Historic landmarks in clinical transplantation: Conclusions from the consensus conference at the University of California, Los Angeles

The transplantation of organs, cells, and tissues has burgeoned during the last quarter century, with the development of multiple new specialty fields. However, the basic principles that made this possible were established over a three-decade period, beginning during World War II and ending in 1974. At the historical consensus conference held at UCLA in March 1999, 11 early workers in the basic science or clinical practice of transplantation (or both) reached agreement on the most significant contribution of this era that ultimately made transplantation the robust clinical discipline it is today. These discoveries and achievements are summarized here is six tables and annotated with references

Three Affliated Tribes Renewable Energy Feasibility Study

The Three Affliated Tribes on the Fort Berthold Reservation studied the feasibility of a commercial wind facility on land selected and owned by the Tribes and examined the potential for the development of renewable energy resources on Tribal Lands

The upper end of climate model temperature projections is inconsistent with past warming

Climate models predict a large range of possible future temperatures for a particular scenario of future emissions of greenhouse gases and other anthropogenic forcings of climate. Given that further warming in coming decades could threaten increasing risks of climatic disruption, it is important to determine whether model projections are consistent with temperature changes already observed. This can be achieved by quantifying the extent to which increases in well mixed greenhouse gases and changes in other anthropogenic and natural forcings have already altered temperature patterns around the globe. Here, for the first time, we combine multiple climate models into a single synthesized estimate of future warming rates consistent with past temperature changes. We show that the observed evolution of near-surface temperatures appears to indicate lower ranges (5–95%) for warming (0.35–0.82 K and 0.45–0.93 K by the 2020s (2020–9) relative to 1986–2005 under the RCP4.5 and 8.5 scenarios respectively) than the equivalent ranges projected by the CMIP5 climate models (0.48–1.00 K and 0.51–1.16 K respectively). Our results indicate that for each RCP the upper end of the range of CMIP5 climate model projections is inconsistent with past warming

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and alzheimer's disease

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer's disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures

Apraxia and motor dysfunction in corticobasal syndrome

Background: Corticobasal syndrome (CBS) is characterized by multifaceted motor system dysfunction and cognitive disturbance; distinctive clinical features include limb apraxia and visuospatial dysfunction. Transcranial magnetic stimulation (TMS) has been used to study motor system dysfunction in CBS, but the relationship of TMS parameters to clinical features has not been studied. The present study explored several hypotheses; firstly, that limb apraxia may be partly due to visuospatial impairment in CBS. Secondly, that motor system dysfunction can be demonstrated in CBS, using threshold-tracking TMS, and is linked to limb apraxia. Finally, that atrophy of the primary motor cortex, studied using voxel-based morphometry analysis (VBM), is associated with motor system dysfunction and limb apraxia in CBS.   Methods: Imitation of meaningful and meaningless hand gestures was graded to assess limb apraxia, while cognitive performance was assessed using the Addenbrooke's Cognitive Examination - Revised (ACE-R), with particular emphasis placed on the visuospatial subtask. Patients underwent TMS, to assess cortical function, and VBM.   Results: In total, 17 patients with CBS (7 male, 10 female; mean age 64.4+/2 6.6 years) were studied and compared to 17 matched control subjects. Of the CBS patients, 23.5% had a relatively inexcitable motor cortex, with evidence of cortical dysfunction in the remaining 76.5% patients. Reduced resting motor threshold, and visuospatial performance, correlated with limb apraxia. Patients with a resting motor threshold <50% performed significantly worse on the visuospatial sub-task of the ACE-R than other CBS patients. Cortical function correlated with atrophy of the primary and pre-motor cortices, and the thalamus, while apraxia correlated with atrophy of the pre-motor and parietal cortices.   Conclusions: Cortical dysfunction appears to underlie the core clinical features of CBS, and is associated with atrophy of the primary motor and pre-motor cortices, as well as the thalamus, while apraxia correlates with pre-motor and parietal atrophy

Neural Correlates of Threat Perception: Neural Equivalence of Conspecific and Heterospecific Mobbing Calls Is Learned

Songbird auditory areas (i.e., CMM and NCM) are preferentially activated to playback of conspecific vocalizations relative to heterospecific and arbitrary noise [1]–[2]. Here, we asked if the neural response to auditory stimulation is not simply preferential for conspecific vocalizations but also for the information conveyed by the vocalization. Black-capped chickadees use their chick-a-dee mobbing call to recruit conspecifics and other avian species to mob perched predators [3]. Mobbing calls produced in response to smaller, higher-threat predators contain more “D” notes compared to those produced in response to larger, lower-threat predators and thus convey the degree of threat of predators [4]. We specifically asked whether the neural response varies with the degree of threat conveyed by the mobbing calls of chickadees and whether the neural response is the same for actual predator calls that correspond to the degree of threat of the chickadee mobbing calls. Our results demonstrate that, as degree of threat increases in conspecific chickadee mobbing calls, there is a corresponding increase in immediate early gene (IEG) expression in telencephalic auditory areas. We also demonstrate that as the degree of threat increases for the heterospecific predator, there is a corresponding increase in IEG expression in the auditory areas. Furthermore, there was no significant difference in the amount IEG expression between conspecific mobbing calls or heterospecific predator calls that were the same degree of threat. In a second experiment, using hand-reared chickadees without predator experience, we found more IEG expression in response to mobbing calls than corresponding predator calls, indicating that degree of threat is learned. Our results demonstrate that degree of threat corresponds to neural activity in the auditory areas and that threat can be conveyed by different species signals and that these signals must be learned

