Functional outcome in dogs undergoing hemilaminectomy for thoracolumbar disc extrusion but without nociception > 96 h: A prospective study.

This prospective study investigated the functional recovery of surgically treated dogs with thoracolumbar intervertebral disc extrusion (IVDE) without deep pain perception (DPP) for > 96 h. Dogs (n = 36) with paraplegia secondary to thoracolumbar intervertebral disc extrusion with loss of deep pain perception ranging from 4 to 60 days were enrolled. All dogs underwent hemilaminectomy and fenestration of the affected intervertebral disc and postoperative follow-up was provided for a maximum of 180 days. Recovery of motor function was satisfactory (based on the owner's assessment) in 22 dogs, 61.1% (47.2% with DPP, and 13.9% without DPP) and unsatisfactory in 38.9% of cases (n = 14). Postoperative physiotherapy, preoperative anti-inflammatory drugs, and age had no effect on recovery. In this study, the longer the time taken to regain pain perception, the longer the recovery time. The median time to recovery was 30 days. A total of 47.2% of dogs with paraplegia and absence of DPP secondary to thoracolumbar IVDE lasting > 96 h, recovered functional ambulation after decompressive surgery.

In vivo biomarkers of structural and functional brain development and aging in humans.

Brain aging is a major determinant of aging. Along with the aging population, prevalence of neurodegenerative diseases is increasing, therewith placing economic and social burden on individuals and society. Individual rates of brain aging are shaped by genetics, epigenetics, and prenatal environmental. Biomarkers of biological brain aging are needed to predict individual trajectories of aging and the risk for age-associated neurological impairments for developing early preventive and interventional measures. We review current advances of in vivo biomarkers predicting individual brain age. Telomere length and epigenetic clock, two important biomarkers that are closely related to the mechanistic aging process, have only poor deterministic and predictive accuracy regarding individual brain aging due to their high intra- and interindividual variability. Phenotype-related biomarkers of global cognitive function and brain structure provide a much closer correlation to age at the individual level. During fetal and perinatal life, autonomic activity is a unique functional marker of brain development. The cognitive and structural biomarkers also boast high diagnostic specificity for determining individual risks for neurodegenerative diseases.

Proposta de sequenciamento das projeções mielográficas na identificação de compressão da medula espinhal em cães com doença do disco intervertebral cervical / [Sequential proposal in the myelographic views for detection of spinal cord compression in dogs with cervical intervertebral disc disease]

O objetivo deste trabalho foi verificar em quais projeções foi possível identificar compressão da medula espinhal em cães com doença do disco intervertebral (DDIV) cervical e propor um sequenciamento das projeções a ser realizado no exame mielográfico dessa região. Foram avaliadas quatro projeções mielográficas (lateral, ventrodorsal e oblíquas esquerda e direita) de 41 pacientes diagnosticados com DDIV cervical. Em 40 pacientes (97,5%), foi possível identificar compressão da medula espinhal na projeção lateral; em 22 (53,6%), nas oblíquas; e em 11 (26,8%), na ventrodorsal (P<0,05). Havia lateralização da compressão em 22 (53,6%) pacientes; 100% delas (n=22) foram detectadas pelas projeções oblíquas e 50% (n=11) pela ventrodorsal. Em 10 (24,4%) cães, foi observado mais que um local de compressão, tendo as projeções ventrodorsal e oblíquas auxiliado na definição do local de compressão em 50% e 70%, respectivamente. Pode-se concluir que todas as projeções mielográficas estudadas permitem identificar compressão na medula espinhal em cães com DDIV cervical, sendo a incidência lateral a que mais a revelou, seguida das oblíquas e da ventrodorsal, estabelecendo-se, assim, uma proposta de sequenciamento das projeções mielográficas a serem realizadas para essa região.(AU)

