Are medical comorbidities contributing to the use of opioid analgesics in patients with knee osteoarthritis?

BACKGROUND: Although opioid analgesics are not generally recommended for treatment of knee osteoarthritis (OA), they are frequently used. We sought to determine the association between medical comorbidities and self-reported opioid analgesic use in these patients. METHODS: This cross-sectional study recruited patients referred to two provincial hip and knee clinics in Alberta, Canada for consideration of total knee arthroplasty. Standardized questionnaires assessed demographic (age, gender, income, education, social support, smoking status) and clinical (pain, function, total number of troublesome joints) characteristics, comorbid medical conditions, and non-surgical OA management participants had ever used or were currently using. Multivariable Poisson regression with robust estimate of the standard errors assessed the association between comorbid medical conditions and current opioid use, controlling for potential confounders. RESULTS: 2,127 patients were included: mean age 65.4 (SD 9.1) years and 59.2% female. Currently used treatments for knee OA were: 57.6% exercise and/or physiotherapy, 61.1% NSAIDs, and 29.8% opioid analgesics. In multivariable regression, controlling for potential confounders, comorbid hypertension (RR 1.18, 95% CI 1.02-1.37), gastrointestinal disease (RR 1.31, 95% CI 1.07-1.60), depressed mood (RR 1.25, 95% CI 1.05-1.48) and a higher number of troublesome joints (RR 1.04 per joint, 95% CI 1.00-1.09) were associated with opioid use, with no association found with having ever used recommended non-opioid pharmacological or non-pharmacological treatments. CONCLUSIONS: In a large cohort of patients with knee OA, of 12 comorbidities assessed, comorbid hypertension, gastrointestinal disease, and depressed mood were associated with current use of opioid analgesics, in addition to total burden of troublesome joints. Improved guidance on the management of painful OA in the setting of common comorbidities is warranted.

Enhanced Recovery After Surgery (ERAS) in gynecologic oncology: System-wide implementation and audit leads to improved value and patient outcomes.

OBJECTIVE: Enhanced recovery pathways have been shown to reduce length of stay without increasing readmission or complications in numerous areas of surgery. Uptake of gynecologic oncology ERAS guidelines has been limited. We describe the effect of ERAS guideline implementation in gynecologic oncology on length of stay, patient outcomes, and economic impact for a province-wide single-payer system. METHODS: We compared pre- and post-guideline implementation outcomes in consecutive staging and debulking patients at two centers that provide the majority of surgical gynecologic oncology care in Alberta, Canada between March 2016 and April 2017. Clinical outcomes and compliance were obtained using the ERAS Interactive Audit System. Patients were followed until 30 days after discharge. Negative binomial regression was employed to adjust for patient characteristics. RESULTS: We assessed 152 pre-ERAS and 367 post-ERAS implementation patients. Mean compliance with ERAS care elements increased from 56% to 77.0% after implementation (p < 0.0001). Median length of stay for all surgeries decreased from 4.0 days to 3.0 days post-ERAS (p < 0.0001), which translated to an adjusted LOS decrease of 31.4% (95% CI = [21.7% - 39.9%], p < 0.0001). In medium/high complexity surgery median LOS was reduced by 2.0 days (p = 0.0005). Complications prior to discharge decreased from 53.3% to 36.2% post-ERAS (p = 0.0003). There was no significant difference in readmission (p = 0.6159), complications up to 30 days (p = 0.6274), or mortality (p = 0.3618) between the cohorts. The net cost savings per patient was $956 (95%CI: $162 to $1636). CONCLUSIONS: Systematic implementation of ERAS gynecologic oncology guidelines across a healthcare system improves patient outcomes and saves resources.

Exploring the short-term impact of community water fluoridation cessation on children's dental caries: a natural experiment in Alberta, Canada.

