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High dose metoclopramide infusions (10 mg/kg) were administered to nineteen patients with bronchial carcinoma who were receiving intravenous cyclophosphamide as single agent chemotherapy. Considerable interindividual variability in metoclopramide disposition was observed. Mean clearance was 0.33 +/- 0.13 (s.d.) l h-1 kg-1, mean volume of distribution at steady state was 3.8 +/- 1.2 (s.d.) l/kg and mean elimination half-life was 8.3 +/- 4.4 (s.d.) h. These results were significantly different from mean values previously reported for young healthy volunteers given conventional doses (0.70 l h-1 kg-1, 2.2 l/kg and 2.6 h respectively). Significant correlations were found between serum urea, serum creatinine and metoclopramide clearance. The metoclopramide regimens were well tolerated and, with the exception of two patients, were completely effective in the prevention of nausea and vomiting. To achieve and maintain target serum metoclopramide concentrations of 1 microgram/ml, we now administer a loading infusion of 3.61 mg/kg over 30 min followed by a maintenance infusion of 0.36 mg kg-1 h-1 for 10 h. Cyclophosphamide is normally administered concurrently with the second infusion. For patients with evidence of mild renal impairment, the maintenance infusion rate of metoclopramide hydrochloride should be adjusted according to the predicted individual clearance value; CL (l h-1 kg-1) = 0.57 - [0.036 X urea (mmol/l)]. [ABSTRACT FROM AUTHOR]

Psychiatric symptoms are common in neurodevelopmental movement disorders, including some types of dystonia. However, research has mainly focused on motor manifestations and underlying circuits. Myoclonus-dystonia is a rare and homogeneous neurodevelopmental condition serving as an illustrative paradigm of childhood-onset dystonias, associated with psychiatric symptoms. Here, we assessed the prevalence of psychiatric disorders and the severity of depressive symptoms in patients with myoclonus-dystonia and healthy volunteers (HV). Using resting-state functional neuroimaging, we compared the effective connectivity within and among non-motor and motor brain networks between patients and HV. We further explored the hierarchical organization of these networks and examined the relationship between their connectivity and the depressive symptoms. Comparing 19 patients to 25 HV, we found a higher prevalence of anxiety disorders and more depressive symptoms in the patient group. Patients exhibited abnormal modulation of the cerebellum on the cerebral cortex in the sensorimotor, dorsal attention, salience, and default mode networks. Moreover, the salience network activity was directed by the cerebellum in patients and was related to depressive symptoms. Altogether, our findings highlight the role of the cerebellar drive on both motor and non-motor cortical areas in this disorder, suggesting cerebellar involvement in the complex phenotype of such neurodevelopmental movement disorders., (© 2024. The Author(s).)

