Sural communicating nerve for application as a vascularized nerve graft: A microneurovascular anatomic study in cadavers.

INTRODUCTION: Sural nerve harvest causes paraesthesia to the lateral heel of the foot, which can debilitate those with already compromised proprioception. To circumvent this, we investigated an alternative donor nerve, branch of the lateral sural nerve complex called the sural communicating nerve (SCoNe), for its harvest and use as a vascularized nerve graft, in cadaver. METHODS: The SCoNe was visualized by dissection in 15 legs from 8 human cadavers and the relationship of the SCoNe to the overall sural nerve complex was documented. The surface markings, dimensions, and the micro-neurovascular anatomy in the super-microsurgery range (up to 0.30 mm) of the SCoNe was recorded and analyzed. RESULTS: SCoNe graft surface marking was confined within a triangle drawn between the fibular head laterally, the popliteal vertical midline medially and the tip of the lateral malleolus inferiorly. The proximal end of the SCoNe was situated at a mean intersection distance of 5 cm from both the fibular head and popliteal midline respectively. The mean length of the SCoNe was 226 ± 43 mm with a mean proximal diameter of 0.82 mm and mean distal diameter of 0.93 mm. In 53% of the cadavers, an arterial input was present in the proximal third of the SCoNe and veins were predominantly (87%) present in the distal third. In 46% and 20% of the 15 legs respectively, there was a nutrient artery and vein perfusing the SCoNe in its central segment. The external mean diameter of this artery was 0.60 ± 0.30 mm, while the vein was slightly larger with a mean diameter of 0.90 ± 0.50 mm. DISCUSSION: SCoNe graft may preserve lateral heel sensation, compared to sural nerve harvest, pending clinical studies. It may have wide applications as a vascularized nerve graft, including being ideal as a vascularized cross-facial nerve graft because its nerve diameter is similar to the distal facial nerve branches. The accompanying artery is a good anastomotic match to the superior labial artery.

Intraoperative stimulation mapping of thalamocortical tracts in asleep and awake settings: novel electrophysiological, anatomical, and tractographic paradigms.

OBJECTIVE: Despite the disabling deficits of motor apraxia and sensory ataxia resulting from intraoperative injury of the superior thalamocortical tracts (TCTs), region-specific electrophysiological localization is currently lacking. Herein, the authors describe a novel TCT mapping paradigm. METHODS: Three patients, 1 asleep and 2 awake, underwent glioma resection affecting primarily the somatosensory cortex and underlying TCT. Stimulation was performed at the median, ulnar, and posterior tibial nerves. Parameters comprised single anodal pulses (duration 200-500 µsec, 2.1-4.7 Hz) with a current ranging from 10 to 25 mA. Recordings were captured with a bipolar stimulation probe, avoiding the classic collision technique. Positive localization sites were used to tractographically reconstruct the TCT in the third case. RESULTS: Employing one electrophysiological paradigm, the TCT was localized subcortically in all 3 cases by using a bipolar probe, peak range of 19.6-29.2 msec, trough of 23.3-34.8 msec, stimulation range of 10-25 mA. In the last case, tractographic reconstruction of the TCT validated a highly accurate TCT localization within a specific region of the posterior limb of the internal capsule. CONCLUSIONS: The authors describe the first electrophysiological technique for intraoperative localization and protection of the TCT in both asleep and awake craniotomies with tractographic validation, while avoiding the collision paradigm. None of the above paradigms have been previously reported. More data are required to further validate this technique.

Understanding beliefs, preferences and actions amongst potential body donors.

Body donation is a prosocial act providing a unique learning experience to students, ultimately impacting on patient care and science. With an increasing number of training professionals, there is an increasing need for body donors, yet little is understood about donors' beliefs and preferences. A four-center study aimed to understand donors' perceptions, 843 responses highlighted a significant relationship between completing a body donor consent form and being both an organ donor and having ever donated blood (p < 0.01). In exploring donor intentions, 69% had been considering donation for fewer than five years, 40% knew another body donor, and 27% had a family member or friend currently registered. Of those who had requested donor information packs, 97% had completed body donation consent forms. Of these, 92% had not selected any time restriction for their donation and 96% had consented to images being taken. Almost all (98%) were aware that their donation might not be accepted. Donors' motives highlighted a wish to: improve education, improve health care, advance science, and contribute to the greater good. A bimodal response was observed with body donation being used to save relatives money and inconvenience. Donors felt comfortable with their bodies being used by medical, dental, and allied health professionals; however, donors were less comfortable with their bodies being used by other groups. Only 57% were comfortable with artists, beauticians and yoga teachers using their remains. Understanding donors' motivations and decision-making process is vital to ensure resources for future and to meet any changing requirements of both donors and those studying them.

