A supervised machine learning approach to characterize spinal network function.

Spontaneous activity is a common feature of immature neuronal networks throughout the central nervous system and plays an important role in network development and consolidation. In postnatal rodents, spontaneous activity in the spinal cord exhibits complex, stochastic patterns that have historically proven challenging to characterize. We developed a software tool for quickly and automatically characterizing and classifying episodes of spontaneous activity generated from developing spinal networks. We recorded spontaneous activity from in vitro lumbar ventral roots of 16 neonatal [postnatal day (P)0-P3] mice. Recordings were DC coupled and detrended, and episodes were separated for analysis. Amplitude-, duration-, and frequency-related features were extracted from each episode and organized into five classes. Paired classes and features were used to train and test supervised machine learning algorithms. Multilayer perceptrons were used to classify episodes as rhythmic or multiburst. We increased network excitability with potassium chloride and tested the utility of the tool to detect changes in features and episode class. We also demonstrate usability by having a novel experimenter use the program to classify episodes collected at a later time point (P5). Supervised machine learning-based classification of episodes accounted for changes that traditional approaches cannot detect. Our tool, named SpontaneousClassification, advances the detail in which we can study not only developing spinal networks, but also spontaneous networks in other areas of the nervous system. NEW & NOTEWORTHY Spontaneous activity is important for nervous system network development and consolidation. Our software uses machine learning to automatically and quickly characterize and classify episodes of spontaneous activity in the spinal cord of newborn mice. It detected changes in network activity following KCl-enhanced excitation. Using our software to classify spontaneous activity throughout development, in pathological models, or with neuromodulation, may offer insight into the development and organization of spinal circuits.

Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging.

BACKGROUND: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. METHODS: Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. RESULTS: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. CONCLUSION: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.

Tumour stage and resection margin status are independent survival factors following partial pancreatoduodenectomy for duodenal adenocarcinoma.

INTRODUCTION: There is limited published evidence on duodenal carcinoma due to its rarity. This study aimed to evaluate gastric outlet obstruction and obstructive jaundice along with pathological variables as survival factors in patients with duodenal adenocarcinoma following resection. METHODS: Survival factor analysis was undertaken in patients undergoing duodenal cancer surgery from 1997 to 2015 in a single centre. RESULTS: There were 57 patients of whom 18 had gastric outlet obstruction and 14 had obstructive jaundice. Fifty-three had a partial pancreatoduodenectomy and four had palliative bypass. Perioperative mortality and morbidity were 4% (2/53) and 47% (25/53) respectively in resected patients. With a median (95% confidence interval, CI) follow-up of 72 (57-86) months, median overall and recurrence-free survival was 38 months (95% CI 28-113) and 27 months (95% CI 18-83) respectively. The 1 and 3-year overall survival rates were 84% (95% CI 74-95) and 52% (95% CI 39-69) respectively. Median overall survival was 19 months in patients with gastric outlet obstruction vs 53 months in those without (p = 0.026) and 28 months in patients with obstructive jaundice vs 38 months in those without (p = 0.611). Univariate analysis revealed that tumour stage, resection margin status, pre-operative albumin status, gastric outlet obstruction and age were associated with poorer overall and recurrence-free survival but multivariate analysis confirmed only tumour stage and resection margin status to be significant. CONCLUSION: Whereas gastric outlet obstruction in duodenal cancer appeared to be an important survival factor following partial pancreatoduodenectomy, multivariate analysis showed that only tumour stage and resection margin status were the key independent survival factors. Further multicentre studies are required to elucidate further characteristics of duodenal carcinoma and develop neoadjuvant/adjuvant management strategies.

Retracing your footsteps: developmental insights to spinal network plasticity following injury.