Background and Purpose: Myoclonus dystonia due to a pathogenic variant in SGCE (MYC/DYT-SGCE) is a rare condition involving a motor phenotype associating myoclonus and dystonia. Dysfunction within the networks relying on the cortex, cerebellum, and basal ganglia was presumed to underpin the clinical manifestations. However, the microarchitectural abnormalities within these structures and related pathways are unknown. Here, we investigated the microarchitectural brain abnormalities related to the motor phenotype in MYC/DYT-SGCE., Methods: We used neurite orientation dispersion and density imaging, a multicompartment tissue model of diffusion neuroimaging, to compare microarchitectural neurite organization in MYC/DYT-SGCE patients and healthy volunteers (HVs). Neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) were derived and correlated with the severity of motor symptoms. Fractional anisotropy (FA) and mean diffusivity (MD) derived from the diffusion tensor approach were also analyzed. In addition, we studied the pathways that correlated with motor symptom severity using tractography analysis., Results: Eighteen MYC/DYT-SGCE patients and 24 HVs were analyzed. MYC/DYT-SGCE patients showed an increase of ODI and a decrease of FA within their motor cerebellum. More severe dystonia was associated with lower ODI and NDI and higher FA within motor cerebellar cortex, as well as with lower NDI and higher ISOVF and MD within the corticopontocerebellar and spinocerebellar pathways. No association was found between myoclonus severity and diffusion parameters., Conclusions: In MYC/DYT-SGCE, we found microstructural reorganization of the motor cerebellum. Structural change in the cerebellar afferent pathways that relay inputs from the spinal cord and the cerebral cortex were specifically associated with the severity of dystonia., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT- SGCE ) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT- SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder., Competing Interests: C.G., C.T., B.B., B.D., I.J.B., V.B., C.A.-C., L.D., P.K., J.-L.H., E.A., A.D., J.-M.P., M.V. and Y.W. have no disclosures relevant to this work. C.T. received a PhD grant from the ‘Fondation pour la Recherche Médicale’. C.D. has received a research grant from the Fédération Internationale de l'Automobile and travel funding from Merz Pharma, Abbvie, Boston Scientific and Medtronic. J.C.C. has served on advisory boards for Biogen, Denali, Idorsia, Prevail Therapeutic, Servier, Theranexus and UCB, and has received grants from Sanofi and the Michael J Fox Foundation for other projects. S.T. received grants from France Parkinson, PHRC and honorarium from Abbvie, Boston, Merz. E.M. has received speaking honoraria from AbbVie, Dutch MDS symposium, travel support from Elivie, served on an advisory board for AbbVie and received research grants from the STAR MD and the RCSI Richard Steeven’s Scholarship. D.G. has received grants from AP-HP (DRC-PHRC) and France Parkinson, served on scientific advisory boards for AbbVie and Zambon; received research funding from Air Liquide and Orkyn; received speech honoraria from Medtronic, Abbvie, Merz, Orkyn, Aguettant and EverPharma, and received travel funding from Abbvie and Merz. E.R. received honorarium for speech from Orkyn, Aguettant, Elivie and for participating in an advisory board from Merz-Pharma. He received research support from Merz-Pharma, Orkyn, Aguettant, Elivie, Ipsen, Everpharma, Fondation Desmarest, AMADYS, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Societé Française de Médecine Esthétique, Dystonia Medical Research Foundation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy-to-use clinical screening tool to help recognize movement disorders., Objective: The aim is to develop a user-friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs., Methods: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter-rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool., Results: A movement disorder was rated as present in 80% of the patients, with a moderate inter-rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter-rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool., Conclusions: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: Therapy-related myelodysplastic syndrome and acute leukemias (t-MDS/AL) are a major cause of nonrelapse mortality among pediatric cancer survivors. Although the presence of clonal hematopoiesis (CH) in adult patients at cancer diagnosis has been implicated in t-MDS/AL, there is limited published literature describing t-MDS/AL development in children., Experimental Design: We performed molecular characterization of 199 serial bone marrow samples from 52 patients treated for high-risk neuroblastoma, including 17 with t-MDS/AL (transformation), 14 with transient cytogenetic abnormalities (transient), and 21 without t-MDS/AL or cytogenetic alterations (neuroblastoma-treated control). We also evaluated for CH in a cohort of 657 pediatric patients with solid tumor., Results: We detected at least one disease-defining alteration in all cases at t-MDS/AL diagnosis, most commonly TP53 mutations and KMT2A rearrangements, including involving two novel partner genes (PRDM10 and DDX6). Backtracking studies identified at least one t-MDS/AL-associated mutation in 13 of 17 patients at a median of 15 months before t-MDS/AL diagnosis (range, 1.3-32.4). In comparison, acquired mutations were infrequent in the transient and control groups (4/14 and 1/21, respectively). The relative risk for development of t-MDS/AL in the presence of an oncogenic mutation was 8.8 for transformation patients compared with transient. Unlike CH in adult oncology patients, TP53 mutations were only detectable after initiation of cancer therapy. Last, only 1% of pediatric patients with solid tumor evaluated had CH involving myeloid genes., Conclusions: These findings demonstrate the clinical relevance of identifying molecular abnormalities in predicting development of t-MDS/AL and should guide the formation of intervention protocols to prevent this complication in high-risk pediatric patients., (©2022 American Association for Cancer Research.)