Anatomy education for medical students in the United Kingdom and Republic of Ireland in 2019: A 20-year follow-up.

Anatomical education in the United Kingdom (UK) and Ireland has long been under scrutiny, especially since the reforms triggered in 1993 by the General Medical Council's "Tomorrow's Doctors." The aim of the current study was to investigate the state of medical student anatomy education in the UK and Ireland in 2019. In all, 39 medical schools completed the survey (100% response rate) and trained 10,093 medical students per year cohort. The teachers comprised 760 individuals, of these 143 were employed on full-time teaching contracts and 103 were employed on education and research contracts. Since a previous survey in 1999, the number of part-time staff has increased by 300%, including a significant increase in the number of anatomy demonstrators. In 2019, anatomy was predominantly taught to medical students in either a system-based or hybrid curriculum. In all, 34 medical schools (87%) used human cadavers to teach anatomy, with a total of 1,363 donors being used per annum. Gross anatomy teaching was integrated with medical imaging in 95% of medical schools, embryology in 81%, living anatomy in 78%, neuroanatomy in 73%, and histology in 68.3%. Throughout their five years of study, medical students are allocated on average 85 h of taught time for gross anatomy, 24 h for neuroanatomy, 24 h for histology, 11 h for living anatomy, and 10 for embryology. In the past 20 years, there has been an average loss of 39 h dedicated to gross anatomy teaching and a reduction in time dedicated to all other anatomy sub-disciplines.

COVID-19 and anatomy: Stimulus and initial response.

The outbreak of COVID-19, resulting from widespread transmission of the SARS-CoV-2 virus, represents one of the foremost current challenges to societies across the globe, with few areas of life remaining untouched. Here, we detail the immediate impact that COVID-19 has had on the teaching and practice of anatomy, providing specific examples of the varied responses from several UK, Irish and German universities and medical schools. Alongside significant issues for, and suspension of, body donation programmes, the widespread closure of university campuses has led to challenges in delivering anatomy education via online methods, a particular problem for a practical, experience-based subject such as anatomy. We discuss the short-term consequences of COVID-19 for body donation programmes and anatomical education, and highlight issues and challenges that will need to be addressed in the medium to long term in order to restore anatomy education and practice throughout the world.

An investigation of the anatomy of the infrapatellar fat pad and its possible involvement in anterior pain syndrome: a cadaveric study.

The infrapatellar fat pad (IFP) is an extrasynovial, intracapsular, adipose body occupying the space in the knee joint between the inferior border of the patella, the femoral condyles, tibial plateau and patellar tendon. Little is known about the anatomy and normal function of the IFP, but it has been suggested to play a role in the aetiology of Anterior knee pain syndrome, including that associated with osteoarthritis. Forty-three knees from 11 male and 15 female embalmed cadavers (mean age 84 years; range 55-97 years) were investigated. The cadavers were donated and the study performed in compliance with the provisions of the UK Human Tissue Act (2004). The quadriceps tendon and the medial and lateral patellar retinacula were dissected from the patella, which was then reflected antero-distally. The IFP was carefully excised and details of its morphology and attachments to components of the knee joint were recorded, together with the presence of articular surface pathology on the patella and femoral condyles. The principal novel findings of the current study were that 81% of IFPs were attached to the superior border of the patella by supero-medial extensions and 65% were attached by supero-lateral extensions; the supero-medial extensions were larger than the supero-lateral extensions. The superior extensions of the IFP were always attached anteriorly to the patellar retinacula and in four individuals the extensions formed a full loop around the superior border of the patella. The volume of IFPs with attachments to the superior border of the patella was significantly greater (p = .007) than those without, and the IFP was attached to the medial meniscus in significantly (p = .009) more knees with IFP attachment to the superior border of the patella than those without. All IFPs were attached to the medial anterior horn of the meniscus and the medial Kaplan's ligament. Ninety-seven per cent were attached to the lateral anterior horn of the meniscus and 97% to the lateral Kaplan's ligament. The length of IFP attachment to the lateral meniscus was significantly longer (p = .004) than that to the medial meniscus. Ninety-seven per cent of IFPs were attached to the superior portion of the patellar tendon with the mean tendon attachment being 60%. Ninety-one per cent of IFPs were attached to the inferior border of the patella. Significantly fewer knees with patellar (p = .001) and femoral (p = .002) articular surface osteophytes exhibited superior IFP extensions and these extensions were significantly shorter in knees with patellar (p = .000) and femoral (p = .006) osteophytes, compared with those without. The IFP was attached to the medial meniscus in significantly fewer knees with femoral (p = .050) and patellar (p = .023) osteophytes than those without. All IFPs not attached to the anterior horn of the lateral menisci, medial Kaplan's ligament, superior patella or inferior border of the patella, were in knees with articular surface osteophytes. This relationship between IFP morphology and knee joint pathology suggests a functional role for the IFP that requires further investigation.