OBJECTIVES: Dental caries (tooth decay) is common and can be serious. Dental caries is preventable, and community water fluoridation is one means of prevention. There is limited current research on the implications of fluoridation cessation for children's dental caries. Our objective was to explore the short-term impact of community water fluoridation cessation on children's dental caries, by examining change in caries experience in population-based samples of schoolchildren in two Canadian cities, one that discontinued community water fluoridation and one that retained it. STUDY DESIGN: We used a pre-post cross-sectional design. METHODS: We examined dental caries indices (deft [number of decayed, extracted, or filled primary teeth] and DMFT [number of decayed, missing, or filled permanent teeth]) among grade 2 schoolchildren in 2004/05 and 2013/14 in two similar cities in the province of Alberta, Canada: Calgary (cessation of community water fluoridation in 2011) and Edmonton (still fluoridated). We compared change over time in the two cities. For Calgary only, we had a third data point from 2009/10, and we considered trends across the three points. RESULTS: We observed a worsening in primary tooth caries (deft) in Calgary and Edmonton, but changes in Edmonton were less consistent and smaller. This effect was robust to adjustment for covariates available in 2013/14 and was consistent with estimates of total fluoride intake from biomarkers from a subsample. This finding occurred despite indication that treatment activities appeared better in Calgary. The worsening was not observed for permanent teeth. For prevalence estimates only (% with >0 deft or DMFT), the three data points in Calgary suggest a trend that, though small, appears consistent with an adverse effect of fluoridation cessation. CONCLUSIONS: Our results suggest an increase in dental caries in primary teeth during a time period when community fluoridation was ceased. That we did not observe a worsening for permanent teeth in the comparative analysis could reflect the limited time since cessation. It is imperative that efforts to monitor these trends continue.

Vitamin D status of Canadians employed in northern latitudes.

BACKGROUND: Vitamin D deficiency and insufficiency are prevalent worldwide, but relatively few studies have examined vitamin D status in working populations. AIMS: To assess the prevalence of vitamin D deficiency and insufficiency in Canadian workers and investigate risk factors in this population. METHODS: A cross-sectional study using data from a health programme enrolling workers mostly from Northern Alberta, Canada. As part of the programme, volunteers were invited to complete a lifestyle questionnaire. Blood was taken to determine plasma 25-hydroxyvitamin D (25(OH)D) levels. Logistic and linear regressions were used to investigate the relationships between individual characteristics and vitamin D status. RESULTS: Between October 2007 and December 2012, 6101 eligible workers enrolled in the health programme. The prevalence of vitamin D deficiency (plasma 25(OH)D, levels <27.5 nmol/l) and insufficiency (<37.5 nmol/l) were 3 and 8%, respectively. Male employees were significantly more likely to be vitamin D deficient and insufficient than females. Residing at a more northern latitude increased the likelihood of vitamin D deficiency and insufficiency. Age, assessments made in summer, better general health and physical activity and use of vitamin D supplementation were all related to lower likelihood of deficiency and insufficiency. CONCLUSIONS: Vitamin D deficiency and insufficiency are a concern in this sample of Canadian workers. Vitamin D supplementation is recommended to reduce the prevalence of deficiency and insufficiency in this group.

Comparative effectiveness of alternative clinical pathways for primary hip and knee joint replacement patients: a pragmatic randomized, controlled trial.

OBJECTIVE: Total hip replacement (THR) and total knee replacement (TKR) (arthroplasty) surgery for end-stage osteoarthritis (OA) are ideal candidates for optimization through an algorithmic care pathway. Using a comparative effectiveness study design, we compared the effectiveness of a new clinical pathway (NCP) featuring central intake clinics, dedicated inpatient resources, care guidelines and efficiency benchmarks vs. the standard of care (SOC) for THR or TKR. METHODS: We compared patients undergoing primary THR and TKR who received surgery in NCP vs. SOC in a randomised controlled trial within the trial timeframe. 1,570 patients (1,066 SOC and 504 NCP patients) that underwent surgery within the study timeframe from urban and rural practice settings were included. The primary endpoint was improvement in Western Ontario and McMaster University osteoarthritis index (WOMAC) overall score over 12 months post-surgery. Secondary endpoints were improvements in the physical function (PF) and bodily pain (BP) domains of the Short Form 36 (SF-36). RESULTS: NCP patients had significantly greater improvements from baseline WOMAC scores compared to SOC patients after adjusting for covariates (treatment effect=2.56; 95% confidence interval (CI) [1.10-4.01]). SF-36 BP scores were significantly improved for both hip and knee patients in the NCP (treatment effect=3.01, 95% CI [0.70-5.32]), but SF-36 PF scores were not. Effects of the NCP were more pronounced in knee patients. CONCLUSION: While effect sizes were small compared with major effects of the surgery itself, an evidence-informed clinical pathway can improve health related quality of life (HRQoL) of hip and knee arthroplasty patients with degenerative joint disorder in routine clinical practice for up to 12 months post-operatively. CLINICALTRIALS.GOV IDENTIFIER: NCT00277186.

