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Abstract Background The human pathogen Haemophilus influenzae was the main cause of bacterial meningitis in children and a major cause of worldwide infant mortality before the introduction of a vaccine in the 1980s. Although the occurrence of serotype b (Hib), the most virulent type of H. influenzae, has since decreased, reports of infections with other serotypes and non-typeable strains are on the rise. While non-typeable strains have been studied in-depth, very little is known of the pathogen’s evolutionary history, and no genomes dating prior to 1940 were available. Results We describe a Hib genome isolated from a 6-year-old Anglo-Saxon plague victim, from approximately 540 to 550 CE, Edix Hill, England, showing signs of invasive infection on its skeleton. We find that the genome clusters in phylogenetic division II with Hib strain NCTC8468, which also caused invasive disease. While the virulence profile of our genome was distinct, its genomic similarity to NCTC8468 points to mostly clonal evolution of the clade since the 6th century. We also reconstruct a partial Yersinia pestis genome, which is likely identical to a published first plague pandemic genome of Edix Hill. Conclusions Our study presents the earliest genomic evidence for H. influenzae, points to the potential presence of larger genomic diversity in the phylogenetic division II serotype b clade in the past, and allows the first insights into the evolutionary history of this major human pathogen. The identification of both plague and Hib opens questions on the effect of plague in immunocompromised individuals already affected by infectious diseases.

Abstract Background Hansen’s disease (leprosy), widespread in medieval Europe, is today mainly prevalent in tropical and subtropical regions with around 200,000 new cases reported annually. Despite its long history and appearance in historical records, its origins and past dissemination patterns are still widely unknown. Applying ancient DNA approaches to its major causative agent, Mycobacterium leprae, can significantly improve our understanding of the disease’s complex history. Previous studies have identified a high genetic continuity of the pathogen over the last 1500 years and the existence of at least four M. leprae lineages in some parts of Europe since the Early Medieval period. Results Here, we reconstructed 19 ancient M. leprae genomes to further investigate M. leprae’s genetic variation in Europe, with a dedicated focus on bacterial genomes from previously unstudied regions (Belarus, Iberia, Russia, Scotland), from multiple sites in a single region (Cambridgeshire, England), and from two Iberian leprosaria. Overall, our data confirm the existence of similar phylogeographic patterns across Europe, including high diversity in leprosaria. Further, we identified a new genotype in Belarus. By doubling the number of complete ancient M. leprae genomes, our results improve our knowledge of the past phylogeography of M. leprae and reveal a particularly high M. leprae diversity in European medieval leprosaria. Conclusions Our findings allow us to detect similar patterns of strain diversity across Europe with branch 3 as the most common branch and the leprosaria as centers for high diversity. The higher resolution of our phylogeny tree also refined our understanding of the interspecies transfer between red squirrels and humans pointing to a late antique/early medieval transmission. Furthermore, with our new estimates on the past population diversity of M. leprae, we gained first insights into the disease’s global history in relation to major historic events such as the Roman expansion or the beginning of the regular transatlantic long distance trade. In summary, our findings highlight how studying ancient M. leprae genomes worldwide improves our understanding of leprosy’s global history and can contribute to current models of M. leprae’s worldwide dissemination, including interspecies transmissions.

In industrial environments, over several decades, Automated Guided Vehicles (AGVs) and Autonomous Mobile Robots (AMRs) have served to improve efficiencies of intralogistics and material handling tasks. However, for system integrators, the choice and effective deployment of improved, suitable and reliable communication and control technologies for these unmanned vehicles remains a very challenging task. Specifics of communication for AGVs and AMRs imposes stringent performance requirements on latency and reliability of communication links which many existing wireless technologies struggle to satisfy. In this paper, a review of latest AGVs and AMRs research results in the past decade is presented. The review encompasses results from different past and present research domains of AGVs. In addition, performance requirements of communication networks in terms of their latencies and reliabilities when they are deployed for AGVs and AMRs coordination, control and fleet management in smart manufacturing environments are discussed. Integration challenges and limitations of present state-of-the-art AGV and AMR technologies when those technologies are used for facilitating AGV-based smart manufacturing and factory of the future applications are also thoroughly discussed. The paper also present a thorough discussion of areas in need of further research regarding the application of 5G networks for AGVs and AMRs fleet management in smart manufacturing environments. In addition, novel integration ideas by which tactile Internet, 5G network slicing and virtual reality applications can be used to facilitate AGV and AMR based factory of the future (FoF) and smart manufacturing applications were motivated.

