fabrics by the engineering of composite textile materials can produce fabrics targeted for use in these applications. We present spectroscopic data for engineered polyester fabric containing varying amounts of ceramic microparticles within the fiber core and report a spectrally-dependent shift in infrared reflectance, transmittance and absorptance. A thermal transport model is subsequently implemented to study the effect of these modified properties on the spectral distribution of infrared radiation incident upon the wearer of a garment constructed of this fabric.

Patients' and clinicians' experiences of holistic needs assessment using a cancer distress thermometer and problem list: A qualitative study.

PURPOSE: Psychosocial needs assessment is recommended for patients undergoing cancer treatment, but trials of effectiveness of assessment tools provide mixed results. This qualitative study aimed to understand how such tools are experienced by patients and clinicians in order to optimise use in the future. METHODS: Qualitative interviews were used in a mixed-methods sequential design following a randomised controlled trial of needs assessment using the Distress Thermometer and Problem List (DT&PL), and explored patients' and clinicians' evaluations of the needs assessment process. RESULTS: Benefits of needs assessment using the DT&PL included the potential to detect hidden distress, allow opportunity for distress to be discussed, and to deliver outcomes to address problems. However, effectiveness and patient willingness to report all forms of distress could be hindered by: clinicians feeling ill-equipped to deal with 'non-physical' distress and patients questioning their appropriateness to do so; time constraints; insufficient support services and referral guidelines; inappropriate timing; and lack of follow-up. CONCLUSIONS: The benefits of a holistic needs assessment cannot be realised without matching time and frequency of administration to the dynamic nature of distress during cancer, and making changes to the context of delivery - for instance, providing protected time, increasing referral options and clinician training. Significant investment is needed to optimise potential benefits for patients.

Extracellular matrix fibronectin initiates endothelium-dependent arteriolar dilatation via the heparin-binding, matricryptic RWRPK sequence of the first type III repeat of fibrillar fibronectin.

KEY POINTS: The local arteriolar dilatation produced by contraction of skeletal muscle is dependent upon multiple signalling mechanisms. In addition to the many metabolic signals that mediate this vasodilatation, we show here that the extracellular matrix protein fibronectin also contributes to the response. This vasodilatory signal requires the heparin-binding matricryptic RWRPK sequence in the first type III repeat of fibrillar fibronectin. The fibronectin-dependent component of the integrated muscle contraction-dependent arteriolar vasodilatation is coupled through an endothelial cell-dependent signalling pathway. Recent studies in contracting skeletal muscle have shown that functional vasodilatation in resistance arterioles has an endothelial cell (EC)-dependent component, and, separately have shown that the extracellular matrix protein fibronectin (FN) contributes to functional dilatation in these arterioles. Here we test the hypotheses that (i) the matricryptic heparin-binding region of the first type III repeat of fibrillar FN (FNIII1H) mediates vasodilatation, and (ii) this response is EC dependent. Engineered FN fragments with differing (defined) heparin- and integrin-binding capacities were applied directly to resistance arterioles in cremaster muscles of anaesthetized (pentobarbital sodium, 65 mg kg(-1)) mice. Both FNIII1H,8-10 and FNIII1H induced dilatations (12.2 ± 1.7 µm, n = 12 and 17.2 ± 2.4 µm, n = 14, respectively) whereas mutation of the active sequence (R(613) WRPK) of the heparin binding region significantly diminished the dilatation (3.2 ± 1.8 µm, n = 10). Contraction of skeletal muscle fibres via electrical field stimulation produced a vasodilatation (19.4 ± 1.2 µm, n = 12) that was significantly decreased (to 7.0 ± 2.7 µm, n = 7, P < 0.05) in the presence of FNIII1Peptide 6, which blocks extracellular matrix (ECM) FN and FNIII1H signalling. Furthermore, FNIII1H,8-10 and FNIII1H applied to EC-denuded arterioles failed to produce any dilatation indicating that endothelium was required for the response. Finally, FNIII1H significantly increased EC Ca(2+) (relative fluorescence 0.98 ± 0.02 in controls versus 1.12 ± 0.05, n = 17, P < 0.05). Thus, we conclude that ECM FN-dependent vasodilatation is mediated by the heparin-binding (RWRPK) sequence of FNIII1 in an EC-dependent manner. Importantly, blocking this signalling sequence decreased the dilatation to skeletal muscle contraction, indicating that there is a physiological role for this FN-dependent mechanism.

National Health Models and the Adoption of E-Health and E-Prescribing in Primary Care - New Evidence from Europe.

