Longitudinal Doppler Assessments in Late Preterm Fetal Growth Restriction.

PURPOSE: To assess the longitudinal variation of the ratio of umbilical and cerebral artery pulsatility index (UCR) in late preterm fetal growth restriction (FGR). MATERIALS AND METHODS: A prospective European multicenter observational study included women with a singleton pregnancy, 32+ 0-36+ 6, at risk of FGR (estimated fetal weight [EFW] or abdominal circumference [AC] < 10th percentile, abnormal arterial Doppler or fall in AC from 20-week scan of > 40 percentile points). The primary outcome was a composite of abnormal condition at birth or major neonatal morbidity. UCR was categorized as normal (< 0.9) or abnormal (≥ 0.9). UCR was assessed by gestational age at measurement interval to delivery, and by individual linear regression coefficient in women with two or more measurements. RESULTS: 856 women had 2770 measurements; 696 (81 %) had more than one measurement (median 3 (IQR 2-4). At inclusion, 63 (7 %) a UCR ≥ 0.9. These delivered earlier and had a lower birth weight and higher incidence of adverse outcome (30 % vs. 9 %, relative risk 3.2; 95 %CI 2.1-5.0) than women with a normal UCR at inclusion. Repeated measurements after an abnormal UCR at inclusion were abnormal again in 67 % (95 %CI 55-80), but after a normal UCR the chance of finding an abnormal UCR was 6 % (95 %CI 5-7 %). The risk of composite adverse outcome was similar using the first or subsequent UCR values. CONCLUSION: An abnormal UCR is likely to be abnormal again at a later measurement, while after a normal UCR the chance of an abnormal UCR is 5-7 % when repeated weekly. Repeated measurements do not predict outcome better than the first measurement, most likely due to the most compromised fetuses being delivered after an abnormal UCR.

Fetal cerebral Doppler changes and outcome in late preterm fetal growth restriction: prospective cohort study.

OBJECTIVES: To explore the association between fetal umbilical and middle cerebral artery (MCA) Doppler abnormalities and outcome in late preterm pregnancies at risk of fetal growth restriction. METHODS: This was a prospective cohort study of singleton pregnancies at risk of fetal growth restriction at 32 + 0 to 36 + 6 weeks of gestation, enrolled in 33 European centers between 2017 and 2018, in which umbilical and fetal MCA Doppler velocimetry was performed. Pregnancies were considered at risk of fetal growth restriction if they had estimated fetal weight and/or abdominal circumference (AC) < 10th percentile, abnormal arterial Doppler and/or a fall in AC growth velocity of more than 40 percentile points from the 20-week scan. Composite adverse outcome comprised both immediate adverse birth outcome and major neonatal morbidity. Using a range of cut-off values, the association of MCA pulsatility index and umbilicocerebral ratio (UCR) with composite adverse outcome was explored. RESULTS: The study population comprised 856 women. There were two (0.2%) intrauterine deaths. Median gestational age at delivery was 38 (interquartile range (IQR), 37-39) weeks and birth weight was 2478 (IQR, 2140-2790) g. Compared with infants with normal outcome, those with composite adverse outcome (n = 93; 11%) were delivered at an earlier gestational age (36 vs 38 weeks) and had a lower birth weight (1900 vs 2540 g). The first Doppler observation of MCA pulsatility index < 5th percentile and UCR Z-score above gestational-age-specific thresholds (1.5 at 32-33 weeks and 1.0 at 34-36 weeks) had the highest relative risks (RR) for composite adverse outcome (RR 2.2 (95% CI, 1.5-3.2) and RR 2.0 (95% CI, 1.4-3.0), respectively). After adjustment for confounders, the association between UCR Z-score and composite adverse outcome remained significant, although gestational age at delivery and birth-weight Z-score had a stronger association. CONCLUSION: In this prospective multicenter study, signs of cerebral blood flow redistribution were found to be associated with adverse outcome in late preterm singleton pregnancies at risk of fetal growth restriction. Whether cerebral redistribution is a marker describing the severity of fetal growth restriction or an independent risk factor for adverse outcome remains unclear, and whether it is useful for clinical management can be answered only in a randomized trial. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer.

Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

Fishes in a changing world: learning from the past to promote sustainability of fish populations.

Populations of fishes provide valuable services for billions of people, but face diverse and interacting threats that jeopardize their sustainability. Human population growth and intensifying resource use for food, water, energy and goods are compromising fish populations through a variety of mechanisms, including overfishing, habitat degradation and declines in water quality. The important challenges raised by these issues have been recognized and have led to considerable advances over past decades in managing and mitigating threats to fishes worldwide. In this review, we identify the major threats faced by fish populations alongside recent advances that are helping to address these issues. There are very significant efforts worldwide directed towards ensuring a sustainable future for the world's fishes and fisheries and those who rely on them. Although considerable challenges remain, by drawing attention to successful mitigation of threats to fish and fisheries we hope to provide the encouragement and direction that will allow these challenges to be overcome in the future.

National registry-based case-control study: comorbidity and stroke in young adults.

OBJECTIVES: Stroke is overrepresented in cohorts of young adults with chronic diseases. The prevalence and impact of comorbidity among young stroke patients have not been compared with individuals without stroke. Our aim was to investigate the association between comorbidity and stroke in young adults. MATERIALS AND METHODS: A nationwide cohort of patients (aged 15-44 years), registered in the Swedish Stroke Register, (Riksstroke) 2001-2009, was identified. Age- and sex-matched controls were randomly selected from the Population Register of Sweden. Discharge diagnoses were retrieved from the National Patient Register and grouped by chapter in the International Classification of Diseases 10th revision. Associations between ICD-10 chapters and stroke were stratified (age, sex, and stroke type) and analyzed by multivariable logistic regression. RESULTS: In 2599 stroke patients analyzed, the prevalence of vascular risk factors (hypertension 25.3%, dyslipidemia 13.0%, diabetes 9.7%, heart failure 3.2%, and atrial fibrillation 2.8%), all ICD-10 chapters (except pregnancy) and prestroke hospitalizations were more frequent among cases than controls. Independent associations were found between stroke and eight ICD-10 chapters: neoplasms (odds ratios (OR) 1.53, 95% CI 1.15-2.05), blood (OR 1.61, 1.11-2.34), endocrine (OR 2.28, 1.77-2.93), psychiatric (OR 1.50, 1.24-1.81), nervous (OR 1.91, 1.46-2.50), eye (OR 1.67, 1.05-2.64), circulatory (OR 3.05, 2.45-3.80), and symptoms (OR 1.31, 1.13-1.52). The risk of stroke increased by 26% per ICD-10 chapter diagnosed. CONCLUSIONS: In addition to vascular risk factors, comorbidity (represented by ICD-10 chapters) was associated with increased risk of stroke in young individuals. The risk of stroke was further increased with the number of diagnosed ICD-10 chapters.

Effects of feeding regimes and early maturation on migratory behaviour of landlocked hatchery-reared Atlantic salmon Salmo salar smolts.

The migratory behaviour of hatchery-reared landlocked Atlantic salmon Salmo salar raised under three different feeding regimes was monitored through the lower part of the River Klarälven, Sweden. The smolts were implanted with acoustic transmitters and released into the River Klarälven, 25 km upstream of the outlet in Lake Vänern. Early mature males, which had matured the previous autumn, were also tagged and released. To monitor migration of the fish, acoustic receivers were deployed along the migratory route. The proportion of S. salar that reached Lake Vänern was significantly greater for fish fed fat-reduced feed than for fish given rations with higher fat content, regardless of ration size. Fish from the early mature male group remained in the river to a greater extent than fish from the three feeding regimes. Smolt status (degree of silvering), as visually assessed, did not differ among the feeding regime groups, and moreover, fully-silvered fish, regardless of feeding regime, migrated faster and had a greater migration success than fish with less developed smolt characteristics. Also, successful migrants had a lower condition factor than unsuccessful ones. These results indicate that the migration success of hatchery-reared S. smolts released to the wild can be enhanced by relatively simple changes in feeding regimes and by matching stocking time with smolt development.