The influence of muscle pennation angle and cross-sectional area on contact forces in the ankle joint.

Data about a muscle's fibre pennation angle and physiological cross-sectional area are used in musculoskeletal modelling to estimate muscle forces, which are used to calculate joint contact forces. For the leg, muscle architecture data are derived from studies that measured pennation angle at the muscle surface, but not deep within it. Musculoskeletal models developed to estimate joint contact loads have usually been based on the mean values of pennation angle and physiological cross-sectional area. Therefore, the first aim of this study was to investigate differences between superficial and deep pennation angles within each muscle acting over the ankle and predict how differences may influence muscle forces calculated in musculoskeletal modelling. The second aim was to investigate how inter-subject variability in physiological cross-sectional area and pennation angle affects calculated ankle contact forces. Eight cadaveric legs were dissected to excise the muscles acting over the ankle. The mean surface and deep pennation angles, fibre length and physiological cross-sectional area were measured. Cluster analysis was applied to group the muscles according to their architectural characteristics. A previously validated OpenSim model was used to estimate ankle muscle forces and contact loads using architecture data from all eight limbs. The mean surface pennation angle for soleus was significantly greater (54%) than the mean deep pennation angle. Cluster analysis revealed three groups of muscles with similar architecture and function: deep plantarflexors and peroneals, superficial plantarflexors and dorsiflexors. Peak ankle contact force was predicted to occur before toe-off, with magnitude greater than five times bodyweight. Inter-specimen variability in contact force was smallest at peak force. These findings will help improve the development of experimental and computational musculoskeletal models by providing data to estimate force based on both surface and deep pennation angles. Inter-subject variability in muscle architecture affected ankle muscle and contact loads only slightly. The link between muscle architecture and function contributes to the understanding of the relationship between muscle structure and function.

The perception of scar cosmesis following thyroid and parathyroid surgery: A prospective cohort study.

INTRODUCTION: Various "scarless" approaches have been described for thyroid and parathyroid surgery. The objective of the current study was to investigate patients' perception of neck scar cosmesis, its impact on quality of life (QoL) and evaluate patient preference with regards to scar location. METHODS: 120 patients undergoing thyroid or parathyroid surgery were followed-up over a 5-year period (2008-2013). Validated tools were used to assess scar perception and its impact on QoL. These were evaluated against sex, age, ethnicity, operation type, histopathology, time following surgery and scar length. RESULTS: Mean follow-up was 2.6 ± 3.8 years. One of the most common post-operative problems was scar-related (n = 18). Caucasian patients and those with benign histology expressed a lower impact on QoL (p < 0.001, p = 0.038). Sex and scar length did not significantly affect patients' perception for scar cosmesis (p > 0.05). Clinicians tended to score scar cosmesis higher than patients (p = 0.02). Most participants (75%) expressed a clear preference for an extracervical "scar-less in the neck" approach. DISCUSSION: Scar-related issues are frequently reported following thyroid and parathyroid surgery. The negative impact, often underestimated by clinicians, is more apparent amongst Asian and Afro-Caribbean patients and can significantly impact on their QoL. This, combined with the lack of correlation between scar length and patient satisfaction, indicates the need to divert research from miniaturising neck scars to concealing them in extracervical sites. CONCLUSION: Patients prefer a scar-less in the neck approach when given the option. A prospective comparative study is required to compare the cervical and extracervical approaches.

