Altered Expression of Umbilical Cord Blood Levels of miR-181b and Its Downstream Target mUCH-L1 in Infants with Moderate and Severe Neonatal Hypoxic-Ischaemic Encephalopathy.

Hypoxic-ischaemic encephalopathy (HIE) remains one of the leading causes of neurological disability worldwide. No blood biomarker capable of early detection and classification of injury severity in HIE has been identified. This study aimed to investigate the potential of miRNA-181b (miR-181b) and its downstream target, ubiquitin C-terminal hydrolase-L1 (UCH-L1), to predict the severity of HIE. Full-term infants with perinatal asphyxia were recruited at birth and observed for the development of HIE, along with healthy controls. Levels of miR-181b and messenger UCH-L1 (mUCH-L1) in umbilical cord blood were determined using qRT-PCR. In total, 131 infants; 40 control, 50 perinatal asphyxia without HIE (PA) and 41 HIE, recruited across two separate cohorts (discovery and validation) were included in this study. Significant and consistent downregulation of miR-181b was observed in infants with moderate/severe HIE compared to all other groups in both cohorts: discovery 0.25 (0.16-0.32) vs 0.61 (0.26-1.39), p = 0.027 and validation 0.33 (0.15-1.78) vs 1.2 (0.071-2.09), p = 0.035. mUCH-L1 showed increased expression in infants with HIE in both cohorts. The expression ratio of miR-181b to mUCH-L1 was reduced in those infants with moderate/severe HIE in both cohorts: discovery cohort 0.23 (0.06-0.44) vs 1.59 (0.46-2.54), p = 0.01 and validation cohort 0.41 (0.10-0.81) vs 1.38 (0.59-2.56) in all other infants, p = 0.009. We have validated consistent patterns of altered expression in miR-181b/mUCH-L1 in moderate/severe neonatal HIE which may have the potential to guide therapeutic intervention in HIE.

Use of the physical environment to support everyday activities for people with dementia: A systematic review.

Difficulty with everyday activities is a key symptom and defining feature of dementia, relating to subjective reports of well-being and overall quality of life. One way to support individuals in their daily activities is by modifying the physical environment to make it easier to interact with during activity performance. This systematic review explores the range of studies available using physical environmental strategies to support performance in everyday activities for people with dementia. Seventy-two relevant studies were identified by the search. Physical environmental strategies included changes to the global environment and to architectural features, use of moveable environmental aids and tailored individual approaches. Strategies supported general everyday activity functioning (N = 19), as well as specific activities, particularly mealtimes (N = 15) and orientation in space (N = 16); however, few studies were found that focused on aspects of personal care such as dressing (N = 1) and showering or the preferred hobbies of individuals (N = 0). Overall, there appeared to be a lack of research within private home environments, and of studies which specify the dementia syndrome or the whole neuropsychological profile of people with dementia. More work is needed to extend theoretical understandings of how people with dementia interact with their environments so that these spaces can be designed to further support activities of daily living performance. Future work in this field could also incorporate the perspectives and preferences of those living with dementia.

A meta-review of stress, coping and interventions in dementia and dementia caregiving.