The second plague pandemic, caused by Yersinia pestis, started in the 14th century and recurred in Europe until the 18th century. Here, the authors reconstruct ancient Y. pestis genomes from human remains spanning this period, shedding light into the phylogeography and population structure of the European strains.

In the fourth millennium BCE a cultural phenomenon of monumental burial structures spread along the Atlantic façade. Megalithic burials have been targeted for aDNA analyses, but a gap remains in East Anglia, where Neolithic structures were generally earthen or timber. An early Neolithic (3762–3648 cal. BCE) burial monument at the site of Trumpington Meadows, Cambridgeshire, UK, contained the partially articulated remains of at least three individuals. To determine whether this monument fits a pattern present in megalithic burials regarding sex bias, kinship, diet and relationship to modern populations, teeth and ribs were analysed for DNA and carbon and nitrogen isotopic values, respectively. Whole ancient genomes were sequenced from two individuals to a mean genomic coverage of 1.6 and 1.2X and genotypes imputed. Results show that they were brothers from a small population genetically and isotopically similar to previously published British Neolithic individuals, with a level of genome-wide homozygosity consistent with a small island population sourced from continental Europe, but bearing no signs of recent inbreeding. The first Neolithic whole genomes from a monumental burial in East Anglia confirm that this region was connected with the larger pattern of Neolithic megaliths in the British Isles and the Atlantic façade.

Objectives: Fall-related injuries occur at a similar prevalence rate in middle-aged and older adults and may increase concerns about falling and future falls. No research to date has examined how experiences of falls and related concerns, differ between middle-aged and older fallers. This study aimed to address this using qualitative interviews., Methods: Ten middle-aged (55-64 years) and ten older adults (68-83 years) were interviewed about their experiences of falls and concerns about falling. Guided by a social constructivist epistemology, reflexive thematic analysis was used to categorise themes within the data., Results: Five overarching themes were identified. Four themes showed distinctions between groups (i) perceptions of age-related decline; (ii) ageism: stigma associated with 'fallers'; (iii) concerns about loss of independence; and (iv) unravelling perceived control. The fifth theme (v) perceptions of falls risk: concerns and awareness, demonstrated the most similarities., Conclusions: Whilst middle-aged and older fallers showed similar ratings of concern about falling, the behaviours underlying these were qualitatively different. For older adults, concerns led to protective adaptations to reduce their fall risk. Contrastingly, middle-aged adults showed a lack of personal responsibility over their fall risk. The findings highlight the importance of early educational intervention to reduce future falls and frailty., (Copyright: © 2024 Hylonome Publications.)

Background: Proper hand hygiene (HH), which includes sanitizing with alcohol-based hand rub (ABHR) (or handwashing with soap and water if ABHR is unavailable), is key for preventing healthcare-associated infections (HCAI), including COVID-19. Understanding drivers of HH is key to improving adherence., Aim: This study aims to explore drivers and barriers to HH practice at two hospitals in the Dominican Republic in the context of the COVID-19 pandemic to inform development of HH behaviour change interventions., Methods: We conducted in-depth interviews with 20 hospital staff during September 2021. We used the COM-B (capability, opportunity, motivation, behaviour) model to explore HH experiences and preferences. Interviews were recorded, transcribed, coded, and analysed using a thematic approach., Results: A total of 11 parent codes and 27 sub-codes were identified, and 1145 coded segments were analysed. Use of handwashing with soap and water and/or sanitizing with ABHR was reported by all participants; handwashing was generally preferred. Participants expressed knowledge of proper HH methods (capability), but inconsistent supplies and lack of time presented HH challenges (opportunity). Interviewees described practicing HH to protect themselves and their families from COVID-19 and other infections (reflective motivation) or out of habit (automatic motivation)., Discussion: By understanding and addressing underlying factors affecting HH, hospitals can decrease the risk of HCAIs. Our findings suggest that interventions implemented to improve HH in these hospitals should target motivation and opportunity. These findings informed a multimodal intervention to increase ABHR access and implement message-tested communications campaigns; end-point assessments will provide insights into the intervention's impact.

