Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation.

BACKGROUND: Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). OBJECTIVES: To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. METHODS: Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)-1beta, IL-6, IL-8 and TNFalpha. RESULTS: Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up-regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL-expression shown when blocking NK1R. CONCLUSION: Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system.

Validation of 'ItchApp©' in Poland and in the USA: multicentre validation study of an electronical diary for the assessment of pruritus.

BACKGROUND: Although chronic pruritus affects a large part of the population, its reliable assessment remains difficult. Electronical diaries (eDiaries) are often used in multicentre clinical trials. The ItchApp© for Android was developed to assess itch intensity and course and was validated for the German language in 2017. OBJECTIVE: To validate ItchApp© for the use in the Polish and US English languages. METHODS: Fifty-three subjects in Poland and thirty subjects in the USA with chronic pruritus completed the paper-based and app-based questionnaires. These questionnaires contained items for measuring the itch intensity, including a numerical rating scale (NRS) and verbal rating scale (VRS), and for detecting the change of pruritus since the beginning of treatment. RESULTS: The ItchApp© showed a high level of test-retest reliability [Intraclass correlation, Kappa and Kendall-Tau B coefficients: 0.915-1.000 (Poland) and 0.863-1.000 (USA)]. The convergent validity showed strong correlation between the itch intensity scales on the ItchApp© (Items II-IV = VRS mean, NRS mean and NRS worst) and the paper-based itch intensity scales (mean and worst: VRS, NRS, VAS) [Spearman-Rho and Pearson correlation coefficients: 0.710-0.987 (Poland) and 0.646-0.954 (USA)]. The ItchApp© items moderately correlated with the ItchyQol scores [Spearman-Rho and Pearson correlation coefficients: 0.303-0.554 (Poland) and 0.275-0.447 (USA)]. After completing the ItchApp© questionnaire, a feasibility questionnaire was completed and showed that subjects feel the app is well suited for assessing pruritus. CONCLUSION: We provide evidence for the ItchApp© as a validated eDiary for the assessment of pruritus in Polish and US English languages, enabling its use in multicentre international clinical trials.

Prurigo Activity Score (PAS): validity and reliability of a new instrument to monitor chronic prurigo.

BACKGROUND: Currently available tools to monitor patients with chronic prurigo over time focus on pruritus and quality of life parameters, while no instrument objectively assessing the pruriginous lesions is yet available. OBJECTIVE: The objective of this study was to develop a physician-assessed Prurigo Activity Score (PAS), a new tool to monitor the distribution and activity of chronic prurigo lesions and to evaluate its reliability and validity. METHODS: The 7-item PAS questionnaire as well as validated pruritus intensity scales (VAS, NRS) and a skin-related quality of life score (DLQI) were completed for 264 patients (172 females, age 61 years) at least twice over a period of 2 years. In addition, a 60-min test-retest reliability test was performed by four experts for a random sample of 12 patients. RESULTS: The PAS showed good test-retest reliability (Cohens κ > 0.61; Cronbach-alpha > 0.76), ordinal or metric items showed high inter-rater reliability (Kendalls > 0.61) and items recording the number of lesions correlated significantly to each other (P < 0.001). The highest correlation to external constructs was achieved with DLQI. The feasibility test conducted by four raters indicated the suitability of PAS for tracking chronic prurigo in the clinical setting. DISCUSSION: The PAS is a useful tool to objectively monitor pruriginous lesions in chronic prurigo patients over time. The sensitivity of change in the PAS score should be analysed in future studies.

Development of genotyping method for functionally relevant variants of cytochromes P450 in cynomolgus macaques.