Do people with knee osteoarthritis use guideline-consistent treatments after an orthopaedic surgeon recommends nonsurgical care? A cross-sectional survey with long-term follow-up.

Objective: Describe "usual care" patterns of education, exercise, weight management, pain medication and other nonsurgical treatments for knee osteoarthritis (OA) in people recommended for nonsurgical care by an orthopaedic surgeon. Methods: We used a telephone-administered questionnaire to capture treatments people with knee OA used over the three to six years after an orthopaedic surgeon recommended nonsurgical care. The primary outcome, guideline-consistent nonsurgical treatments, was an aggregate measure defined as using education, exercise, weight management, and at least one recommended medication. Secondary outcomes were first-line (education, exercise, and weight management) and guideline-inconsistent treatments (orthoses, opioids, hyaluronic acid, platelet rich plasma, and stem cell therapy). Multivariable robust Poisson regression assessed the association between participant characteristics and use of guideline-consistent, first-line and guideline-inconsistent treatments. Results: 479 people were invited and 250 participated (52%). Participants were 58% female with a mean age 66.2 years. Participants received education by a healthcare professional (64%), exercised regularly (74%), used weight management (38%), and used recommended pain medications (91%). All guideline-consistent nonsurgical treatments were used by 19% of participants, 19% of participants used first-line treatments, and 42% used guideline-inconsistent treatments. Over six years, 34% had another consult then underwent arthroplasty. Older participants were less likely to use any treatment. People without post-secondary education were less likely to use first-line treatments (RR 0.54, 95% CI: 0.30-0.96), and females were less likely to use guideline-inconsistent treatments (RR 0.62, 95% CI:0.47-0.81). Conclusions: Nonsurgical usual care for people with knee OA was not consistent with international clinical guidelines.

Gene transfer, expression, and sarcomeric incorporation of a headless myosin molecule in cardiac myocytes: evidence for a reserve in myofilament motor function.

The purpose of this study was to implement a living myocyte in vitro model system to test whether a motor domain-deleted headless myosin construct could be incorporated into the sarcomere and affect contractility. To this end we used gene transfer to express a "headless" myosin heavy chain (headless-MHC) in complement with the native full-length myosin motors in the cardiac sarcomere. An NH2-terminal Flag epitope was used for unique detection of the motor domain-deleted headless-MHC. Total MHC content (i.e., headless-MHC+endogenous MHC) remained constant, while expression of the headless-MHC in transduced myocytes increased from 24 to 72 h after gene transfer until values leveled off at 96 h after gene transfer, at which time the headless-MHC comprised ∼20% of total MHC. Moreover, immunofluorescence labeling and confocal imaging confirmed expression and demonstrated incorporation of the headless-MHC in the A band of the cardiac sarcomere. Functional measurements in intact myocytes showed that headless-MHC modestly reduced amplitude of dynamic twitch contractions compared with controls (P<0.05). In chemically permeabilized myocytes, maximum steady-state isometric force and the tension-pCa relationship were unaltered by the headless-MHC. These data suggest that headless-MHC can express to 20% of total myosin and incorporate into the sarcomere yet have modest to no effects on dynamic and steady-state contractile function. This would indicate a degree of functional tolerance in the sarcomere for nonfunctional myosin molecules.

Obstructive sleep apnoea is associated with diabetes in sleepy subjects.