OBJECTIVE: Recent research from the European Commission (EC) suggests that the development and adoption of eHealth in primary care is significantly influenced by the context of the national health model in operation. This research identified three national health models in Europe at this time - the National Health Service (NHS) model, the social insurance system (SIS) model and the transition country (TC) model, and found a strong correlation between the NHS model and high adoption rates for eHealth. The objective of this study is to establish if there is a similar correlation in one specific application area - electronic prescribing (ePrescribing) in primary care. METHODS: A review of published literature from 2000 to 2014 was undertaken covering the relevant official publications of the European Union and national government as well as the academic literature. An analysis of the development and adoption of ePrescribing in Europe was extracted from these data. RESULTS: The adoption of ePrescribing in primary care has increased significantly in recent years and is now practised by approximately 32% of European general practitioners. National ePrescribing services are now firmly established in 11 countries, with pilot projects underway in most others. The highest adoption rates are in countries with the NHS model, concentrated in the Nordic area. The electronic transmission of prescriptions continues to pose a significant challenge, especially in SIS countries and TCs. CONCLUSIONS: There is a strong correlation between the NHS model and high adoption rates for ePrescribing similar to the EC findings on the adoption of eHealth. It may be some time before many SIS countries and TCs reach the same adoption levels for ePrescribing and eHealth in primary care as most NHS countries.

Are needs assessments cost effective in reducing distress among patients with cancer? A randomized controlled trial using the Distress Thermometer and Problem List.

PURPOSE: Patients with cancer have a high prevalence of distress. We evaluated whether distress monitoring and needs assessment using the Distress Thermometer and Problem List (DT&PL) improved patient outcomes. PATIENTS AND METHODS: We conducted an unblinded, two-arm, parallel randomized controlled trial at two sites among patients starting radiotherapy or chemotherapy. The intervention group completed the DT&PL, rating distress and discussing sources of distress with a trained radiographer/nurse. No specific triage algorithms were followed. The control group received usual care. The main outcome measure was psychological distress (Profile of Mood States [POMS], short form) up to 12 months; secondary outcomes were quality of life (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30) and health care costs. RESULTS: Of 220 patients randomly assigned, 112 patients were allocated to the DT&PL. Ninety-five percent completed the primary outcome at 12 months. The DT&PL took 25 minutes; one third of patients had high levels of distress, and most reported physical (84%) or emotional (56%) problems. There was no evidence of an effect of the DT&PL on adjusted POMS scores over follow-up (difference between groups, -1.84; 95% CI, -5.69 to 2.01; P = .35) or in secondary outcomes. The DT&PL cost £19 ($28) per patient and did not lower subsequent health care costs. Few patients (< 3%) in either arm of the trial were referred to a clinical psychologist. CONCLUSION: Patients with cancer have a high prevalence of distress. Needs assessment can be performed quickly and inexpensively. However, the DT&PL was not cost effective in improving patient mood states. It is important to explore the reasons for this so that oncology units can design better services to support patients.

A discursive psychology analysis of emotional support for men with colorectal cancer.

Recent research into both masculinity and health, and the provision of social support for people with cancer has focused upon the variations that may underlie broad assumptions about masculine health behaviour. The research reported here pursues this interest in variation by addressing the discursive properties of talk about emotional support, by men with colorectal cancer - an understudied group in the social support and cancer literature. Semi-structured interviews were conducted with eight men with colorectal cancer, and the transcripts were analysed using an intensive discursive psychology approach. From this analysis, two contrasting approaches to this group of men's framing of emotional support in the context of cancer are described. First, talk about cancer was positioned as incompatible with preferred masculine identities. Second, social contact that affirms personal relationships was given value, subject to constraints arising from discourses concerning appropriate emotional expression. These results are discussed with reference to both the extant research literature on masculinity and health, and their clinical implications, particularly the advice on social support given to older male cancer patients, their families and friends.

Long-term outcomes after transmyocardial revascularization.