The aim of this study was to verify in which of the myelographic views it was possible to identify spinal cord compression in dogs with cervical intervertebral disc disease (IVDD), and to establish a sequence in which myelographic views should be obtained for this region. Four myelographic views (lateral, ventrodorsal, left oblique and right oblique) of 41 patients diagnosed with cervical IVDD were evaluated. In 40 patients (97.5%) it was possible to identify spinal cord compression by lateral view, 22 (53.6%) by the oblique view, and 11 (26.8%) by the ventrodorsal view (P< 0.05). There were lateralized compressions in 22 (53.6%) patients, detected by all oblique views (100%) and by 11 (50%) of the ventrodorsal views. In 10 (24.4%) dogs, more than one compression site was observed, where the ventrodorsal view helped to decide the site in 50% of the cases and oblique in 70%. It can be concluded that all the tested myelographic views allow the identification of spinal cord compressions in dogs with cervical IVDD, the lateral view being the most relevant, followed by the oblique and ventrodorsal view, therefore establishing a sequence of myelographic views should be obtained for this region.(AU)

Association Between Systemic Inflammation, Carotid Arteriosclerosis, and Autonomic Dysfunction.

Systemic inflammation is associated with arteriosclerotic disease progression and worse stroke outcome in patients with carotid arteriosclerotic disease. We hypothesize that systemic inflammation is mediated by impaired carotid baroreceptor and chemoreceptor function induced by carotid arteriosclerosis rather than by the generalized inflammatory arteriosclerotic process.Heart rate variability (HRV), serum levels of inflammatory markers, demographic and life style factors, and concomitant diseases with potential impact on systemic inflammation were determined in 105 patients with asymptomatic carotid stenosis of varying degree. Multivariate linear regression analyses were performed to ascertain independent determinants of carotid stenosis severity, autonomic function, and inflammation.Systemic inflammation (C-reactive protein, beta = .255; P = .014), age (beta = .232; P < .008), and arterial hypertension (beta = .206; P = .032) were associated with carotid stenosis severity. Only carotid stenosis severity and not generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia, hypothyroidism), life style factors (smoking, obesity), or age was associated with a reduction in vagal tone (HRV HF band power beta = - .193; P < 0.049). Systemic inflammation was related to a reduction in vagal tone (HRV HF band power, beta = - .214; P = .031), and not to generalized arteriosclerotic disease, concomitant diseases (arterial hypertension, diabetes mellitus, dyslipidemia), life style factors (smoking, obesity), and age.In conclusion, systemic inflammation is associated with carotid rather than with generalized arteriosclerotic disease. The association between systemic inflammation and carotid arteriosclerosis is mediated by a reduction in vagal tone which indicates a major role of carotid arteriosclerosis-mediated autonomic dysfunction in the pathogenesis of systemic inflammation in arteriosclerotic disease.

Controlling the Self-Injection Threshold in Laser Wakefield Accelerators.

Controlling the parameters of a laser plasma accelerated electron beam is a topic of intense research with a particular focus placed on controlling the injection phase of electrons into the accelerating structure from the background plasma. An essential prerequisite for high-quality beams is dark-current free acceleration (i.e., no electrons accelerated beyond those deliberately injected). We show that small-scale density ripples in the background plasma are sufficient to cause the uncontrolled (self-)injection of electrons. Such ripples can be as short as ∼50 µm and can therefore not be resolved by standard interferometry. Background free injection with substantially improved beam characteristics (divergence and pointing) is demonstrated in a gas cell designed for a controlled gas flow. The results are supported by an analytical theory as well as 3D particle in cell simulations.

The NTCP-inhibitor Myrcludex B: Effects on Bile Acid Disposition and Tenofovir Pharmacokinetics.

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.