BACKGROUND: There has been a substantial number of systematic reviews of stress, coping and interventions for people with dementia and their caregivers. This paper provides a meta-review of this literature 1988-2014. METHOD: A meta-review was carried out of systematic reviews of stress, coping and interventions for people with dementia and their caregivers, using SCOPUS, Google Scholar and CINAHL Plus databases and manual searches. RESULTS: The meta-review identified 45 systematic reviews, of which 15 were meta-analyses. Thirty one reviews addressed the effects of interventions and 14 addressed the results of correlational studies of factors associated with stress and coping. Of the 31 systematic reviews dealing with intervention studies, 22 focused on caregivers, 6 focused on people with dementia and 3 addressed both groups. Overall, benefits in terms of psychological measures of mental health and depression were generally found for the use of problem focused coping strategies and acceptance and social-emotional support coping strategies. Poor outcomes were associated with wishful thinking, denial, and avoidance coping strategies. The interventions addressed in the systematic reviews were extremely varied and encompassed Psychosocial, Psychoeducational, Technical, Therapy, Support Groups and Multicomponent interventions. Specific outcome measures used in the primary sources covered by the systematic reviews were also extremely varied but could be grouped into three dimensions, viz., a broad dimension of "Psychological Well-Being v. Psychological Morbidity" and two narrower dimensions of "Knowledge and Coping" and of "Institutionalisation Delay". CONCLUSIONS: This meta-review supports the conclusion that being a caregiver for people with dementia is associated with psychological stress and physical ill-health. Benefits in terms of mental health and depression were generally found for caregiver coping strategies involving problem focus, acceptance and social-emotional support. Negative outcomes for caregivers were associated with wishful thinking, denial and avoidance coping strategies. Psychosocial and Psychoeducational interventions were beneficial for caregivers and for people with dementia. Support groups, Multicomponent interventions and Joint Engagements by both caregivers and people with dementia were generally found to be beneficial. It was notable that virtually all reviews addressed very general coping strategies for stress broadly considered, rather than in terms of specific remedies for specific sources of stress. Investigation of specific stressors and remedies would seem to be a useful area for future research.

Nanotechnology: current concepts in orthopaedic surgery and future directions.

Nanotechnology is the study, production and controlled manipulation of materials with a grain size < 100 nm. At this level, the laws of classical mechanics fall away and those of quantum mechanics take over, resulting in unique behaviour of matter in terms of melting point, conductivity and reactivity. Additionally, and likely more significant, as grain size decreases, the ratio of surface area to volume drastically increases, allowing for greater interaction between implants and the surrounding cellular environment. This favourable increase in surface area plays an important role in mesenchymal cell differentiation and ultimately bone-implant interactions. Basic science and translational research have revealed important potential applications for nanotechnology in orthopaedic surgery, particularly with regard to improving the interaction between implants and host bone. Nanophase materials more closely match the architecture of native trabecular bone, thereby greatly improving the osseo-integration of orthopaedic implants. Nanophase-coated prostheses can also reduce bacterial adhesion more than conventionally surfaced prostheses. Nanophase selenium has shown great promise when used for tumour reconstructions, as has nanophase silver in the management of traumatic wounds. Nanophase silver may significantly improve healing of peripheral nerve injuries, and nanophase gold has powerful anti-inflammatory effects on tendon inflammation. Considerable advances must be made in our understanding of the potential health risks of production, implantation and wear patterns of nanophase devices before they are approved for clinical use. Their potential, however, is considerable, and is likely to benefit us all in the future.

Megaesophagus in a line of transgenic rats: a model of achalasia.

Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.

Heterotopic ossification after central nervous system trauma: A current review.

Neurogenic heterotopic ossification (NHO) is a disorder of aberrant bone formation affecting one in five patients sustaining a spinal cord injury or traumatic brain injury. Ectopic bone forms around joints in characteristic patterns, causing pain and limiting movement especially around the hip and elbow. Clinical sequelae of neurogenic heterotopic ossification include urinary tract infection, pressure injuries, pneumonia and poor hygiene, making early diagnosis and treatment clinically compelling. However, diagnosis remains difficult with more investigation needed. Our pathophysiological understanding stems from mechanisms of basic bone formation enhanced by evidence of systemic influences from circulating humor factors and perhaps neurological ones. This increasing understanding guides our implementation of current prophylaxis and treatment including the use of non-steroidal anti-inflammatory drugs, bisphosphonates, radiation therapy and surgery and, importantly, should direct future, more effective ones.

Progress in understanding of inhibitory purinergic neuromuscular transmission in the gut.

