Preoperative anaemia management in patients undergoing vascular surgery.

CAVIAR is a multicentre prospective stepped observational study encompassing 160 patients undergoing vascular intervention. The aim was to identify whether it was feasible to establish a preoperative anaemia pathway and, if so, the efficacy of intravenous iron for treatment of preoperative anaemia. Large barriers prevented implementation of an intravenous iron pathway, with only ten patients receiving intravenous iron and a small increase in haemoglobin level (mean 5·7 (95 per cent c.i. 4·5 to 6·9) g/l). Preoperative anaemia was associated with a longer hospital stay and greater transfusion requirement. Anaemia common and dedicated pathway difficult to instigate.

The uptake of the hip fracture core outcome set: analysis of 20 years of hip fracture trials.

BACKGROUND: clinical trials test the effectiveness or efficacy of treatments. It is important that researchers evaluate interventions with the most meaningful outcome measures. The 2014 hip fracture core outcome set recommended that mortality, mobility, pain, activities of daily living and health-related quality of life (HRQOL) should be assessed in all trials of patient with hip fracture. The purpose of this analysis was to determine the uptake of these recommendation. METHODS: all trials registered from 1997 to 2018 recruiting participants following hip fracture were identified from the ClinicalTrials.gov trials registry. The frequency of each core domain adopted annually were assessed. RESULTS: 311 trials were identified and analysed. On analysing trial registries for years which presented a minimum of 10 registrations, full core outcome set adoption ranged from 0% (2017; 2018) to 24% (2009). Mortality and mobility were the most consistently reported domains (mortality: 27% (2017) to 56% (2011); mobility: 36% (2015) to 60% (2004)). In contrast, pain and HRQOL were least reported (pain: 14% (2017) to 61% (2015); HRQOL: 10% (2010) to 11% (2008)). There was no clear change in core outcome domain set adoption following the publication of Hayward et al.'s (2014) core outcome set. CONCLUSIONS: there has been limited adoption of the hip fracture core outcome set from its publication in 2014. Further consideration to improve implementation is required to improved uptake.

The effect of high-flow nasal oxygen on hospital length of stay in cardiac surgical patients at high risk for respiratory complications: a randomised controlled trial.

There has been increased interest in the prophylactic and therapeutic use of high-flow nasal oxygen in patients with, or at risk of, non-hypercapnic respiratory failure. There are no randomised trials examining the efficacy of high-flow nasal oxygen in high-risk cardiac surgical patients. We sought to determine whether routine administration of high-flow nasal oxygen, compared with standard oxygen therapy, leads to reduced hospital length of stay after cardiac surgery in patients with pre-existing respiratory disease at high risk for postoperative pulmonary complications. Adult patients with pre-existing respiratory disease undergoing elective cardiac surgery were randomly allocated to receive high-flow nasal oxygen (n = 51) or standard oxygen therapy (n = 49). The primary outcome was hospital length of stay and all analyses were carried out on an intention-to-treat basis. Median (IQR [range]) hospital length of stay was 7 (6-9 [4-30]) days in the high-flow nasal oxygen group and 9 (7-16 [4-120]) days in the standard oxygen group (p=0.012). Geometric mean hospital length of stay was 29% lower in the high-flow nasal group (95%CI 11-44%, p = 0.004). High-flow nasal oxygen was also associated with fewer intensive care unit re-admissions (1/49 vs. 7/45; p = 0.026). When compared with standard care, prophylactic postoperative high-flow nasal oxygen reduced hospital length of stay and intensive care unit re-admission. This is the first randomised controlled trial examining the effect of prophylactic high-flow nasal oxygen use on patient-centred outcomes in cardiac surgical patients at high risk for postoperative respiratory complications.

Effect on the mechanical properties of type I collagen of intra-molecular lysine-arginine derived advanced glycation end-product cross-linking.