Defective Peripheral Nerve Development Is Linked to Abnormal Architecture and Metabolic Activity of Adipose Tissue in Nscl-2 Mutant Mice

BACKGROUND: In mammals the interplay between the peripheral nervous system (PNS) and adipose tissue is widely unexplored. We have employed mice, which develop an adult onset of obesity due to the lack the neuronal specific transcription factor Nscl-2 to investigate the interplay between the nervous system and white adipose tissue (WAT). METHODOLOGY: Changes in the architecture and innervation of WAT were compared between wildtype, Nscl2-/-, ob/ob and Nscl2-/-//ob/ob mice using morphological methods, immunohistochemistry and flow cytometry. Metabolic alterations in mutant mice and in isolated cells were investigated under basal and stimulated conditions. PRINCIPAL FINDINGS: We found that Nscl-2 mutant mice show a massive reduction of innervation of white epididymal and paired subcutaneous inguinal fat tissue including sensory and autonomic nerves as demonstrated by peripherin and neurofilament staining. Reduction of innervation went along with defects in the formation of the microvasculature, accumulation of cells of the macrophage/preadipocyte lineage, a bimodal distribution of the size of fat cells, and metabolic defects of isolated adipocytes. Despite a relative insulin resistance of white adipose tissue and isolated Nscl-2 mutant adipocytes the serum level of insulin in Nscl-2 mutant mice was only slightly increased. CONCLUSIONS: We conclude that the reduction of the innervation and vascularization of WAT in Nscl-2 mutant mice leads to the increase of preadipocyte/macrophage-like cells, a bimodal distribution of the size of adipocytes in WAT and an altered metabolic activity of adipocytes

The impact of routine surveillance screening with magnetic resonance imaging (MRI) to detect tumour recurrence in children with central nervous system (CNS) tumours : Protocol for a systematic review and meta-analysis

Background: The aim of this study is to assess the impact of routine MRI surveillance to detect tumour recurrence in children with no new neurological signs or symptoms compared with alternative follow-up practices, including periodic clinical and physical examinations and the use of non-routine imaging upon presentation with disease signs or symptoms. Methods: Standard systematic review methods aimed at minimising bias will be employed for study identification, selection and data extraction. Ten electronic databases have been searched, and further citation searching and reference checking will be employed. Randomised and non-randomised controlled trials assessing the impact of routine surveillance MRI to detect tumour recurrence in children with no new neurological signs or symptoms compared to alternative follow-up schedules including imaging upon presentation with disease signs or symptoms will be included. The primary outcome is time to change in therapeutic intervention. Secondary outcomes include overall survival, surrogate survival outcomes, response rates, diagnostic yield per set of images, adverse events, quality of survival and validated measures of family psychological functioning and anxiety. Two reviewers will independently screen and select studies for inclusion. Quality assessment will be undertaken using the Cochrane Collaboration's tools for assessing risk of bias. Where possible, data will be summarised using combined estimates of effect for time to treatment change, survival outcomes and response rates using assumption-free methods. Further sub-group analyses and meta-regression models will be specified and undertaken to explore potential sources of heterogeneity between studies within each tumour type if necessary. Discussion: Assessment of the impact of surveillance imaging in children with CNS tumours is methodologically complex. The evidence base is likely to be heterogeneous in terms of imaging protocols, definitions of radiological response and diagnostic accuracy of tumour recurrence due to changes in imaging technology over time. Furthermore, the delineation of tumour recurrence from either pseudo-progression or radiation necrosis after radiotherapy is potentially problematic and linked to the timing of follow-up assessments. However, given the current routine practice of MRI surveillance in the follow-up of children with CNS tumours in the UK and the resource implications, it is important to evaluate the cost-benefit profile of this practice. Systematic review registration: PROSPERO CRD4201603680

Irreducible uncertainty in near-term climate projections

Model simulations of the next few decades are widely used in assessments of climate change impacts and as guidance for adaptation. Their non-linear nature reveals a level of irreducible uncertainty which it is important to understand and quantify, especially for projections of near-term regional climate. Here we use large idealised initial condition ensembles of the FAMOUS global climate model with a 1 %/year compound increase in CO2 levels to quantify the range of future temperatures in model-based projections. These simulations explore the role of both atmospheric and oceanic initial conditions and are the largest such ensembles to date. Short-term simulated trends in global temperature are diverse, and cooling periods are more likely to be followed by larger warming rates. The spatial pattern of near-term temperature change varies considerably, but the proportion of the surface showing a warming is more consistent. In addition, ensemble spread in inter-annual temperature declines as the climate warms, especially in the North Atlantic. Over Europe, atmospheric initial condition uncertainty can, for certain ocean initial conditions, lead to 20 year trends in winter and summer in which every location can exhibit either strong cooling or rapid warming. However, the details of the distribution are highly sensitive to the ocean initial condition chosen and particularly the state of the Atlantic meridional overturning circulation. On longer timescales, the warming signal becomes more clear and consistent amongst different initial condition ensembles. An ensemble using a range of different oceanic initial conditions produces a larger spread in temperature trends than ensembles using a single ocean initial condition for all lead times. This highlights the potential benefits from initialising climate predictions from ocean states informed by observations. These results suggest that climate projections need to be performed with many more ensemble members than at present, using a range of ocean initial conditions, if the uncertainty in near-term regional climate is to be adequately quantified

Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure