Active treatment in low-risk prostate cancer: a population-based study.

Background: Active surveillance instead of active treatment (at) is preferred for patients with low-risk prostate cancer (lr-pca), but practice varies widely. We conducted a population-based study to assess the proportion of patients who underwent at between January 2011 and December 2014, and to evaluate factors associated with at. Methods: The provincial cancer registry was linked to administrative health datasets to identify patients with lr-pca and to acquire demographic, tumour, and treatment data. The primary outcome was receipt of at during the first 12 months after diagnosis, defined as any receipt of external-beam radiotherapy, brachytherapy, radical prostatectomy, cryotherapy, or androgen deprivation. Univariate and multivariate logistic regression were used to analyze the correlation between patient and tumour factors and at. Results: Of 1565 patients with lr-pca, 554 (35.4%) underwent at within 12 months of diagnosis. Radical prostatectomy was the most common treatment (58%), followed by brachytherapy (29.6%). Younger age [odds ratio (or) 0.92; 95% confidence interval (ci): 0.91 to 0.94], lower score (≥3) on the Charlson comorbidity index (OR: 0.36; 95% ci: 0.19 to 0.68), T2 stage (or: 3.05; 95% ci: 2.03 to 4.58), higher prostate-specific antigen (psa) at diagnosis (or: 1.13; 95% ci: 1.06 to 1.21), radiation oncologist consultation (or: 3.35; 95% ci: 2.55 to 4.39), and earlier diagnosis year (2012 or: 0.46; 95% ci: 0.34 to 0.63; 2013 or: 0.45; 95% ci: 0.32 to 0.63; 2014 or: 0.33; 95% ci: 0.23 to 0.47) were associated with a higher probability of at. Conclusions: This contemporary population-based study demonstrates that approximately one third of patients with lr-pca undergo at. Patients of younger age, with less comorbidity, a higher tumour stage, higher psa, earlier year of diagnosis, and radiation oncologist consultation were more likely to undergo at. Further investigation is needed to identify strategies that could minimize overtreatment.

Deep evolutionary origin of limb and fin regeneration.

Salamanders and lungfishes are the only sarcopterygians (lobe-finned vertebrates) capable of paired appendage regeneration, regardless of the amputation level. Among actinopterygians (ray-finned fishes), regeneration after amputation at the fin endoskeleton has only been demonstrated in polypterid fishes (Cladistia). Whether this ability evolved independently in sarcopterygians and actinopterygians or has a common origin remains unknown. Here we combine fin regeneration assays and comparative RNA-sequencing (RNA-seq) analysis of Polypterus and axolotl blastemas to provide support for a common origin of paired appendage regeneration in Osteichthyes (bony vertebrates). We show that, in addition to polypterids, regeneration after fin endoskeleton amputation occurs in extant representatives of 2 other nonteleost actinopterygians: the American paddlefish (Chondrostei) and the spotted gar (Holostei). Furthermore, we assessed regeneration in 4 teleost species and show that, with the exception of the blue gourami (Anabantidae), 3 species were capable of regenerating fins after endoskeleton amputation: the white convict and the oscar (Cichlidae), and the goldfish (Cyprinidae). Our comparative RNA-seq analysis of regenerating blastemas of axolotl and Polypterus reveals the activation of common genetic pathways and expression profiles, consistent with a shared genetic program of appendage regeneration. Comparison of RNA-seq data from early Polypterus blastema to single-cell RNA-seq data from axolotl limb bud and limb regeneration stages shows that Polypterus and axolotl share a regeneration-specific genetic program. Collectively, our findings support a deep evolutionary origin of paired appendage regeneration in Osteichthyes and provide an evolutionary framework for studies on the genetic basis of appendage regeneration.

Fins into limbs: Recent insights from sarcopterygian fish.

Limbs with digits evolved as sarcopterygian fish transitioned to a terrestrial life, giving rise to modern tetrapods. Since the Devonian, most of the sarcopterygian fish diversity became extinct, with the only surviving representatives being two coelacanth and six lungfish species. As the sister group of tetrapods, sarcopterygian fish constitute the ideal models to address questions regarding the transition of vertebrates from water to land. However, distantly related yet experimentally amenable teleost fish species have instead become the organisms of choice for geneticists and developmental biologists. Comparative studies using teleosts, such as zebrafish, have greatly enriched our knowledge on the genetic and regulatory mechanisms underlying fin development. However, their highly derived fin anatomy provides limited insights on the origin of limbs and the teleost-specific whole-genome duplication represents a further complication to comparisons of gene function and regulation. In recent years, refined morphological and behavioral studies and access to lungfish embryos and availability of genetic resources have underscored the value of nontetrapod sarcopterygians as model organisms. Here we review recent studies using lungfishes and coelacanths that shed light on various aspects of the evolution of the tetrapod limb, including the origin of the tetrapod pelvis, limb musculature, digits, locomotion, and regenerative capacity.

Comparative multidisciplinary prediction of survival in patients with advanced cancer.

PURPOSE: The expected survival of patients with metastatic cancer can significantly impact decisions regarding treatment, care setting, and future planning. We evaluated the prognostication ability of a multidisciplinary team (MDT) experienced in providing supportive care and palliative radiotherapy. METHODS: After clinical assessment of consecutive patients, survival predictions were independently made by each MDT member. Patient demographics, factors influencing predictions, and dates of death were collected. Clinical predictions of survival (CPS) were considered correct if within 30 days of actual survival (AS). Summary statistics and Kaplan-Meier estimates of overall survival were obtained. Correlations between actual and CPS were calculated using Spearman's correlation coefficient. Multivariate logistic regression analysis identified factors associated with prognostication accuracy. RESULTS: A total of 395 predictions (06/2010-07/2012) were made by eight disciplines. Average age was 68 years, 68.3 % of patients were male, and 48.4 % had lung cancer. Median AS was 87 days (95 % CI 66-102 days). Survival was over-estimated 72.4 % (286/395) of the time with r = 0.54 (p < 0.0001) for all predictions across all disciplines. In addition, 30.3 % (36/119) of radiation therapist (RTT) predictions were correct compared to 30.1 % (22/73) of nurses', 28.7 % (43/150) of physicians', and 15.1 % (8/53) of allied health (AH) providers. There were no differences in accuracy by discipline except for the RTT versus AH groups (p = 0.04). Factors most frequently cited as influencing correct predictions were Karnofsky performance status (KPS), extent of disease, and histology. KPS was the only significant variable on multivariate analysis (p ≤ 0.04). CONCLUSION: MDT members providing collaborative care for advanced cancer patients utilize similar factors in predicting survival with comparable accuracy.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

International practice survey on the management of brain metastases: Third International Consensus Workshop on Palliative Radiotherapy and Symptom Control.

AIM: To evaluate international patterns of practice for the management of metastatic disease to the brain. MATERIALS AND METHODS: An online international practice survey was conducted from April to June 2010. Most of the survey questions were based on common management issues for which optimal management using level 1 evidence was lacking. The survey consisted of three sections: respondent demographics, 13 general questions regarding surgery, whole brain radiotherapy (WBRT) and radiosurgery and 13 questions related to specific scenarios. RESULTS: In total, 445 individuals responded to the survey over a 3 month period. Ninety per cent of respondents worked in a hospital-based setting. Ninety-three per cent of respondents were radiation oncologists. Thirty-seven per cent worked in an academic setting. Only three of 26 survey questions generated at least 70% agreement for a favoured response. Eighty-eight per cent of respondents chose comfort measures only for patients with multiple brain metastases who have been previously treated with WBRT and who now present 6 months later with two to four brain metastases (all less than 4 cm in size) with uncontrolled extracranial disease and bedridden state. Seventy-eight per cent of respondents would use WBRT alone for initial treatment in patients with two to four brain metastases (all less than 4 cm in size), with active, uncontrolled extracranial disease and a Karnofsky performance status of 70. Seventy-eight per cent of respondents chose surgical resection for an enlarging single brain metastasis that has been previously treated with radiosurgery. The enlarging single brain metastasis is in a surgically accessible site and is now symptomatic. The patient has controlled extracranial disease, good performance status and magnetic resonance spectroscopy was not diagnostic. CONCLUSIONS: There is a lack of uniform agreement for many common management issues (not well answered by level 1 evidence) in patients with metastatic disease to the brain.

Palliative radiotherapy for women with breast cancer.

AIMS: Palliative radiotherapy (PRT) plays an important role in women with metastatic breast cancer. However, not all cancer patients with an indication for PRT receive it. The aim of this study was to measure the use of PRT for women who have died of breast cancer in the Canadian province of Alberta, and to identify factors that might affect this use. MATERIALS AND METHODS: All women who died of breast cancer in Alberta between 2000 and 2004 were identified from the Alberta Cancer Registry. PRT, defined as any radiotherapy given with palliative intent, was abstracted from the radiotherapy databases of the treatment facilities of the Alberta Cancer Board (ACB). The variables evaluated were: age at death, regional health authority (RHA), driving distance to nearest radiotherapy facility, receipt of initial treatment at an ACB facility, receipt of radiotherapy as part if initial treatment, residence in a city with an ACB facility, residence in a city with radiotherapy facilities or visiting radiation oncologists, median household income, and municipality population. Backwards stepwise logistic regression was used to determine the final set of predictor variables for the use of PRT. RESULTS: In total, 1906 women were identified as having died of breast cancer between 2000 and 2004, inclusive. Of these, 50.4% received at least one course of PRT. Factors associated with not receiving PRT in the final multiple logistic regression model for women who lived outside of the cities with radiotherapy facilities were: age>75 years, community size>10,000, median income<$47,000, and residence in RHA 4. For women living in cities with radiotherapy facilities, only age was significant. CONCLUSIONS: There are many factors that influence the receipt of PRT in Alberta that are unrelated to patient need. The education of physicians and patients, as well as the establishment of more radiotherapy facilities, will help to improve the use of PRT.

Treatment of anaemia in inflammatory bowel disease with iron sucrose.

BACKGROUND: Inflammatory bowel disease (IBD)-associated anaemia usually responds to intravenous iron. If not, additive treatment with erythropoietin has been proposed. The objective of the present retrospective study was to evaluate the effectiveness of treatment with iron sucrose alone. METHODS: Sixty-one patients with IBD and anaemia (average haemoglobin 97 g/L) were treated with iron sucrose (iron dose 1.4 +/- 0.5 g). The indications for iron sucrose were poor response and/or intolerance to oral iron. Treatment response was defined as an increase in haemoglobin of > or = 20 g/L or to normal haemoglobin levels (> or = 120 g/L). Two independent investigators retrospectively assessed laboratory variables, clinical findings, and concomitant medication. RESULTS: Two patients were transferred to other hospitals after treatment and therefore could not be evaluated. Fifty-four of the remaining 59 patients (91%) responded within 12 weeks. Sixty percent of the patients had responded within 8 weeks. Five patients had no or only a partial response to iron sucrose of which three had prolonged gastrointestinal blood losses. Eight patients with normal or elevated levels of ferritin could be considered to have anaemia of chronic disease, and all of them responded to iron sucrose. During a follow-up period of 117 +/- 85 (4-291) (mean +/- s (standard deviation) (range)) weeks 19 patients (32%) needed at least one second course of iron sucrose because of recurrent disease. CONCLUSIONS: Anaemia associated with IBD can be successfully treated with intravenously administered iron sucrose, provided that bowel inflammation is treated adequately and enough iron is given. Treatment with iron sucrose is safe. Follow-up of haemoglobin and iron parameters to avoid further iron deficiency anaemia is recommended.

Axially loaded magnetic resonance image of the lumbar spine in asymptomatic individuals.