Non-enzymatic advanced glycation end product (AGE) cross-linking of collagen molecules has been hypothesised to result in significant changes to the mechanical properties of the connective tissues within the body, potentially resulting in a number of age related diseases. We have investigated the effect of two of these cross-links, glucosepane and DOGDIC, on the tensile and lateral moduli of the collagen molecule through the use of a steered molecular dynamics approach, using previously identified preferential formation sites for intra-molecular cross-links. Our results show that the presence of intra-molecular AGE cross-links increases the tensile and lateral Young's moduli in the low strain domain by between 3.0-8.5% and 2.9-60.3% respectively, with little effect exhibited at higher strains.

Brain Penetration of the ROS1/ALK Inhibitor Lorlatinib Confirmed by PET.

The Massachusetts General Hospital Radiochemistry Program, in collaboration with Pfizer, has developed unique 11C and 18F-labeling strategies to synthesize isotopologs of lorlatinib (PF-06463922) which is undergoing phase III clinical trial investigations for treatment of non-small-cell lung cancers with specific molecular alterations. A major goal in cancer therapeutics is to measure the concentrations of this drug in the brain metastases of patients with lung cancer, and penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Our recent publication in Nature Communications employed radiolabeled lorlatinib and positron emission tomography (PET) studies in preclinical models including nonhuman primates (NHPs) that demonstrated high brain permeability of this compound. Our future work with radiolabeled lorlatinib will include advanced PET evaluations in rodent tumor models and normal NHPs with the goal of clinical translation.

The ACTA PORT-score for predicting perioperative risk of blood transfusion for adult cardiac surgery.

BACKGROUND: A simple and accurate scoring system to predict risk of transfusion for patients undergoing cardiac surgery is lacking. METHODS: We identified independent risk factors associated with transfusion by performing univariate analysis, followed by logistic regression. We then simplified the score to an integer-based system and tested it using the area under the receiver operator characteristic (AUC) statistic with a Hosmer-Lemeshow goodness-of-fit test. Finally, the scoring system was applied to the external validation dataset and the same statistical methods applied to test the accuracy of the ACTA-PORT score. RESULTS: Several factors were independently associated with risk of transfusion, including age, sex, body surface area, logistic EuroSCORE, preoperative haemoglobin and creatinine, and type of surgery. In our primary dataset, the score accurately predicted risk of perioperative transfusion in cardiac surgery patients with an AUC of 0.76. The external validation confirmed accuracy of the scoring method with an AUC of 0.84 and good agreement across all scores, with a minor tendency to under-estimate transfusion risk in very high-risk patients. CONCLUSIONS: The ACTA-PORT score is a reliable, validated tool for predicting risk of transfusion for patients undergoing cardiac surgery. This and other scores can be used in research studies for risk adjustment when assessing outcomes, and might also be incorporated into a Patient Blood Management programme.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

BDNF in the Aged Brain: Translational Implications for Parkinson's Disease.

Brain Derived Neurotrophic Factor (BDNF) is a member of the neurotrophin family of secreted growth factors. BDNF signaling is known to exert both chronic, pro-survival effects related to gene expression and protein synthesis ("canonical signaling"), and acute effects as a modulator of neurotransmission ("non-canonical signaling"). BDNF has received a great deal of attention for its role in neurodegenerative diseases including Huntington's Disease (HD), Alzheimer's Disease (AD), and Parkinson's Disease (PD) and has been extensively reviewed elsewhere in this regard (e.g., [1-6]). However aging-related changes in BDNF function and expression have been studied only rarely, with the majority of studies characterizing changes in structures such as the hippocampus and neocortex. In this review, we attempt to briefly summarize the extent of the existing literature on age-related BDNF changes, and discuss the relevance of these changes as a factor potentially impacting therapeutics in aged parkinsonian subjects.

The incidence and importance of anaemia in patients undergoing cardiac surgery in the UK - the first Association of Cardiothoracic Anaesthetists national audit.