Myoclonus-dystonia (MD) is a syndrome characterized by myoclonus of subcortical origin and dystonia, frequently associated with psychiatric comorbidities. The motor and psychiatric phenotypes of this syndrome likely result from cortico-striato-thamalo-cerebellar-cortical pathway dysfunction. We hypothesized that reactive and proactive inhibitory control may be altered in these patients. Using the Stop Signal Task, we assessed reactive and proactive inhibitory control in MD patients with (n = 12) and without (n = 21) deep brain stimulation of the globus pallidus interna and compared their performance to matched healthy controls (n = 24). Reactive inhibition was considered as the ability to stop an already initiated action and measured using the stop signal reaction time. Proactive inhibition was assessed through the influence of several consecutive GO or STOP trials on decreased response time or inhibitory process facilitation. The proactive inhibition was solely impaired in unoperated MD patients. Patients with deep brain stimulation showed impairment in reactive inhibition, independent of presence of obsessive-compulsive disorders. This impairment in reactive inhibitory control correlated with intrinsic severity of myoclonus (i.e. pre-operative score). The results point to a dissociation in reactive and proactive inhibitory control in MD patients with and without deep brain stimulation of the globus pallidus interna.

Three-dimensional imaging and printed heart models have become increasingly valuable in the management of patients with complex congenital heart disease. We successfully simulated a stenting procedure on a 3-dimensional printed model of a patient with d-transposition of the great arteries status post-Mustard operation with caval baffle atresia and stenosis. ( Level of Difficulty: Advanced. )., (© 2020 The Authors.)

Background: Abnormal sensory processing, including temporal discrimination threshold, has been described in various dystonic syndromes., Objective: To investigate visual sensory processing in DYT-SGCE and identify its structural correlates., Methods: DYT-SGCE patients without DBS (DYT-SGCE-non-DBS) and with DBS (DYT-SGCE-DBS) were compared to healthy volunteers in three tasks: a temporal discrimination threshold, a movement orientation discrimination, and movement speed discrimination. Response times attributed to accumulation of sensory visual information were computationally modelized, with μ parameter indicating sensory mean growth rate. We also identified the structural correlates of behavioral performance for temporal discrimination threshold., Results: Twenty-four DYT-SGCE-non-DBS, 13 DYT-SGCE-DBS, and 25 healthy volunteers were included in the study. In DYT-SGCE-DBS, the discrimination threshold was higher in the temporal discrimination threshold (P = 0.024), with no difference among the groups in other tasks. The sensory mean growth rate (μ) was lower in DYT-SGCE in all three tasks (P < 0.01), reflecting a slower rate of sensory accumulation for the visual information in these patients independent of DBS. Structural imaging analysis showed a thicker left primary visual cortex (P = 0.001) in DYT-SGCE-non-DBS compared to healthy volunteers, which also correlated with lower μ in temporal discrimination threshold (P = 0.029). In DYT-SGCE-non-DBS, myoclonus severity also correlated with a lower μ in the temporal discrimination threshold task (P = 0.048) and with thicker V1 on the left (P = 0.022)., Conclusion: In DYT-SGCE, we showed an alteration of the visual sensory processing in the temporal discrimination threshold that correlated with myoclonus severity and structural changes in the primary visual cortex. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P =0.077) and 3.83 (95%CI: 1.51-9.74; P =0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% vs 2 of 18, 11%; P =0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML., (Copyright© 2019 Ferrata Storti Foundation.)