STUDY DESIGN: For this study, 43 asymptomatic individuals underwent magnetic resonance imaging of the lumbar spine in both supine psoas-relaxed position and supine axial compression in extension. The change in dural cross-sectional area between positions at each disc level was calculated. OBJECTIVES: To evaluate the effect of axial loading on asymptomatic individuals, as compared with the effect on patients who have clinical signs of lumbar spinal canal stenosis, and to assess the effect that different magnitude and duration of the applied load have on the dural cross-sectional area. SUMMARY OF BACKGROUND DATA: Degenerative changes in the spine are found in both symptomatic and asymptomatic individuals. A study of patients with suspected clinical lumbar spine encroachment examined in both psoas-relaxed position and axial compression in extension with computed tomographic myelography or magnetic resonance imaging of the lumbar spine is reported. A significant decrease in dural cross-sectional area was found, respectively, in 80% and 76% of the patients. METHODS: The study subjects underwent magnetic resonance imaging examinations in both psoas-relaxed position and axial compression in extension. The examination of the subject under axial compression in extension was performed with the lumbar spine in a supine position using a compression device. Degenerative changes in and adjacent to the spinal canal were registered. The dural cross-sectional areas were determined for psoas-relaxed position and axial compression in extension, then compared. In seven reexamined individuals, the dural cross-sectional area was calculated after an axial load corresponding to 25% and 50% of their body weight and a loading time of 5 to 60 minutes. RESULTS: A significant decrease in dural cross-sectional area from psoas-relaxed position to axial compression in extension was found in 24 individuals (56%), most frequently at L4-L5, and increasingly with age. In four individuals (5 disc levels), a decrease in dural cross-sectional area to less than 100 mm2 from psoas-relaxed position to axial compression in extension was found. In seven reexamined individuals, a significant decrease in dural cross-sectional area was found: in five after 5 minutes load of 25% of their body weight, and in two with 50% of their body weight. CONCLUSIONS: Using magnetic resonance imaging, a significant decrease in dural cross-sectional area after axial loading was found less frequently in asymptomatic than in symptomatic subjects. The decrease was more frequent at L4-L5, and increasingly with age. The load should be 50% of the subject's body weight applied for at least 5 minutes.

The diagnostic effect from axial loading of the lumbar spine during computed tomography and magnetic resonance imaging in patients with degenerative disorders.

STUDY DESIGN: Patients with low back pain, sciatica, and neurogenic claudication were observed during computed tomographic myelography or magnetic resonance imaging in psoas-relaxed position and axially compressed supine position of the lumbar spine. OBJECTIVE: To estimate the clinical value of axially loaded imaging in patients with degenerative disorders of the lumbar spine. SUMMARY OF BACKGROUND DATA: Computed tomography and magnetic resonance imaging still are performed with the lumbar spine in a supine relaxed position, which results in unloading of the spine and enlargement of the canal. METHODS: A device for axial loading of the lumbar spine in computed tomography and magnetic resonance imaging was used. Altogether, 172 patients were examined in psoas-relaxed position and axially compressed supine position of the lumbar spine: 50 patients with computed tomographic myelography and 122 patients with magnetic resonance imaging. If a significant decrease (>15 mm2) in the dural sac cross-sectional area to values smaller than 75 mm2 (the borderline value for stenosis) was found during examination in axial loading, or if a suspected disc herniation, narrow lateral recess, narrow intervertebral foramen, or intraspinal synovial cyst changed to being obvious at the axial loading examination, this was regarded as additional information important for the treatment. RESULTS: Additional valuable information was found in 50 of 172 patients (29%) during examination in axial loading. In the different diagnostic groups, additional valuable information was found in 69% of the patients with neurogenic claudication, in 14% of the patients with sciatica, and in 0% of the patients with low back pain. The percentage of additional valuable information increased to 50% in the patients with sciatica, if recommended inclusion criteria for examinations in axial loading were used. A narrowing of the lateral recess causing compression of the nerve root was found at 42 levels in 35 patients at axial loading. CONCLUSION: According to the study results, axially loaded imaging adds frequent additional valuable information, as compared with conventional imaging methods, especially in patients with neurogenic claudication, but also in patients with sciatica if defined inclusion criteria are used.

Comparing methods for monitoring serum creatinine to predict late renal allograft failure.

Few studies have systematically investigated what changes in chronic renal allograft function best predict subsequent graft failure, when these changes occur, and whether they occur soon enough to allow possible intervention. We collected serum creatinine values (mean, 183 +/- 75 values/patient) measured over a maximum follow-up of 22 years in 101 consecutive renal transplant recipients (excluding creatinine levels from periods of acute rejection). We determined the dates of first decline in inverse creatinine (Delta1/Cr; < -20%, -30%, -40%, -50%, and -70%), declines in estimated creatinine clearance (CCr; <55, 45, 35, 25, and 15 mL/min), and declines in measured slope of 1/Cr over time. We used time-dependent covariates in Cox proportional hazards analyses to determine the relative effect of each renal function parameter on outcomes while adjusting for other risk factors. The best predictor of subsequent graft failure was Delta1/Cr. Delta1/Cr less than -40% first occurred at a median of 1.28 years after transplantation in 73 patients, and 67 patients went on to have graft failure a median of 3.28 years after Delta1/Cr less than -40%. The independent relative risk for graft failure attributable to Delta1/Cr less than -40% was 5.91 (95% confidence interval, 3.25 to 10.8; P < 0.0001). A decline in CCr, eg, less than 45 mL/min, also was a strong predictor of subsequent graft failure. Conversely, declines in allograft function estimated from slopes of 1/Cr were poor predictors of graft failure. In analysis limited to patients followed up for 2.5 years or less, Delta1/Cr continued to predict graft failure, suggesting that Delta1/Cr will be a useful predictor in populations with shorter follow-up. If confirmed in other populations, eg, patients treated with calcineurin inhibitors, this simple marker of chronic allograft dysfunction may prove to be a practical tool for defining patients at high risk for late graft failure.