Determination of biometric measures to evaluate patient suitability for transoral robotic surgery.

BACKGROUND: Transoral robotic surgery (TORS) represents a novel treatment for oropharyngeal cancer and obstructive sleep apnea. Appropriate patient selection is crucial. The purpose of this study was to investigate whether anatomic biometric measures are useful to determine the feasibility of performing TORS. METHODS: Three surgeons independently evaluated feasibility in 51 soft-fix cadavers. Transoral visualization was performed with 2 retractors commonly used in TORS. Seven anthropometric parameters and the degree of mouth opening were recorded. RESULTS: Mandibular body height, hyoid-mental length, and neck circumference demonstrated significant differences between "suboptimal" and "adequate" visualization of base of tongue and epiglottis (p < .05). Limited mouth opening was associated with suboptimal visualization. Neck circumference had the strongest influence on predicting TORS feasibility. CONCLUSION: Mandibular body height, hyoid-mental length, and neck circumference in conjunction with the degree of mouth opening may determine patient suitability for TORS. Clinical evaluation is essential to validate their collective usefulness.

Caecal ligation and puncture induced sepsis in the rat results in increased brain water content and perimicrovessel oedema.

To investigate brain water content and ultrastructure in a rat caecal ligation and puncture (CLP) model of sepsis, adult male Wistar rats were assigned to one of the following experimental groups: CLP, Un-operated or Sham. CLP was performed under anaesthesia, Sham rats were exposed to anaesthesia, laparotomy and caecal mobilisation and Un-operated rats did not experience anaesthesia or surgery. CLP and Sham rats were sacrificed 18-20 h following recovery from surgery and Un-operated rats were sacrificed at the same time. Frontal cortex samples (CLP n = 9; Un-operated n = 10; Sham n = 8) were taken immediately post mortem and their water content determined using gravimetry. Similar samples were taken from other rats (CLP n = 8; Un-operated n = 8; Sham n = 8), processed for electron microscopy and subjected to morphometric analysis. There was significantly more brain water in CLP than Un-operated (P < 0.01) and Sham (P < 0.05) rats. Electron microscopy revealed significantly more peri-microvessel oedema in CLP than Un-operated (P < 0.001) and Sham rats (P < 0.05). Microvessel endothelial cell lumen cross-sectional area was significantly smaller in CLP than Un-operated (P < 0.001) and Sham (P < 0.05) rats and microvessel endothelial cell cross-sectional area was significantly smaller in CLP than Un-operated (P < 0.05) rats. Significantly more endothelial cell cytoplasmic area was occupied by mitochondria in CLP than Un-operated (P < 0.05) and Sham (P < 0.05) rats. However, experimental group did not affect the number of mitochondria present in endothelial cell profiles, or their cross-sectional area. Therefore, sepsis-induced cerebral oedema involves an increase in and a redistribution of brain water, together with ultrastructural changes to cerebral microvessels and adjacent tissue.

Specialist anatomy: Is the structure of teaching adequate?

BACKGROUND: A knowledge and understanding of specialist anatomy, which includes radiological, laparoscopic, endoscopic and endovascular anatomy is essential for interpretation of imaging and development of procedural skills. METHODS AND MATERIALS: Medical students, specialist trainees and specialists from the London (England, UK) area were surveyed to investigate individual experiences and recommendations for: (1) timing of the introduction of specialist anatomy teaching, and (2) pedagogical methods used. Opinions relating to radiological, laparoscopic, endoscopic and endovascular anatomy were collected. Non-parametric tests were used to investigate differences in recommendations between specialist trainees and specialists. RESULTS: Two hundred and twenty-eight (53%) individuals responded to the survey. Imaging was most commonly used to learn radiological anatomy (94.5%). Procedural observation was most commonly used to learn laparoscopic (89.0%), endoscopic (87.3%) and endovascular anatomy (66.2%). Imaging was the most recommended method to learn radiological anatomy (92.1%). Procedural observation was the most recommended method for learning laparoscopic (80.0%), endoscopic (81.2%) and endovascular anatomy (42.5%). Specialist trainees and specialists recommended introduction of specialist anatomy during undergraduate training. CONCLUSION: Although the methods for specialist anatomy learning are in practice, there is no consensus on timing and structure within the anatomy curriculum. Recommendations from trainees and specialists should be considered so that the existing curriculum can be refined to maximise learning outcomes.