In cynomolgus macaques (Macaca fascicularis), widely used in drug metabolism studies, CYP2C9, CYP2C76, CYP2D6, CYP3A4, and CYP3A5, important drug-metabolizing enzymes, are abundantly expressed in liver and metabolize cytochrome P450 substrates. CYP2C9 (c.334A>C), CYP2C76 (c.449TG>A), CYP2D6 (c.891A>G), CYP3A4 (IVS3 + 1G>del), and CYP3A5 (c.625A>T) substantially influence metabolic activity of enzymes, and thus are important variants in drug metabolism studies. In this study, a real-time PCR method was developed for genotyping these variants. The validity of the methods was verified by genotyping two wild type, two heterozygous, and two homozygous DNAs and was used to genotype 41 cynomolgus macaques (from Cambodia, Indonesia, the Philippines, or Vietnam) for the five variants, along with another important variant CYP2C19 (c.308C>T). The CYP2C9 and CYP2C19 variants were found only in Cambodian and Vietnamese animals, while the CYP2C76 and CYP2D6 variants were found only in Indonesian and Philippine animals. The CYP3A4 and CYP3A5 variants were not found in any of the animals analyzed. Mauritian animals, genotyped using next-generation sequencing data for comparison, possessed the CYP2C19 and CYP2D6 variants, but not the other variants. These results indicated differences in prevalence of these important variants among animal groups. Therefore, the genotyping tool developed is useful for drug metabolism studies using cynomolgus macaques.

Chronic pruritus: evaluation of patient needs and treatment goals with a special regard to differences according to pruritus classification and sex.

BACKGROUND: Chronic pruritus (CP) is present in approximately one-third of all dermatological patients. Diagnostics and treatment are challenging and impair patients' quality of life. OBJECTIVES: To analyse therapeutic needs in terms of the importance of treatment goals in a large sample of patients with CP. METHODS: Routine data of 2747 patients with CP were analysed with descriptive methods and significance tests (univariate and multivariate variance analyses). The importance of 27 need items was measured using the Patient Needs Questionnaire of the Patient Benefit Index. RESULTS: The most important needs were to find a clear diagnosis and treatment, to no longer experience itching and to have confidence in the therapy, which were quite or very important to > 90% of the patients. The least important goals concerned a normal working or sex life. Nine needs related mostly to disease and psychological symptoms, and some social needs differed in importance between sexes (P ≤ 0·05). Patients with pruritus on inflamed skin or with chronic scratch lesions judged more than half of all needs as more important than did patients with pruritus on noninflamed skin (P ≤ 0·05). In the multivariate model, age, pruritus intensity and quality of life had a significant effect on the importance of therapeutic needs besides sex and pruritus classification. CONCLUSIONS: Patients with CP present high levels of various therapeutic needs with differences by sex and clinical phenotype. The most important needs can be addressed through medical activities such as appropriate itch medication and a trustful doctor-patient relationship.

Photoexcited carrier dynamics of double-layered CdS/CdSe quantum dot sensitized solar cells measured by heterodyne transient grating and transient absorption methods.

The charge dynamics in the double-layered quantum dot sensitized solar cell (QDSSC) was studied to clarify the reason why the cell performance was much improved by a double-layer coating, by using the heterodyne transient grating (HD-TG) and transient absorption methods, based on a previous study for a conventional QDSSC (N. Maeda et al., Phys. Chem. Chem. Phys., 2013, 15, 11006.) In the double-layered QDSSC, the layer order of CdS and CdSe affected the cell performance. When CdS is in between TiO2 and CdSe, the conversion efficiency was enhanced by 70%, while it was lowered by 50% in the opposite order. From the information on charge dynamics, it was found that electrons were efficiently injected to TiO2 by appropriate band alignment of CdS and CdSe, while only a part of the electrons were transferred to the TiO2 when the layer order was opposite. Furthermore, the reverse electron transfer does not matter for the conversion efficiency, because the process increased even for the appropriate layer order.

Gender differences in chronic pruritus: women present different morbidity, more scratch lesions and higher burden.