Cytomegalovirus disease is not a major risk factor for ischemic heart disease after renal transplantation.

BACKGROUND: It has been suggested that cytomegalovirus infection increases the risk of ischemic heart disease. Both cytomegalovirus and ischemic heart disease are common after renal transplantation, suggesting a possible causal association in this population. METHODS AND PATIENTS: We studied 1004 consecutive renal transplants with no prior history of ischemic heart disease and grafts that functioned at least 12 months. We performed univariate and multivariate analyses to examine the effect of cytomegalovirus disease and other risk factors (measured during the first posttransplant year) on the development of primary ischemic heart disease events after the first posttransplant year. RESULTS: More than 1 year after transplantation, 116 patients (11.6%) experienced their first ischemic event (75 myocardial infarction, 12 percutaneous angioplasty, 18 bypass grafting, and 11 deaths). Patients with ischemic heart disease were more likely to have known risk factors (age, diabetes, smoking, hypercholesterolemia, systolic blood pressure, low serum albumin, and acute rejections). However, the incidence of cytomegalovirus disease was not different for those with or without ischemic heart disease (36.2% vs. 31.1%). Moreover, a similar proportion of those with and without ischemic heart disease (19.8% vs. 15.5%) had a rise in cytomegalovirus antibodies during follow-up. By multivariate analysis, risk factors for ischemic heart disease (P<0.05) were age, diabetes, smoking, low serum albumin, and two or more acute rejections during the first year. Cytomegalovirus disease was not associated with ischemic heart disease events: unadjusted relative risk=1.14 (95% confidence interval 0.78-1.67, P=0.485). After adjusting for multiple risk factors, the relative risk was 0.91 (0.60-1.37, P=0.657). CONCLUSION: These data suggest that cytomegalovirus disease is not a significant risk factor for the development of primary ischemic heart disease after renal transplantation.

Fluid balance in patients with chronic renal failure assessed with N-terminal proatrial natriuretic peptide, atrial natriuretic peptide and ultrasonography.

The N-terminal proatrial natriuretic peptide (proANP) has become an important parameter for assessing the prognosis of patients with cardiac disease. Its use for evaluating the hydration status in patients with chronic renal failure, however, is still under investigation. The present study comprised 12 haemodialysis (HD) and 17 pre-dialysis patients. In the HD patients, the inferior vena cava diameter during quiet expiration (IVCe) was estimated by ultrasonography and plasma concentrations of N-terminal proANP, atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) were measured before and 4 h after termination of HD. In the pre-dialysis patients venous blood samples were taken during rest to measure plasma N-terminal proANP and ANP and serum creatinine. Normal values for N-terminal proANP and ANP were obtained from 18 healthy volunteers. The plasma concentrations of N-terminal proANP and ANP in healthy volunteers were 328 +/- 92 and 11.4.0 +/- 3.1 pM L-1, respectively. In pre-dialysis patients, serum creatinine ranged from 110 to 447 microM L-1 and was significantly correlated to plasma N-terminal proANP (r = 0.60, P < 0.05) but not to ANP. This may indicate that N-terminal proANP is more dependent on renal function for its clearance than ANP, which is probably cleared by extrarenal mechanisms as well. In HD patients, IVCe was significantly correlated to the three hormones before HD, most strongly to N-terminal proANP. After dialysis, IVCe was significantly correlated to ANP and cGMP but was not correlated to N-terminal proANP. This may suggest that proANP takes a longer time than other hormones to reflect changes in intravascular volume. In conclusion, N-terminal proANP is a hormone closely related to degree of renal function. Furthermore, it is a sensitive marker reflecting the interdialytic hydration status in HD patients, as indicated by its high correlation to IVCe, a standard method which is used frequently nowadays to assess the body hydration. However N-terminal proANP could not reflect the acute changes in fluid volume induced by HD, probably because it is slowly metabolized.

