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Background The tufted duck is a non-model organism that experiences high mortality in highly pathogenic avian influenza outbreaks. It belongs to the same bird family (Anatidae) as the mallard, one of the best-studied natural hosts of low-pathogenic avian influenza viruses. Studies in non-model bird species are crucial to disentangle the role of the host response in avian influenza virus infection in the natural reservoir. Such endeavour requires a high-quality genome assembly and transcriptome. Findings This study presents the first high-quality, chromosome-level reference genome assembly of the tufted duck using the Vertebrate Genomes Project pipeline. We sequenced RNA (complementary DNA) from brain, ileum, lung, ovary, spleen, and testis using Illumina short-read and Pacific Biosciences long-read sequencing platforms, which were used for annotation. We found 34 autosomes plus Z and W sex chromosomes in the curated genome assembly, with 99.6% of the sequence assigned to chromosomes. Functional annotation revealed 14,099 protein-coding genes that generate 111,934 transcripts, which implies a mean of 7.9 isoforms per gene. We also identified 246 small RNA families. Conclusions This annotated genome contributes to continuing research into the host response in avian influenza virus infections in a natural reservoir. Our findings from a comparison between short-read and long-read reference transcriptomics contribute to a deeper understanding of these competing options. In this study, both technologies complemented each other. We expect this annotation to be a foundation for further comparative and evolutionary genomic studies, including many waterfowl relatives with differing susceptibilities to avian influenza viruses.

Background: The SIOPE-Brain Tumor Group recently published a guideline on craniospinal target volume delineation for highly conformal radiotherapy. In order to spare critical structures like e.g., the lens or cochlea, highly conformal techniques can underdose the cerebrospinal fluid (CSF) in the dural reflections around cranial and sacral nerves. The purpose of this study is to generate evidence for CSF extension within the dural sheaths of the cranial and sacral nerves in order to improve accuracy in target volume delineation. Material and methods: Ten healthy volunteers, age 21 till 41 years, underwent an MRI-scan of the skull-base and sacral plexus. To evaluate CSF extension, cT2-weighted images with fat suppression, low signal to noise ratio and little to no motion-related artifacts were used. Two observers measured the extension of CSF from the inner table of the skull for the cranial nerves, and outside the spinal canal for the sacral nerves. Results: CSF extension (mean distance [95% CI]) was visible within the dural sheaths surrounding the majority of the cranial nerves: optic nerve (40 mm [38–42]), trigeminal nerve (16 mm [15–19]), facial-vestibulocochlear nerve (11 mm [11–12]), glossopharyngeal-vagus-accessory nerve (7 mm [7–9]) and hypoglossal nerve (8 mm [7–9]). No CSF was observed outside the spinal canal at sacral level. No significant difference between both observers was measured. Conclusion: This study generates evidence for significant CSF extension outside the inner table of the skull. Despite the vicinity of the lens and cochlea, we therefore recommend the inclusion of both optic nerves and internal auditory canals in the clinical target volume for craniospinal irradiation when using highly conformal delivery techniques.

Exercise facilitates hippocampal neurogenesis and neuroplasticity that in turn, promotes cognitive function. Our previous studies have demonstrated that in male mice, voluntary exercise enables hippocampus-dependent learning in conditions that are normally subthreshold for long-term memory formation in sedentary animals. Such cognitive enhancement can be maintained long after exercise has ceased and can be re-engaged by a subsequent subthreshold exercise session, suggesting exercise-induced benefits are temporally dynamic. In females, the extent to which the benefits of exercise can be maintained and the mechanisms underlying this maintenance have yet to be defined. Here, we examined the exercise parameters required to initiate and maintain the benefits of exercise in female C57BL/6J mice. Using a subthreshold version of the hippocampus-dependent task called object-location memory (OLM) task, we show that 14d of voluntary exercise enables learning under subthreshold acquisition conditions in female mice. Following the initial exercise, a 7d sedentary delay results in diminished performance, which can be re-facilitated when animals receive 2d of reactivating exercise following the sedentary delay. Assessment of estrous cycle reveals enhanced wheel running activity during the estrus phase relative to the diestrus phase, whereas estrous phase on training or test had no effect on OLM performance. Utilizing the same exercise parameters, we demonstrate that 14d of exercise enhances long-term potentiation (LTP) in the CA1 region of the hippocampus, an effect that persists throughout the sedentary delay and following the reactivating exercise session. Previous studies have proposed exercise-induced BDNF upregulation as the mechanism underlying exercise-mediated benefits on synaptic plasticity and cognition. However, our assessment of hippocampal Bdnf mRNA expression following memory retrieval reveals no difference between exercise conditions and control, suggesting that persistent Bdnf upregulation may not be required for maintenance of exercise-induced benefits. Together, our data indicate that 14d of voluntary exercise can initiate long-lasting benefits on neuroplasticity and cognitive function in female mice, establishing the first evidence on the temporal endurance of exercise-induced benefits in females.

Researchers have proposed a variety of behavioral traits that may lead to weight gain and obesity; however, little is known about the neurocognitive mechanisms underlying these weight-related eating behaviors. In this study, we measured activation of reward circuitry during a task requiring response and inhibition to food stimuli. We assessed participants’ emotional eating, external eating, and two subscales of dietary restraint—routine restraint and compensatory restraint—using the Weight-Related Eating Questionnaire. For routine restraint, we found positive associations with activation in the insula, dorsolateral prefrontal cortex, anterior cingulate cortex, orbitofrontal cortex and ventromedial prefrontal cortex in response to high-calorie versus low-calorie foods. For emotional eating, we found positive associations with insula and dorsolateral prefrontal cortex activation in response to high-calorie versus low-calorie foods. We also found positive associations between emotional eating and dorsolateral prefrontal cortex activation in response to approach versus inhibition towards high-calorie foods. Thus, our results demonstrate an increase in activation across brain regions related to self-control and urges in response to high-calorie food associated with both emotional eating and routine restraint. Overall, these results support the construct validity of both emotional eating and routine restraint and provide preliminary evidence that these subscales have similar neural correlates.

The aim of this study was to determine the effect of ischemic preconditioning (IPC) on several measures of aerobic function and 4-km cycling time-trial performance. An acute cross-over design was adopted involving eight well-trained cyclists (age 27.0 ± 7.0 years) who completed incremental and square-wave exercise tests for determination of peak O

How does face recognition emerge in the newborn brain? To address this question, we used an automated controlled-rearing method with a newborn animal model: the domestic chick (Gallus gallus). This automated method allowed us to examine chicks' face recognition abilities at the onset of both face experience and object experience. In the first week of life, newly hatched chicks were raised in controlled-rearing chambers that contained no objects other than a single virtual human face. In the second week of life, we used an automated forced-choice testing procedure to examine whether chicks could distinguish that familiar face from a variety of unfamiliar faces. Chicks successfully distinguished the familiar face from most of the unfamiliar faces-for example, chicks were sensitive to changes in the face's age, gender, and orientation (upright vs. inverted). Thus, chicks can build an accurate representation of the first face they see in their life. These results show that the initial state of face recognition is surprisingly powerful: Newborn visual systems can begin encoding and recognizing faces at the onset of vision.