BACKGROUND: Although sex and gender are increasingly perceived as important factors in medicine, there is only very little knowledge on these issues in patients with chronic pruritus (CP). OBJECTIVES: The aim of this retrospective study was to compare multiple parameters of CP in a large representative group of patients and to assess any sex and gender differences. METHODS: Patients (n = 1037, 54·8% women) with CP (> 6 weeks' duration) were analysed concerning gender differences in multiple parameters, including quality of life, CP-underlying diseases, co-morbidities and clinics. We used McNemar tests for dependent variables, and χ(2) tests and t-tests for independent variables, to evaluate gender-specific differences. RESULTS: Men were significantly older (P < 0·001) than women and had significantly more often cardiovascular (P < 0·001) and urogenital (P < 0·0001) co-morbidities, a higher number of co-medications (P = 0·041), and more often dermatological and systemic diseases leading to CP. Women had more neuropathic and psychosomatic diseases underlying the CP. They significantly more often showed a worsening of the CP by emotional (P = 0·002) and psychosomatic factors (P = 0·046). Women reported more often on localized itching occurring in attacks, with stinging, warmth and painful qualities (P < 0·05). Women significantly more often showed chronic scratch lesions and prurigo nodularis (P = 0·001), in contrast to men who significantly more frequently had CP on noninflamed skin (P = 0·004). In addition, women obtained higher visual analogue scale scores (P = 0·031) and reported a higher impact on quality of life (P = 0·033) than men. CONCLUSIONS: There are gender-specific differences not only in the quality, localization and triggering of CP but also in the underlying disease and scratching behaviour. These facts must be taken into account in the medical care of patients with CP and when conducting any kind of clinical research on itch. Further research is needed to achieve a gender-specific and gender-adapted diagnostics and treatment of CP.

[Histopathology and microbiology of joint infections: extension of diagnostic safety in patients with chronic polyarthritis]. / Histopathologie und Mikrobiologie bei Gelenkinfekten : Erweiterung der Diagnostiksicherheit bei Patienten mit chronischer Polyarthritis.

BACKGROUND: It can be difficult to distinguish between synovitis due to rheumatism and synovitis due to a bacterial infection. Microbiological detection of bacteria is not always successful and the clinical significance of low virulent bacteria often remains uncertain. Therefore, the histopathological finding of inflammatory reactions is very important. STUDY DESIGN AND METHODS: From patients with clinically clear signs of infections and rheumatoid arthritis who underwent surgery between April and August 2011, samples were taken during surgery. Histopathological diagnosis was carried out by conventional enzyme and immunohistochemical techniques based on defined criteria of bacterial infection in tissues, synovial tissue and bone. RESULTS: A total of 20 patients were included, 10 males and 10 females with a mean age of 61.7 years. Staphylococcus aureus was the most commonly detected bacteria and in 4 cases bacteria could not be demonstrated. The correlation between the histopathological signs of an infection and microbiological detection of bacteria was 93.3 %. CONCLUSIONS: In patients with rheumatoid arthritis the combination of histopathology and microbiology significantly increased the safety of detecting an infection or contamination.

Perioperative use of aspirin for patients undergoing carotid endarterectomy.

BACKGROUND: This study was initiated to evaluate the cardiovascular benefit of perioperative use of acetylsalicylic acid (ASA) in patients undergoing carotid surgery. PATIENTS AND METHODS: A prospective two-arm comparative study was conducted and focused on cardiac, neurological and bleeding complications for patients with high-grade (> 80 %) asymptomatic or symptomatic (> 60 %), internal carotid artery stenosis based on NASCET criteria who were treated by surgery. Between March 2008 and November 2010, 540 patients underwent carotid endarterectomy in two European vascular centers. In particular, 267 consecutive patients (49.4 %) had taken perioperative ASA in one center; in 273 consecutive patients in the other center ASA administration was stopped 5 days preoperatively. RESULTS: The overall complication rate was lower in the ASA group (5.2 % versus 17.6 %), p < 0.001, 95 %CI [2.1;7.2], OR 3.8. In detail, the myocardial event rate was lower in the ASA arm: 0.7 versus 4.4 %; p = 0.012, OR 6.1 (95 %CI [1.4;27.45]. Concerning stroke, ASA patients benefit from oral antiaggregation as well: 1.5 vs. 5.5 %; p = 0.036), OR 4.5, 95 %CI[1.3;11.7], respectively. The bleeding complications were similar in both subgroups, 8 for the ASA group (3.0 %) and 10 (3.7 %) for the non-ASA group, p = 0.66. Multivariate logistic regression analysis showed significant benefit of the ASA-treatment in patients with hypertension, diabetes mellitus and hypercholesterolemia, p < 0.001. Additionally, female patients of the ASA group also had significantly less overall (p = 0.10, OR5.3), cardiac (p = 0.021, OR 3.6) and neurologic (p = 0.042, OR 6.7) complications. Bleeding risk was not higher in female patients receiving ASA (p = 0.25). CONCLUSIONS: Perioperative use of ASA for patients undergoing carotid endarterectomy is associated with a lower risk of cardiac and neurological events without significant increase of postoperative bleeding necessitating revision.