Background: An abnormal temporal discrimination threshold in cervical dystonia (CD) is considered to be a mediational endophenotype; in unaffected relatives it is hypothesized to indicate non-manifesting gene carriage. The pathogenesis underlying this condition remains unknown. Investigation of the neural networks involved in disordered temporal discrimination may highlight its pathomechanisms. Objective: To examine resting state brain function in unaffected relatives of CD patients with normal and abnormal temporal discrimination. We hypothesized that the endophenotype, an abnormal temporal discrimination, would manifest as altered connectivity in relatives in regions associated with CD, thereby illuminating the neural substrates of the link between temporal discrimination and CD. Methods: Rs-fMRI data was analyzed from two sex- and age-matched cohorts: 16 unaffected relatives of CD patients with normal temporal discrimination and 16 with abnormal temporal discrimination. Regional and whole brain functional connectivity measures were extracted via Independent Component Analysis (ICA), Regional Homogeneity (ReHo), and Amplitude of Low Frequency (ALFF) analyses. Results: Our ICA analysis revealed increased connectivity within both the executive control and cerebellar networks and decreased connectivity within the sensorimotor network in relatives with abnormal temporal discrimination when compared to relatives with normal temporal discrimination. The ReHo and ALFF analyses complimented these results and demonstrated connectivity differences in areas corresponding to motor planning, movement coordination, visual information processing, and eye movements in unaffected relatives with abnormal temporal discrimination. Conclusion: Disordered connectivity in unaffected relatives with abnormal temporal discrimination illuminates neural substrates underlying endophenotype expression and supports the hypothesis that genetically determined aberrant connectivity, when later coupled with unknown environmental triggers, may lead to disease penetrance.

Purpose of Review: This review will discuss the expanding clinical spectrum of paroxysmal movement disorders and therapeutic options in light of emerging genotypic heterogeneity in these conditions., Recent Findings: Paroxysmal movement disorders comprise a heterogeneous group of rare neurological conditions characterized by intermittent episodes of abnormal movement associated with various triggers. As the clinical and genotypic spectrum of these disorders evolves, so also has the range of therapeutic options. Triheptanoin has recently been shown to be a very promising alternative to the ketogenic diet in paroxysmal exercise-induced dyskinesia. Four-aminopyridine is now considered first-line symptomatic therapy for episodic ataxia type-2, with pre-clinical findings indicating cerebellar neuroprotection., Summary: In light of the newly emerging therapies, careful clinical phenotyping is needed to ensure diagnostic precision and timely initiation of appropriate therapies.

The temporal discrimination threshold (TDT) is the shortest time interval at which an observer can discriminate two sequential stimuli as being asynchronous (typically 30-50 ms). It has been shown to be abnormal (prolonged) in neurological disorders, including cervical dystonia, a phenotype of adult onset idiopathic isolated focal dystonia. The TDT is a quantitative measure of the ability to perceive rapid changes in the environment and is considered indicative of the behavior of the visual neurons in the superior colliculus, a key node in covert attentional orienting. This article sets out methods for measuring the TDT (including two hardware options and two modes of stimuli presentation). We also explore two approaches of data analysis and TDT calculation. The application of the assessment of temporal discrimination to the understanding of the pathogenesis of cervical dystonia and adult onset idiopathic isolated focal dystonia is also discussed.

Background: Primary orthostatic tremor (POT) is a movement disorder characterized by unsteadiness upon standing still due to a tremor affecting the legs. It is a gradually progressive condition with limited treatment options. Impairments in health-related quality of life (HQoL) seem to far exceed the physical disability associated with the condition., Methods: A multi-center, mixed-methodology study was undertaken to investigate 40 consecutive patients presenting with POT to four movement disorder centers in France. HQoL was investigated using eight quantitative scales and a qualitative study which employed semi-structured interviews. Qualitative data were analyzed with a combination of grounded-theory approach., Results: Our results confirm that HQoL in POT is severely affected. Fear of falling was identified as the main predictor of HQoL. The qualitative arm of our study explored our initial results in greater depth and uncovered themes not identified by the quantitative approach., Conclusion: Our results illustrate the huge potential of mixed methodology in identifying issues influencing HQoL in POT. Our work paves the way for enhanced patient care and improved HQoL in POT and is paradigmatic of this modern approach for investigating HQoL issues in chronic neurological disorders.