Recent studies with genetic deletion of P2Y1 receptor (P2Y1-/-) have clinched its role in enteric purinergic inhibitory neurotransmission and suggested that ß-NAD may be the purinergic inhibitory neurotransmitter in the colon. In this issue of the Journal, Gil and colleagues extend their earlier observations to the cecum and gastric antrum, showing that P2Y1 receptor mediated purinergic inhibition may be a general phenomenon in the gut. However, the authors made an unexpected observation in contrast with their earlier findings in the colon that neither the selective P2Y1 receptor antagonist MRS2500, nor P2Y1 receptor deletion, blocked the hyperpolarizing action of ß-NAD in the cecum. These observations suggest that ß-NAD may be the purinergic inhibitory neurotransmitter in the colon, but not in the cecum. This group had previously reported that the selective P2Y1 receptor antagonist MRS 2179 suppressed the hyperpolarizing action of ATP or ADP. Further studies are now needed to determine whether the hyperpolarizing actions of ATP and ADP are suppressed by the more potent P2Y1 antagonist MRS2500, and in P2Y1-/- mutants to test the intriguing possibility that different purines serve as purinergic inhibitory neurotransmitters in the colon and cecum and perhaps in different parts of the gut. Studies in P2Y1-/- mice will resolve other issues in purinergic neurotransmission including cellular localization of the ß-NAD or ATP-activated P2Y1 receptors on either smooth muscle cells or PDGFRα+ fibroblast-like cells, relationship of purinergic to nitrergic neurotransmission and understanding the physiological and clinical importance of purinergic transmission in gastrointestinal motility and its disorders.

Therapeutic aerosol bioengineering of targeted, inhalable microparticle formulations to treat Mycobacterium tuberculosis (MTb).

Therapeutic aerosol bioengineering (TAB) of Mycobacterium tuberculosis (MTb) therapies using inhalable microparticles offers a unique opportunity to target drugs to the site of infection in the alveolar macrophages, thereby increasing dosing in the lungs and limiting systemic exposure to often toxic drugs. Previous work by us used sophisticated, high content analysis to design the optimal poly(lactide-co-glycolic) acid (PLGA) microparticle for delivery of drugs to alveolar macrophages. Herein, we applied this technology to three different anti-MTb drugs. These formulations were then tested for encapsulation efficiency, drug-release, in vitro killing against MTb and aerosol performance. Methods for encapsulating each of the drugs in the PLGA microparticles were successfully developed and found to be capable of controlling the release of the drug for up to 4 days. The efficacy of each of the encapsulated anti-MTb drugs was maintained and in some cases enhanced post-encapsulation. A method of processing these drug-loaded microparticles for inhalation using standard dry powder inhaler devices was successfully developed that enabled a very high respirable dose of the drug to be delivered from a simple dry powder inhaler device. Overall, TAB offers unique opportunities to more effectively treat MTb with many potential clinical and economic benefits resulting.

Cellular targeting and trafficking of drug delivery systems for the prevention and treatment of MTb.

Targeted delivery of anti-tubercular therapeutics to alveolar macrophages via inhalation aims to achieve optimal concentration of the therapeutic in the mycobacteria's niche environment. However, several challenges need to be overcome when designing a system to achieve this targeted, intracellular delivery. The first objective is to design a system that is suitable for inhalation, i.e. it must be capable of deposition in the alveolar region of the lungs. The theme of this commentary will be on the biological barriers for intracellular targeting to alveolar macrophages once particles are deposited in the lungs with emphasis on the delivery of anti-tubercular therapy and implications for novel vaccine formulations. The commentary focuses on four key features: 1) How Mycobacterium tuberculosis enters and is trafficked through macrophages, 2) the mechanism by which current drug delivery systems (DDS) enter and are trafficked through cells and 3) How an ideal DDS for anti-tubercular therapy would be trafficked through the macrophage and 4) the potential for using DDS for novel anti-tubercular therapy and vaccine development. These four features of targeted DDS shall be discussed in relation to some new findings from our own research.

Smooth muscle caveolae differentially regulate specific agonist induced bladder contractions.