Role of aquaporin-4 in the development of brain oedema in liver failure.

BACKGROUND & AIMS: Liver failure is associated with progressive cytotoxic brain oedema (astrocyte swelling), which underlies hepatic encephalopathy (HE). Ammonia and superimposed inflammation are key synergistic factors in HE, but the mechanism(s) involved remain unknown. We aimed to determine whether aquaporin-4 (AQP4), an astrocyte endfeet bi-directional water channel, is associated with the brain oedema of HE. METHOD: Rats (n=60) received sham-operation (sham), 5 days hyperammonaemia-inducing diet (HD), galactosamine (GALN) induced acute liver failure (ALF), 4 weeks bile duct-ligation (BDL) induced cirrhosis, or caecal ligation and puncture (CLP), a 24h model of bacterial peritonitis. Rats from every group (except CLP) were randomised to receive intraperitoneal injections of lipopolysaccharide (LPS; 1mg/kg) or saline, prior to termination 3h later. Brain water, AQP4 protein expression (western blot) and AQP4 localisation by immunogold electron microscopy were investigated. RESULTS: Significant hyperammonaemia was observed in saline-injected BDL (p<0.05), GALN (p<0.01), and HD (p<0.01), compared to sham rats. LPS injection did not affect arterial ammonia or plasma biochemistry in any of the treatment groups. Increased brain water was observed in saline-injected GALN (p<0.05), HD (p<0.01), and CLP (p<0.001) compared to sham rats. Brain water was numerically increased in BDL rats, but this failed to reach significance (p=0.09). LPS treatment further increased oedema significantly in all treatment groups (p<0.05, respectively). AQP4 expression was significantly increased in saline-injected BDL (p<0.05), but not other treatment groups, compared to sham rats. Membrane polarisation was maintained in BDL rats. CONCLUSION: The results suggest that AQP4 is not directly associated with the development of brain oedema in liver failure, hyperammonaemia, or sepsis. In cirrhosis, there is increased AQP4 protein expression, but membrane polarisation, is maintained, possibly in a compensatory attempt to limit severe brain oedema.

L-ornithine and phenylacetate synergistically produce sustained reduction in ammonia and brain water in cirrhotic rats.

UNLABELLED: Treatment of hyperammonemia and hepatic encephalopathy in cirrhosis is an unmet clinical need. The aims of this study were to determine whether L-ornithine and phenylacetate/phenylbutyrate (administered as the pro-drug phenylbutyrate) (OP) combined are synergistic and produce sustained reduction in ammonia by L-ornithine acting as a substrate for glutamine synthesis, thereby detoxifying ammonia, and the phenylacetate excreting the ornithine-derived glutamine as phenylacetylglutamine in the urine. Sprague-Dawley rats were studied 4 weeks after bile duct ligation (BDL) or sham operation. Study 1: Three hours before termination, an internal carotid sampling catheter was inserted, and intraperitoneal saline (placebo), OP, phenylbutyrate, or L-ornithine were administered after randomization. BDL was associated with significantly higher arterial ammonia and brain water and lower brain myoinositol (P < 0.01, respectively), compared with sham-operated controls, which was significantly improved in the OP-treated animals; arterial ammonia (P < 0.001), brain water (P < 0.05), brain myoinositol (P < 0.001), and urinary phenylacetylglutamine (P < 0.01). Individually, L-ornithine or phenylbutyrate were similar to the BDL group. In study 2, BDL rats were randomized to saline or OP administered intraperitoneally for 6 hours or 3, 5, or 10 days and were sacrificed between 4.5 and 5 weeks. The results showed that the administration of OP was associated with sustained reduction in arterial ammonia (P < 0.01) and brain water (P < 0.01) and markedly increased arterial glutamine (P < 0.01) and urinary excretion of phenylacetylglutamine (P < 0.01) in each of the OP treated groups. CONCLUSION: The results of this study provide proof of the concept that L-ornithine and phenylbutyrate/phenylacetate act synergistically to produce sustained improvement in arterial ammonia, its brain metabolism, and brain water in cirrhotic rats.

AQP4 gene deletion in mice does not alter blood-brain barrier integrity or brain morphology.

The glial cell water channel aquaporin-4 (AQP4) plays an important role in brain edema, astrocyte migration, and neuronal excitability. Zhou et al. [Zhou J, Kong H, Hua X, Xiao M, Ding J, Hu G (2008) Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport 19:1-5] recently reported that AQP4 deletion significantly altered blood-brain barrier integrity and glial fibrillary acidic protein (GFAP) immunoreactivity in their AQP4 null mice. Here we describe a detailed characterization of baseline brain properties in our AQP4 null mice, including gross appearance, neuronal, astrocyte and oligodendrocyte characteristics, and blood-brain barrier integrity. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood-brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. There were no differences in brain and ventricle sizes between wild type and AQP4 null mice, nor were there differences in the cerebral cortical density of NeuN positive nuclei, perimicrovessel and glia limitans GFAP immunoreactivity, or the thickness and myelination of the corpus callosum. The ultrastructure of microvessels in the frontal cortex and caudate nucleus of wild type vs. AQP4 null mice was indistinguishable, with features including intact endothelial tight junctions, absence of perimicrovessel astrocyte foot process edema, and absence of horseradish peroxidase extravasation. In contrast to the report by Zhou et al. (2008), our data show that AQP4 deletion in mice does not produce major structural abnormalities in the brain.

Dissection of soft-preserved cadavers in the training of gynaecological oncologists: report of the first UK workshop.

OBJECTIVE: To assess the surgical anatomy knowledge of gynaecological oncology (GO) trainees and to evaluate the impact of a cadaveric dissection course on postgraduate surgical training. METHODS: An intensive 3-day cadaveric dissection course with illustrated lectures and supervised dissection, with a multiple-choice questionnaire (MCQ) on surgical anatomy at the beginning and end of the course was organised in the Anatomy Facility of a London Medical School. Each cadaver was embalmed with a mixture of alcohol, phenol and glycerol ("soft-preserved") rather than fixed in formalin, to more closely preserve in vivo conditions of the body. There were ten dissecting delegates, two per cadaver. The delegates dissected the abdomen and pelvis with the emphasis on surgical approaches rather than the classical descriptive anatomy approaches. Delegates also completed a course evaluation. RESULTS: Without negative marking, the mean initial MCQ score was 57%, and final mean score 64%. With negative marking, the mean initial score was 43%, and mean final score 53%. Delegates rated the course highly, would recommend it to other trainees and considered that such a course should be incorporated into subspecialty training. CONCLUSION: The surgical anatomy knowledge of subspecialty trainees was weak but improved as a result of the dissection course. The most positive finding was the course evaluation. Postgraduate surgical training in GO would likely be enhanced by, and arguably requires, cadaveric dissection. "Soft-preserved" rather than formalin-fixed cadavers should be used.

Deficits of neuronal density in CA1 and synaptic density in the dentate gyrus, CA3 and CA1, in a mouse model of Down syndrome.

Ts65Dn mice are partially trisomic for the distal region of MMU16, which is homologous with the obligate segment of HSA21 triplicated in Down syndrome (DS). Ts65Dn mice are impaired in learning tasks that require an intact hippocampus. In order to investigate the neural basis of these deficits in this mouse model of Down syndrome, quantitative light and electron microscopy were used to compare the volume densities of neurons and synapses in the hippocampus of adult Ts65Dn (n=4) and diploid mice (n=4). Neuron density was significantly lower in the CA1 of Ts65Dn compared to diploid mice (p<0.01). Total synapse density was significantly lower in the dentate gyrus (DG; p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. The synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice. When the data were broken down by synapse type, asymmetric synapse density was found to be significantly lower in the DG (p<0.001), CA3 (p<0.05) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, while such a difference in symmetric synapse density was only present in the DG (p<0.01). The asymmetric synapse-to-neuron ratio was significantly lower in the DG (p<0.001), CA3 (p<0.01) and CA1 (p<0.001) of Ts65Dn compared to diploid mice, but there were no such significant differences in symmetric synapse-to-neuron ratios. These results suggest that impaired synaptic connectivity in the hippocampus of Ts65Dn mice underlies, at least in part, their cognitive impairment.