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia., (Copyright © 2021. Published by Elsevier Inc.)

Background: Parkinson's disease (PD) causes difficulties with hand movements, which few studies have addressed therapeutically. Training with action observation (AO) and motor imagery (MI) improves performance in healthy individuals, particularly when the techniques are applied simultaneously (AO + MI). Both AO and MI have shown promising effects in people with PD, but previous studies have only used these separately., Objective: This article describes the development and pilot testing of an intervention combining AO + MI and physical practice to improve functional manual actions in people with PD., Methods: The home-based intervention, delivered using a tablet computer app, was iteratively designed by an interdisciplinary team, including people with PD, and further developed through focus groups and initial field testing. Preliminary data on feasibility were obtained via a six-week pilot randomised controlled trial (ISRCTN 11184024) of 10 participants with mild to moderate PD (6 intervention; 4 treatment as usual). Usage and adherence data were recorded during training, and semistructured interviews were conducted with participants. Exploratory outcome measures included dexterity and timed action performance., Results: Usage and qualitative data provided preliminary evidence of acceptability and usability. Exploratory outcomes also suggested that subjective and objective performance of manual actions should be tested in a larger trial. The importance of personalisation, choice, and motivation was highlighted, as well as the need to facilitate engagement in motor imagery., Conclusions: The results indicate that a larger RCT is warranted, and the findings also have broader relevance for the feasibility and development of AO + MI interventions for PD and other conditions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Judith Bek et al.)

Background: Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment., Objective: To evaluate associations between sub-regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD., Methods: 99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub-regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post-mortem histology. Univariate analyses evaluated cross-sectional associations between sub-regional volumes and gait. Linear mixed-effects models assessed whether volumes predicted longitudinal gait changes., Results: There were no cross-sectional, age-independent relationships between sub-regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041)., Conclusions: This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose of Review: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders., Recent Findings: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels., Summary: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration., Competing Interests: Conflict of Interest The authors declare no competing interests. The authors have received research funding support from the National Institutes of Health, Department of Veterans Affairs, the Michael J. Fox Foundation and the Wellcome Trust.

Background: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease., Objectives: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms., Methods: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF β-amyloid 1-42 levels at baseline; as well as longitudinal progression motor symptoms over 72-months., Results: Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow-up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone., Conclusion: Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

We investigated whether postural aftereffects witnessed during transitions from a moving to a stable support are accompanied by a delayed perception of platform stabilization in older adults, in two experiments. In experiment 1, postural sway and muscle cocontraction were assessed in 11 healthy young, 11 healthy older, and 11 fall-prone older adults during blindfolded stance on a fixed platform, followed by a sway-referenced platform and then by a fixed platform again. The sway-referenced platform was more compliant for young adults, to induce similar levels of postural sway in both age groups. Participants were asked to press a button whenever they perceived that the platform had stopped moving. Both older groups showed significantly larger and longer postural sway aftereffects during platform stabilization compared with young adults, which were pronounced in fall-prone older adults. In both older groups elevated muscle cocontraction aftereffect was also witnessed. Importantly, these aftereffects were accompanied by an illusory perception of prolonged platform movement. After this, experiment 2 examined whether this illusory perception was a robust age effect or an experimental confound due to greater surface compliance in young adults, which could create a larger perceptual discrepancy between moving and stable conditions. Despite exposure to the same surface compliance levels during sway-reference, the perceptual illusion was maintained in experiment 2 in a new group of 14 healthy older adults compared with 11 young adults. In both studies, older adults took five times longer than young adults to perceive platform stabilization. This supports that sensory reweighting is inefficient in older adults. NEW & NOTEWORTHY This is the first paper to show that postural sway aftereffects witnessed in older adults after platform stabilization may be due to a perceptual illusion of platform movement. Surprisingly, in both experiments presented it took older adults five times longer than young adults to perceive platform stabilization. This supports a hypothesis of less efficient sensory reintegration in this age group, which may delay the formation of an accurate postural percept.