The importance and variability of pre-operative anaemia in cardiac surgical patients across the UK is not known, and there is debate about its association with patient outcomes. The Association of Cardiothoracic Anaesthetists carried out its first national audit on anaemia and transfusion, and analysed data from 19,033 patients operated on in 12 cardiac surgical centres between 2010 and 2012; 5895 (31%) had pre-operative anaemia. Centre-specific prevalence of anaemia varied from 23% to 45%; anaemia was associated with older patients, diabetes and surgical risk (EuroSCORE). Nevertheless, controlling for these factors, regional variation remained an independent effect (p < 0.001). Multivariable analysis demonstrated an independent association of anaemia with transfusion (odds ratio (95% confidence interval) 2.75 (2.55-2.95), p < 0.001), mortality (1.42 (1.18-1.71), p < 0.001) and hospital stay (geometric mean ratio (95% confidence interval) 1.15 (1.13-1.17), p < 0.001). Haemoglobin concentration per se was also independently associated with worse outcomes; a 10 g.l(-1) decrease in haemoglobin was associated with a 43% increase (95% confidence interval 40-46%) in the odds of transfusion and a 16% increase (95% confidence interval 10-22%) in the odds of mortality (both p < 0.001). This large UK-wide audit has demonstrated marked regional variation in both anaemia and transfusion, with a consistently high incidence of both. The independent association between pre-operative anaemia and worse outcomes in UK practice has also been confirmed, and robust prospective study of anaemia treatment before cardiac surgery is required; these data will assist in designing such trials.

Investigating associations between biting time in the malaria vector Anopheles arabiensis Patton and single nucleotide polymorphisms in circadian clock genes: support for sub-structure among An. arabiensis in the Kilombero valley of Tanzania.

BACKGROUND: There is growing evidence that the widespread use of Long-Lasting Insecticidal Nets (LLINs) is prompting malaria vectors to shift their biting towards times and places where people are not protected, such as earlier in the evening and/or outdoors. It is uncertain whether these behavioural shifts are due to phenotypic plasticity and/or ecological changes within vector communities that favour more exophilic species, or involve genetic factors within vector species to limit their contact with LLINs. Possibly variation in the time and location of mosquito biting has a genetic basis, but as yet this phenomenon has received little investigation. Here we used a candidate gene approach to investigate whether polymorphisms in selected circadian clock genes could explain variation in the time and location of feeding (indoors versus outside) within a natural population of the major African malaria vector Anopheles arabiensis. METHODS: Host-seeking An. arabiensis were collected from two villages (Lupiro and Sagamaganga) in Tanzania by Human Landing Catch (HLC) technique. Mosquitoes were classified into phenotypes of "early" (7 pm-10 pm) or "late" biting (4 am -7 am), and host-seeking indoors or outdoors. In these samples we genotyped 34 coding SNPs in 8 clock genes (PER, TIM, CLK, CYC, PDP1, VRI, CRY1, and CRY2), and tested for associations between these SNPs and biting phenotypes. SNPs in 8 mitochondrial genes (ATP6, ATP8, COX1, COX2, COX3, ND3, ND5 and CYTB) were also genotyped to test population subdivision within An. arabiensis. RESULTS: The candidate clock genes exhibited polymorphism within An. arabiensis, but it was unrelated to variation in the timing and location of their biting activity. However, there was evidence of strong genetic structure within An. arabiensis populations in association with the TIM, which was unrelated to geographic distance. Substructure within An. arabiensis was also detected using mitochondrial markers. CONCLUSIONS: The variable timing and location of biting in An. arabiensis could not be linked to candidate clock genes that are known to influence behaviour in other Diptera. This finding does not rule out the possibility of a genetic basis to biting behaviour in this malaria vector, but suggests these are complex phenotypes that require more intensive ecological, neuronal and genomic analyses to understand.

Acute kidney injury in stable COPD and at exacerbation.