Neuroinflammation may be a critical component of the neurobiology of alcohol use disorders, yet the exact nature of this relationship is not well understood. This work compared the brain and peripheral immune profile of alcohol-dependent subjects and controls. Brain levels of 18-kDa translocator protein (TSPO), a marker of microglial activation and neuroinflammation, were measured with [ 11 C]PBR28 positron emission tomography imaging in 15 healthy controls and 15 alcohol-dependent subjects. Alcohol-dependent subjects were imaged 1-4 days (n=14) or 24 days (n=1) after their last drink. Linear mixed modeling of partial-volume-corrected [ 11 C]PBR28 data revealed a main effect of alcohol dependence (P=0.034), corresponding to 10% lower TSPO levels in alcohol-dependent subjects. Within this group, exploratory analyses found a negative association of TSPO levels in the hippocampus and striatum with alcohol dependence severity (P<0.035). Peripheral immune response was assessed in a subset of subjects by measuring cytokine expression from monocytes cultured both in the presence and absence of lipopolysaccharide. Peripheral monocyte response to lipopolysaccharide stimulation was lower in alcohol-dependent subjects compared with controls for the proinflammatory cytokines interleukin-6 and interleukin-8. Thus, alcohol-dependent individuals exhibited less activated microglia in the brain and a blunted peripheral proinflammatory response compared with controls. These findings suggest a role for pharmaceuticals tuning the neuroimmune system as therapeutics for alcohol dependence.

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis.

Background: Vitamin D deficiency is implicated in neoplastic processes in multiple organs, including the pancreas. While animal and human data have established a relationship between serum vitamin D (25(OH)D) and the development of pancreatic cancer, few studies have examined the effects of 25(OH)D on time to progression (TTP) and overall survival (OS) in this patient population. We hypothesize that lower baseline serum concentrations (BSC) of 25(OH)D will be associated with decreased TTP and OS., Methods: This retrospective analysis of 1222 patients with pancreatic cancer aims to identify potential relationships between 25(OH)D and both TTP and OS, while controlling for the effects of ethnicity and body mass index (BMI). Baseline 25(OH)D was divided into quartiles defined as deficient (<20 ng/mL), insufficient (20-39 ng/mL), sufficient (40-59 ng/mL), and optimal (≥60 ng/ml). Statistical significance was declared if the two-sided p-value was ≤ 0.05., Results: For the 627 subjects included for analysis, the median 25(OH)D was 27 ng/mL (range 4 to 114), 30.0 % were 25(OH)D deficient (<20 ng/mL), and 47.2 % were insufficient (20-39 ng/mL). Ethnicity (p < 0.0001) and BMI (p = 0.05) were significantly associated with (BSC)of 25(OH)D, while TTP (p = 0.39) and OS (p = 0.37) were not associated., Conclusion: Suboptimal vitamin D levels (<60 ng/mL) occurred in 96 % of patients analyzed. Both ethnicity and BMI were statistically significantly associated with vitamin D deficiency and insufficiency. Similar to results previously reported in the literature, this analysis did not identify a significant association between BSC of 25(OH)D and OS or TTP in patients with pancreatic cancer.

Background: Urinary tract infections (UTIs) are one of the most common conditions seen in female patients within primary care. Community pharmacists are familiar with symptomatic UTI management and supplying trimethoprim under patient group direction (PGD) for moderate-to-severe uncomplicated UTIs could improve patient access to treatment., Aim: To compare the care pathway of patients with UTI symptoms attending GP services with those receiving management, including trimethoprim supply under PGD, via community pharmacies., Design and Setting: Prospective, cross-sectional, mixed methods approach in 10 community pharmacies within NHS Greater Glasgow and Clyde., Method: Pharmacies invited a purposive sample of female patients to participate. Pharmacists had the option of supplying trimethoprim under PGD to patients with moderate-to-severe infection meeting the PGD inclusion criteria. Data from patient (questionnaires and semi-structured telephone interviews) and pharmacist (questionnaires and semi-structured, face-to-face interviews) were quantitatively and qualitatively analysed., Results: Data were recorded on 153 patients, 97 presenting with GP prescriptions and 56 presenting directly in the pharmacy with symptoms suggestive of UTI, of whom 41 received trimethoprim via PGD and 15 received symptomatic management. Both GP adherence to local infection management guidelines and pharmacist application of PGD inclusion/exclusion criteria required improvement. There was demand and support, from patients and pharmacists, for access to antibiotic treatments for UTIs, without prescription, through community pharmacies., Conclusion: Operating within PGD controls, antibiotic treatments for UTIs could be provided via community pharmacy to improve patient access to treatment which may also maintain antibiotic stewardship and reduce GP workload.