Summary Background Drug interaction references report that initiation of levothyroxine potentiates the effects of warfarin, and recommend more frequent International Normalized Ratio (INR) monitoring, but the mechanism is not well understood. Objective To assess the impact of levothyroxine initiation on INR response. Patients/Methods A retrospective, self-controlled study was performed on patients aged ≥ 18 years receiving chronic warfarin therapy who were started on levothyroxine between 1 January 2006 and 30 June 2013, and who were followed for 90 days prior to and after levothyroxine initiation. The included patients had at least one elevated thyroid-stimulating hormone laboratory value in the pre-period, continuous warfarin therapy for 100 days prior to levothyroxine initiation, no purchases of medications known to interact with warfarin, no procedures requiring warfarin interruption, and no bleeding or thromboembolic event during the study period. The primary outcome was a comparison of the warfarin dose/INR ratio recorded before the initiation of levothyroxine with the ratio recorded during the post-period after two consecutive INRs with no warfarin dose change. Results One hundred and two patients were included in the primary outcome. The mean warfarin dose/INR ratios in the pre-period and post-period were equivalent (P = 0.825). Although the mean warfarin dose was numerically lower in the post-period than in the pre-period, this difference did not reach statistical significance (P = 0.068). Conclusion No difference in the mean warfarin dose/INR ratio before and after initiation of levothyroxine was detected. The results suggest that there is not a clinically significant interaction between warfarin and levothyroxine, and so additional monitoring may not be necessary.

Summary Background Adherence is a major factor in determining disease activity in ulcerative colitis (UC). There are limited data on long-term nationwide adherence levels among patients with UC. Aim To evaluate the long-term adherence levels to oral mesalazine (mesalamine) in the Veterans Affairs (VA) healthcare system, to determine the impact of non-adherence on the risk of flares, and to evaluate the different pharmacy data-based adherence indicators. Methods Nationwide data were obtained from the VA for the period 2001–2011. UC patients who started mesalazine maintenance during the inclusion period were included. Level of adherence was assessed using three different indicators: medication possession ratio (MPR), continuous single-interval medication availability (CSA) and continuous multiple-interval medication gaps (CMG). Cox regression modelling was used to predict disease flares and assess the predictive value of each adherence indicator. Results We included 13 062 patients into the analysis with median follow-up time of 6.1 years. Percentage of patients with high adherence was 47%, 43%, 31% as identified by CSA, MPR and CMG respectively. Low adherers had a significant increase in the risk of flares compared with high adherers (Hazard ratio: 2.8, 1.7 and 1.8, P

Although frontal patients show impaired decision-making on the Iowa Gambling Task (IGT), there has been no follow-up study to date to determine whether there is recovery of function over time. We examined neurological participants’ performance on repeated administrations of the IGT over the course of 6 years. We found that, while non-neurological participants showed considerable improvement due to practice effects on the IGT, patients with ventromedial prefrontal cortex (VMPFC) damage persisted in showing impaired performance on each retest. These results validate the clinical observations that VMPFC dysfunction does not appear to be subject to autonomous recovery over time in real-life. (JINS, 2012, 18, 1–4)

The human X chromosome contains ∼ 1600 genes, about 15% of which have been associated with a specific genetic condition, mainly affecting males. Blue cone monochromacy (BCM) is an X-linked condition caused by a loss-of-function of both the OPN1LW and OPN1MW opsin genes. The cone opsin gene cluster is composed of 2-9 paralogs with 99.8% sequence homology and is susceptible to deletions, duplications, and mutations. Current diagnostic tests employ polymerase chain reaction (PCR)-based technologies; however, alterations remain undetermined in 10% of patients. Furthermore, carrier testing in females is limited or unavailable. High-resolution X chromosome-targeted CGH microarray was applied to test for rearrangements in males with BCM and female carriers from three unrelated families. Pathogenic alterations were revealed in all probands, characterized by sequencing of the breakpoint junctions and quantitative real-time PCR. In two families, we identified a novel founder mutation that consisted of a complex 3-kb deletion that embraced the cis-regulatory locus control region and insertion of an additional aberrant OPN1MW gene. The application of high-resolution X-chromosome microarray in clinical diagnosis brings significant advantages in detection of small aberrations that are beyond the resolution of clinically available aCGH analysis and which can improve molecular diagnosis of the known conditions and unravel previously unrecognized X-linked diseases.

Aim An audit of the use of intravenous ketamine for the provision of conscious sedation in paediatric dentistry was carried out over a three-year period. Audit design In the audit, 3,751 children were treated and an evaluation was carried out for safety and effectiveness of the drug and procedure, the quality of sedation and clinical procedures provided. In addition, the occurrence of any adverse effects and parental satisfaction were noted along with recovery. All children were ASA I and II, with an average age of 7.5 years. Children were referred because of management problems and were assessed to be at the high anxious level of four and five on the Venham scale. A weight related 0.25 mg/kg was initially administered with additional increments of 0.25 mg/kg given if required. The average total dose provided was 0.41 mg/kg. Results The majority of children (76%) accepted all treatment with no problems, with 19% experiencing a small amount of resistance. Although a range of dental treatment was provided, it was mostly exodontias of carious primary dentition. A 27% response was provided assessing satisfaction which was very favourable. No adverse reactions occurred although the most common postoperative experience was nausea. Conclusion This audit demonstrated the safety and effectiveness of using intravenous ketamine for paediatric conscious sedation and implications for training and appropriate service delivery were discussed.

In a previous study we examined whether frontal patients with impaired decision-making on the Iowa Gambling Task (IGT) would recover over time if retested on the IGT. However, a major limitation of repeated administration of the IGT is practice effects, where control participants show improvement with retesting (Bechara, Damasio, & Damasio, 2000). Therefore, the primary goal of this study was to design two alternative versions of the IGT to eliminate practice effects. We found that control participants did not show improvement in performance across the different versions of the task, thus reflecting success in our attempt to design alternative versions of the IGT. Compared to control participants, patients with damage to the ventromedial prefrontal cortex (vmPFC) performed worse on all three versions of the IGT, even after controlling for age, sex, and education. The development of alternative versions of the IGT provides a valuable tool for clinicians and researchers to utilize the IGT as a way to track how the decision-making abilities of patients change over time. Additionally, these results are consistent with findings from the original studies using the IGT with patients with damage to the vmPFC which showed that decision-making impairments do not recover over time.