BACKGROUND: While acute kidney injury (AKI) alone is associated with increased mortality, the incidence of hospital admission with AKI among stable and exacerbating COPD patients and the effect of concurrent AKI at COPD exacerbation on mortality is not known. METHODS: A total of 189,561 individuals with COPD were identified from the Clinical Practice Research Datalink. Using Poisson and logistic regressions, we explored which factors predicted admission for AKI (identified in Hospital Episode Statistics) in this COPD cohort and concomitant AKI at a hospitalization for COPD exacerbation. Using survival analysis, we investigated the effect of concurrent AKI at exacerbation on mortality (n=36,107) and identified confounding factors. RESULTS: The incidence of AKI in the total COPD cohort was 128/100,000 person-years. The prevalence of concomitant AKI at exacerbation was 1.9%, and the mortality rate in patients with AKI at exacerbation was 521/1,000 person-years. Male sex, older age, and lower glomerular filtration rate predicted higher risk of AKI or death. There was a 1.80 fold (95% confidence interval: 1.61, 2.03) increase in adjusted mortality within the first 6 months post COPD exacerbation in patients suffering from AKI and COPD exacerbation compared to those who were AKI free. CONCLUSION: In comparison to previous studies on general populations and hospitalizations, the incidence and prevalence of AKI is relatively high in COPD patients. Coexisting AKI at exacerbation is prognostic of poor outcome.

Validation of viscoelastic coagulation tests during cardiopulmonary bypass.

BACKGROUND: Viscoelastic point-of-care tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM) are increasingly used to guide hemostatic therapy after cardiac surgery. The aim of this study was to assess their clinical utility during cardiopulmonary bypass to predict postbypass coagulation status and to guide therapy. METHODS: In this prospective study, TEG and ROTEM tests were performed in 52 adult patients undergoing elective cardiac surgery at two time points: near the end of cardiopulmonary bypass and after heparin reversal with protamine. The 95% confidence intervals of the mean difference were compared with a prespecified clinically relevant limit of ± 20% of the value after protamine. RESULTS: Both viscoelastic fibrinogen assays were well within the prespecified clinically relevant limit (≥ 79% of patients). The laboratory Clauss fibrinogen was much lower during cardiopulmonary bypass than after protamine (mean difference 1.2 g L(-1) , 95% CI 1.03-1.4, which was outside a clinically acceptable difference. For intrinsically activated tests, clotting times (CT) were different and outside the prespecified limit on TEG (mean difference -1.2 min, 95% CI -1.8 to -0.6) but not on ROTEM (mean difference 2.3 sec, 95% CI -8.6 to 13.2), while clot strength was well within the clinical limit on both devices (≥ 94% of patients). For extrinsically activated tests, clot strength on both TEG and ROTEM was within the pre-specified limit in 98% of patients. CONCLUSIONS: Results from TEG and ROTEM tests performed toward the end of cardiopulmonary bypass are similar to results after reversal of heparin. Amplitudes indicating clot strength were the most stable parameters across all tests, whereas CT showed more variability. In contrast, laboratory testing of fibrinogen using the Clauss assay was essentially invalid during cardiopulmonary bypass.

Haemoconcentration of residual cardiopulmonary bypass blood using Hemosep ®: a randomised controlled trial.

Cardiac surgery and cardiopulmonary bypass are associated with haemodilution, activation of haemostasis and blood transfusion. We undertook a randomised controlled trial that included 53 patients in order to compare autotransfusion of residual cardiopulmonary bypass blood with residual blood concentrated using the novel Hemosep(®) device. There was no difference in patients' mean (SD) haemoglobin concentration after autotransfusion of unprocessed blood compared with Hemosep; 103.5 (10.2) g.l(-1) vs 106.2 (12.4) g.l(-1), respectively, p = 0.40. The mean (SD) change in haemoglobin concentration after autotransfusion was 5.9 (5.3) g.l(-1) in the control group compared with 4.9 (6.3) g.l(-1) in the Hemosep group, p = 0.545. Adjusted for baseline haemoglobin concentrations, the estimated mean (95% CI) difference in change in haemoglobin concentration (control vs Hemosep) was 0.57 (-2.65 to 3.79) g.l(-1), p = 0.72. This was despite Hemosep's reducing the weight of the blood from a mean (SD) of 778.7 (243.0) g to 607.3 (248.2) g, p < 0.001. The haemoglobin concentration in the processed blood increased from a mean (SD) of 87.0 (15.1) g.l(-1) to 103.7 (17.4) g.l(-1), p < 0.001. We conclude that Hemosep is capable of haemoconcentration when employed to process residual cardiopulmonary bypass blood, but that this is insufficient to increase patient haemoglobin.

Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways.

Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.

Survey of pathogens in hatchery Chinook salmon with different out-migration histories through the Snake and Columbia rivers.

The operation of the Federal Columbia River Power System (FCRPS) has negatively affected threatened and endangered salmonid populations in the Pacific Northwest. Barging Snake River spring Chinook salmon Oncorhynchus tshawytscha through the FCRPS is one effort to mitigate the effect of the hydrosystem on juvenile salmon out-migration. However, little is known about the occurrence and transmission of infectious agents in barged juvenile salmon relative to juvenile salmon that remain in-river to navigate to the ocean. We conducted a survey of hatchery-reared spring Chinook salmon at various points along their out-migration path as they left their natal hatcheries and either migrated in-river or were barged through the FCRPS. Salmon kidneys were screened by polymerase chain reaction for nine pathogens and one family of water molds. Eight pathogens were detected; the most prevalent were Renibacterium salmoninarum and infectious hematopoietic necrosis virus. Species in the family Saprolegniaceae were also commonly detected. Pathogen prevalence was significantly greater in fish that were barged through the FCRPS than in fish left to out-migrate in-river. These results suggest that the transmission of infectious agents to susceptible juvenile salmon occurs during the barging process. Therefore, management activities that reduce pathogen exposure during barging may increase the survival of juvenile Chinook salmon after they are released.

Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer.

Microfluidic technology has been used to perform [(11)C]carbonylation reactions using solutions containing [(11)C]CO in the form of the complex, copper(i)tris(3,5-dimethylpyrazolyl)borate-[(11)C]carbonyl (Cu(Tp*)[(11)C]CO). The synthesis of the model compound [(11)C]N-benzylbenzamide and the known tracer molecule [(11)C]trans-N-[5-(2-flurophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofurane-1(3H),1'-cyclohexane]-4'-carboxamide ([(11)C]MK-0233), a ligand for the neuropeptide Y Y5 receptor, have been performed using this technique. Following semi-preparative HPLC purification and reformulation, 1262 ± 113 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 30 GBq µmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.2 ± 0.7%. Using a 3 mL vial as the reaction vessel, and following semi-preparative HPLC purification and reformulation, 1255 ± 392 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 15 GBq µmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.1 ± 2.2%.

Biomarker responses and disease susceptibility in juvenile rainbow trout Oncorhynchus mykiss fed a high molecular weight PAH mixture.