During development of the spinal cord, a precise interaction occurs between descending projections and sensory afferents, with spinal networks that lead to expression of coordinated motor output. In the rodent, during the last embryonic week, motor output first occurs as regular bursts of spontaneous activity, progressing to stochastic patterns of episodes that express bouts of coordinated rhythmic activity perinatally. Locomotor activity becomes functionally mature in the 2nd postnatal wk and is heralded by the onset of weight-bearing locomotion on the 8th and 9th postnatal day. Concomitantly, there is a maturation of intrinsic properties and key conductances mediating plateau potentials. In this review, we discuss spinal neuronal excitability, descending modulation, and afferent modulation in the developing rodent spinal cord. In the adult, plastic mechanisms are much more constrained but become more permissive following neurotrauma, such as spinal cord injury. We discuss parallel mechanisms that contribute to maturation of network function during development to mechanisms of pathological plasticity that contribute to aberrant motor patterns, such as spasticity and clonus, which emerge following central injury.

Modulatory and plastic effects of kinins on spinal cord networks.

KEY POINTS: Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown. In the present study, kinins were shown to have short- and long-term effects on motor networks. The short-term effects included direct depolarization of interneurons and motoneurons in the ventral horn accompanied by modulation of transient receptor potential vanilloid 1-sensitive nociceptors in the dorsal horn. Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. In a model of spinal cord injury, we observed an increase in microglia numbers in both the dorsal and ventral horn and, in a microglia cell culture model, we observed bradykinin-induced expression of glial-derived neurotrophic factor. ABSTRACT: The expression and function of inflammatory mediators in the developing spinal cord remain poorly characterized. We discovered novel, short and long-term roles for the inflammatory nonapeptide bradykinin (BK) and its receptor bradykinin receptor B2 (B2R) in the neuromodulation of developing sensorimotor networks following a spinal cord injury (SCI), suggesting that BK participates in an excitotoxic cascade. Functional expression of B2R was confirmed by a transient disruptive action of BK on fictive locomotion generated by a combination of NMDA, 5-HT and dopamine. The role of BK in the dorsal horn nociceptive afferents was tested using spinal cord attached to one-hind-limb (HL) preparations. In the HL preparations, BK at a subthreshold concentration induced transient disruption of fictive locomotion only in the presence of: (1) noxious heat applied to the hind paw and (2) the heat sensing ion channel transient receptor potential vanilloid 1 (TRPV1), known to be restricted to nociceptors in the superficial dorsal horn. BK directly depolarized motoneurons and ascending interneurons in the ventrolateral funiculus. We found a key mechanism for BK in promoting long-term plasticity within the spinal cord. Using a model of neonatal SCI and a microglial cell culture model, we examined the role of BK in inducing activation of microglia and expression of glial-derived neurotrophic factor (GDNF). In the neonatal SCI model, we observed an increase in microglia numbers and increased GDNF expression restricted to microglia. In the microglia cell culture model, we observed a BK-induced increased expression of GDNF via B2R, suggesting a novel mechanism for BK spinal-mediated plasticity.

What affected UK adults' adherence to medicines during the COVID-19 pandemic? Cross-sectional survey in a representative sample of people with long-term conditions.

Aim: Medicines non-adherence is associated with poorer outcomes and higher costs. COVID-19 affected access to healthcare, with increased reliance on remote methods, including medicines supply. This study aimed to identify what affected people's adherence to medicines for long-term conditions (LTCs) during the pandemic. Subject and methods: Cross-sectional online survey of UK adults prescribed medicines for LTCs assessing self-reported medicines adherence, reasons for non-adherence (using the capability, opportunity and motivation model of behaviour [COM-B]), medicines access and COVID-19-related behaviours. Results: The 1746 respondents reported a mean (SD) of 2.5 (1.9) LTCs, for which they were taking 2.4 (1.9) prescribed medicines, 525 (30.1%) reported using digital tools to support ordering or taking medicines and 22.6% reported medicines non-adherence. No access to at least one medicine was reported by 182 (10.4%) respondents; 1048 (60.0%) reported taking at least one non-prescription medicine as a substitute; 409 (23.4%) requested emergency supply from pharmacy for at least one medicine. Problems accessing medicines, being younger, male, in the highest socioeconomic group and working were linked to poorer adherence. Access problems were mostly directly or indirectly related to the COVID-19 pandemic. Respondents were generally lacking in capabilities and opportunities, but disruptions to habits (automatic motivation) was the major reason for non-adherence. Conclusion: Navigating changes in how medicines were accessed, and disruption of habits during the COVID-19 pandemic, was associated with suboptimal adherence. People were resourceful in overcoming barriers to access. Solutions to support medicines-taking need to take account of the multiple ways that medicines are prescribed and supplied remotely. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-022-01813-0.

Contribution of solid fuel, gas combustion, or tobacco smoke to indoor air pollutant concentrations in Irish and Scottish homes.

UNLABELLED: There are limited data describing pollutant levels inside homes that burn solid fuel within developed country settings with most studies describing test conditions or the effect of interventions. This study recruited homes in Ireland and Scotland where open combustion processes take place. Open combustion was classified as coal, peat, or wood fuel burning, use of a gas cooker or stove, or where there is at least one resident smoker. Twenty-four-hour data on airborne concentrations of particulate matter<2.5 µm in size (PM2.5), carbon monoxide (CO), endotoxin in inhalable dust and carbon dioxide (CO2), together with 2-3 week averaged concentrations of nitrogen dioxide (NO2) were collected in 100 houses during the winter and spring of 2009-2010. The geometric mean of the 24-h time-weighted-average (TWA) PM2.5 concentration was highest in homes with resident smokers (99 µg/m3--much higher than the WHO 24-h guidance value of 25 µg/m3). Lower geometric mean 24-h TWA levels were found in homes that burned coal (7 µg/m3) or wood (6 µg/m3) and in homes with gas cookers (7 µg/m3). In peat-burning homes, the average 24-h PM2.5 level recorded was 11 µg/m3. Airborne endotoxin, CO, CO2, and NO2 concentrations were generally within indoor air quality guidance levels. PRACTICAL IMPLICATIONS: Little is known about indoor air quality (IAQ) in homes that burn solid or fossil-derived fuels in economically developed countries. Recent legislative changes have moved to improve IAQ at work and in enclosed public places, but there remains a real need to begin the process of quantifying the health burden that arises from indoor air pollution within domestic environments. This study demonstrates that homes in Scotland and Ireland that burn solid fuels or gas for heating and cooking have concentrations of air pollutants generally within guideline levels. Homes where combustion of cigarettes takes place have much poorer air quality.

Development of an intervention to increase adherence to nebuliser treatment in adults with cystic fibrosis: CFHealthHub.

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic condition in which daily therapies to maintain lung health are critical, yet treatment adherence is low. Previous interventions to increase adherence have been largely unsuccessful and this is likely due to a lack of focus on behavioural evidence and theory alongside input from people with CF. This intervention is based on a digital platform that collects and displays objective nebuliser adherence data. The purpose of this paper is to identify the specific components of an intervention to increase and maintain adherence to nebuliser treatments in adults with CF with a focus on reducing effort and treatment burden. METHODS: Intervention development was informed by the Behaviour Change Wheel (BCW) and person-based approach (PBA). A multidisciplinary team conducted qualitative research to inform a needs analysis, selected, and refined intervention components and methods of delivery, mapped adherence-related barriers and facilitators, associated intervention functions and behaviour change techniques, and utilised iterative feedback to develop and refine content and processes. RESULTS: Results indicated that people with CF need to understand their treatment, be able to monitor adherence, have treatment goals and feedback and confidence in their ability to adhere, have a treatment plan to develop habits for treatment, and be able to solve problems around treatment adherence. Behaviour change techniques were selected to address each of these needs and were incorporated into the digital intervention developed iteratively, alongside a manual and training for health professionals. Feedback from people with CF and clinicians helped to refine the intervention which could be tailored to individual patient needs. CONCLUSIONS: The intervention development process is underpinned by a strong theoretical framework and evidence base and was developed by a multidisciplinary team with a range of skills and expertise integrated with substantial input from patients and clinicians. This multifaceted development strategy has ensured that the intervention is usable and acceptable to people with CF and clinicians, providing the best chance of success in supporting people with CF with different needs to increase and maintain their adherence. The intervention is being tested in a randomised controlled trial across 19 UK sites.