Effects of feed quality and quantity on growth, early maturation and smolt development in hatchery-reared landlocked Atlantic salmon Salmo salar.

The effects of feed quality and quantity on growth, early male parr maturation and development of smolt characteristics were studied in hatchery-reared landlocked Atlantic salmon Salmo salar. The fish were subjected to two levels of feed rations and two levels of lipid content from first feeding until release in May of their second year. Salmo salar fed high rations, regardless of lipid content, grew the most and those fed low lipid feed with low rations grew the least. In addition, fish fed low lipid feed had lower body lipid levels than fish fed high lipid feed. Salmo salar from all treatments showed some reduction in condition factor (K) and lipid levels during their second spring. Smolt status was evaluated using both physiological and morphological variables. These results, based on gill Na(+) , K(+) -ATPase (NKA) enzyme activity, saltwater tolerance challenges and visual assessments, were consistent with each other, showing that S. salar from all treatments, except the treatment in which the fish were fed low rations with low lipid content, exhibited characteristics associated with smolting at 2 years of age. Sexually mature male parr from the high ration, high lipid content treatment were also subjected to saltwater challenge tests, and were found to be unable to regulate plasma sodium levels. The proportion of sexually mature male parr was reduced when the fish were fed low feed rations, but was not affected by the lipid content of the feed. Salmo salar fed low rations with low lipid content exhibited the highest degree of severe fin erosion.

Temperature-dependent prey capture efficiency and foraging modes of brown trout Salmo trutta.

Prey capture success and foraging mode were studied in brown trout Salmo trutta at temperatures ranging from 5.7 to 14.0° C. At low temperatures, there was a positive correlation between prey capture success and the proportion of time that the fish spent holding feeding stations. This correlation was not found at temperatures >10° C.

Why don't they know enough about anatomy? A narrative review.

BACKGROUND: Publications in a variety of journals have described the problem of medical students' decreasing anatomical knowledge. Interestingly, the number of people making this assertion is growing, despite a lack of empirical evidence that today's medical graduates actually know less about anatomy than medical students in the past. Nevertheless, many people are claiming that students' anatomical knowledge is impaired due to negative effects from several factors, including teaching by non-medically qualified teachers, diminished use of cadaver dissection as a teaching tool and neglect of vertical integration of anatomy teaching. AIM: To find empirical evidence for the factors claimed to have an influence on anatomical knowledge of students. METHOD: A literature search. RESULTS: There is a lack of sufficient quantity and quality of information within the existing literature to support any of the claims, but the gathered literature did reveal some fascinating insights which are discussed. CONCLUSION: Anatomy education should be made as effective as possible, as nobody will deny that medical students cannot do without anatomical knowledge. Because of promising findings in the areas of teaching in context, vertical integration and assessment strategies, it is recommended that future research into anatomy education should focus on these factors.

Serological status of cattle to bovine viral diarrhoea virus and bovine herpesvirus 1 at entry to and exit from Australian feedlot backgrounding facilities.

A total of 6195 cattle were enrolled in this observational study. Serum antibody concentrations to bovine herpesvirus 1 (BHV1) and bovine viral diarrhoea virus (BVDV) were measured at entry to and exit from backgrounding facilities to assess their statuses on arrival and the extent of seroconversion to these viruses during backgrounding. The backgrounding facilities were contiguous with five feedlots in: Queensland (two sites), New South Wales, South Australia and Western Australia. Cattle were held in the backgrounding facilities for a minimum of 29 days and a median of 34 days. On backgrounding facility entry, 32.7% of the study population was seronegative to BVDV, but 85.7% was seronegative to BHV1. After commingling in the backgrounding facilities, of the cattle that were seronegative on backgrounding facility entry, 33.9% and 30.3% showed a serological increase to BVDV and BHV1, respectively. At backgrounding facility exit, when cattle were placed in their feedlots, 19.6% and 59.1% were seronegative to BVDV and BHV1, respectively, and 0.26% were persistently infected with BVDV. There was a strong association between seroincrease to BVDV and seroincrease to BHV1 (P = 0.005) at animal level in cohorts known to contain an animal persistently infected with BVDV.