A retrospective evaluation of the functional results after reconstructive treatment with levator scapulae transfer and scapulo-spinal fasciodesis by fascia lata slings for complete chronic trapezius palsy is presented. Five patients (ages 6 to 40 years) were operated on between 1988 and 1991 because of incapacitating pain and/or functional limitations. Treatment was recommended after failure to alleviate symptoms by a shoulder-girdle muscle-strengthening program or after unsuccessful nerve graft. The descriptions of the results are drawn from the last follow-up evaluation available for each patient (minimum: 14 months post-operative). They are expressed in terms of functional recovery, residual pain, and patient satisfaction. Three patients had an excellent result, with at least 80 percent of normal abduction and forward elevation of the arm, no residual pain, and a high satisfaction rate. One patient showed good improvement in function, with 90 percent of normal shoulder function, but complained of some residual pain. The last patient was not improved by the surgery. Levator scapulae transfer and scapulo-spinal fasciodesis by fascia lata slings, substitute for the function of the upper trapezius and enhance the function of the serratus anterior, thus helping to relieve pain and to improve shoulder function after chronic trapezius palsy. The procedure warrants consideration in patients who are not candidates for nerve repair and reconstruction.

Acyclovir treatment of acute herpes zoster speeds rash healing and decreases pain and ocular complications. The limited oral bioavailability of acyclovir necessitates frequent dosing. Valaciclovir, the l-valyl ester of acyclovir, is rapidly and almost completely converted to acyclovir in vivo and gives three- to fivefold increases in acyclovir bioavailability. In a randomized, double-blind, multicenter study, the safety and efficacy of oral valaciclovir given at a dosage of 1,000 mg three times daily for 7 or 14 days and oral acyclovir given at a dosage of 800 mg five times daily for 7 days were compared in immunocompetent adults aged > or = 50 years with herpes zoster. Patients were evaluated for 6 months. The intent-to-treat analysis (1,141 patients) showed that valaciclovir for 7 or 14 days significantly accelerated the resolution of herpes zoster-associated pain (P = 0.001 and P = 0.03, respectively) compared with acyclovir; median pain durations were 38 and 44 days, respectively, versus 51 days for acyclovir. Treatment with valaciclovir also significantly reduced the duration of postherpetic neuralgia and decreased the proportion of patients with pain persisting for 6 months (19.3 versus 25.7%). However, there were no differences between treatments in pain intensity or quality-of-life measures. Cutaneous manifestations resolved at similar rates in all groups. Adverse events were similar in nature and prevalence among groups, and no clinically important changes occurred in hematology or clinical chemistry parameters. Thus, in the management of immunocompetent patients > or = 50 years of age with localized herpes zoster, valaciclovir given at 1,000 mg three times daily for 7 days accelerates the resolution of pain and offers simpler dosing, while it maintains the favorable safety profile of acyclovir.

Although avian malarial parasites are globally distributed, the factors that affect the geographical distribution and local prevalence of different parasite lineages across host populations or species are still poorly understood. Based on the intense screening of avian malarial parasites in nine European blue tit populations, we studied whether distribution ranges as well as local adaptation, host specialization and phylogenetic relationships can determine the observed prevalences within populations. We found that prevalence differed consistently between parasite lineages and host populations, indicating that the transmission success of parasites is lineage specific but is partly shaped by locality-specific effects. We also found that the lineage-specific estimate of prevalence was related to the distribution range of parasites: lineages found in more host populations were generally more prevalent within these populations. Additionally, parasites with high prevalence that were also widely distributed among blue tit populations were also found to infect more host species. These findings suggest that parasites reaching high local prevalence can also realize wide distribution at a global scale that can have further consequences for host specialization. Although phylogenetic relationships among parasites did not predict prevalence, we detected a close match between a tree based on the geographic distance of the host populations and the parasite phylogenetic tree, implying that neighbouring host populations shared a related parasite fauna.

The interaction of the enantiomers of mianserin with the 5-HT3 receptor was determined. Using [3H]granisetron binding, (–)-mianserin was more potent than (+)-mianserin (pKi 8·46 and 6·95, respectively). The enantiomers competitively antagonized the depolarizing effect of 5-hydroxytryptamine in the rat vagus nerve preparation (pKapp: (–)-mianserin 8·13, (+)-mianserin 6·58). This stereoselectivity was maintained in-vivo as determined using ex-vivo inhibition of [3H]granisetron binding. Therefore, in contrast to its enantiomeric selectivity for the 5-HT1C and 5-HT2 receptors, where the (+)-isomer is more potent, the enantiomeric selectivity of mianserin for the 5-HT3 receptor was reversed. This differential selectivity of the enantiomers of mianserin may be useful in elucidating its utility in anxiety states.

882C87 [1-(beta-D-arabinofuranosyl)-5-propynyluracil] is a nucleoside analogue with potent and specific antiviral activity against varicella-zoster virus (VZV). The IC50 of 882C87 against VZV ranges from 0.6 to 3.8 microM. Potentially therapeutic plasma concentrations are readily achieved in humans; the pharmacokinetics have been previously evaluated in healthy young and elderly (65 years) volunteers following single oral doses of 50-400 mg. Thirty immunocompetent patients with localised herpes zoster were treated with 882C87. Groups of patients received 50 mg, 100 mg, or 200 mg tablets of 882C87 every 12 hours for 7 or 7.5 days (14 or 15 doses). Six patients in each group were over 60 years of age. Blood samples for determination of 882C87 concentrations were taken at entry, steady state, and during the elimination phase following the last dose. After the final doses of the 50 mg 100 mg, and 200 mg dosage regimens, the Cmax of 882C87 in patients over 60 years old was 7.7 +/- 3.1 microM, 12.6 +/- 3.5 microM, and 24.8 +/- 14.0 microM, respectively, and the AUCs 0-12 were 78.4 +/- 31.8 microM.hr, 137.5 +/- 22.8 microM.hr, and 272.5 +/- 170.5 microM.hr, respectively. Preliminary estimates of the elimination half-life ranged from 15.1 to 20.0 hr. These preliminary pharmacokinetic data confirmed good dose proportionality for AUC and Cmax with values between those predicted from single dose data in the young and those in elderly volunteers. The plasma concentration profiles at these doses were in excess of IC50 values and support the use of once- or twice-daily regimens in future studies of 882C87 in herpes zoster.