During conditions of increased postural instability, older adults exhibit greater lower limb muscle co-contraction. This response has been interpreted as a compensatory postural strategy, which may be used to increase proprioceptive information from muscle spindles or to stiffen the lower limb as a general response to minimise postural sway. The current study aimed to test these two hypotheses by investigating use of muscle co-contraction during sensory transitions that manipulated proprioceptive input. Surface EMG was recorded from the bilateral tibialis anterior and gastrocnemius medialis muscles, in young (aged 18-30) and older adults (aged 68-80) during blind-folded postural assessment. This commenced on a fixed platform (baseline: 2 min), followed by 3 min on a sway-referenced platform (adaptation) and a final 3 min on a fixed platform again (reintegration). Sensory reweighting was slower in older adults, as shown by a significantly larger and longer postural sway after-effect once a stable platform was restored. Muscle co-contraction showed similar after-effects, whereby older adults showed a larger increase in co-contraction once the stable platform had been restored, compared to young adults. This co-contraction after-effect did not return to baseline until after 1 min. Our evidence for high muscle co-contraction during the reintroduction of veridical proprioceptive input suggests that increased co-contraction in older adults is not dependent on contemporaneous proprioceptive input. Rather, it is more likely that co-contraction is a general postural strategy used to minimise postural sway, which is increased during this sensory transition. Future research should examine whether muscle co-contraction is typically a reactive or anticipatory response., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

We investigated whether stimulating the cerebellum and primary motor cortex (M1) using transcranial direct current stimulation (tDCS) could affect postural control in young and older adults. tDCS was employed using a double-blind, sham-controlled design, in which young (aged 18-35) and older adults (aged 65+) were assessed over three sessions, one for each stimulatory condition-M1, cerebellar and sham. The effect of tDCS on postural control was assessed using a sway-referencing paradigm, which induced platform rotations in proportion to the participant's body sway, thus assessing sensory reweighting processes. Task difficulty was manipulated so that young adults experienced a support surface that was twice as compliant as that of older adults, in order to minimise baseline age differences in postural sway. Effects of tDCS on postural control were assessed during, immediately after and 30 minutes after tDCS. Additionally, the effect of tDCS on corticospinal excitability was measured by evaluating motor evoked potentials using transcranial magnetic stimulation immediately after and 30 minutes after tDCS. Minimal effects of tDCS on postural control were found in the eyes open condition only, and this was dependent on the measure assessed and age group. For young adults, stimulation had only offline effects, as cerebellar stimulation showed higher mean power frequency (MPF) of sway 30 minutes after stimulation. For older adults, both stimulation conditions delayed the increase in sway amplitude witnessed between blocks one and two until stimulation was no longer active. In conclusion, despite tDCS' growing popularity, we would caution researchers to consider carefully the type of measures assessed and the groups targeted in tDCS studies of postural control., Competing Interests: The authors have declared that no competing interests exist.

Older adults use a different muscle strategy to cope with postural instability, in which they 'co-contract' the muscles around the ankle joint. It has been suggested that this is a compensatory response to age-related proprioceptive decline however this view has never been assessed directly. The current study investigated the association between proprioceptive acuity and muscle co-contraction in older adults. We compared muscle activity, by recording surface electromyography (EMG) from the bilateral tibialis anterior (TA) and gastrocnemius medialis (GM) muscles, in young (aged 18-34) and older adults (aged 65-82) during postural assessment on a fixed and sway-referenced surface at age-equivalent levels of sway. We performed correlations between muscle activity and proprioceptive acuity, which was assessed using an active contralateral matching task. Despite successfully inducing similar levels of sway in the two age groups, older adults still showed higher muscle co-contraction. A stepwise regression analysis showed that proprioceptive acuity measured using variable error was the best predictor of muscle co-contraction in older adults. However, despite suggestions from previous research, proprioceptive error and muscle co-contraction were negatively correlated in older adults, suggesting that better proprioceptive acuity predicts more co-contraction. Overall, these results suggest that although muscle co-contraction may be an age-specific strategy used by older adults, it is not to compensate for age-related proprioceptive deficits., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