Modalidades fisioterapêuticas na reabilitação de cães com doença do disco intervertebral toracolombar submetidos à cirurgia descompressiva: 30 casos (2008-2016) / Physiotherapeutic modalities in the rehabilitation of dogs with thoracolumbar intervertebral disc disease that underwent to decompressive surgery: 30 cases (2008-2016)

Este estudo retrospectivo teve como objetivo demonstrar as modalidades fisioterapêuticas empregadas no tratamento de cães com doença do disco intervertebral (DDIV) toracolombar após descompressão cirúrgica da medula espinhal, bem como relatar os fatores que determinaram as alterações das modalidades. Foram incluídos 30 cães que apresentavam sinais neurológicos desde paraparesia ambulatória a paraplegia com dor profunda na primeira sessão de fisioterapia. As modalidades utilizadas nos protocolos de todos os pacientes foram a crioterapia, massagem, alongamento passivo, movimentação passiva articular, estímulo do reflexo flexor e estimulação elétrica neuromuscular. A inclusão ou exclusão de exercícios terapêuticos, como a tipoia corporal, a plataforma proprioceptiva circular, a natação, a hidroesteira, os obstáculos e a caminhada em colchão, foi de acordo com a evolução clínica e a adaptação de cada paciente. Oitenta por cento (80%) dos cães alteraram o grau de disfunção neurológica antes de iniciar a fisioterapia e 93% retornaram à habilidade de caminhar (paraparesia ambulatória) ao final da fisioterapia. O número de sessões e o tempo de recuperação foram maiores quanto pior foi o grau de lesão do paciente.(AU)

This retrospective study aimed to demonstrate the physiotherapeutic modalities used in the treatment of dogs with thoracolumbar intervertebral disc disease (IVDD) after surgical spinal cord decompression and to report elements that determined the modalities changes. Thirty dogs with deep pain perception were selected in the first physiotherapy session, presenting a range of clinical signs from ambulatory paraparesis to paraplegia. The modalities used in the protocols of all patients were cryotherapy, massage, passive stretching, passive range of motion, flexor reflex stimulation and neuromuscular electrical stimulation. The inclusion or exclusion of the therapeutic exercises how body sling (walking sling), circular proprioceptive platform, swimming, underwater treadmill, cavaletti rails and foam mattress walking were according to the clinical evolution and acceptance of each patient. Eighty percent (80%) of the dogs manifested improvement in their neurological dysfunction degree before starting physical therapy and 93% were able to walk again (ambulatory paraparesis) at the end of physiotherapy. The number of sessions and recovery times were higher in patients with higher neurological dysfunction degrees.(AU)

Optogenetically stimulating intact rat corticospinal tract post-stroke restores motor control through regionalized functional circuit formation.

Current neuromodulatory strategies to enhance motor recovery after stroke often target large brain areas non-specifically and without sufficient understanding of their interaction with internal repair mechanisms. Here we developed a novel therapeutic approach by specifically activating corticospinal circuitry using optogenetics after large strokes in rats. Similar to a neuronal growth-promoting immunotherapy, optogenetic stimulation together with intense, scheduled rehabilitation leads to the restoration of lost movement patterns rather than induced compensatory actions, as revealed by a computer vision-based automatic behavior analysis. Optogenetically activated corticospinal neurons promote axonal sprouting from the intact to the denervated cervical hemi-cord. Conversely, optogenetically silencing subsets of corticospinal neurons in recovered animals, results in mistargeting of the restored grasping function, thus identifying the reestablishment of specific and anatomically localized cortical microcircuits. These results provide a conceptual framework to improve established clinical techniques such as transcranial magnetic or transcranial direct current stimulation in stroke patients.

Patient Education in a 14-month Randomised Trial Fails to Improve Adherence in Ulcerative Colitis: Influence of Demographic and Clinical Parameters on Non-adherence.