Chlamydia psittaci is the major cause of infectious disease in the koala (Phascolarctos cinereus). It causes four disease syndromes in the koala, namely, conjunctivitis, rhinitis, cystitis, and infertility (females only). Diagnosis of chlamydial infections in koalas relies primarily on isolation of the organism in cell culture. Serology has generally not been useful, and little use has previously been made of the commercially available antigen detection kits. We examined the sensitivity, specificity, and usefulness of three direct fluorescent-antibody kits (Vet-IF [Cell Labs], IMAGEN [Celltech], Chlamydia-Direct IF [Bio Merieux]) and six antigen detection enzyme-linked immunosorbent assay (ELISA) kits (Clearview [Unipath], Surecell [Kodak], Pathfinder [Kallestad], Chlamydia-EIA [Pharmacia], Chlamydiazyme [Abbott], IDEIA [Celltech]) for the detection of urogenital infections in koalas. Laboratory studies showed that the direct fluorescent-antibody kits were the least sensitive in this case and did not detect fewer than 10(4) elementary bodies per ml, while most ELISA kits detected between 130 and 600 elementary bodies per ml. Field study results showed that the Clearview kit was the most sensitive (91%) compared with the IDEIA (88%) and the Surecell (73%) kits. All three kits were more sensitive than cell culture (36%), highlighting viability loss problems that occur during transport. This study showed that the Clearview kit is sensitive, specific, and easy to use for the detection of type II (urogenital) C. psittaci from koalas in the field and warrants further evaluation.

A new technique for wrist fusion using vascularized bone graft is described. A distally based, pedicled segment of the distal ulna, nourished by the ulnar artery or the distally based palmar-ulnar branch of the anterior interosseus artery was used in three patients to restore carpal height after infection ( n = 2) or tumour resection ( n = 1). The forearm is converted to a situation similar to a wide ulnar resection. All three wrist fusions healed uneventfully. This new technique is suitable in cases where a vascularized bone graft is required, but microsurgical techniques are not appropriate or are rejected by the patient.

The personality systems of Cloninger (as measured by the Tridimensional Personality Questionnaire [TPQ]) and Eysenck (as measured by the Eysenck Personality Questionnaire [EPQ]) both have been linked to substance use and abuse. The current study examined the predictive utility of both systems for substance use disorder (SUD) diagnoses, both cross-sectionally and prospectively. Participants (N = 489 at baseline) completed the EPQ and TPQ and were assessed via structured diagnostic interview at baseline and 6 years later (N = 457 at follow-up). Both the EPQ and TPQ scales demonstrated bivariate cross-sectional and prospective associations with SUDs. Within each system, those dimensions marking a broad impulsive sensation-seeking or behavioral disinhibition trait were the best predictors prospectively, although the 2 systems were differentially sensitive to specific diagnoses. These relations remained significant even with autoregressivity, other concurrent SUD diagnoses, and multiple personality dimensions statistically controlled.

Ibutilide fumarate is indicated for the termination of atrial fibrillation and atrial flutter. It's mechanism of action is unclear but may involve activation of a late inward Na(+) current.Twenty seven experiments were performed using an isolated perfused rabbit right ventricle preparation. In each experiment effective refractory periods (ERP) and transmembrane 90% action potential durations (APD) were measured. In 8 experiments ERP and APD were measured at baseline, in the presence of ibutilide (0. 1[emsp4 ]uM), and in the presence of both ibutilide and tetrodotoxin (TTX, 2[emsp4 ]uM). In 8 experiments lidocaine (10[emsp4 ]uM) was used in place of TTX. Measures were made at 200, 400, and 800[emsp4 ]msec paced cycle lengths under each condition. The baseline values for APD at 200, 400 and 800[emsp4 ]msec cycle lengths for the experiments treated with ibutilide and TTX were 111+/-8, 140+/-14 and 159+/-22[emsp4 ]msec, respectively. In the presence of ibutilide, APD increased to 130+/-19, 192+/-26 and 217+/-35[emsp4 ]msec at 200, 400 and 800[emsp4 ]msec cycle lengths, respectively (all por =0.03). After the addition of TTX there was no shortening of APD or ERP compared to treatment with ibutilide alone at any cycle length (all por =0.062). Similarly, in the presence of ibutilide and lidocaine there were no changes in APD or ERP compared to treatment with ibutilide alone (all por =0.41). In 11 control experiments, there were no changes in APD or ERP on serial measures after placebo and TTX or lidocaine.Ibutilide induced prolongation of ventricular repolarization is not affected by Na(+) channel blockade with lidocaine or TTX in the isolated rabbit heart. These findings suggest that the effects of ibutilide are not mediated by a Na(+) channel dependent late current or that this mechanism contributes minimally to its action in this model.

Implantable cardioverter defibrillators (ICDs) with dual chamber and dual chamber rate responsive pacing may offer hemodynamic advantages for some ICD patients. Separate ICDs and DDDR pacemakers can result in device to device interactions, inappropriate shocks, and underdetection of ventricular fibrillation (VF). The objectives of this study were to compare the VF detection times between the Ventak AV II DR and the Ventak AV during high rate DDDR and DDD pacing and to test the safety of dynamic ventricular refractory period shortening. Patients receiving an ICD were randomized in a paired comparison to pacing at 150 beats/min (DDD pacing) or 175 beats/min (DDDR pacing) during ICD threshold testing to create a "worst case scenario" for VF detection. The VF detection rate was set to 180 beats/min, and VF was induced during high rate pacing with alternating current. The device was then allowed to detect and treat VF. The induction was repeated for each patient at each programmed setting so that all patients were tested at both programmed settings. Paired analysis was performed. Patient characteristics were a mean age of 69 +/- 11 years, 78% were men, coronary artery disease was present in 85%, and a mean left ventricular ejection fraction of 0.34 +/- 0.11. Fifty-two episodes of VF were induced in 26 patients. Despite the high pacing rate, all VF episodes were appropriately detected. The mean VF detection time was 2.4 +/- 1.0 seconds during DDD pacing and 2.9 +/- 1.9 seconds during DDDR pacing (P = NS). DDD and DDDR programming resulted in appropriate detection of all episodes of VF with similar detection times despite the "worst case scenario" tested. Delays in detection may be seen with long programmed ventricular refractory periods which shorten the VF sensing window and may be avoided with dynamic ventricular refractory period shortening.

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.

Eight patients with idiopathic ventricular tachycardia (VT) underwent mapping and radiofrequency ablation. Mapping showed VT originating in the high posterolateral left ventricular outflow tract in proximity to the left main and proximal circumflex coronary arteries. Ablation was not attempted due to this proximity to the left main and proximal circumflex coronary arteries. Ablation was not attempted due to this proximity in 2 patients and limited in 1 patient. It was successful in VT suppression in 5 of 6 patients.

A prospective trial was carried out to assess the outcome of children aged from 2 to 6 weeks with stable but dysplastic hips, treated with abduction splintage or by observation. Forty-four patients with 63 dysplastic hips were entered into the study and allocated into the two treatment groups at random. The ultrasound measured percentage acetabular cover in the splinted group improved in the first 3 months from an average of 32.8 to 54.3%. In the unsplinted group, the increase in cover was from 36.7 to 48.6%. The changes in cover for the splinted group were significantly more than those for the unsplinted group (p0.003) There was, however, no significant difference between the two groups in acetabular angle measurements on plain radiographs taken at 3 months. At 24 months, similarly, there was no significant difference in the acetabular angles of the two groups. These results support the view that stable dysplastic hips will correct with growth and that there is no sustained benefit from early splintage.