'Disruptive behaviour disorders' are the most common reason for referral to Child and Adolescent Mental Health Services (CAMHS). Current treatment guidelines focus on parent-training programmes. Difficulties are often reported when engaging families, with parental attributions and attitudes towards help-seeking proposed as influential factors. Previous research has tended to privilege pre-existing frameworks; this study utilised qualitative methods to add to the current understanding of the ways in which parents make sense of their children's behaviour. Semi-structured interviews were carried out with six mothers, recruited through CAMHS. Interpretative Phenomenological Analysis (IPA) revealed four master themes: 'Understanding the Emotional Child', 'The Emotional Parent', 'Getting Help' and 'The Journey'. Participants used a variety of explanations in order to make sense of their children's behaviour, including the impact of loss and trauma. Help-seeking was associated with feelings of shame, and services were often viewed as inconsistent and stigmatising. In contrast, positive experiences were those which were characterised as being non-judgemental, normalising and took into account the wider family context, including mothers' own emotional needs. These findings were discussed in relation to existing research and implications for clinical practice., (© The Author(s) 2014.)

Our study purpose examined salivary hormonal responses to high-speed resistive exercise. Healthy subjects (n = 45) performed 2 elbow flexor workouts on a novel (inertial kinetic exercise; Oconomowoc, WI, USA) strength training device. Our methods included saliva sample collection at both preexercise and immediately postexercise; workouts entailed two 60-second sets separated by a 90-second rest period. The samples were analyzed in duplicate for their testosterone and cortisol concentrations ([T], [C]). Average and maximum elbow flexor torque were measured from each exercise bout; they were later analyzed with a 2(gender) × 2(workout) analysis of variance (ANOVA) with repeated measures for workout. The [T] and [C] each underwent a 2(gender) × 2(time) ANOVA with repeated measures for time. A within-subject design was used to limit error variance. Average and maximum torque each had gender (men > women; p < 0.05) effects. The [T] elicited a 2-way interaction (p < 0.05), as men incurred a significant 14% increase over time, but women's values were unchanged. Yet multivariate regression revealed that 3 predictor variables (body mass and average and maximum torques) did not account for a significant amount of variance associated with the rise in male [T]. Changes in [C] were not significant. In conclusion, changes in [T] concur with the results from other studies that showed significant elevations in male [T], despite the brevity of current workouts and the rather modest volume of muscle mass engaged. Practical applications imply that salivary assays may be a viable alternative to blood draws from athletes, yet coaches and others who may administer this treatment should know that our results may have produced greater pre-post hormonal changes if postexercise sample collection had occurred at a later time point.

Older adults dying from chronic illness in rural areas are understudied and of concern because of their limited access to health services. The purpose of this qualitative descriptive study was to describe the perspectives of primary family caregivers regarding experiences with formal and informal care at the end of life for dying older adults in one rural, agricultural county. Semi-structured interviews were conducted with 23 caregivers following the death of an older relative. Major themes that emerged from the data were the benefits and challenges associated with care services. Benefits included neighbors, friends, and other volunteers who offered household help and provided respite care. Challenges included limited resources for continuity of care, geographical service boundaries, and lack of knowledge about end-of-life care by paid caregivers. Further research that addresses the perspective of rural service providers is needed to better understand the benefits and challenges of end-of-life care in this setting., (Copyright 2012, SLACK Incorporated.)

Objectives: To examine the outcomes of 2 commonly performed urologic office procedures as a part of a process to align these with the Joint Commission standards to ensure patient safety. We determined whether cystoscopy and transrectal ultrasound-guided prostate biopsy performed in the office setting pose minimal risk to patients., Methods: An evaluation of urologic office procedures in the office clinic setting of an academic medical center was prospectively performed during 3 different periods to document patient and system events. The patients included those undergoing cystoscopy for workup of hematuria, history of bladder cancer, or other indicated conditions (n = 554) and patients undergoing transrectal ultrasound-guided prostate biopsy for suspicion of prostate cancer (n = 367). All consecutive patients were evaluated., Results: A total of 7 patient events (0.76%) and 101 system events (10.97%) were documented. The most significant adverse patient event was 1 case of acute bacterial prostatitis due to quinolone-resistant Escherichia coli. In most cases, the system event rate reflected a delay of >15 minutes in the initiation of the procedure. No patient experienced significant bleeding, perforation, or a major cardiopulmonary event., Conclusions: The results of our study have shown that cystoscopy and transrectal ultrasound-guided prostate biopsy procedures performed in the office setting pose a minimal risk to patients. This information could be useful for hospitals and practices that are undergoing efforts to align their individual policies with current Joint Commission standards.