Juvenile rainbow trout were fed a diet containing an environmentally relevant mixture of 10 high molecular weight polycyclic aromatic hydrocarbons (PAHs) at a dose of 0.66 or 7.82 µg PAH · g fish(-1) · d(-1). At 3, 7, 14, and 28 d, biomarkers of aryl hydrocarbon receptor activation (AHR), hepatic microsomal ethoxyresorufin-O-deethylase (EROD) activity, and cytochrome P4501A (CYP1A)-associated staining increased 14- to 26-fold and 6- to 14-fold, respectively, in fish fed 7.82 µg PAH · g fish (-1) · d(-1). Cytochrome P4501A-associated staining increased 2- to 9-fold on days 3, 7, and 28 in fish fed 0.66 µg PAH · g fish(-1) · d(-1). Bile fluorescent aromatic compounds served as a biomarker of exposure and confirmed that PAH exposure was consistent over 50 d. DNA damage in blood cells, protein oxidation, and lipid peroxidation in the kidney were biomarkers of oxidative stress and all increased in fish fed 7.82 µg PAH · g fish(-1) · d(-1). Fish fed 0.66 µg PAH · g fish(-1) · d(-1) had elevated DNA damage in blood cells but increased protein oxidation or lipid peroxidation in the kidney were not observed. Challenge with Aeromonas salmonicida, at lethal concentration (LC) 20, decreased survival in fish previously fed either 0.66 µg PAH · g fish(-1) · d(-1) or 7.82 µg PAH · g fish(-1) · d(-1) relative to fish fed the control diet. In general, biomarkers of both AHR activation and oxidative stress peaked at 3 to 14 d then declined at 28 to 50 d of PAH exposure and an increase in susceptibility to disease was observed at 50 d. These results link PAH exposure to biomarker responses that may be useful as early indicators of population level responses, such as mortality resulting from an increase in disease susceptibility.

Patients with schizophrenia show increased aversion to angry faces in an associative learning task.

BACKGROUND: We were interested in examining the relationship between socially relevant stimuli and decision processes in patients with schizophrenia. METHOD: We tested patients with schizophrenia and healthy controls on a stochastically rewarded associative learning task. Participants had to determine, through trial and error, which of two faces was associated with a higher chance of reward: one face was angry, the other happy. RESULTS: Both patients and healthy controls were able to perform the task at above-chance accuracy, and there was no significant difference in overall accuracy between the groups. Both groups also reliably preferred the happy face, such that they selected it more often than the angry face on the basis of the same amount of positive versus negative feedback. However, patients were significantly more averse to the angry face, such that they chose it less often than control participants when the reward feedback strongly supported the angry face as the best choice. CONCLUSIONS: Patients show an increased aversion to angry faces, in a task in which they must learn to associate rewards with expressions.

A functionally relevant and long-term model of deep brain stimulation of the rat subthalamic nucleus: advantages and considerations.

In this review we outline some relevant considerations with regards to the rat model of deep brain stimulation of the subthalamic nucleus (STN DBS). In order to optimize the rat STN DBS model in terms of predictive validity for the clinical situation we propose that the STN stimulation experimental design parameters in rodents should incorporate the following features: (i) stimulation parameters that demonstrate functional alleviation of symptoms induced by nigrostriatal dopamine (DA) denervation; (ii) stimulation duration that is relatively long-term and continuous; (iii) stimulation that is initiated at a time when the denervation status of the nigrostriatal system is known to be partial and progressing; (iv) stimulation current spread that is minimized and optimized to closely approximate the clinical situation; (v) the appropriate control conditions are included; and (vi) implantation to the STN target is verified post-mortem. Further research that examines the effect of long-term STN DBS on the neurophysiology and neurochemistry of STN circuitry is warranted. The rat model of functionally relevant long-term STN DBS provides a most favorable preclinical experimental platform in which to conduct these studies.

Stimulation of the rat subthalamic nucleus is neuroprotective following significant nigral dopamine neuron loss.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is efficacious in treating the motor symptoms of Parkinson's disease (PD). However, the impact of STN-DBS on the progression of PD is unknown. Previous preclinical studies have demonstrated that STN-DBS can attenuate the degeneration of a relatively intact nigrostriatal system from dopamine (DA)-depleting neurotoxins. The present study examined whether STN-DBS can provide neuroprotection in the face of prior significant nigral DA neuron loss similar to PD patients at the time of diagnosis. STN-DBS between 2 and 4 weeks after intrastriatal 6-hydroxydopamine (6-OHDA) provided significant sparing of DA neurons in the SN of rats. This effect was not due to inadvertent lesioning of the STN and was dependent upon proper electrode placement. Since STN-DBS appears to have significant neuroprotective properties, initiation of STN-DBS earlier in the course of PD may provide added neuroprotective benefits in addition to its ability to provide symptomatic relief.