B cell receptor (BCR)-mediated antigen processing and presentation involves both the BCR-mediated internalization and processing of cognate antigen as well as the formation and expression of antigenic peptide-MHC class II complexes. While BCR signaling is known to result in changes in the biosynthesis and intracellular trafficking of class II molecules, the effect of BCR signaling on the cell biology of antigen endocytosis and processing is less clear. Therefore, the effect of BCR signaling on the cell biology of fluid phase antigen endocytosis, processing and presentation was analyzed in both B cell lines or in normal splenic B cells. The results demonstrate that BCR signaling alters neither the global level of fluid phase antigen endocytosis nor the duration of intracellular persistence of fluid phase internalized antigen. Moreover, while BCR signal does result in an increase in the level of total cell surface MHC class II molecules as well as specific peptide-class II complexes, stimulation failed to alter the fraction of class II molecules loaded with antigen-derived peptide. These results indicate that while BCR-mediated signaling elicits an increase in the expression of antigenic peptide-class II complexes, signaling does not augment antigen presentation by profoundly altering the basic biology of antigen endocytosis and processing. These results also demonstrate that the high efficiency of BCR-mediated antigen processing (when compared to fluid phase antigen processing) is likely to occur independent of BCR signaling-induced global alterations in the biology of endocytosis, processing and presentation. This finding suggests that if BCR signaling augments the efficiency of processing of cognate antigen, it must impact unique aspects of BCR-mediated antigen processing, such as the intracellular persistence of internalized antigen-BCR complexes.

Background: Lactic acidosis after cardiac surgery is a manifestation of excess cytokine production. Cytokine-related genetic polymorphisms account for variability in cytokine response and may predispose to the development of lactic acidosis after cardiac surgery., Methods: Routine postoperative cardiac surgery patients were studied. Lactic acid levels were greater than 4 mmol/L in study patients and less than 4 mmol/L in controls. Polymerase chain reaction-based techniques were used to examine carriage of tumor necrosis factor beta (TNF-beta), TNF G-308A, and interleukin 10 (IL-10) G-1082A alleles., Results: Demographic characteristics and details of surgery were similar for 30 control and 21 study patients. Lactic acid levels after intensive care admission changed over time and were related to both TNF-beta and IL-10 G-1082A polymorphisms. All 4 study patients homozygous for TNF-beta1 and carrying an IL-10-1082A allele developed lactic acidosis (p = 0.02). There was no relation between the rate of epinephrine infusion or duration of cardiopulmonary bypass and lactic acid levels., Conclusions: Genetic factors have a role in the development of lactic acidosis after cardiac surgery.

Objective: The aim of this study was to evaluate patient knowledge and assess the management of angina for patients receiving sublingual glyceryl trinitrate (GTN) METHOD: Prospective data collection and patient interview was undertaken in 17 community pharmacies., Results: During the study 488 angina patients presented to the participating pharmacies. Data were collected for 347 patients receiving sublingual GTN. Problems with administration technique were identified for 108 patients (31%) and knowledge of when to seek medical help appropriately after failed GTN use was unsure for 134 patients (39%) or poor for 88 patients (25%). Eighty five patients (24%) were not receiving regular symptomatic therapy. Aspirin was prescribed or purchased by 253 patients (73%). Seven pharmacies participated in GP referral (data collected for 201 patients); 31 patients (15%) were referred usually with a recommendation to add aspirin. The outcome of 20 of these referrals was assessed; advice was taken for 13 patients, 3 patients failed to attend GP, aspirin was contraindicated for 3 patients and one patient already attended pharmacist medication review., Conclusion: This study demonstrated the potential contribution community pharmacists could make at the time of dispensing to the management of patients with angina.

Nonseminomatous germ cell testicular neoplasm is a disease cured primarily by platinum-based combination chemotherapy. Operation is reserved for those patients who continue to harbor residual masses after chemotherapy. Locoregional lymph nodes and lungs are common sites for residual deposits. Intracardiac metastases are very rare. We report a case of successful resection of bilateral lung and single intracardiac secondary deposits from a malignant teratoma, treated by orchidectomy 6 years previously.