Health and production effects of killed vaccines against Mannheimia haemolytica, bovine viral diarrhoea virus and bovine herpesvirus 1, in locally backgrounded feedlot cattle.

OBJECTIVES: This study evaluates the effects of respiratory vaccines on health and growth rates in cattle placed in local backgrounding facilities then feedlots. METHODS: A total of 7011 cattle entering backgrounding facilities contiguous with six feedlots in Australia were allocated to eight respiratory vaccine categories, including an untreated control category. The vaccines, against Mannheimia haemolytica, bovine viral diarrhoea virus and bovine herpesvirus 1, were administered in various combinations at backgrounding facility entry and subsequent feedlot entry. Cattle were held in the backgrounding facilities for a minimum of 28 days. RESULTS: During their feedlot phase, 3.7% of study animals were detected with bovine respiratory disease (BRD). BRD sub hazard was lowest in cattle vaccinated with Bovilis MH + infectious bovine rhinotracheitis® (sub hazards ratio: 0.47; 95% confidence interval: 0.27-0.83; P = 0.010), and point estimates for other vaccine combinations did not differ (P > 0.10) from controls. Six of the respiratory vaccine combinations decreased growth rate during backgrounding relative to untreated controls (P ≤ 0.003). Overall, the feedlot growth rate was not significantly affected by the vaccine category (overall Wald P = 0.191). CONCLUSIONS: Use of these respiratory vaccines in cattle held for at least 28 days in backgrounding facilities contiguous with their feedlots before feedlot entry reduces growth rate during the backgrounding period and does not result in large beneficial effects on either BRD risk or average daily live weight gain during the feedlot phase.

The effect of acute administration of rifampicin and imatinib on the enterohepatic transport of rosuvastatin in vivo.

Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80 mg rosuvastatin in pigs (control group, n = 2 + 6). The transport inhibitors, rifampicin (20 mg/kg, n = 6) and imatinib (14 mg/kg, n = 6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5 h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.1-32, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.1-3.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.

The use of CT and CT arthrography in diagnosing equine stifle injury in a Rheinlander gelding.

A 5-year-old Rheinlander gelding was evaluated for left hindlimb stifle lameness. The lameness was localised to the stifle, but source of the lameness was not specifically diagnosed from the physical, radiographic and ultrasonographic examinations. Computed tomography (CT) and CT arthrography were therefore used for further investigation since these imaging techniques image bony structures, cartilage and soft tissues. This examination showed multiple lesions in the stifle: an osteochondrosis dissecans like lesion of the medial femoral condyle, bony fragments, cartilage trauma and caudal cruciate ligament injury. The prognosis for continuing use as a sports horse was regarded as unfavourable. Therefore, the horse was subjected to euthanasia. All CT findings were confirmed by gross pathology. The CT and CT arthrography examination in this case provided a diagnosis not achieved with other conventional imaging techniques.

Introduction and elimination of Bovine Viral Diarrhoea Virus in a commercial beef herd: a case study.

Routine Bovine Viral Diarrhoea Virus (BVDV) monitoring of a commercial beef herd in southern New South Wales over a 10-year period provided an opportunity to assess the impact of the introduction of BVDV on that herd. BVDV antibody testing provided strong evidence that the herd was initially free of BVDV (2009-2011). Testing from 2012 suggested BVDV had been introduced into the herd and this was confirmed in 2015 with the identification of persistently infected (PI) animals. Having become established in the herd, the owners then set out to eliminate BVDV from the herd. Antigen testing aimed at identifying PI animals revealed BVDV was already absent from the herd. Subsequent antibody testing confirmed that the herd was now free from BVDV. Despite the incursion of BVDV in this herd, there was little measurable impact on reproductive performance (pregnancy rates), although suspected increased calf losses from birth to calf marking were reported. This is the first time such self-clearance has been documented as part of a longitudinal study under Australian conditions.