[Pain and pruritus : differences and similarities as revealed by the PainDetect questionnaire parameters]. / Schmerzen und Jucken : Unterschiede und Gemeinsamkeiten veranschaulicht anhand von per PainDetect-Fragebogen erhobenen Parametern.

Chronic pruritus and chronic pain are frequent symptoms of a variety of underlying diseases. Painful sensations usually suppress acute itching. In chronic states, both may be present in parallel and be a part of one event. Patients with chronic pruritus should be asked for the presence of pain, which can be identified and characterized using specific and validated questionnaires. The early detection of (neuropathic) pain in patients with chronic pruritus can be done using the PainDetect questionnaire. In general, patients suffering from both itch and pain have a highly impaired quality of life, high degree of objective health burden, need a more intensive health care and a complex analgetic and antipruritic therapy.

Is the function of all cardiac valves after the arterial switch operation influenced by an associated ventricular septal defect?

A ventricular septal defect in transposition of the great arteries is frequently closely related to the cardiac valves. The valvar function after arterial switch operation of patients with transposition of the great arteries and ventricular septal defect or intact ventricular septum was compared. We analysed the function of all cardiac valves in patients who underwent the arterial switch operations pre- and post-operatively, 1 year after the procedure and on follow-up. The study included 92 patients - 64 with transposition of the great arteries/intact ventricular septum and 28 with transposition of the great arteries/ventricular septal defect. The median age at surgery was 5.5 days in transposition of the great arteries/intact ventricular septum (0-73 days) and 7.0 days in transposition of the great arteries/ventricular septal defect (4-41 days). Follow-up was 51.7 months in transposition of the great arteries/intact ventricular septum (3.3-177.3 months) and 55 months in transposition of the great arteries/ventricular septal defect (14.6-164.7 months). Neo-aortic, neo-pulmonary, and mitral valvar function did not differ. Tricuspid regurgitation was more frequent 1 year post-operatively in transposition of the great arteries/ventricular septal defect (n = 4) than in transposition of the great arteries/intact ventricular septum. The prevalence of neo-aortic regurgitation and pulmonary stenosis increased over time, especially in patients with transposition of the great arteries/intact ventricular septum. The presence of a ventricular septal defect in patients undergoing arterial switch operation for transposition of the great arteries only has a minor bearing for the development of valvar dysfunction on the longer follow-up.

[Long-term results of thrust plate prostheses: comparison of patients younger than and older than 50 years]. / Langfristige Analyse der Druckscheibenendoprothese: Vergleich von Patienten unter und über 50 Jahren.

BACKGROUND: Hip replacement in patients younger than 50 years old is no longer an exception in view of the increasing necessity for care. The aim of the present study was to analyze whether the results after implantation of thrust plate prosthesis (TPP) with metaphyseal anchorage are equal for patients below 50 years compared to older patients. PATIENTS AND METHODS: The investigation comprised 465 TPP implantations. In 149 TPP the patient age was below 50 years (group A) und in 316 TPP cases above 50 years (group B). Clinical and radiological evaluation of the results for both groups was carried out as well as a differentiated survival analysis with defined endpoints. RESULTS: Survival analysis of group A (96%/13.2 years) showed a significantly improved survival rate compared to group B (86%/12.5 years). Additionally, the risk of prosthesis and/or radiological signs loosening of was significantly lower in group A than in group B (p <0.05). CONCLUSION: Comparison of long-term results of prostheses with intramedullary fixation shows that the anchorage principle of TPP with bone-saving implantation to the proximal femur is justified especially for patients below 50 years of age.

[Effectiveness of nephroprotection by the selection of contrast media used during vascular interventions in patients with chronic renal failure?]. / Ist Nephroprotektion durch die Auswahl des Röntgen-Kontrastmittels im Rahmen von Gefäßinterventionen bei vorbestehender Niereninsuffizienz möglich?

BACKGROUND: The increasing number of endovascular procedures made aware of a kidney disease induced by contrast media (CM). Contrast-induced nephropathy (= CIN) can develop in 0.6-44 % of the treated patients by angiography and / or endovascular intervention. The incidence in high-risk patients ranges from 50 to 70 %. In most cases CIN is inconspicuous and reversible. But pre-existing chronic kidney disease, diabetes mellitus, age and variable different risk factors (e. g., PAOD) can induce irreversible renal impairment. The purpose of the presented trial is to investigate incidence, predictors, and out-come of CIN in chronic renal failure patients using two different CM; one non-ionic isoosmolar -iodixanol and the other non-ionic low-osmolar iopromide. METHODS: To evaluate the incidence of CIN after endovascular diagnostics and intervention two collectives of 100  patients with chronic renal insufficiency were treated with different contrast media (CM). Inclusion followed prospectively in two collectives. One collective received iopromide (Ultravist™, Bayer Health Care, Lever-kusen, Germany), and the second hundred patients received iodixanol (Visipaque™, Nycomed Amersham, Princeton, New Jersey). Demographics, comorbidities, procedure-related data were completed by serum creatinine levels and GFR (= glomerular filtration rate). Inclusion criteria were a serum creatinine level ≥ 1.5 mg% and a GFR ≤ 60 mL / min. Those parameters were measured twice pre-interventionally, and one time 48-72  hours after the endovascular procedure. RESULTS: Collectives were homogenous and comparable concerning pre-existing risk factors, age and gender. Renal function stayed at a constant level and was independent of contrast medium selection, repectively. Average creatinine levels ranged around 1.77 mg% ±â€Š0.75  standard deviation (SD) pre-interventionally; postinterventional measurement exposed a creatinine level of 1.74 mg% ±â€Š0.74 SD as mean of both collectives. GFR (preinterventional 39.64 mL / min ±â€Š12.48 SD) increased non-significantly to 45.48 mL / min ±â€Š16.82 SD. Pre-existing chronic kidney disease had no effect on renal function parameters; no other risk factors could be evaluated. CONCLUSION: According to cost-effectiveness a low-osmolar monomeric contrast medium (LOCM) is a sufficient selection, under careful renal function control.

[Chest compression quality : Can feedback technology help?]. / Thoraxkompressionsqualität : Hilft Feedback-Technologie?

BACKGROUND: The outcome of cardiopulmonary resuscitation (CPR) depends on the quality of chest compressions. Current European Resuscitation Council (ERC) guidelines promote the development of feedback systems. However, no studies presenting satisfactory results of feedback use have been published. METHODS: A total of 60 patients with cardiac arrest (> or =18 years of age) received resuscitation attempts using an automated external defibrillator (AED) with real-time feedback by the ambulance service of the City of Münster. The frequency of chest compressions, no-flow time (NFT) and depth of chest compressions were analyzed for the first three cycles of CPR and compared to the ERC guidelines 2005. RESULTS: Chest compression frequency did not differ significantly from the ideal as set out in the guidelines. Analysis of NFTs showed significantly longer NFT for the first cycle but NFT for the second and third cycles did not differ significantly from the ideal. The target depth of 4-5 cm was achieved in 80% of all chest compressions in the first 3 cycles. CONCLUSION: With the AED real-time feedback technology used in this study standardized performance of chest compressions could be maintained in a professional ambulance service. Implementation of a feedback system requires training of ambulance staff.