The use of pretransplant erythropoietin to normalize hemoglobin levels has no deleterious effects on renal transplantation outcome.

BACKGROUND: The aim of this study was to establish the outcome of renal transplantation in patients given pretransplant erythropoietin (EPO) treatment targeted at reaching a normal hemoglobin concentration (Hb), compared to those given EPO-treatment aimed at maintaining subnormal Hb. METHODS: A total of 416 patients from Scandinavian countries and with renal anaemia were enrolled to examine the effects of increasing Hb from a subnormal level (90-120 g/liter) to a normal level (135-160 g/liter) by EPO treatment. Half of the patients were randomized to have their Hb increased, with the other half randomized to maintain a subnormal Hb. Thirty-two patients from the normal Hb group and 24 patients from the subnormal group received a renal graft during the study period. The outcomes of these transplantations were examined prospectively for 6 months. RESULTS: Preoperative Hb levels were 143+/-17 and 121+/-14 g/liter in the two groups, respectively (P<0.0001). The Hb remained higher in the normal Hb group during the first 2 weeks after transplantation. The percentage of patients requiring postoperative blood transfusions in the normal Hb group was 16%, compared with 50% in the subnormal group (P<0.01). No statistically significant difference in the proportion of functioning grafts or in the serum creatinine levels could be detected. No correlation between EPO treatment and creatinine levels after transplantation was found. The frequency of adverse events was similar in the two groups. CONCLUSIONS: EPO treatment aimed at reaching a normal Hb in renal transplant recipients reduces the postoperative requirement for blood transfusions and has no deleterious effects on kidney graft function.

Normalization of haemoglobin concentration with recombinant erythropoietin has minimal effect on blood haemostasis.

BACKGROUND: Elevation of haemoglobin (Hb) with recombinant erythropoietin (rHuEpo) in patients with chronic renal failure has raised concern of increased risk of thromboembolic diseases. In this study, a substudy of the Scandinavian multicentre trial, we examined the influence on haemostatic parameters of normalization of Hb levels from subnormal levels in patients with chronic renal failure. METHODS: Twenty-six patients, 17 males (before study start Hb 113+/-6 g/l) and nine females (Hb 111+/-8 g/l), with end-stage renal disease were included. Both dialysis and predialysis patients were included. After 3 months of rHuEpo therapy Hb levels reached 136+/-14 g/l for males and 128+/-13 g/l for females, and after 1 year 142+/-11 g/l and 126+/-14 g/l respectively. The increase in Hb was significant both at 3 months and 1 year, compared to baseline. At baseline, after 3 months and 1 year haemostatic and prothrombotic parameters were measured, including prothrombin complex test, activated partial thromboplastin time, platelet aggregation and retention, von Willebrand factor antigen, antithrombin, protein C, total and free protein S, activated protein C resistance, FV-Leiden mutation, D-dimers, plasminogen activator inhibitor-1 and prothrombin fragments 1+2 (PF 1+2). RESULTS: The only statistically significant change was a transient decrease in total levels of protein S at 3 months from 131 to 120% (P=0.0093). The free and active form of protein S showed no significant change. After 1 year the difference was not seen. CONCLUSIONS: Apart from a transient and clinically insignificant decrease in total protein S, we found no prothrombotic changes after normalization of Hb from subnormal levels. Our findings indicate that rHuEpo treatment may aim at normalizing Hb levels without significant effects on haemostatic parameters in patients with chronic renal failure compared to patients with subnormal Hb levels.

TTX blocks baclofen-induced phase shifts of the mammalian circadian pacemaker in vitro.

The mammalian circadian pacemaker, located in the suprachiasmatic nucleus (SCN), expresses 24-h rhythms when isolated in vitro. The GABA(A) agonist, muscimol, induces phase advances during the mid-subjective day, while the GABA(B) agonist, baclofen, induces both daytime phase advances and nighttime phase delays. Here, we present evidence that tetrodotoxin (TTX) completely blocks baclofen-induced phase shifts in vitro, but does not block in vitro phase advances induced by muscimol. These results suggest that GABA(A), but not GABA(B), receptors are located on SCN pacemaker cells.