Diversification of intrinsic motoneuron electrical properties during normal development and botulinum toxin-induced muscle paralysis in early postnatal mice.

During early postnatal development, between birth and postnatal days 8-11, mice start to achieve weight-bearing locomotion. In association with the progression of weight-bearing locomotion there are presumed developmental changes in the intrinsic electrical properties of spinal -motoneurons. However, these developmental changes in the properties of -motoneuron properties have not been systematically explored in mice. Here, data are presented documenting the developmental changes of selected intrinsic motoneuron electrical properties, including statistically significant changes in action potential half-width, intrinsic excitability and diversity (quantified as coefficient of variation) of rheobase current, afterhyperpolarization half-decay time, and input resistance. In various adult mammalian preparations, the maintenance of intrinsic motoneuron electrical properties is dependent on activity and/or transmission-sensitive motoneuron-muscle interactions. In this study, we show that botulinum toxin-induced muscle paralysis led to statistically significant changes in the normal development of intrinsic motoneuron electrical properties in the postnatal mouse. This suggests that muscle activity during early neonatal life contributes to the development of normal motoneuron electrical properties.

Modulation of AMPA currents by D(1)-like but not D(2)-like receptors in spinal motoneurons.

Dopamine can modulate and excite spinal locomotor networks, affect afferent transmission and increase motoneuronal excitability. One of the mechanisms whereby dopamine increases motoneuronal excitability is to potentiate AMPA channel-mediated glutamatergic transmission onto motoneurons. However, it is not known which dopaminergic receptor subtypes or the intracellular mechanisms contribute to these effects. In this study, we used whole-cell patch clamp techniques to record chemically evoked AMPA currents in neonatal mouse motoneurons. Bath application of D(1)-like receptor agonist (SKF 39383) increased the AMPA current amplitude and prolonged the decay time constant. In the presence of D(1) receptor antagonist LE300, the effects of DA on AMPA currents were blocked. In contrast, bath-application of the D(2)-like receptor agonist quinpirole did not modulate AMPA currents. In the presence of D(2) receptor antagonist L-741626, dopaminergic modulation of AMPA currents was unaffected. These results suggest that augmentation of AMPA transmission by dopamine is accomplished by D(1) receptor-based mechanisms. This short-term modulation does not appear to involve cycling of AMPA receptor into the membrane, since blocking insertion with botulinum toxin C did not affect the augmentation of AMPA currents after activating D(1) receptors. On the other hand, blocking protein kinase A (PKA) with H-89 completely abolished the effects of D(1) agonists. In addition, we used cell-attached single channel recording to demonstrate that stimulating D(1) receptors increased individual AMPA channel open probability and open duration. Our data demonstrate that dopamine increases the efficacy of glutamatergic transmission onto motoneurons by increasing AMPA conductances via a D(1) PKA-based signaling system.

Preoperative resolution of jaundice following biliary stenting predicts more favourable early survival in resected pancreatic ductal adenocarcinoma.

INTRODUCTION: Despite the widespread use of endoscopic biliary stenting in patients presenting with potentially resectable pancreatic cancer, there is no general consensus regarding whether this represents a superior management approach over expeditious surgical intervention. The objective of this study was to investigate the influence of preoperative biliary stenting and resolution of jaundice on subsequent postoperative survival following resection for pancreatic cancer. METHODS: 155 patients undergoing partial pancreatoduodenectomy for pancreatic ductal adenocarcinoma between January 1997 and August 2007 were identified from a prospectively maintained database. RESULTS: There was no survival difference when comparing patients undergoing preoperative biliary drainage (n = 130) with those who did not (n = 25) (log rank, P = 0.981). When analysing individual prognostic factors as continuous variables in univariate Cox analysis, lower albumin levels (P = 0.016), elevated alkaline phosphatase levels (P = 0.011) and elevated CRP levels (P = 0.021) were associated with poorer overall survival. Multivariable Cox regression demonstrated that both albumin (P = 0.008) and CRP (P = 0.038) remained significant independent predictors of overall survival alongside lymph node ratio (P = 0.018). Although preoperative bilirubin levels were not associated with overall survival when analysed as a continuous variable (Cox, P = 0.786), the presence of jaundice (i.e., bilirubin >35 micromol/l) at the time of surgery was a significant adverse predictor of early survival in patients undergoing preoperative biliary drainage (Breslow-Gehan-Wilcoxon, P = 0.013) and remained a significant predictor of early survival when included in a further Cox analysis with censoring of cases who survived beyond 6 months (Cox, P = 0.017). CONCLUSION: These results suggest that the presence of jaundice at the time of resection has an adverse impact on early, but not overall, postoperative survival in pancreatic cancer patients undergoing preoperative biliary drainage.