Linear scleroderma is a subtype of localized scleroderma that most commonly affects children. The disease is rare, and the course is unpredictable. Most cases spontaneously resolve in 3-5 years. A small number, however, slowly progress to involve deeper subcutaneous tissues, muscles, and periosteum. Subsequent joint contractures and gross disturbances are frequent. Little on treatment is recorded in the literature. We report on four children who, in addition to bony procedures and release of joint and ligamentous contractures, had excision of the diseased skin and free soft-tissue transfer for coverage.

The aim of the present study was to examine the relationship between measures of novelty and sensation seeking and both psychophysiological and subjective measures of stimulation after a pharmacological challenge with an indirect dopamine agonist, d-amphetamine. Prepulse inhibition (PPI) of the startle reflex and subjective responses were assessed after the challenge. The results indicated that the Novelty Seeking scale of the Tridimensional Personality Questionnaire (TPQ; M. Zuckerman, 1994). TPQ was a significant predictor of lower PPI and greater subjective stimulation. The Disinhibition scale of the Sensation Seeking Scale (SSS; M. Zuckerman, S. B. G. Eysenck,M. J. Eysenck, 1978) moderated the effects of amphetamine on stimulation and elation, whereas the Boredom Susceptibility and Experience Seeking subscales of the SSS moderated subjective stimulation. These findings indicate that higher scores on novelty and sensation seeking correspond to heightened sensitivity to the effects of a stimulant medication.

Exposure to repeated high +Gz loads and the methods to prevent loss of consciousness cause unique stresses on the cardiovascular system. The purpose of this study was to determine if the +Gz environment is associated with an increased occurrence of valvular regurgitation in pilots of high performance aircraft.There were 247 subjects who were divided into pilot (n = 46) and non-pilot (n = 201) groups. Pilots were defined as those individuals who had flown at least 1000 h in high performance aircraft. The echocardiographic data of these subjects were examined retrospectively.We found a statistically significant association between pulmonic insufficiency and exposure to high +Gz stress in pilots vs. non-pilots (chi2 = 13.09, p = 0.0002). In addition, there was a greater incidence of tricuspid regurgitation (chi2 = 4.97, p = 0.025) and concurrent pulmonic insufficiency and tricuspid regurgitation (chi2 = 14.1, p = 0.0002) in the pilot group.There is a direct relationship between repetitive exposure to a +Gz environment and pulmonic insufficiency, tricuspid regurgitation, or concurrent pulmonic insufficiency and tricuspid regurgitation. This may be secondary to the transient increase in right ventricular pressure due to acceleration forces or straining maneuvers utilized to prevent or postpone +Gz induced loss of consciousness (G-LOC).

This Phase I study was designed to determine the maximally tolerated dose (MTD) of paclitaxel with standard doses of cisplatin and etoposide for patients with untreated extensive stage small cell lung cancer (SCLC). Secondary objectives were to determine the toxicities, response rate, response duration, and overall survival in this cohort. Twenty-eight SCLC patients were enrolled into four dose levels. All patients received a fixed dose of cisplatin at 80 mg/m2, i.v., day 1. The first group received etoposide 50 mg/m2, i.v. day 1 and 100 mg/m2 p.o., days 2-3, whereas all subsequent groups received etoposide 80 mg/m2, i.v., day 1 and 160 mg/m2, p.o., days 2-3. The paclitaxel starting dose was 135 mg/m2, i.v., over a 3-h period and was escalated to 175 and 200 mg/m2. Cycles were repeated every 21 days for a maximum of six cycles. Granulocyte-colony stimulating factor was not given prophylactically but was allowed in subsequent cycles according to the American Society of Clinical Oncologists guidelines. All 28 SCLC patients were evaluable for toxicity, and 23 patients were evaluable for response. Myelosuppression was the major toxicity, with grade 4 neutropenia occurring in 23 of 28 patients (82%), but febrile neutropenia was uncommon and developed in 4 patients (14%). Grade 4 thrombocytopenia and anemia were rare, occurring as isolated events in one patient each. Dose-limiting peripheral neuropathy was observed at a paclitaxel dose of 200 mg/m2. Grade 4 nausea/vomiting and diarrhea were also noted at this dose level. Five patients had complete responses (22%), and 14 patients had partial responses (61%). The overall response rate was 83% with a median time to progression of 7.5 months, a median survival of 10 months, and a 1-year survival rate of 39%. This three-drug combination of paclitaxel with cisplatin and etoposide is active with acceptable toxicity. Neurotoxicity was dose limiting at 200 mg/m2 of paclitaxel. Neutropenia was frequent but not associated with significant morbidity. The recommended doses for future clinical trials are 175 mg/m2 paclitaxel, i.v., over a 3-h period on day 1 with 80 mg/m2 cisplatin, i.v., on day 1 and 80 mg/m2 etoposide, i.v., on day 1 and 160 mg/m2 p.o. on days 2 and 3 with growth factor support. The Southwestern Oncology Group has instituted a Phase II study with this dose schedule.

Previous studies showed that intratracheal instillation of endotoxin induces transient type II cell hyperplasia in the rat lung and described some of the mechanisms involved in the proliferative response of type II cells. The purpose of the present study was to investigate how long the type II cell hyperplasia persists and how it is resolved. The portion of epithelial cells in hyperplastic lesions of the rat lung expressing cyclin D1, an indicator for cells in the G1 phase of the cell cycle, was greatest at 3 d post instillation and decreased after 4 and 6 d. The fate of the proliferating epithelial cells was traced by injecting the rats with 5-bromo-2' deoxy uridine (BrdU) 2 d post instillation, the peak time point for maximum incorporation of BrdU. Exfoliated BrdU-positive epithelial cells were detected in the alveolar spaces in tissue sections from rats 4, 5, and 6 d post instillation. BrdU-positive epithelial cells showed flattened nuclei at 6 and 10 d post instillation. Expression of the 116 kD poly(ADP-ribose) polymerase (PARP) was low in type II cells from control rats, and was increased at 3, 4, and 6 d post instillation. In cells obtained by lavage, only a 35 kD cleavage product of PARP was detected, which is an indicator of necrotic cell death. In isolated type II cells from rats 3, 4, and 6 d post endotoxin instillation, progressive cleavage of the PARP to its 89 kD residual fragment was detected, which is a direct evidence for the activation of caspases. Furthermore, apoptotic epithelial cells with condensed nuclei were identified by electron microscopy in rats 4 d post instillation. These results indicate that apoptosis is an additional mechanism for the resolution of endotoxin-induced lung epithelial hyperplasias.