Complex regional pain syndrome type-1: a rare complication of arteriovenous graft placement.

Complex regional pain syndrome (CRPS) type-1 (previously termed reflex sympathetic dystrophy syndrome) may be manifested as sympathetically mediated pain and swelling in an extremity. Among the numerous causes of reflex sympathetic dystrophy, the most common is trauma. We describe a 71-year-old diabetic man with endstage renal disease who presented with CRPS type-1 of the left hand one month after construction of a PTFE (polytetrafluroethylene) arteriovenous graft. The symptoms of CRPS improved greatly with stellate ganglion blocks and physical therapy.

Chart-recorded psychiatric diagnoses in women giving birth in California in 1992.

OBJECTIVE: Although major advances have been made in the diagnosis and treatment of mental disorders in primary care, few population-based investigations have focused on the obstetrical sector. This study examines the occurrence of chart-recorded psychiatric discharge diagnoses among all women delivering in California hospitals in 1992. METHOD: The authors undertook an archival analysis of the California Health Information for Policy Project data set, which consists of linked hospital discharge and birth certificate data for 580,282 deliveries. Frequencies of ICD-9 psychiatric diagnoses were ascertained. RESULTS: Among all women delivering, 1.5% received psychiatric or substance use diagnoses. Of diagnoses recorded, 75% were substance use disorders, 21% were classified generically as "mental disorder of pregnancy," and other psychiatric disorders accounted for 4%. CONCLUSIONS: The occurrence of psychiatric diagnoses in these women is markedly lower than expected, suggesting an underreporting of psychiatric disorders at delivery. Further investigations into the detection of mental disorders in the obstetrical sector are needed.

Effect of normalization of hematocrit on brain circulation and metabolism in hemodialysis patients.

Full correction of anemia with recombinant human erythropoietin (rhEPO) has been reported to reduce the risk of cardiovascular morbidity and mortality and improve the quality of life in hemodialysis (HD) patients. Effects of normalization of hematocrit on cerebral blood flow and oxygen metabolism were investigated by positron emission tomography. Regional cerebral blood flow (rCBF), cerebral blood volume (rCBV), oxygen extraction ratio (rOER), and metabolic rate for oxygen (rCMRO2) were measured in seven HD patients before and after correction of anemia and compared with those in six healthy control subjects. In addition, blood rheology before and on rhEPO therapy was measured in HD patients, which included blood viscosity, plasma viscosity, erythrocyte fluidity, and erythrocyte aggregability. The results showed that plasma viscosity was high (1.51+/-0.19 mPa x s) and erythrocyte fluidity was low (85.8+/-4.8 Pa(-1) x s(-1)), while whole blood viscosity was within the normal range (3.72+/-0.38 mPa x s) before rhEPO therapy. After treatment, the hematocrit rose significantly from 29.3+/-3.3 to 42.4+/-2.2% (P<0.001), accompanied by a significant increase in the whole blood viscosity to 4.57+/-0.16 mPa x s, nonsignificant decrease in erythrocyte fluidity to 79.9+/-7.4 mPa(-1) x s(-1) and nonsignificant change in plasma viscosity (1.46+/-1.3 mPa x s). Positron emission tomography measurements revealed that by normalization of hematocrit, rCBF significantly decreased from 65+/-11 to 48+/-12 ml/min per 100 cm3 (P<0.05). However, arterial oxygen content (caO2) significantly increased from 5.7+/-0.7 to 8.0+/-0.4 mmol/L (P<0.0001), rOER of the hemispheres significantly increased from 44+/-3 to 51+/-6% (P<0.05) and became significantly higher than healthy control subjects (P<0.05). In addition, rCBV significantly increased from 3.5+/-0.5 to 4.6+/-0.6 ml/100 cc brain tissue. The results showed that oxygen supply to the brain tissue increased with normalization of hematocrit, but it was accompanied by increased oxygen extraction in the brain tissue. This may be assumed to be related to the decrease of erythrocyte velocity in the cerebral capillaries as a result of the decreased blood deformability and the increased plasma viscosity.