Automatic seed initialization for the expectation-maximization algorithm and its application in 3D medical imaging.

Statistical partitioning of images into meaningful areas is the goal of all region-based segmentation algorithms. The clustering or creation of these meaningful partitions can be achieved in number of ways but in most cases it is achieved through the minimization or maximization of some function of the image intensity properties. Commonly these optimization schemes are locally convergent, therefore initialization of the parameters of the function plays a very important role in the final solution. In this paper we perform an automatically initialized expectation-maximization algorithm to partition the data in medical MRI images. We present analysis and illustrate results against manual initialization and apply the algorithm to some common medical image processing tasks.

Control of locomotion in the decerebrate cat.

Many of the general concepts regarding the control of walking were described years ago by: Sherrington (1906) Integrative Actions of the Nervous System. Yale University Press: New Haven, CT; Sherrington (1910a) Remarks on the reflex mechanism of the step, Brain 33, 1-25; Sherrington (1910b) Flexor-reflex of the limb, crossed extension reflex, and reflex stepping and standing (cat and dog), J. Physiol. (Lond.) 40, 28-121; Sherrington (1931) Quantitative management of contraction in lowest level coordination, Brain 54, 1-28; Graham-Brown (1912) The intrinsic factors in the act of progression in the mammal, Proc. R. Soc. Lond. 84, 308-319; Graham-Brown (1914) On the nature of the fundamental activity of the nervous centres; together with an analysis of the conditioning of rhythmic activity in progression, and a theory of the evolution of function in the nervous system, J. Physiol. 49, 18-46; Graham-Brown (1915) On the activities of the central nervous system of the unborn foetus of the cat, with a discussion of the question whether progression (walking, etc.) is a 'learnt' complex, J. Physiol. 49, 208-215; Graham-Brown (1922) The physiology of stepping, J. Neur. Psychopathol. 3, 112-116. Only in recent years, however, have the mechanisms been analyzed in detail. Quite a few of these mechanisms have been described using the decerebrate cat. Locomotion is initiated in decerebrate cats by activation of the mesencephalic locomotor region (MLR) that activates the medial medullary reticular formation (MRF) which in turn projects axons to the spinal cord which descend within the ventrolateral funiculus (VLF). The MRF region regulates as well as initiates the stepping pattern and is thought to be involved in interlimb coordination. Afferent feedback from proprioceptors and exteroceptors can modify the ongoing locomotor pattern. Recently, the types of afferents responsible for signaling the stance to swing transition have been identified. A general rule states that if the limb is unloaded and the leg is extended, then swing will occur. The afferents that detect unloading of the limb are the Golgi tendon organs and stimulation of these afferents (at group I strengths) prolongs the stance phase in walking cats. The afferents that detect the extension of the leg have been found to be the length- and velocity-sensitive muscle afferents located in flexor muscles. Plasticity of locomotor systems is discussed briefly in this article. Descerebrate animals can adapt locomotor behaviors to respond to new environmental conditions. Oligosynaptic reflex pathways that control locomotion can be recalibrated after injury in a manner that appears to be functionally related to the recovery of the animal.

Left-ventricle myocardium segmentation using a coupled level-set with a priori knowledge.