Aims: To determine the frequency of extramedullary haematopoiesis (EMH) in massive hepatic necrosis (MHN)., Methods and Results: Explanted livers of 11 adult patients transplanted consecutively for MHN were examined histologically and immunohistochemically for the presence of EMH. The aetiology of the liver damage was unknown in seven cases and drug induced in four. The presence of stem cell markers (CD34, c-kit), erythroid precursors (glycophorin A), myeloid precursors (myeloperoxidase) and megakaryocyte precursors (CD31) was investigated by immunohistochemistry. Erythroid, myeloid and megakaryocyte precursors were observed in all cases. Morphologically, haematopoietic blast cells were clustered in areas of collapse, separating islands of regenerating ductules and scattered between ductules, in a similar distribution to immunohistochemically identified c-kit-positive putative stem cells. No CD34+ cells other than endothelial cells were seen. All 11 patients were anaemic at the time of transplantation., Conclusions: EMH is a frequent finding in patients undergoing liver transplantation for MHN. This may be a consequence of the anaemia associated with this condition. Alternatively, the possibility that intrahepatic haematopoiesis is linked with hepatopoiesis is an additional, intriguing possibility that deserves further study.

Massive hepatic necrosis (MHN) is a condition that offers an opportunity to study the remarkable ability of the liver to become repopulated with hepatocytes. A maximal regenerative stimulus is expected in cases of MHN (Roskams et al. APMIS Suppl 1991;23:32-39). Sequential chronological observations, after a severe degree of liver cell loss, permit study of the human equivalent of the situation in animal models in which circulating and bone marrow-derived stem and liver progenitor cells are recruited to the hepatopoietic process. To date, the bone marrow and circulating precursors have not been identified morphologically in human material. We present data that suggest that the circulating liver progenitor could have a lymphoblastoid morphological appearance. Similar cells are seen among the cellular infiltrate of MHN. We have found that combinations of markers, such as CD117/CD133 positive CD45/tryptase negative are useful to isolate these cells using cell-sorting technology. This may facilitate their expansion in vitro and the development of their use for therapeutic purposes. In MHN, the residual portal tracts and ductular reaction with the associated lymphoid infiltrate (some of which are probably liver cell progenitors derived from the circulation) constitute the fundamental regenerative community unit in which hepatopoiesis takes place. Defining the hepatopoietic process is hindered by the lack of morphological transitional forms in the period between the progenitors within the circulation and when they assume recognizable hepatocytic form as "metaplastic" hepatocytes associated with the ductular reaction. By achieving a better comprehension of these processes of liver cell restoration, we will be better placed to accelerate liver recovery in MHN, for example by the administration of granulocyte colony stimulating factor (GCSF). Thus, more patients will be able to restore their own livers and avoid liver transplantation.

A 75 year old woman was treated for over three years with the somatostatin analogue, octreotide for an insulinoma. She had presented in a hypoglycaemic coma. C-peptide and insulin concentrations were both raised and an area of increased vascularity within the pancreas was shown by angiography. No lesion was found at laparotomy and no resection was performed. After over three years of octreotide treatment it was withdrawn for a week. Her insulin and C-peptide concentrations were greatly reduced at this time and remained so.

Study Design: Adverse factors during pregnancy may permanently stunt the growth of the spinal canal. Subsequently, even in an optimal environment the canal cannot catch up in growth with the trunk and long bones because of its early maturation. The degree of retardation in canal size depends on the severity and timing of the adverse effect. The catch-up growth of the long bones mask the narrow canal, because the latter does not have growth potential, resulting in an adult of sufficient height and good proportions, but with a canal at risk for stenosis., Objectives: To investigate the influence of the antenatal environment on the growth of the lumber spinal canal., Summary of Background Data: To date, little is known about the effects of an adverse environment on the growth of the spinal canal, and no data have been reported on antenatal influencing factors., Methods: Lumbar magnetic resonance imaging scans from 58 patients were examined. Dimensions of the central spinal canals were measured by computerized image analysis and compared with the subjects' obstetric data from their mothers' pregnancies., Results: The L3 canal was found to be the most sensitive to the influence of the examined factors. Gestational age was the most significant factor; if short, it resulted in small adult canal. Small placental weight, greater maternal age, primiparity, low socioeconomic class, and low birth weight were also found to be significant in affecting the growth of the canal., Conclusions: An adverse antenatal environment does have a permanent, retarding effect on the growth of the lumbar spinal canal.