[Long stents for long femoropopliteal lesions--first results of 128 Protégé stents]. / Lange femoro-popliteale Läsionen erfordern lange Stents--erste Erfahrungen mit 128 Protégé-Stents.

BACKGROUND: In the endovascular therapy for the superficial femoral artery (SFA) a variety of stent devices can be used. Indications for endovascular intervention are increasing, since the 2007 TASC II consensus changed. Several, also multicentric -trials, evaluated the use and effectiveness of stent devices. AIM: The present trial studied efficacy of long ev3 Protégé Everflex stents used in the treatment of long and complex occlusive lesions of the -superficial femoral artery (SFA) and the popliteal artery. MATERIALS AND METHODS: The ev3 Protégé Everflex device (ev3 Inc., Plymouth, MN, USA) is a self-expandable nitinol stent consisting of a helical structure with spiral cell interconnections, making high flexibility and low fragility possible. Using a prospective follow-up programme, 103 consecutive patients who received 128 stents (150 mm average length) were included in this study. Pre- and postinterventional parameters were walk-ing distance, ABI, Rutherford categorisation and duplex ultrasound examination. In addition, stent fracture was excluded by radiograms. The mean follow-up period was 6 months. RESULTS: 128 stents were implanted in 103 patients. The average age was 71.1 years (range: 52-90 years). 44 % of the collective suffered from TASC II C and D lesions. The technical success was 100 %. Restenosis was found in 11.8 % of the cases (n = 16) and recanalised (n = 9). 4 bypass implantations and 2 major amputations were performed. A total of 6 stent fractures was found (4.7 %). CONCLUSIONS: The Protégé stent is a safe device with favourable short-term results. Restenosis and fracture rates are low, but long-term results still have to be evaluated in the future.

Epigenetic repression of RASSF1A but not CASP8 in supratentorial PNET (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of childhood.

Supratentorial primitive neuroectodermal tumors (sPNET) and atypical teratoid/rhabdoid tumors (AT/RT) of the CNS represent a biological and clinical enigma, despite advances in both molecular techniques and clinical management for these two rare embryonal brain tumors of childhood. Epigenetic changes hold great potential as possible disease mechanisms and may be manipulated therapeutically. We thus studied aberrant methylation of the genes RASSF1A and CASP8 and its consequence on expression in cell lines and primary tumors using a combination of semiquantitative methylation specific PCR (MSP), bisulfite sequencing and RT-PCR. In all, 17 samples of autopsy-derived normal appearing brain served as controls. Opposed to control tissues 19/24 sPNET and 4/6 AT/RT demonstrated aberrant methylation for the RASSF1A promoter region. Treatment of cell lines using 5-Aza-2'-deoxycytidine (5AZA) alone or in combination with trichostatin A (TSA) succeeded in re-establishing expression of RASSF1A in cell lines derived from a renal rhabdoid, an AT/RT and a medulloblastoma. A 5' CpG-rich region of CASP8 was methylated in normal tissues and in tumors. However, CASP8 showed inconsistent expression patterns in normal and tumor tissues. Our results indicate that aberrant methylation of the RASSF1A promoter region may be of importance in the origin and progression of sPNET and AT/RT while the analysed 5'-CpG rich region of the CASP8 gene does not seem to play an important role in these tumors. Further studies of epigenetic changes in these rare tumors are warranted as their biology remains obscure and treatment efforts have been rather unsuccessfull.

Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation.

OBJECTIVES: The 3-year survival rates of 500 patients with congestive heart failure (CHF) referred for heart transplantation were assessed to evaluate the clinical and exercise variables most useful for estimating prognostic risk. BACKGROUND: Detailed prognostic risk stratification of patients with a peak exercise oxygen consumption (VO2) < or = 14 ml/min per kg to identify lower risk patient subsets has been limited in earlier series by relatively small sample size. METHODS: Cardiopulmonary exercise testing was performed in 500 patients with CHF referred for heart transplantation; 154 (31%) had a peak exercise VO2 < or = 14 ml/min per kg. Univariate and multivariate analyses were performed to identify the 3-year prognostic risk. RESULTS: The 55% 3-year survival rate of the 77 patients with a peak exercise VO2 < or = 14 ml/min per kg unable to reach a peak exercise systolic blood pressure (SBP) of 120 mm Hg was significantly lower than the 83% survival rate in the 74 patients able to reach this exercise blood pressure (p = 0.004). Multivariate analysis revealed that peak exercise SBP (p = 0.0005) and percent predicted peak VO2 < or = 50% (p = 0.04) were the two most important predictors for the combined end point of death or listing as Status 1. CONCLUSIONS: Peak exercise SBP and percent predicted peak exercise VO2 are two inexpensive and easily measured noninvasive variables that can be used to further prognostically risk stratify ambulatory patients with CHF referred for heart transplantation with a peak exercise VO2 < or = 14 ml/min per kg.

Assignment of 118 novel cDNAs of cynomolgus monkey brain to human chromosomes.

In order to isolate genes that may not be represented in current human brain cDNA libraries, we have sequenced about 20,000 sequence tags of cDNA clones derived from cerebellum and parietal lobe of cynomolgus monkeys (Macaca fascicularis). We determined the entire cDNA sequence of approximately 700 clones whose 5'-terminal sequences showed no homology to annotated putative genes or expressed sequence tags in current databases of genetic information. From this, 118 clones with sequences encoding novel open reading frames of more than 100 amino acid residues were selected for further analysis. To localize the genes corresponding to these 118 newly identified cDNA clones on human chromosomes, we performed a homology search using the human genome sequence and fluorescent in situ hybridization. In total, 108 of 118 clones were successfully assigned to specific regions of human chromosomes. This result demonstrates that genes expressed in cynomolgus monkey are highly conserved throughout primate evolution, and that virtually all had human homologs. Furthermore, we will be able to discover novel human genes in the human genome using monkey homologs as probes.

Long-term cardiopulmonary exercise performance after heart transplantation.

Functional capacity is an important outcome variable for heart transplantation, but there are few data that examine the temporal relation and duration of improvement in cardiopulmonary exercise performance after cardiac transplantation. Cardiopulmonary exercise performance was measured in 140 patients who underwent 426 treadmill exercise tests up to 9 years after cardiac transplantation. Univariate and multivariate analyses were used to predict postoperative improvement in functional capacity. Peak oxygen consumption (VO2) significantly improved from 14.2 +/- 3.7 ml/min/kg before to 21.4 +/- 5.6 ml/min/kg at a mean of 11.2 +/- 3.0 months after the transplant procedure (p < 0.001). When peak aerobic capacity was compared with a normal population, peak VO2 was < 50% of predicted in only 9 patients (12%), from 50% to 70% in 34 patients (44%), from 70% to 90% of predicted in 24 patients (31%); 10 patients (13%) were able to achieve > 90% of peak predicted VO2. The improvement seen at 6 months did not significantly change over 9 years of follow-up. Significant preoperative univariate predictors of.1-year postoperative improvement in peak VO2 were preoperative peak VO2 (p = 0.004), age (p < 0.001), ischemic cardiomyopathy (p = 0.007), and preoperative left ventricular ejection fraction (p < 0.001). Peak VO2 at 1 year in patients able to perform the test was not significantly influenced by acute rejection episodes, donor body surface area, or donor/recipient size ratio. In conclusion, exercise capacity is significantly improved within 6 months after cardiac transplantation, and maintained as long as 9 years after procedure. The magnitude of postoperative improvement is inversely related to preoperative peak VO2 and age.