This paper presents a coupled level-set segmentation of the myocardium of the left ventricle of the heart using a priori information. From a fast marching initialisation, two fronts representing the endocardium and epicardium boundaries of the left ventricle are evolved as the zero level-set of a higher dimension function. We introduce a novel and robust stopping term using both gradient and region-based information. The segmentation is supervised both with a coupling function and using a probabilistic model built from training instances. The robustness of the segmentation scheme is evaluated by performing a segmentation on four unseen data-sets containing high variation and the performance of the segmentation is quantitatively assessed.

Automatic segmentation of the left ventricle cavity and myocardium in MRI data.

A novel approach for the automatic segmentation has been developed to extract the epi-cardium and endo-cardium boundaries of the left ventricle (lv) of the heart. The developed segmentation scheme takes multi-slice and multi-phase magnetic resonance (MR) images of the heart, transversing the short-axis length from the base to the apex. Each image is taken at one instance in the heart's phase. The images are segmented using a diffusion-based filter followed by an unsupervised clustering technique and the resulting labels are checked to locate the (lv) cavity. From cardiac anatomy, the closest pool of blood to the lv cavity is the right ventricle cavity. The wall between these two blood-pools (interventricular septum) is measured to give an approximate thickness for the myocardium. This value is used when a radial search is performed on a gradient image to find appropriate robust segments of the epi-cardium boundary. The robust edge segments are then joined using a normal spline curve. Experimental results are presented with very encouraging qualitative and quantitative results and a comparison is made against the state-of-the art level-sets method.

Adaptive locomotor plasticity in chronic spinal cats after ankle extensors neurectomy.

After lateral gastrocnemius-soleus (LGS) nerve section in intact cats, a rapid locomotor compensation involving synergistic muscles occurs and is accompanied by spinal reflex changes. Only some of these changes are maintained after acute spinalization, indicating the involvement of descending pathways in functional recovery. Here, we address whether the development of these adaptive changes is dependent on descending pathways. The left LGS nerve was cut in three chronic spinal cats. Combined kinematics and electromyographic (EMG) recordings were obtained before and for 8 d after the neurectomy. An increased yield at the ankle was present early after neurectomy and, as in nonspinal cats, was gradually reduced within 8 d. Compensation involved transient changes in step cycle structure and a longer term increase in postcontact medial gastrocnemius (MG) EMG activity. Precontact MG EMG only increased in one of three cats. In a terminal experiment, the influence of group I afferents from MG and LGS on stance duration was measured in two cats. LGS effectiveness at increasing stance duration was largely decreased in both cats. MG effectiveness was only slightly changed: increased in one cat and decreased in another. In cat 3, the plantaris nerve was cut after LGS recovery. The recovery time courses from both neurectomies were similar (p > 0.8), suggesting that this spinal compensation is likely a generalizable adaptive strategy. From a functional perspective, the spinal cord therefore must be considered capable of adaptive locomotor plasticity after motor nerve lesions. This finding is of prime importance to the understanding of functional plasticity after spinal injury.

The quality of life of patients with newly diagnosed M1 prostate cancer: experience with EORTC clinical trial 30853.

This study was undertaken to evaluate the quality of life (QoL) of previously untreated patients with M1 prostate cancer before and during androgen-suppressive treatment. Assessment of QoL was included as an optimal component of EORTC protocol 30853, a phase III trial comparing LH-RH (luteinising hormone-releasing hormone) analogue combined with a non-steroidal anti-androgen versus orchiectomy in patients with M1 prostate cancer. At pretreatment and during the follow-up period, patients were asked to complete a questionnaire assessing their physical and psychosocial functioning, and their symptom levels. Physicians rated the patients' performance status, pain, urological symptoms and erectile function. Due to its optional nature, only a minority of the patients in the trial were recruited for the QoL investigation. 63 patients completed a pretreatment questionnaire, of whom 49 completed a second questionnaire at least once during the initial 15 month follow-up period. While statistically significant correlations were observed between patients' and physicians' ratings of physical functioning and pain, these were of only a moderate magnitude (r = 0.43 and 0.30, respectively). No significant association was observed between physicians' and patients' ratings of micturation problems or of erectile function. Before treatment, fatigue, pain and decreased social role and sexual functioning were the problems most frequently reported by patients. With an average of approximately 1 year follow-up, statistically significant improvements were observed in patients' self-reported urological symptoms and metastatic pain. No significant changes were noted for the other QoL domains assessed. The results of this study confirm earlier findings that physicians' ratings may not reflect accurately the functional health and symptom experience of their patients. Patient-based QoL questionnaires offer the most direct means of evaluating the subjective morbidity associated with prostate cancer and its treatment. To increase participation and compliance rates in future studies, it is recommended that QoL assessment be made mandatory in those clinical trials in which QoL is considered to be an important study endpoint.