Although mercaptopurine is the thiopurine antimetabolite predominantly used in the treatment of childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is more potent than mercaptopurine in in vitro cytotoxicity studies in human leukemic cell lines and leukemic cells from patients with ALL. We conducted a pediatric Phase I trial of TG administered as a continuous i.v. infusion (CIV). A pharmacokinetically guided dose escalation was performed to define the dose rate of TG required to achieve a steady-state plasma concentration (Css) exceeding the target concentration of 1 microM, and then the maximum tolerated duration of infusion of TG at this dose rate was defined. Eighteen patients (median age, 18 years; range, 4-25 years) with refractory malignancies (16 solid tumors and 2 ALL) were enrolled in this study. The starting dose rate of 10 mg/m2/h administered for 24 h achieved an average Css of 0.9 microM (range, 0.7-1.2 microM). Therefore, the dose rate was escalated to 20 mg/m2/h, which achieved an average Css of 4.1 microM (range, 1. 0-8.3 microM). This disproportionate increase in the Css of TG suggested a capacity-limited (saturable) elimination process, and a pharmacokinetic model incorporating two compartments with capacity-limited elimination from the central compartment was developed to describe the disposition of TG. The TG clearances (derived from model parameters) at the 10- and 20-mg/m2/h dose rates were 987 and 608 ml/min/m2, respectively. Dose-limiting myelosuppression (absolute granulocyte count < 500/mm3 and platelet count < 25,000/mm3) was observed in two of three patients treated with a dose rate of 20 mg/m2/h administered for 36 h. Administration of CIV of TG at 20 mg/m2/h for 24 h was well tolerated in nine patients. Nonhematological toxicities included nonneutropenic infections and mild, reversible changes in hepatic function tests. The recommended dose rate and duration for CIV of TG is 20 mg/m2/h for 24 h.

Platelet monoamine oxidase (MAO) activity levels were measured in 47 male inpatient alcoholics to determine whether this biological marker might be useful in differentiating subtypes of alcoholics. Of the subgrouping methods tested, only type 2 alcoholics defined by the criteria of Gilligan et al had significantly lower platelet MAO activity than type 1 alcoholics at intake, but this finding was not stable over time in a subset of subjects. Neither separating male veteran alcoholics into either of two other variations of the type 1/type 2 subtypes, nor classifying the sample into primary alcoholics versus primary ASPD with secondary alcoholism categories, yielded significant differences between subgroups. Generally, enzyme activity levels (Vmax) were higher about 10 days after stopping drinking compared to platelet MAO values determined in thrombocytes obtained after approximately 4 weeks abstinence; these levels remained relatively stable 3 months later in a cohort of subjects. Tobacco smoking was significantly negatively correlated to platelet MAO activity levels.

Purpose: Cyclophosphamide is commonly used in the treatment of children with malignant brain tumors. The purpose of this study was to develop a multicycle, high-dose intensity cyclophosphamide regimen with granulocyte-macrophage colony-stimulating factor (GM-CSF) and to assess its activity against malignant glioma and primitive neuroectodermal tumor (PNET)., Methods: Twenty-three patients with brain tumors, including 15 with malignant glioma and six with PNET, were enrolled. Cyclophosphamide (1.8-2.25 g/m2/day for 2 days i.v.; total dose 3.6-4.5 g/m2) was administered and was followed by recombinant human GM-CSF (5 micrograms/kg/day s.c.) on days 3-11 or until the absolute granulocyte count reached 1.5 x 10(9)/L., Results: With a total of 83 cycles administered, the mean dose intensity of cyclophosphamide ranged from 1.5 g/m2/week through cycle 2 (22 patients) to 0.8 g/m2/week through cycle 8 (two patients). No activity was seen against malignant glioma, and five of six patients with PNET had partial responses. The mean duration of a neutrophil count of < 0.5 x 10(9)/L was only 8 days; the platelet recovery was substantially longer. Fever during neutropenia occurred in 54 of 83 cycles. One patient died from transfusion-related graft-versus-host disease., Conclusions: A cyclophosphamide regimen equal to twice the dose intensity of that used in conventional therapy was administered. The regimen was active against PNET but inactive against malignant glioma.