Quantitative studies of the metabolism of chylomicron triglycerides and cholesterol by liver and extrahepatic tissues of sheep and dogs.

Unanesthetized sheep and dogs, previously fitted with indwelling catheters in the aorta, lower vena cava, mesenteric, portal, left hepatic and jugular veins, were given constant intravenous infusions of lymph in which the chylomicron lipids were variously labeled with (3)H or (14)C. Para-aminohippuric acid was infused into the mesenteric venous catheter for measurement of portal and hepatic venous blood flow. In some animals, alternately labeled free fatty acids bound to albumin were mixed with the lymph to be infused. In both species, chylomicron triglyceride fatty acids were taken up in the region drained by the lower vena cava and portal vein and free fatty acids derived from hydrolysis of these triglycerides were extensively recycled in the blood. Direct uptake of triglyceride fatty acids also occurred in liver and accounted for about 10% of the total triglyceride fatty acids removed from the blood in sheep and 22% in dogs. In sheep, 10% and, in dogs, about 40% of these triglyceride-fatty acids were released into the blood as free fatty acids. The free fatty acids recycled from various regions accounted for a substantial fraction of the chylomicron fat eventually deposited in each tissue. Uptake of chylomicron cholesterol from the blood of sheep occurred primarily in liver and to a small extent in certain tissues drained by the portal vein. The results obtained, together with other available data, demonstrate that chylomicron triglycerides are removed primarily in extrahepatic tissues of both species, while the liver removes cholesterol contained in chylomicron "skeletons" from which most of the triglycerides have been removed. The quantitative differences between transport of chylomicron lipid in sheep and dogs may be related to known differences in the structure of their hepatic sinusoids.

Glucose-dose dependent characteristics of insulin secretion in obese and lean sheep.

We previously reported that obesity in sheep and cattle was associated with basal hyperinsulinemia, insulin resistance, and an exaggerated insulin response to a single dose (350 mg/kg) of glucose. In this study, the glucose-dose dependency of insulin secretion in obese and lean sheep was determined by 1) using jugular venous concentrations of insulin (Exp 1) and 2) arteriovenous differences in insulin concentrations across the pancreas together with plasma flow rates in the portal vein (Exp 2). Sheep were injected with glucose doses of 0 (water), 10, 30, 100, and 350 mg glucose/kg body weight in Exp 1 (six sheep per group) and with a low (20 mg/kg) and high (200 mg/kg) dose of glucose in exp 2 (four sheep per group). In Exp 1, mean (+/- SE) pretreatment plasma concentrations of insulin (22.0 +/- 1.7 vs. 9.4 +/- 0.4 microU/ml) and glucose (56.1 +/- 0.5 vs. 52.4 +/- 0.8 mg/dl) were greater (P less than 0.01) in obese than lean sheep fasted for 12 h. The glucose-induced rises in insulin concentrations above pretreatment levels were always greater (P less than 0.05) in obese than lean sheep regardless of glucose dose. Eadie-Scatchard plot analysis of the hyperbolic relationship between the acute insulin and acute glucose response areas (0 to +10 min) indicated that the maximum (Vmax) early phase insulin response was greater (P less than 0.025) in obese than lean sheep (568 +/- 148 vs. 156 +/- 33 microU ml-1 X min). In Exp 2, pretreatment concentrations of insulin (25.1 +/- 3.4 vs. 5.6 +/- 1.2 microU/ml) and glucose (58.3 +/- 1.8 vs. 45.5 +/- 1.1 mg/dl) in arterial plasma were greater (P less than 0.01) in obese than in lean sheep fasted 18 to 22 h. Similarly, pretreatment pancreatic secretion rates of insulin were greater (P less than 0.01) in obese (17.8 +/- 5.8 mU/min) than in lean (4.9 +/- 1.3 mU/min) sheep. Glucose-induced acute (0 to +10 min) increments in pancreatic secretory rates of insulin also were greater (P less than 0.05) in obese than in lean sheep after the low (215 +/- 73 vs. 11 +/- 15 mU) and high (881 +/- 281 vs. 232 +/- 66 mU) doses of glucose. It was concluded that insulin secretion in response to a range of stimulatory concentrations of glucose was greater in obese than in lean sheep because the obese sheep had greater maximum (i.e. Vmax) acute phases of glucose-induced insulin secretion.