The autopsy reports and clinical data of 96 patients presenting to St. James's Hospital with trauma of fatal outcome, between January 1, 1986 and December 31, 1990, were analysed. Eighty-one (84%) deaths were due to road traffic accidents and all were the result of blunt trauma. Ninety-five (99%) had an Abbreviated Injury Scale (AIS) score > or = 3 in at least one anatomical category. Cerebral trauma (41%) and shock and haemorrhage secondary to multiple injuries (40%) were the commonest causes of death. Sixty-eight (71%) patients were dead on arrival at the hospital. Of the twenty-eight deaths occurring after admission to hospital nine (32%) were potentially preventable. The mean (sem) Injury Severity Score (ISS) for those with preventable deaths was 24.1 (3.8). These data have implications for the development of trauma care facilities in Ireland.

Gastrointestinal complications after cardiac surgery are uncommon, but are associated with a high morbidity and mortality. Over 11 years 8559 procedures requiring cardiopulmonary bypass were performed in this unit and 35 patients were identified who developed gastrointestinal complications after surgery, an incidence of 0.41%. There were nine deaths in this group, a mortality of 25.7% compared with an overall mortality after cardiac surgery in Ireland ranging from 3.24% to 4.81%. These complications required surgery in 21 patients. The most common indication for surgical intervention was upper gastrointestinal bleeding in 10 patients, three patients had acute pancreatitis, two patients had perforated peptic ulcer; two patients had intestinal ischaemia, with five cases of colon pathology. The difficulties of making an early diagnosis are outlined and a low threshold to exploratory laparotomy is recommended.

Invasive pulmonary aspergillosis is a specific form of pulmonary Aspergillus infection that occurs almost exclusively in immunocompromised patients. It differs both histologically and in its clinical course from classic aspergillomas. During a 5-year period (1986-1990), 8 patients underwent resection for cavitating invasive pulmonary aspergillosis that developed as a consequence of neutropenia during chemotherapy for malignancy. There were no perioperative deaths and no complications. This contrasts with reports of operation for classic aspergillomas. Histologic examination of the resected specimens showed that cavitating invasive pulmonary aspergillosis differed from classic aspergillomas. They consisted of necrotic lung tissue invaded by fungus with separation from the surrounding lung so that the sequestrum had the appearance of a fungus ball. Pulmonary aspergillosis is a common complication of profound neutropenia. The first hemoptysis in this group of patients is often life-threatening. The excellent results of operation in our series of patients may be attributed to their young age, good pulmonary function, and limited operation. This has lead us to recommend early surgical intervention in invasive aspergillosis once cavitation develops.

The population pharmacokinetics of theophylline were studied in 35 neonates receiving aminophylline suppositories for the treatment of apnoea of prematurity. Routinely measured theophylline serum concentrations (n = 138, range 3-20 mg/L) were modelled in NONMEM according to a one-compartment model. The influence of a number of clinical and demographic factors, e.g., weight (range 0.8-2.5 kg) and postnatal age (2-80 days), on clearance/bioavailability (CL/F) and volume/bioavailability (V/F) was investigated. Both these parameters were found to significantly correlate to weight alone in a directly proportional manner: CL/F = 40 +/- 2 ml/h/kg and V/F = 1.3 +/- 0.2 L/kg. The absorption was best described by a first-order process, having a half-life of 1.6 +/- 0.7 h. The interindividual variability in CL/F was 25%, whereas the same estimates in V/F and in the first-order absorption rate constant could not be obtained. The residual variability in theophylline concentrations was modelled with additive error with an estimated standard deviation of 1.78 mg/L. From these results, it was concluded that rectal administration of aminophylline in neonates is a therapeutically acceptable alternative to oral administration. The convenience gained by rectal, compared to oral, administrations may compensate, in many instances, for the possibly slightly higher variability in CL/F of the former.