BACKGROUND: Two independent reports documented substantially higher operative mortality associated with transmyocardial revascularization (TMR) when used in isolation than that reported in the premarket clinical trials. To clarify the state of the art, this article assesses temporal trends in the use of TMR, short-term and long-term outcomes, and outcomes stratified by procedure type (TMR only and TMR + coronary artery bypass graft [CABG]) and by the 2 specific TMR devices. METHODS: The study population included all patients undergoing TMR in isolation or in combination with CABG at 435 cardiothoracic hospitals in the United States participating in the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD) from January 2000 through November 2006 (n = 15,386). Analysis of long-term outcomes was accomplished through linkage to Medicare claims data. Short-term and long-term (7 years) adverse outcomes were assessed and compared between the 2 TMR device types. RESULTS: The use of TMR in conjunction with CABG surgery is increasing. This study showed modest differences in short-term morbidity and mortality between the 2 devices. In combination with CABG, after risk adjustment, patients treated with the holmium:YAG laser (experienced a higher rate of operative mortality (3.5% vs 2.5%; adjusted hazard ratio 1.39, 95% confidence level 1.03 to 1.87) but no difference in the composite short-term rate of major morbidity or mortality, compared with the Heart Laser CO2 transmyocardial revascularization system (PLC Medical Systems, Inc, Milford, MA). However, there were no clinically meaningful differences in long-term results. CONCLUSIONS: Modest differences in short-term morbidity and mortality between the 2 devices suggest the usefulness of further research.

Refinement of the distress management problem list as the basis for a holistic therapeutic conversation among UK patients with cancer.

OBJECTIVE: Originally devised in the USA, the Distress Thermometer is being deployed in many cancer settings in the UK. It is commonly used with a Problem List (PL), which has never been validated with a UK population. This study aimed to refine the PL items based upon the concerns of a sample of UK patients attending a regional cancer centre. METHODS: Existing versions of the PL were scrutinised by a focus group comprising five ex-patients, six health care staff and two academics. This group considered the intelligibility, ambiguity and redundancy of items, sometimes making alternative suggestions or pooling items. The resulting 46 candidate items were sent to 735 patients with mixed cancer, asking them to endorse items that had been 'a source of concern or distress' during their recently finished treatment. We used multivariate logistic regression to evaluate the association between the prevalence of problems and patient characteristics. RESULTS: In this study, 395 (53%) people responded. 'Fatigue, exhaustion or extreme tiredness' (70%), 'worry, fear or anxiety' (45%) and 'sleep problems' (38%) were the most frequently endorsed items. Items not appearing on the original PL were commonly endorsed such as 'memory or concentration' (30%) and 'loneliness or isolation' (15%), suggesting that they should be routinely included in the Distress Thermometer Problem List. CONCLUSIONS: The current study offers a more comprehensive PL, on the basis of actual patients' concerns, using words that are understood by UK patients. The reluctance of some patients to volunteer their concerns suggests that screening for distress should be undertaken within the context of a structured conversation.

The E-box binding factors Max/Mnt, MITF, and USF1 act coordinately with FoxO to regulate expression of proapoptotic and cell cycle control genes by phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase 3 signaling.

Phosphatidylinositol (PI) 3-kinase/Akt signaling plays a critical role in cell proliferation and survival, partly by regulation of FoxO transcription factors. Previous work using global expression profiling indicated that inhibition of PI 3-kinase in proliferating cells led to induction of genes that promote cell cycle arrest and apoptosis. The upstream regulatory regions of these genes had binding sites not only for FoxO, but also for Myc/Max transcription factors. In the present study, we have addressed the role of Myc family members and related E-box-binding proteins in the regulation of these genes. Chromatin immunoprecipitations and RNA interference indicated that transcription was repressed by Max-Mnt-Sin3a-histone deacetylase complexes in proliferating cells. Inhibition of PI 3-kinase led to a loss of Max/Mnt binding and transcriptional induction by MITF and USF1, as well as FoxO. Both MITF and USF1 were activated by glycogen synthase kinase (GSK) 3, with GSK3 phosphorylation sites on USF1 identified as the previously described activating site threonine 153 as well as serine 186. siRNA against MITF as well as against FoxO3a protected cells from apoptosis following PI 3-kinase inhibition. These results define a novel E-box-regulated network that functions coordinately with FoxO to regulate transcription of apoptotic and cell cycle regulatory genes downstream of PI 3-kinase/Akt/GSK3 signaling.

Fully integrated microfluidic platform enabling automated phosphoprofiling of macrophage response.