Although past research has examined correlates of HIV testing, much of it has focused on demographic differences between tested and nontested individuals. The present study examined psychosocial differences between individuals seeking a voluntary HIV test at a college student health center and individuals who have never had an HIV test. Variables included in the model were four components of the health belief model (perceived susceptibility, perceived severity, perceived benefits, perceived barriers), as well as perceived norms, consideration of future consequences, and risky sexual behavior. Results suggest that individuals seeking an HIV test perceived more benefits of having a test, tended to perceive fewer barriers to having a test, were higher in consideration of Future Consequences, and engaged in riskier sexual behavior than individuals never having had an HIV test. Implications for both HIV testing interventions and the health belief model are discussed.

To determine whether declining semen quality associated with health problems may be due to certain antibiotic or anti-inflammatory treatments, semen was collected 3 times per week for up to 42 d from 6 normal bulls after treatment with oxytetracycline, tilmicosin, dihydrostreptomycin, or phenylbutazone. No adverse effects on semen quality were observed.

Pacemaker lead technology has changed considerably over the past decades. The widespread use of low polarization highly porous electrodes and steroid elution electrodes has resulted in low chronic pacing thresholds, as well as a decrease in the incidence of exit block. Efforts to develop pacing leads with high impedance might theoretically lead to lower lead current drain, which is a component of battery capacity. Pulse generator longevity can be increased without sacrificing pacemaker capabilities if pacing current drain can be decreased. Decreasing the size of the stimulation electrode results in increased pacing impedance, and if pacing thresholds are unchanged, a decreased current drain is predicted by Ohm's law (I = V/R). There is limited data available on the pacing characteristics of large numbers of patients with high impedance leads, despite their recent general availability and increasing widespread use. This multicenter, controlled trial examined the differences in performance between standard steroid-eluting pacing leads in the atrium (Medtronic model 5524) and ventricle (Medtronic model 5024), and new high impedance steroid-eluting pacing leads in the atrium (Medtronic model 5534) and ventricle (Medtronic model 5034). Measurements of bipolar pacing thresholds at 2.5 V, pacing impedance, and sensing thresholds were determined within 24 hours of pacemaker implantation, and at 0.5, 1, 3, 6 and 12 months after pacemaker implantation in 609 patients. Pacing and sensing thresholds were similar for the control and high impedance leads at all times except for a slightly larger R wave with the high impedance leads at implantation and 12 months. The mean impedance of the high impedance pacing leads in the atrium and ventricle at 12 months was 992 +/- 175 and 1,080 +/- 220 omega, compared to 522 +/- 69 and 600 +/- 89 omega for the standard pacing leads in the atrium and ventricle (Por = 0.001 for the high impedance leads compared to standard leads in each chamber). The mean atrial lead current (measured at 2.5 V) at 12 months was 2.6 +/- 0.5 mA with the high impedance lead, and 4.9 +/- 0.7 mA with the standard lead in the atrium (Por = 0.001). In the ventricle, the mean lead current at 12 months was 2.4 +/- 0.4 mA with the high impedance pacing lead and 4.3 +/- 0.6 mA with the standard lead (Por = 0.001). High impedance leads are associated with lower lead current drain than standard pacing leads in the atrium and ventricle for up to 1 year. No clinically important differences in sensing characteristics was noted with the high impedance leads in the atrium or ventricle compared to standard pacing leads. High impedance leads may result in increased pulse generator longevity.

Electrical remodeling describes atrial electrophysiologic changes that occur following atrial fibrillation. The mechanism(s) responsible for this phenomenon is not well understood. The purpose of this study was to examine the effects of rapid atrial pacing on atrial action potential duration, conduction time and refractoriness in the isolated rabbit heart. The effects of Ca++ and K+ blockade in this model were also studied.Monophasic action potential recordings were made from 12 epicardial atrial sites in 50 isolated perfused rabbit heart preparations. These recordings were analyzed for activation time (AT), 90% action potential duration (APD) and conduction times (CT) measured at a 250 msec cycle length. Atrial effective refractory periods (ERP) were determined at a 200 msec cycle length. All measurements were made at baseline and repeated after 2 hours of biatrial pacing at 250 msec (control group, n = 10) or 2 hours of rapid biatrial pacing (approximately 80 msec) in 4 groups: rapid pacing alone (rapid pacing group); rapid pacing in the presence of 0.1 mM verapamil (verapamil group) for L-type Ca++ channel blockade; rapid pacing with 1 mM 4-aminopyridine (4-AP group) for K+ channel blockade; and rapid pacing with 50 microM nickel chloride (Ni++ group) for T-type Ca++ channel blockade (n = 10 each group). All baseline and post pacing measurements were taken in the presence of Ca++ or K+ blockers for the respective groups. After rapid atrial pacing alone the average APD shortened by 8.2 +/- 10.4 msec compared to 3.6 +/- 12.5 msec shortening for control group (p = 0.002). The shortening of APD was uniform at all recording sites. For the rapid pacing group, CT was unchanged for right to left atrial conduction but shortened significantly for left to right atrial conduction (26.8 +/- 1.9 msec at baseline to 22.3 +/- 4.1 msec post pacing, p = 0.005). Conduction times were unchanged in the control group. The dispersion of repolarization was unchanged by rapid pacing alone. The decrease in APD from baseline to post rapid pacing was similar to the control group for those hearts treated with verapamil and 4-AP (1.5 +/- 12.3 and 4.7 +/- 10.4 msec, respectively, both por = 0.18 vs control group). The decrease in APD was significantly greater for the Ni++ group (11.8 +/- 14.3 msec) than for either the control group or rapid pacing group (both por = 0.023). The dispersion of repolarization was increased only in the 4-AP group post rapid pacing (41.7 +/- 6.2 msec at baseline to 53.5 +/- 9.6 msec post pacing, p = 0.01). ERPs were unchanged in any of the 5 groups except for a decrease in left atrial ERP in the Ni++ group after rapid pacing (98 +/- 14 msec at baseline to 88 +/- 8 msec post rapid pacing, p = 0.005).In the isolated rabbit heart model: 1) atrial APD is shortened after rapid pacing; 2) the shortening of APD is attenuated by verapamil and 4-AP but exaggerated by Ni++; 3) atrial conduction times are shortened in a direction specific manner after rapid pacing; and 4) shortening of ERP in this model is measured only in the presence of Ni++. These findings suggest that both L-type Ca++ and 4-AP sensitive channels may participate in atrial electrical remodeling.