BACKGROUND: Although obstructive sleep apnoea (OSA) has been linked to insulin resistance and glucose intolerance, it is unclear whether there is an independent association between OSA and diabetes mellitus (DM) and whether all patients with OSA are at risk. The objective of this study was to determine the association between OSA and DM in a large cohort of patients referred for sleep diagnostic testing. METHODS: A cross-sectional analysis of participants in a clinic-based study was conducted between July 2005 and August 2007. DM was defined by self-report and concurrent use of diabetic medications (oral hypoglycaemics and/or insulin). Sensitivity analysis was performed using a validated administrative definition of diabetes. OSA was defined by the respiratory disturbance index (RDI) using polysomnography or ambulatory monitoring. Severe OSA was defined as an RDI > or = 30/h. Subjective sleepiness was defined as an Epworth Sleepiness Scale score > or = 10. RESULTS: Complete data were available for 2149 patients. The prevalence of DM increased with increasing OSA severity (p<0.001). Severe OSA was associated with DM following adjustment for patient demographics, weight and neck circumference (odds ratio (OR) 2.18; 95% CI 1.22 to 3.89; p<0.01). Following a stratified analysis, this relationship was observed exclusively in sleepy patients (OR 2.59 (95% CI 1.35 to 4.97) vs 1.16 (95% CI 0.31 to 4.37) in non-sleepy patients). CONCLUSIONS: Severe OSA is independently associated with DM in patients who report excessive sleepiness. Future studies investigating the impact of OSA treatment on DM may wish to focus on this patient population.

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

Morphine analgesia potentiated but tolerance not affected by active immunization against cholecystokinin.

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

The patient-specific Triflange acetabular implant for revision total hip arthroplasty in patients with severe acetabular defects: planning, implantation, and results.

AIMS: Few reconstructive techniques are available for patients requiring complex acetabular revisions such as those involving Paprosky type 2C, 3A and 3B deficiencies and pelvic discontinuity. Our aim was to describe the development of the patient specific Triflange acetabular component for use in these patients, the surgical technique and mid-term results. We include a description of the pre-operative CT scanning, the construction of a model, operative planning, and surgical technique. All implants were coated with porous plasma spray and hydroxyapatite if desired. PATIENTS AND METHODS: A multicentre, retrospective review of 95 complex acetabular reconstructions in 94 patients was performed. A total of 61 (64.2%) were female. The mean age of the patients was 66 (38 to 85). The mean body mass index was 29 kg/m2 (18 to 51). Outcome was reported using the Harris Hip Score (HHS), complications, failures and survival. RESULTS: The mean follow-up was 3.5 years (1 to 11). The mean HHS improved from 46 (15 to 90) pre-operatively to 75 (14 to 100). A total of 21 hips (22%) had at least one complication with some having more than one; including dislocation (6%), infection (6%), and femoral complications (2%). The implant was subsequently removed in five hips (5%), only one for suspected aseptic loosening. CONCLUSION: The Triflange patient specific acetabular component provides predictable fixation with complication rates which are similar to those of other techniques. Cite this article: Bone Joint J 2018;100-B(1 Supple A):50-4.

Myofilament calcium sensitivity and cardiac disease: insights from troponin I isoforms and mutants.