The ability to monitor cell signaling events is crucial to the understanding of immune defense against invading pathogens. Conventional analytical techniques such as flow cytometry, microscopy, and Western blot are powerful tools for signaling studies. Nevertheless, each approach is currently stand-alone and limited by multiple time-consuming and labor-intensive steps. In addition, these techniques do not provide correlated signaling information on total intracellular protein abundance and subcellular protein localization. We report on a novel phosphoFlow Chip (pFC) that relies on monolithic microfluidic technology to rapidly conduct signaling studies. The pFC platform integrates cell stimulation and preparation, microscopy, and subsequent flow cytometry. pFC allows host-pathogen phosphoprofiling in 30 min with an order of magnitude reduction in the consumption of reagents. For pFC validation, we monitor the mitogen-activated protein kinases ERK1/2 and p38 in response to Escherichia coli lipopolysaccharide (LPS) stimulation of murine macrophage cells (RAW 264.7). pFC permits ERK1/2 phosphorylation monitoring starting at 5 s after LPS stimulation, with phosphorylation observed at 5 min. In addition, ERK1/2 phosphorylation is correlated with subsequent recruitment into the nucleus, as observed from fluorescence microscopy performed on cells upstream of flow cytometric analysis. The fully integrated cell handling has the added advantage of reduced cell aggregation and cell loss, with no detectable cell activation. The pFC approach is a step toward unified, automated infrastructure for high-throughput systems biology.

Clinical outcomes and complications associated with pedicle screw fixation-augmented lumbar interbody fusion.

OBJECT: The authors conducted a prospective study to evaluate the clinical and radiological outcomes and complications associated with uni- and bilateral transforaminal lumbar interbody fusion (TLIF) performed using carbon fiber Brantigan I/F Cages and pedicle screw fixation. METHODS: Forty-two consecutive patients who had undergone uni- or bilateral TLIF between February 1999 and July 2000 were prospectively evaluated. Clinical outcome was graded using a modified Prolo Scale, the McGill Pain Index Scale, a follow-up questionnaire, and charts. An independent radiologist assessed radiological outcomes. All patients were followed for at least 1 year. Based on Prolo Scale scores, an excellent or good 1-year outcome was achieved in 73% of patients; 90% of patients responded that they would undergo the procedure again. At 1 year, radiographic fusion was demonstrated in 74% and was statistically related to clinical outcome (p < 0.05). There were no deaths or major hardware failures. Complications requiring repeated surgery included one case of cerebrospinal fluid (CSF) leakage and one case in which the hemovac drain was retained. There were four cases involving minor wound infections, eight involving CSF leaks, and none requiring repeated surgery. On routine follow-up radiography one pedicle screw was found to be broken; the patient remained asymptomatic and fusion occurred. CONCLUSIONS: Unilateral and bilateral TLIF involving placement of carbon fiber cages and pedicle screw fixation are effective treatment options in patients with indications for lumbar arthrodesis. The procedures result in acceptable rates of fusion and clinical success, and a minimal incidence of morbidity when performed by an experienced surgeon.

Treatment of C4d-positive acute humoral rejection with plasmapheresis and rabbit polyclonal antithymocyte globulin.

BACKGROUND: Alloantibody-mediated acute rejection is a major cause of renal allograft loss despite aggressive therapy. Patients with humoral rejection can be identified with high sensitivity and specificity by the presence of peritubular capillary C4d staining on renal biopsy and donor-specific anti-human leukocyte antigen antibodies. Standard therapy for acute humoral rejection (AHR) has been removal of donor-specific antibodies by plasmapheresis (PPH) in conjunction with intravenous immunoglobulin therapy. We describe a series of seven patients with C4d positive AHR who received combined therapy with PPH and polyclonal rabbit antithymocyte globulin (rATG). METHODS: PPH (1.4 volume exchange) was initiated on diagnosis of AHR on an alternate day basis for a mean number of 6.8 treatments, in conjunction with rATG (0.75 mg/kg/day 5-10 days) until the serum creatinine returned to 120% of nadir. RESULTS: The nadir posttreatment creatinine was significantly lower than pretreatment creatinine (1.0+/-1.2 vs. 2+/-1.4, P <0.007) with only one episode of graft loss. On follow-up there was no difference in renal allograft survival between the AHR group and the 60 patients without AHR who underwent transplantation during the same period. We describe the ability of rATG to induce apoptosis in vitro peripheral blood and activated B cells. CONCLUSION: Combination therapy using PPH and rATG is an effective means of reversing AHR in renal allografts.

Immunohistochemical labeling of normal melanocytes.

Comparison of seven antibodies for the demonstration of normal melanocytes in formalin-fixed, paraffin-embedded surgical discard skin showed that the monoclonal antibody Mel-5 (clone TA99) directed against pigment associated antigen was the most sensitive. Quantitative data were obtained for the sensitivity of the antibodies NKI/beteb, S100, T311, Melan A (clone A103), c-kit, and Mel-5 in parallel sections of human skin. An anticytokeratin antibody (CK34betaE12) was also used to stain basal keratinocytes and provide a negative image of the melanocytes present. Optimal conditions for the use of Mel-5 in paraffin sections of skin are described.