Tissue PO2 and the effects of hypoxia on the generation of locomotor-like activity in the in vitro spinal cord of the neonatal mouse.

The neonatal mouse en bloc spinal cord-brainstem preparation used in combination with advances in mouse genomics provides a novel strategy for studying the spinal control of locomotion. How well the mouse en bloc preparation is oxygenated however, is unknown. This is an important consideration given that (a) other superfused mammalian en bloc preparations have anoxic cores and (b) hypoxia can have profound effects on neuronal activity. Here we measure the level of tissue oxygenation in the mouse preparation and determine how neuronal activity within the spinal cord is influenced by poor superfusion and/or low oxygen. To measure tissue oxygenation, oxygen depth profiles were obtained (P0-1 and P2-3; Swiss Webster mice). At P0-1, spinal cords were oxygenated throughout under resting conditions. When fictive locomotor activity was evoked (5-HT 10 microM, dopamine 50 microM, NMA 5 microM), there was a substantial reduction in tissue PO(2) starting within 5 min of drug application. Following washout, the PO(2) slowly returned to control levels over a period of 30 min. The experiments described above were repeated using P2-3 preparations. In this older age group, the spinal cord preparations had a hypoxic/anoxic core that was exacerbated during metabolically demanding tasks such as drug-evoked rhythmic activity. To examine how an anoxic core affects neuronal activity within the spinal cord we either altered the flow-rate or manipulated superfusate PO(2). When the flow-rate was reduced a transient disruption in the rhythmicity of drug-induced locomotion occurred during the first 15 min (P0-1 preparations). However, the motor output adapted and stabilized. During prolonged superfusion with hypoxic artificial cerebrospinal fluid on the other hand, both the motor bursts in spinal nerves and the activity of most neurons near the center of the tissue were abolished.Overall, this study suggests that while oxygenation of P0-P1 preparations is adequate for studies of locomotor function, oxygenation of older preparations is more problematic. Our data also show that neonatal spinal neurons require oxygen to maintain activity; and the spinal locomotor rhythm generator continues to function providing the peripheral tissue of the cord is oxygenated. Together, these results are consistent with the results of a previous study which suggest that the locomotor pattern generator is located close to the surface of the spinal cord.

Concentration of ondansetron in cerebrospinal fluid following oral dosing in volunteers.

This study measured the concentrations of ondansetron in plasma and cerebrospinal fluid (CSF) in six volunteers after oral dosing to steady state. Ondansetron concentrations ranged from 39.5-147 ng ml-1 in plasma and from 2.6-15.4 ng ml-1 in CSF. There was good correlation between plasma and CSF concentrations (r = 0.89, p = 0.017). CSF concentrations were less than 15% of plasma concentrations in all cases, indicating that the rate of penetration of the blood brain barrier by ondansetron is low.

Soluble forms of the adhesion molecule E-cadherin in urine.

The adhesion molecule E-cadherin is essential for maintaining epithelial intercellular adhesion. Loss or reduced expression of E-cadherin has been related to invasive behaviour in a wide range of carcinomas. Using immunoblotting techniques, the existence of multiple soluble forms of E-cadherin was demonstrated in urine from healthy volunteers and patients with benign urinary tract disorders or bladder cancer. The existence of soluble forms of E-cadherin in the urine may reflect shedding from the urinary tract epithelium as part of the normal turnover of this molecule. The possibility that enhanced shedding may contribute to the loss of E-cadherin expression/function in malignancy is discussed.