The heightened Ca2+ sensitivity of force found with hypertrophic cardiomyopathy (HCM)-associated mutant cardiac troponin I (cTnIR145G; R146G in rodents) has been postulated to be an underlying cause of hypertrophic growth and premature sudden death in humans and in animal models of the disease. Expression of slow skeletal TnI (ssTnI), a TnI isoform naturally expressed in developing heart, also increases myofilament Ca2+ sensitivity, yet its expression in transgenic mouse hearts is not associated with overt cardiac disease. Gene transfer of TnI isoforms or mutants into adult cardiac myocytes is used here to ascertain if expression levels or functional differences between HCM TnI and ssTnI could help explain these divergent organ-level effects. Results showed significantly reduced myofilament incorporation of cTnIR146G compared with ssTnI or wild-type cTnI. Despite differences in myofilament incorporation, ssTnI and cTnIR146G expression each resulted in enhanced myofilament tension in response to submaximal Ca2+ under physiological ionic conditions. Myofilament expression of an analogous HCM mutation in ssTnI (ssTnIR115G) did not further increase myofilament Ca2+ sensitivity of tension compared with ssTnI. In contrast, there was a divergent response under acidic pH conditions, a condition associated with the myocardial ischemia that often accompanies hypertrophic cardiomyopathy. The acidic pH-induced decrease in myofilament Ca2+ sensitivity was significantly greater in myocytes expressing cTnIR146G and ssTnIR115G compared with ssTnI. These results suggest that differences in pH sensitivities between wild-type ssTnI and mutant TnI proteins may be one factor in helping explain the divergent organ and organismal outcomes in TnI HCM- and ssTnI-expressing mice.

Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: direct evidence for collateral inhibition.

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

Phenomenological and pharmacological study of provoked obsessive/anxiety symptoms in obsessive-compulsive disorder: a preliminary study.

BACKGROUND: Inclusion of obsessive-compulsive disorder (OCD) as an anxiety disorder in DSM-i.v. assumes that anxiety is the primary symptom of OCD; however, persuasive empirical evidence in support of this view has not been presented yet. In the present study we hypothesized that provoked anxiety symptoms respond better to intravenous diazepam than would provoked obsessions. We, therefore, reasoned that anxiety symptoms are secondary symptoms of OCD. METHODS: To test the hypothesis we designed a double-blind, randomized, placebo-controlled crossover study. Patients underwent four experimental conditions in which the sequence of symptom provocation and i.v. injection of (placebo or diazepam) were alternated. Baseline and i.v. injection-induced symptom changes were assessed using visual analogs. RESULTS: Obsessions and anxiety correlated strongly for all four experimental conditions in which the sequence of the symptom provocation and diazepam i.v. injections was alternated. i.v. diazepam injection before and after symptom provocation failed to preferentially modulate anxiety symptoms over obsessions. Unexpectedly, in the group in which i.v. diazepam injection preceded the symptom provocation, reduction of mean obsessions was even more pronounced. CONCLUSIONS: Strong correlations between anxiety and obsessions at baseline, during symptom provocation, and after i.v. diazepam infusion suggest that anxiety and obsessions are tightly coupled phenomena in OCD.

Elevated pain threshold in anorexia nervosa subjects.

BACKGROUND: Conflicting data have been published regarding pain threshold in subjects with anorexia nervosa (AN), with some studies indicating elevated pain threshold and others indicating normal thresholds. Previous research has indicated the presence of elevated pain threshold in eating disorder subjects with binge-eating behavior. METHODS: In this study pressure pain detection thresholds (PDT) (assessed by a pressure analgesiometer) in binge-eating/purging and restricting subtypes of AN subjects were compared to control subjects. RESULTS: PDT was elevated in AN compared to control subjects at baseline. There was no difference in PDT between the subgroups of AN subjects. CONCLUSIONS: The etiology of elevated PDT in AN subjects is most likely different from the etiology of elevated PDT in bulimia nervosa subjects.

Immunohistochemical localization of chicken gonadotropin-releasing hormones I and II (cGnRH I and II) in turkey hen brain.