The efficacy of early versus late treatment with acyclovir and valaciclovir on zoster-associated pain was assessed from two databases (1076 patients) that were compiled from randomized trials. Early treatment was started48 h and late treatment was started 48-72 h after the onset of cutaneous herpes zoster. Median times to complete resolution of zoster-associated pain were 28 and 62 days, respectively, for patients (or = 18 years of age) treated with acyclovir and placebo within 48 h (hazard ratio [HR], 1.68; 95% confidence limit [95% CL], 1.19, 2.38) and 28 and 58 days, respectively, for those treated later (HR, 2.20; 95% CL, 1.03, 4.71). In the valaciclovir versus acyclovir study (in patientsor = 50 years of age), the corresponding figures were 44 and 51 days for patients treated early (HR, 1.28; 95% CL, 1.03, 1.60) and 36 and 48 days for those treated later (HR, 1.40; 95% CL, 1.04, 1.87). Acyclovir significantly shortened the time to complete resolution of zoster-associated pain compared with placebo (and valaciclovir was superior to acyclovir in this regard) even when therapy was delayed up to 72 h after rash onset.

The largest outbreak of the zoonotic disease Q fever recorded in the United Kingdom (UK) occurred in Birmingham in 1989. One hundred and forty-seven cases were identified, 125 of whom were males, and 130 of whom were between 16 and 64 years of age. Fewer cases of Asian ethnic origin were observed than expected (p0.01), and more smokers (p0.005). A case control study (26 cases and 52 matched controls) produced no evidence that direct contact with animals or animal products had caused the outbreak. The epidemic curve suggested a point source exposure in the week beginning 10 April. The home addresses of cases were clustered in a rectangle 11 miles (18.3 km) north/south by 4 miles (6.7 km) east/ west, and attack rates became lower towards the north. Directly south of this area were farms engaged in outdoor lambing and calving, a potent source of coxiella spores. A retrospective computerised analysis showed that the geographical distribution of cases was associated with a source in this area (p0.00001). On 11 April, unusual southerly gales of up to 78 mph (130 km/h) were recorded. The probable cause of the outbreak was windborne spread of coxiella spores from farmland to the conurbation.

The patency rates of microsurgical end-to-end and end-to-side anastomosis in the rat carotid artery were studied. Seventy end-to-end and seventy end-to-side arterial anastomoses, using 10-0 nylon interrupted sutures, were performed on 140 Sprague-Dawley rats. Findings indicated 100% patency in end-to-end as well as end-to-side immediately and 1 week post-anastomosis. This investigation suggests that there is no significant advantage between the methods studied based on vessel patency alone. The decision to perform an end-to-end vs. an end-to-side arterial anastomosis should be based upon the clinical circumstances encountered, since no significant difference in patency rates exists.

Synovitis of the wrist induced by particles of silicone debris is a destructive inflammatory process. Many silicone-rubber carpal implants remain in place, and there are few reports regarding the treatment of this condition. The purpose of the present study was to examine the results of treatment of synovitis induced by particles of silicone debris. Twenty-eight patients were identified, with use of computerized indexing, as having been evaluated for silicone-induced synovitis between 1972 and 1992. Seventeen of the twenty-eight patients were included in the study. At the time of the latest follow-up, twelve of the seventeen patients had pain, thirteen of the fourteen patients for whom radiographs were available had evidence of osteolysis typical of that associated with debris-induced synovitis, and eight of the seventeen patients reported difficulty with activities of daily living because of problems with the wrist. Seven patients had been treated non-operatively, and ten had been treated operatively. With the small number of patients available for study, we could not detect a significant difference between the two groups with respect to pain, perceived limitation of motion, difficulty with activities of daily living, grip strength, or the total range of motion of the wrist. There was no significant difference between the two groups with regard to the age at the time of the initial procedure, the time to the diagnosis of the synovitis, and the duration of follow-up after treatment. There was no clear advantage to removal of the implant and débridement with or without arthrodesis of the wrist or other reconstructive procedures. We recommend caution when a reconstructive or salvage procedure in the wrist is selected for a patient who has synovitis induced by particles of silicone debris.

We have reviewed 30 patients at a mean of 36 months after free vascularised fibular transfer to reconstruct massive skeletal defects after resection of primary bone tumours. There were 23 malignant and 7 benign neoplasms, half in the lower limb and half in the upper. Arthrodesis was performed in 15 and intercalary bone replacement in 15. The mean fibular graft length was 189 mm. Union was achieved in 27 (90%) at an average of 7.6 months, and the 3-year survival was 89%. There was a high complication rate (50%), but most resolved without greatly influencing the final outcome. There was local recurrence in two (6.7%), but 16 of the 24 assessed patients (67%) had satisfactory functional results. This is a reasonably effective means of reconstruction for limb salvage after resection of tumours.

This article presents the results of the process analysis of the evaluation of the Project NetWork demonstration, a Federal demonstration undertaken by the Social Security Administration (SSA) in 1991 to test alternative methods of providing rehabilitation and employment services to SSA's Disability Insurance beneficiaries and Supplemental Security Income disabled and blind applicants and recipients. The major findings are: (1) from an operational standpoint, it is feasible to expand access to vocational rehabilitation (VR) services to a broad spectrum of SSA beneficiaries, and (2) roughly similar results are achieved, in terms of client intake and provision of services, when case management services are provided by SSA staff, contracted out to State VR agencies, or contracted with private VR providers. Later evaluation reports will trace demonstration impacts on earnings and disability benefits and report the overall benefits and costs of return-to-work services for this population.

Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter.Two hundred sixty-six patients with sustained atrial fibrillation (n = 133) or flutter (n = 133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo (P.0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%, P.0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%).Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.

Netivudine is a nucleoside analogue with potent anti-varicella zoster virus activity. We now report two open studies of the pharmacokinetics and tolerability of netivudine in doses of 50, 100 and 200 mg twice daily. In one study, healthy volunteers received an initial, single dose followed, a week later, by repeat dosing for 9 1/2 days; in the other, patients with shingles were treated for 8 days and data were also recorded for rash resolution and pain duration and intensity. Netivudine was well tolerated in both studies. Plasma concentrations were similar in patients and healthy volunteers and increased in proportion to dose. Steady state concentrations were 15-25% lower than expected from single dose data, probably because of slightly decreased netivudine absorption after food. Elimination half-life was l4-20 h. Plasma concentrations of 5-propynyluracil (5-PU), the main metabolite of netivudine, did not increase in proportion to the netivudine dose and tended to be higher in patients than volunteers. 5-PU concentrations remained elevated for up to 72 h after the last netivudine dose, suggesting continued but slow release from unabsorbed netivudine in the gut lumen. New lesion formation ceased and vesicles crusted most quickly in the 200 mg group; zoster-associated pain intensity, was reduced in a dose-related manner.