High-dose metoclopramide has found an established place in the prophylaxis of nausea and vomiting which may be induced by cancer chemotherapy. A simple reliable high pressure liquid chromatographic technique for the measurement of this drug in serum has been developed and evaluated. The methodology will find application in the study of metoclopramide pharmacokinetics and in the monitoring of high-dose metoclopramide therapy in individual patients with neoplastic disease.

The introduction of new cytotoxic drug regimens has been associated with an increase in the incidence and severity of adverse effects. This in turn has highlighted the need for more effective adjuvant therapy. The use of metoclopramide for the prophylaxis of nausea and vomiting, in high intravenous doses (50 to 1000 mg), has become established since 1981. As a lipid-soluble drug, metoclopramide has a large volume of distribution. The reported mean values after high doses range between 2.8 and 4.6 L/kg. The mean values for total body clearance and terminal half-life range from 0.31 to 0.69 L/kg/h and from 4.5 to 8.8 hours, respectively. The values of these pharmacokinetic parameters are essentially similar to those obtained after conventional doses (less than 50mg). Pharmacokinetic parameters appear unaffected by age, although no high-dose study has been conducted in children. Bodyweight is apparently correlated with clearance. An influence of renal function indices on terminal half-life and clearance has been shown, which is rather surprising since renal clearance accounts for only 20% of the total clearance. No thorough investigations exist which examine the influence of hepatic disease, cancer type and cytotoxic drug regimen on the disposition of metoclopramide. A relationship between dose (or concentration) and therapeutic or adverse effects of metoclopramide is outlined. The therapeutic benefit of high doses (up to 14 mg/kg) may be dependent on age, and on the combination of cytotoxic drugs. The advantages of high doses of metoclopramide are most apparent when the drug is used as protection against the adverse effects of high doses of cisplatin (greater than 60 mg/m2). Despite considerable pharmacokinetic variability, intravenous administration of high doses of metoclopramide is relatively safe due to its large therapeutic index.

The performance of a new dry-phase, strip immunoassay technique for the analysis of serum carbamazepine concentrations (Seralyzer), was compared to a standard high performance liquid chromatography (HPLC) method. One hundred blood samples were collected from 87 patients and analysed using both techniques. There was no significant difference between the concentrations measured by either technique, and the results were highly correlated (r = 0.97). The Seralyzer is a rapid and accurate method for use in carbamazepine therapeutic drug monitoring.

Phenytoin is an established therapy for post-herpetic neuralgia. In order to maintain serum phenytoin levels in the normal therapeutic range, serum phenytoin monitoring is required. This range may, however, be misleading in certain clinical conditions. We report here a patient with hypoalbuminaemia who developed marked clinical phenytoin toxicity despite maintenance of the serum total phenytoin concentration within the therapeutic range.

The influence of a number of clinical characteristics on the population pharmacokinetics of gentamicin were examined using routine drug-monitoring data from a group of 113 neonates. The data were analyzed using the programme NONMEM. Clearance was 0.053 litres.h-1.kg-1 and was reduced in neonates with postconceptional age less than or equal to 34 weeks (X 0.83) and 5-min Apgar score less than 7 (X 0.82). Volume of distribution was 0.47 litres.kg-1. These population mean parameter estimates were used to generate dosage regimens to achieve concentrations within the therapeutic range.

From 1958 through 1985, a total of 113 consecutive patients had completion pneumonectomy (CP). Indications for pulmonary resection resulting in CP were lung cancer (LC) in 64 patients, pulmonary metastases (PM) in 20, and benign lung disease (BLD) in 29. Operative mortality was 12.4% (14 deaths) but varied according to the indication for CP. Mortality was 9.4% for LC, 0% for PM, and 27.6% for BLD. Forty-three patients (38.1%) had major complications (26 of 64 with LC, 40.6%; 1 of 20 with PM, 5.0%; and 16 of 29 with BLD, 55.2%). Five-year actuarial survival for patients with LC was 26.4% but varied according to stage. Five-year survival for patients with PM was 40.8% and with BLD was 27.2%. We conclude that CP for BLD carries marked operative mortality and morbidity, usually due to intense reaction around hilar structures and concurrent active infection or fistula. In contrast, CP for LC and PM can be performed with low mortality, acceptable morbidity, and gratifying long-term survival.