The distribution of cells and fibers immunoreactive (ir) for either chicken gonadotropin-releasing hormone I (cGnRH I; [Gln8]GnRH) or II ([His5,Trp7,Tyr8]GnRH) was determined in brains of turkey hens to reveal whether these peptides occur in separate neuronal systems. ir-cGnRH I cells were located: along the medial aspect of the ventriculus lateralis, nucleus accumbens, and bed nucleus of the stria terminalis; ventral to the tractus septomesencephalicus and extending medially to the third ventricle, and caudally into the lateral hypothalamic area; and in a diffuse band extending from the nucleus preopticus medialis to the nucleus dorsomedialis anterior thalami. cGnRH I fibers were evident in these areas in addition to the hippocampus, nucleus subhabenularis medialis, nucleus ventromedialis hypothalami, and median eminence. Two groups of ir-cGnRH II cells were observed: a magnocellular group lying between the substantia grisea centralis and the nucleus ruber; and a parvicellular group lying medial to the nucleus of the basal optic root and extending into the lateral hypothalamic area. ir-cGnRH II fibers were prominent in limbic structures (cortex piriformis, lateral to nucleus taeniae, hippocampus); olfactory areas (tuberculum olfactorium, nucleus subhabenularis lateralis, nucleus septalis lateralis); areas that in other avian species have steroid-concentrating cells or receptors (medial edge of lobus parolfactorius, nucleus septalis medialis, nucleus periventricularis magnocellularis, nucleus dorsomedialis posterior thalami); and areas containing ir-GnRH I cells or fibers but not in median eminence. These results suggest that cGnRH I and II occur in separate neuronal systems and that cGnRH II does not directly promote pituitary gonadotropin secretion.

Immunohistochemical localization of neuropeptides in the vocal control regions of two songbird species.

Immunohistochemistry was used to map the distribution of four neuropeptides in song control regions of two songbird species, the European starling (Sturnus vulgaris) and the song sparrow (Melospiza melodia). We searched for positively stained cell bodies or apparent terminals containing vasoactive intestinal peptide (VIP), methionine-enkephalin (MET), cholecystokinin (CCK), and substance P (SUB P). Intraventricular colchicine pretreatment was administered to enhance the visualization of peptide-containing cell bodies. Four areas implicated in the central control of song were examined. Three of these areas are sexually dimorphic telencephalic nuclei characteristic of songbirds: the caudal nucleus of the ventral hyperstriatum (HVc), the robust nucleus of the archistriatum (RA), and the magnocellular nucleus of the anterior neostriatum (MAN). The fourth region is the mesencephalic nucleus intercollicullaris (ICo), common to all birds, which contains the dorsomedial nucleus (DM) that appears to be specifically involved in the motor control of song. The pattern of neuropeptide localization was similar between the two species. However, the neuropeptides were heterogeneously dispersed among the four areas. VIP and MET were the most widely distributed, whereas CCK and SUB P were seen only in DM. MAN and HVc revealed remarkably similar patterns of staining for both MET and VIP. Fine varicosities immunolabeled for both these peptides appear to encircle nonreactive somata. In both these nuclei positively stained somata were observed for MET but not for VIP. In RA there was a dense accumulation of MET-positive multipolar cell bodies. VIP-containing neurons were seen in the surrounding archistriatum and caudal neostriatum but not in RA itself. Cell bodies and fibers for all four peptides were observed in DM; in no case were they limited to this subregion, but rather seemed to encompass the surrounding intercollicular area as well. The widespread distribution of VIP and MET strongly suggests a role for these peptides in the acquisition or production of passerine song.

Use of recombinant human erythropoietin in the perioperative period of orthopedic surgery.

In a double-blind, multicenter study, 200 patients who could not or would not donate autologous blood before major orthopedic surgery requiring transfusion of at least 2 units of whole blood were randomized to receive placebo (n = 69) or recombinant human erythropoietin (Epoetin alfa) in daily doses of 300 U/kg (n = 60) or 100 U/kg (n = 71) for 15 consecutive days, starting 10 days before surgery and extending through the fourth postoperative day. Of these, 185 patients who received active medication or placebo and underwent surgery were qualified for evaluation of efficacy (n = 67, n = 54, and n = 64, respectively). All patients received concomitant oral iron supplementation. Compared with placebo-treated patients, a significantly lower proportion of patients who received either dose of Epoetin alfa required allogeneic blood transfusions (54% for placebo, 17% for 300 U/kg, 25% for 100 U/kg; p < 0.01), as well as fewer mean units of blood (1.42 units for placebo, 0.37 units for 300 U/kg, 0.58 units for 100 U/kg; p < 0.01). The differences between the Epoetin alfa treatment groups were not statistically significant. On the basis of these results, perioperative Epoetin alfa therapy in conjunction with iron supplementation may have a place as an adjunct to elective orthopedic surgery, particularly if dosing regimens less frequent than once daily can be established.