BACKGROUND AND AIM: Recent observational studies document that non-adherence to mesalamine therapy during remission is frequent. We aimed to investigate patient impact of patient education using objective assessments of adherence. METHODS: A 14-month randomised, prospective clinical trial of adherence to mesalamine was conducted in 248 patients with ulcerative colitis [UC], Colitis Activity Index [CAI] ≤ 9, receiving standard care [n = 122] versus a standardised patient education programme [n = 126]. Primary endpoint was adherence at all visits (5-aminosalicylic acid [5-ASA] urine levels). Secondary endpoints included quality of life (inflammatory bowel disease questionnaise [IBDQ]), disease activity, partial adherence, and self-assessment of adherence. RESULTS: Patient allocation was well balanced. Baseline non-adherence was high in quiescent/mildly active UC [52.4%] without difference between the groups (52.4% of patients in the education group versus 52.5% in the standard care group [p = 0.99]). No difference between the intervention group and standard care was seen in IBDQ, partial adherence, self-assessment of adherence, or therapy satisfaction at all visits. We suggest a model in which individual risks for non-adherence are driven by patients with young age, short disease duration, and low education levels. CONCLUSIONS: Non-adherence is frequent in a population with quiescent/mildly active UC. Although more than 25% of the population was not in remission at the various time points, no relationship between disease activity and adherence was seen over the 14-month observation period. Physicians should maximise their efforts to motivate high-risk patients for adherence. Future trials should use objective exposure assessments to examine the impact of continuous education and consultations on the background of individual risks to develop non-adherence.

Prenatal steroid administration leads to adult pericardial and hepatic steatosis in male baboons.

Developmental programming studies indicate that glucocorticoids modify fetal development. We hypothesized that administration of the synthetic glucocorticoid (sGC) betamethasone to pregnant baboons at doses and stages of fetal life equivalent to human obstetric practice to decrease premature offspring morbidity and mortality, programs lipid metabolism. In 10-year-old male baboons (human equivalent 40) exposed in fetal life to betamethasone or saline, we quantified pericardial fat and hepatic lipid content with magnetic resonance imaging and spectroscopy. sGC offspring delivered at term as do most sGC-exposed human neonates. Pericardial fat thickness (7.7±3.6 mm vs 3.1±1.1 mm, M±s.d.; P=0.022; n=5) and hepatic fatty acids (13.3±11.0% vs 2.5±2.2%; P=0.046; n=5) increased following sGC without birth weight or current body morphometric differences. Our results indicate that antenatal sGC therapy caused abnormal fat deposition and adult body composition in mid-life primate offspring. The concern raised is that this degree of pericardial and hepatic lipid accumulation can lead to harmful local lipotoxicity. In summary, developmental programing by sGC produces a mid-life metabolically obese but normal weight phenotype. Prior studies show sexually dimorphic responses to some programming challenges thus female studies are necessary.

Electromagnetic-radiation absorption by water.

Why does a microwave oven work? How does biological tissue absorb electromagnetic radiation? Astonishingly, we do not have a definite answer to these simple questions because the microscopic processes governing the absorption of electromagnetic waves by water are largely unclarified. This absorption can be quantified by dielectric loss spectra, which reveal a huge peak at a frequency of the exciting electric field of about 20 GHz and a gradual tailing off toward higher frequencies. The microscopic interpretation of such spectra is highly controversial and various superpositions of relaxation and resonance processes ascribed to single-molecule or molecule-cluster motions have been proposed for their analysis. By combining dielectric, microwave, THz, and far-infrared spectroscopy, here we provide nearly continuous temperature-dependent broadband spectra of water. Moreover, we find that corresponding spectra for aqueous solutions reveal the same features as pure water. However, in contrast to the latter, crystallization in these solutions can be avoided by supercooling. As different spectral contributions tend to disentangle at low temperatures, this enables us to deconvolute them when approaching the glass transition under cooling. We find that the overall spectral development, including the 20 GHz feature (employed for microwave heating), closely resembles the behavior known for common supercooled liquids. Thus water's absorption of electromagnetic waves at room temperature is not unusual but very similar to that of glass-forming liquids at elevated temperatures, deep in the low-viscosity liquid regime, and should be interpreted along similar lines.