OBJECTIVE: To identify the experience and willingness of family physicians to accept follow-up care of patients treated for stage I breast cancer. DESIGN: Mailed questionnaire. PARTICIPANTS: One hundred eighty-nine family physicians in southwestern Ontario with oversampling of female physicians and physicians practising more than 20 km from a cancer clinic. MAIN OUTCOME MEASURE: Willingness to follow breast cancer patients and time after treatment family physicians would be willing to begin follow-up care. RESULTS: We had an 81.5% response rate. Of the 154 respondents, 53% had been involved previously in the 5-year, follow-up care of a patient with breast cancer and 77.1% believed it appropriate for family physicians to assume responsibility for follow-up care in all or most cases. If asked by a patient, the family, or an oncologist to provide follow-up care, 90.1% of family physicians reported they would accept this responsibility. Willingness to follow breast cancer patients was not associated with sex, years in practice, proximity to a cancer clinic, or certification status but was associated with having previously provided such care (P = .043). Of those willing to care for these patients, almost 90% would prefer to start within 1 year of treatment. CONCLUSION: Although only half the respondents had experience in providing follow-up care to breast cancer patients, most were willing to take on this role, especially if asked.

Several parameters of shingles' pain can be measured and each provides meaningful information. Generally, the more comprehensive the assessment the better, but there are significant difficulties in measuring the duration of post-herpetic neuralgia (PHN). Patients with herpes zoster usually feel pain as a continuum and, although acute pain and PHN have different qualities and pathophysiologies, we lack the sophistication to determine when PHN commences. Use of an arbitrarily defined starting point is meaningless for the patient and may introduce statistical bias (particularly if acute pain and PHN are divided by the point of rash healing). Thus, measurement of the pain as a continuum ('zoster-associated pain') is advocated. We also need to decide what degree of pain intensity is meaningful and whether complete cessation of pain or loss of pain (or only 'moderate/severe' pain) for a finite period is a better assessment. This approach to pain measurement was recently adopted in a meta-analysis of the placebo-controlled trials of oral aciclovir in herpes zoster. When 'time to complete cessation of all pain' was assessed, the hazard ratio was 2.13 in favour of aciclovir, with a 95% confidence interval (CI) of 1.42 to 3.19. For 'time to complete cessation of moderate/severe pain' the hazard ratio was 1.46 (95% CI; 1.11, 1.93); for 'time to first pain-free period' it was 1.31 (95% CI; 1.08, 1.60). These results indicate that aciclovir significantly speeds pain resolution in shingles.

Functional MRI (fMRI) can detect changes from resting levels of blood flow and oxygenation during task performance (i.e. activation). We used a simple electrical nerve stimulation technique together with fMRI to study pain process in the human cortex. Images of the primary somatosensory (SI) and cingulate cortex (Cg) were obtained from subjects during stimulation at painful and non-painful intensities. Stimuli that evoked non-painful tingling sensations activated the contralateral SI but not Cg. Stimuli that evoked painful sensations activated both the contralateral SI and Cg. These data indicate that fMRI can detect pain-related changes in SI and Cg evoked by electrical stimulation of peripheral nerves. These findings add to the evidence for a role of SI and Cg in human pain processes and provide a simple method of stimulus delivery for its study.

The effect of donor-recipient strain combination and supplemental rapamycin (Rapa) on tolerance induction by intrathymic (IT) injection of donor splenocytes was examined in a mouse skin allograft model. In an MHC class I-mismatched C3H/He skin to (C57BL/6 x A)F1 (B6AF1) mouse combination, IT injection of 50 x 10(6) donor splenocytes with transient immunosuppression by rabbit anti-mouse lymphocyte serum (ALS) induced significant prolongation of skin allograft survival with a median survival time (MST) of 115 days versus an MST of 24.5 days in controls given ALS alone. With an additional short course of supplemental Rapa treatment at a dose of 1.5 mg/kg i.p. every other day from day 0 to 12, all C3H/He skin allografts survived indefinitely (350 days) in ALS-treated, donor splenocyte intrathymically injected B6AF1 recipient mice. Tolerance was antigen-specific, since the second donor-type skin allografts were accepted while third-party skin allografts were acutely rejected in these mice bearing long-term C3H/He skin allografts. In MHC class I- and II-disparate (DBA/2 to B6AF1) and fully MHC-incompatible (AKR to B6) strain combinations, IT injection of donor splenocytes and ALS treatment failed to prolong skin allograft survival over ALS controls. When supplemental Rapa was used, long-term skin allograft acceptance was observed with an MST of 127 days for the DBA/2 to B6AF1 combination and 70 days for the AKR to B6 combination. In contrast, supplemental treatment with cyclosporine was not effective in these combinations, which suggests that supplemental Rapa may have a unique effect in augmenting IT tolerance induction. Thymectomy within 7 days after IT injection significantly shortened the allograft survival, which suggests that interaction of the host thymus and the injected donor splenocytes, which takes place early after IT injection, plays an important role in the induction of allograft tolerance in this model.

A clinicopathologic study of 70 cases of cellular schwannoma was performed to assess their distribution, response to therapy, and rate of recurrence relative to modern prognostic indicators.Seventy-one cellular schwannomas from 70 patients were retrieved from the files of the Mayo Clinic Tissue Registry. The significance of mitotic index, proliferative marker staining (proliferating cell nuclear antigen and MIB1), immunochemical p53 expression, and DNA ploidy were assessed relative to tumor behavior, particularly recurrence. All parameters were subject to statistical analysis (Student's t test).Cellular schwannomas represented 4.6% of benign peripheral nerve tumors operated on at the Mayo Clinic. In 15% of the cases, an initial diagnosis of malignancy had been made. The median patient age was 47.7 years (range, 15-80 years) and the female-to-male ratio was 1.6:1. The principle tumor locations were the para- and intraspinal regions, including the sacrum (64%), extremities (25%), and intracranial space (8%). All tumors consisted primarily of hypercellular, compact, Antoni A tissue. Mitoses (or = 4/10 hPF]) were observed in 71% of the cases. Foci of necrosis were noted in 11% of cases. Ultrastructural studies and immunohistochemistry clearly demonstrated features of schwannian differentiation. Surgery was the treatment in all cases. Excision was intralesional to gross total in the majority; total resection with wide margins was undertaken in three tumors, each of which had initially been considered malignant. Follow-up in 47 patients (67%) ranged from 1 to 29 years (mean, 7.7 years) and revealed recurrences in 11 patients (23.4%): no patient experienced metastasis or died of tumor. Although no correlation existed between recurrence and DNA ploidy, percent S-phase determinations, proliferation marker (PCNA, MIB1) staining, or the frequency of p53 immunoreactivity, a statistically significant correlation (P0.001) was observed, however, between recurrence and mitotic indices.Proliferation indices, as defined by immunochemical analysis, are not useful predictors of recurrence in cellular schwannoma. In lesions not completely resected, tumor recurrence is significantly correlated with mitotic count. The significant overall frequency of recurrence in this series is attributable to a high proportion of intraspinal and intracranial tumors. Our study confirms the benign nature of cellular schwannoma and underscores the necessity of distinguishing them from malignant peripheral nerve sheath tumors, lesions that often require adjuvant therapy.