Regulation of neurotrophin signaling in aging sensory and motoneurons: dissipation of target support?

A hallmark of senescence is sensorimotor impairment, involving locomotion and postural control as well as fine-tuned movements. Sensory and motoneurons are not lost to any significant degree with advancing age, but do show characteristic changes in gene-expression pattern, morphology, and connectivity. This review covers recent experimental findings corroborating that alterations in trophic signaling may induce several of the phenotypic changes seen in primary sensory and motoneurons during aging. Furthermore, the data suggests that target failure, and/or breakdown of neuron-target interaction, is a critical event in the aging process of sensory and motoneurons.

Loss of primary sensory neurons in the very old rat: neuron number estimates using the disector method and confocal optical sectioning.

Loss of neurons has been considered to be a prime cause of nervous disturbances that occur with advancing age. However, the notion of a constitutive aging-related loss of neurons has been challenged recently in several studies that used up-to-date methods for counting neurons. In this study, we have applied stereological techniques with the objective of obtaining quantitative data on total neuron numbers and the distribution of neuron cross-sectional areas in the fifth cervical (C5) and fourth lumbar (L4) dorsal root ganglion (DRG) of 3- and 30-month-old Sprague-Dawley rats. Tissue data were recorded on a confocal laser-scanning microscope with the use of the optical-disector technique and random, systematic sampling. Aged rats of both sexes disclosed only a small decrease (approximately 12%) in the number of cervical and lumbar DRG neurons. Furthermore, there was no significant correlation between the degree of neuron loss and the extent of behavioral deficits among the aged individuals. The DRG neurons of aged rats had a smaller mean cross-sectional area (approximately 15%; P < 0.001) at both DRG levels. Further analysis of the male cohorts was carried out by using isolectin B4 and neurofilament subunit (phosphorylated 200 kDa; RT97) immunoreactivity (IR) as selective markers for unmyelinated and myelinated axons, respectively, and disclosed no significant change in the relative frequencies of immunoreactive neuron profiles in the old rats. However, RT97-IR DRG neurons of the aged rats had significantly smaller cross-sectional areas (approximately 9% in C5; approximately 16% in L4; P < 0.001) than the young adult rats, indicating a selective cell body atrophy among myelinated primary afferents during aging. The results indicate that loss of primary sensory neurons cannot exclusively explain the functional deficits in sensory perception among senescent individuals. It seems likely that other factors at the subcellular level and/or target interaction(s) contribute substantially to the sensory impairments observed with advancing age.

Effects of aging and axotomy on the expression of neurotrophin receptors in primary sensory neurons.