Polymorphic variation in TPMT is the principal determinant of TPMT phenotype: A meta-analysis of three genome-wide association studies.

Thiopurine-related hematotoxicity in pediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 pediatric ALL cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including the TPMT gene region, were significantly associated with TPMT activity (P < 5.0 × 10-8 ) in each of the three GWAS and a joint meta-analysis of 1,212 cases (top hit P = 1.2 × 10-72 ). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize mercaptopurine dosage.

Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium.

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.

Development of somatosensory-evoked potentials in foetal sheep: effects of betamethasone.

AIM: Antenatal glucocorticoids are used to accelerate foetal lung maturation in babies threatened with premature labour. We examined the influence of glucocorticoids on functional and structural maturation of the central somatosensory pathway in foetal sheep. Somatosensory-evoked potentials (SEP) reflect processing of somatosensory stimuli. SEP latencies are determined by afferent stimuli transmission while SEP amplitudes reveal cerebral processing. METHODS: After chronic instrumentation of foetal sheep, mothers received saline (n = 9) or three courses of betamethasone (human equivalent dose of 2 × 110 µg kg-1 betamethasone i.m. 24 h apart, n = 12) at 0.7, 0.75 and 0.8 of gestational age. Trigeminal SEP were evoked prior to, 4 and 24 h after each injection and at 0.8 of gestational age before brains were histologically processed. RESULTS: Somatosensory-evoked potentials were already detectable at 0.7 of gestation age. The early and late responses N20 and N200 were the only reproducible peaks over the entire study period. With advancing gestational age, SEP latencies decreased but amplitudes remained unchanged. Acutely, betamethasone did not affect SEP latencies and amplitudes 4 and 24 h following administration. Chronically, betamethasone delayed developmental decrease in the N200 but not N20 latency by 2 weeks without affecting amplitudes. In parallel, betamethasone decreased subcortical white matter myelination but did not affect network formation and synaptic density in the somatosensory cortex. CONCLUSION: Somatosensory stimuli are already processed by the foetal cerebral cortex at the beginning of the third trimester. Subsequent developmental decrease in SEP latencies suggests ongoing maturation of afferent sensory transmission. Antenatal glucocorticoids affect structural and functional development of the somatosensory system with specific effects at subcortical level.

Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2.

Heritability of caffeine pharmacokinetics and cytochrome P450 1A2 (CYP1A2) activity is controversial. Here, we analyzed the pharmacokinetics of caffeine, an in vivo probe drug for CYP1A2 and arylamine N-acetyltransferase 2 (NAT2) activity, in monozygotic (MZ) and dizygotic (DZ) twins. In the entire group, common and unique environmental effects explained most variation in caffeine area under the curve (AUC). Apparently, smoking and hormonal contraceptives masked the genetic effects on CYP1A2 activity. However, when excluding smokers and users of hormonal contraceptives, 89% of caffeine AUC variation was due to genetic effects and, even in the entire group, 8% of caffeine AUC variation could be explained by a CYP1A1/1A2 promotor polymorphism (rs2470893). In contrast, nearly all of the variations (99%) of NAT2 activity were explained by genetic effects. This study illustrates two very different situations in pharmacogenetics from an almost exclusively genetic determination of NAT2 activity with no environmental modulation to only moderate genetic effects on CYP1A2 activity with strong environmental modulation.

Epigenetics in Drug Response.

Hereditary genetic variation has been identified to contribute significantly to drug response. More recently, there is increasing evidence that individual phenotypic differences may also result from epigenetic alterations such as histone-acetylation or DNA-methylation. Moreover, interactions with noncoding RNAs contribute to protein expression and may modulate drug action. Currently, intriguing developments of novel therapeutic approaches through epigenetic drugs are emerging. The overall complexity of epigenetics in drug action, however, is so far only little understood.