Psychoeducational group increases vaginal dilation for younger women and reduces sexual fears for women of all ages with gynecological carcinoma treated with radiotherapy.

PURPOSE: The association between radiotherapy for gynecological carcinoma and sexual dysfunction is well established. Regular vaginal dilation is widely recommended to these women as a way for them to maintain vaginal health and good sexual functioning. However, the compliance rate with this recommendation is low. The purpose of this study was to test the effectiveness of a group psychoeducational program based on the "information-motivation-behavioral skills" model of behavior change in increasing the rate of compliance. METHODS AND MATERIALS: Thirty-two women with Stage I or II cervical or endometrial carcinoma who were being treated with radiotherapy were randomized and received either the experimental group program or the control intervention that consisted of written information and brief counseling. Outcome measures included global sexual health, knowledge about sexuality and cancer, fears about sexuality after cancer, and vaginal dilation compliance. RESULTS: Younger women attending the experimental program (44.4%) were significantly more likely to follow recommendations for vaginal dilation than those who received the control intervention (5.6%). Women, regardless of age, who received the experimental intervention reported less fear about sex after cancer treatment. The older women who received the experimental intervention gained more sexual knowledge. There was no evidence that the experimental intervention improved global sexual health. CONCLUSIONS: This is the first controlled study to provide evidence of an intervention's effectiveness 1. in increasing women's vaginal dilation following radiotherapy for gynecological carcinoma and 2. in reducing their fears about sex after cancer. Most women, particularly younger women, are unlikely to follow the recommendation to dilate unless they are given assistance in overcoming their fears and taught behavioral skills.

Characterization of the extent of pontomesencephalic cholinergic neurons' projections to the thalamus: comparison with projections to midbrain dopaminergic groups.

We sought to determine whether pontomesencephalic cholinergic neurons which we have been shown previously to project to the substantia nigra and ventral tegmental area also contribute to the thalamic activation projection from the pedunculopontine and laterodorsal tegmental nuclei. Retrograde tracing, immunohistochemical localization of choline acetyltransferase and statistical methods were used to determine the full extent of the cholinergic projection from the pedunculopontine and laterodorsal tegmental nuclei to the thalamus. Progressively larger Fluoro-Gold injections in to the thalamus proportionally labeled increasing numbers of pontomesencephalic cholinergic cells both ipsi- and contralaterally in the pedunculopontine and laterodorsal tegmental nuclei. Multiple large thalamic injections left only a small fraction of the ipsilateral pontomesencephalic cholinergic group unlabeled. This small remainder did not correspond to the populations which project to the substantia nigra and ventral tegmental area, thereby indicating that substantia nigra- and ventral tegmental area-projecting cholinergic neurons must also project to the thalamus. We examined whether there existed any set of cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei which did not innervate a thalamic target. The distribution of descending projections of the pedunculopontine and laterodorsal tegmental nuclei demonstrated that the unlabeled remainder cannot correspond to a purely descending group. We also show that substance P-positive cholinergic cells in the laterodorsal tegmental nucleus project to the thalamus. Further studies demonstrated that the small population of cholinergic cells left unlabeled from the thalamus were the smallest sized cholinergic cells, and included two groups of small, light-staining cholinergic cells located in the parabrachial area and central gray, adjacent to the main pedunculopontine and laterodorsal tegmental nuclei cholinergic groups. These small cells, in contrast to thalamic-projecting cholinergic cells, did not stain positively for reduced nicotinamide adenine dinucleotide phosphate-diaphorase. Taken together, these results indicated that all of the reduced nicotinamide adenine dinucleotide phosphate diaphorase-positive/choline acetyltransferase-positive neurons of the pedunculopontine/laterodorsal tegmental nuclei ascend to innervate some portion of the thalamus, in addition to the other targets they innervate. These findings indicate that the diverse physiological and behavioral effects attributed to the activity of pontomesencephalic cholinergic neurons should not be dissociated from their activating effects in the thalamus.