Aging is accompanied by declined sensory perception, paralleled by widespread dystrophic and degenerative changes in both central and peripheral sensory pathways. Several lines of evidence indicate that neurotrophic interactions are of importance for a maintained plasticity in the adult and aging nervous system, and that changes in the expression of neurotrophins and/or their receptors may underpin senile neurodegeneration. We have here examined the expression of neurotrophin receptor (p75NTR, trkA, trkB, and trkC) mRNA and protein in intact and axotomized primary sensory neurons of young adult (3 months) and aged (30 months) rats. To examine possible differences among primary sensory neuron populations, we have studied trigeminal ganglia (TG) as well as cervical and lumbar dorsal root ganglia (DRG). In intact aged rats, a decrease in trk (A/B/C) mRNA labeling densities and protein-like immunoreactivities was observed. The decrease was most pronounced in lumbar DRG. In contrast, a small, not statistically significant, increase of p75NTR expression was observed in aged DRG neuron profiles. After axotomy, a down-regulation of mRNA and protein levels was observed for all neurotrophin receptors (p75NTR, trkA, trkB and trkC) in both young adult and aged rats. Consistent with the higher expression levels of neurotrophin receptors in unlesioned young adult primary sensory neurons, the relative effect of axotomy was more pronounced in the young adult than aged rats. Although a decrease in mean cell profile cross-sectional areas was found during aging and after axotomy, the characteristic distribution of neurotrophin receptor expression in different populations of NRG neurons was conserved. The present findings suggest an attenuation of neurotrophic signaling in primary sensory neurons with advancing age and that the expression of p75NTR and trks is regulated differently during aging. A similar dissociation of p75NTR and trk regulation has previously been reported in other neuronal systems during aging, suggesting that there may be a common underlying mechanism. Decreased access to ligands, disturbed axon function and systemic changes in androgen/estrogen levels are discussed as inducing and/or contributing factors.

Neuropeptides and neurotrophin receptor mRNAs in primary sensory neurons of aged rats.

Neuropeptides and neurotrophin receptors are regulated in primary sensory neurons in response to axonal injury, and axonal lesions are characteristic stigmata of aging primary sensory neurons. We have therefore examined the expression of neuropeptides and neurotrophin receptor mRNAs in 30-month-old (median survival age) Sprague-Dawley rats to see if similar adaptive mechanisms operate in senescence. The content of neuropeptides was examined with immunohistochemistry (IHC) and in situ hybridization (ISH), and the cellular mRNA expression of neurotrophin receptors was studied with ISH. All of the aged rats had symptoms of hind limb incapacity (posterior paralysis), but fore limbs did not seem affected. The size-distribution of neuronal profiles in cervical and lumbar dorsal root ganglia (DRGs) was similar in aged and young adult (2-3 months old) rats. In aged rats, the DRG neurons showed an increase in both immunolabelling and mRNA content of neuropeptide tyrosine (NPY), as well as an increased cellular expression of galanin mRNA. In the same animals, there were decreased cellular levels of calcitonin gene-related peptide (CGRP; IHC and ISH) and substance P (SP; IHC and ISH), while the difference in neuronal somatostatin (IHC and ISH) was small. The distribution of neuropeptide immunoreactivities in the dorsal horn of the corresponding spinal cord segments revealed a decreased labelling for CGRP-, SP-, and somatostatin-like immunoreactivities (LI) in the aged rats at both cervical and lumbar levels. NPY- and galanin-LI had a similar distribution in aged and young adult rats. NPY-immunoreactive fibers were also encountered in the dorsal column of aged but not young adult rats. ISH revealed that most of the primary sensory neurons express mRNA for the p75 low-affinity neurotrophin receptor (p75-LANR) and that there was no discernible difference between young adult and aged rats. The labelling intensity for mRNA encoding high-affinity tyrosine kinase receptors (TrkA, TrkB, and TrkC) was decreased in aged rat DRG neurons, while the percentage of neuronal profiles expressing mRNA for TrkA/B/C was similar in young adult and aged rats. The changed pattern of neuropeptide expression in primary sensory neurons of aged rats resembled that seen in young adult rats subjected to axonal injury of peripheral sensory nerves and may, thus, indicate aging-related lesions of sensory fibers. Since NPY is primarily present in large and galanin in small DRG neurons, the stronger effect on NPY as compared to galanin expression may indicate that aging preferentially affects neurons associated with mechanoreception (A alpha and A beta fibers) as compared to nociceptive units (A delta and C fibers). Furthermore, the observed changes in neuropeptide expression were most pronounced in lumbar DRGs, that harbors the sensory neurons supplying the affected hindlimbs of the rats.