Adrenergic agents modify cerebral edema and microvessel ultrastructure in porcine sepsis.

OBJECTIVE: To investigate the effects of adrenergic agents on the cerebral response to sepsis. DESIGN: Prospective, randomized, controlled, experimental animal study. SETTING: Medical school research laboratories. SUBJECTS: Twenty-eight middle white pigs (25-30 kg). INTERVENTIONS: Pigs were anesthetized, mechanically ventilated, and randomly assigned to one of the following groups: cecal peritonitis (n = 5), cecal peritonitis with dopexamine (n = 5), cecal peritonitis with dopexamine and the beta2-adrenergic receptor antagonist ICI 118,551 (n = 4), cecal peritonitis with methoxamine (n = 5), cecal peritonitis with dopexamine and methoxamine (n = 4), and sham-operated (n = 5). Sham-operated pigs were killed after laparotomy, and pigs with cecal peritonitis were killed 8 hrs after its induction. Samples of frontal cerebral cortex were taken immediately after death, processed for light and electron microscopy, and then subjected to morphometric analysis. MEASUREMENTS AND MAIN RESULTS: There was significantly more (p <.0005) cerebral perimicrovessel edema in pigs with cecal peritonitis (80.2 microm2 +/- 5.3 sem) than in sham-operated pigs (26.2 microm2 +/- 2.7 sem) and significantly less (p <.0005) perimicrovessel edema in dopexamine-treated pigs with cecal peritonitis (39.8 microm2 +/- 5.5 sem) than in pigs with cecal peritonitis alone (80.2 microm2 +/- 5.3 sem). There was no significant difference between the amount of perimicrovessel edema in pigs with cecal peritonitis treated with dopexamine plus ICI118,551 and pigs with cecal peritonitis alone. The mean cerebral microvessel endothelial cell cross-sectional area in methoxamine-treated pigs with cecal peritonitis (26.3 microm2 +/- 2.6 sem) was significantly greater than that in pigs with cecal peritonitis alone (16.3 microm2 +/- 2.1 sem, p =.008) or in sham-operated pigs (12.3 microm2 +/- 1.3 sem, p =.0005). CONCLUSIONS: Dopexamine protects against cerebral edema formation in sepsis by stimulation of beta2-adrenergic receptors, whereas the alpha1 adrenoceptor agonist methoxamine induces cerebral microvessel endothelial cell swelling.

Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgenes.

Several transgenic mouse models of Alzheimer's disease (AD) have been developed that exhibit beta-amyloid (Abeta) neuropathology and behavioural deficits. However, not all studies have investigated the relationship between the development of cognitive impairment and neuropathology. Therefore, temporal changes in cognition were investigated in male and female double-mutant APPswexPS1.M146V (TASTPM) transgenic mice using an object recognition test and correlated with the development of cerebral Abeta neuropathology. Both male and female TASTPM mice exhibited similar significant cognitive impairment at 6, 8 and 10 months of age in the object recognition test, compared to wild-type littermates. There was no such cognitive impairment at 3 or 4 months of age. Quantitative immunohistochemistry using a battery of Abeta antibodies demonstrated that cerebral Abeta deposition was first apparent in 3-month-old mice, and it increased with age. The early appearance of cerebral Abeta deposits in the double-transgenic TASTPM mice supports the evidence that mutations in the PS1 gene accelerate Abeta deposition. The cerebral Abeta load was greater in female than in male TASTPM mice at all ages investigated. In the electron microscope, mature Abeta plaques comprising a fibrillar core surrounded by degenerating neurites and reactive glia were first observed in the cortex of TASTPM mice at 6 months of age, the same age at which cognitive impairment became apparent. These results suggest that the cognitive impairment in TASTPM mice is related to the disruption of neural connectivity and not simply Abeta deposition, which first occurs 3 months earlier.