AIMS: Caveolae are cholesterol-rich plasmalemmal microdomains that serve as sites for sequestration of signaling proteins and thus may facilitate, organize, and integrate responses to extracellular stimuli. While previous studies in the bladder have demonstrated alterations in caveolae with particular physiologic or pathologic conditions, little attention has been focused on the functional significance of these organelles. Therefore, the purpose of this study was to investigate the role of caveolae in the modulation of receptor-mediated signal transduction and determine the presence and localization of caveolin proteins in bladder tissue. METHODS: Contractile responses to physiologic agonists were measured in rat bladder tissue before and after disruption of caveolae achieved by depleting membrane cholesterol with methyl-beta-cyclodextrin. Stimulation with agonists was repeated after caveolae were restored as a result of cholesterol replenishment. RT-PCR, immmunohistochemistry, and Western blotting were used to determine the expression and localization of caveolin mRNA and proteins. RESULTS: Following caveolae disruption, contractile responses to angiotensin II and serotonin were attenuated, whereas responses to bradykinin and phenylephrine were augmented. Cholesterol replenishment restored responses towards baseline. Carbachol and KCl induced contractions were not affected by caveolae disruption. Ultrastructure analysis confirmed loss of caveolae following cholesterol depletion with cyclodextrin and caveolae restoration following cholesterol replacement. Gene and protein expression of caveolin-1, -2, and -3 was detected in bladder tissue. Immunoreactivity for all three caveolins was observed in smooth muscle cells throughout the bladder. CONCLUSIONS: The functional effects of cholesterol depletion on specific agonist-induced contractile events and the expression of all three caveolins in bladder smooth muscle support a central role for caveolae in regulation of selective G-protein-coupled receptor signaling pathways in bladder smooth muscle. Thus, caveolae serve to differentially regulate bladder smooth muscle by a stimulus-dependent potentiation or inhibition of bladder contraction.

MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease.

With high resolution, quantitative magnetic resonance imaging (MRI) techniques, it is now possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In this study, we compared MRI-derived entorhinal and hippocampal volume in healthy elderly controls, patients who presented at the clinic with cognitive complaints, but did not meet criteria for dementia (non-demented), and patients with very mild AD. The two patient groups differed significantly from controls in entorhinal volume, but not from each other; in contrast, they differed from each other, as well as from controls, in hippocampal volume, with the mild AD cases showing the greatest atrophy. Follow-up clinical evaluations available on 23/28 non-demented patients indicated that 12/23 had converted to AD within 12-77 months from the baseline MRI examination. Converters could be best differentiated from non-converters on the basis of entorhinal, but not hippocampal volume. These data suggest that although both the EC and hippocampal formation degenerate before the onset of overt dementia, EC volume is a better predictor of conversion.

Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting.

Women with acquired immune deficiency syndrome wasting are at an increased risk of osteopenia because of low weight, changes in body composition, and hormonal alterations. Although women comprise an increasing proportion of human immunodeficiency virus-infected patients, prior studies have not investigated bone loss in this expanding population of patients. In this study we investigated bone density, bone turnover, and hormonal parameters in 28 women with acquired immune deficiency syndrome wasting and relative androgen deficiency (defined as free testosterone < or =3.0 pg/ml, weight < or =90% ideal body weight, weight loss > or =10% from preillness maximum weight, or weight <100% ideal body weight with weight loss > or =5% from preillness maximum weight). Total body (1.04 +/- 0.08 vs. 1.10 +/- 0.07 g/cm2, human immunodeficiency virus-infected vs. control respectively; P < 0.01), anteroposterior lumbar spine (0.94 +/- 0.12 vs. 1.03 +/- 0.09 g/cm2; P = 0.005), lateral lumbar spine (0.71 +/- 0.14 vs. 0.79 +/- 0.09 g/cm2; P = 0.02), and hip (Ward's triangle; 0.68 +/- 0.14 vs. 0.76 +/- 0.12 g/cm2; P = 0.05) bone density were reduced in the human immunodeficiency virus-infected compared with control subjects. Serum N-telopeptide, a measure of bone resorption, was increased in human immunodeficiency virus-infected patients, compared with control subjects (14.6 +/- 5.8 vs. 11.3 +/- 3.8 nmol/liter bone collagen equivalents, human immunodeficiency virus-infected vs. control respectively; P = 0.03). Although body mass index was similar between the groups, muscle mass was significantly reduced in the human immunodeficiency virus-infected vs. control subjects (16 +/- 4 vs. 21 +/- 4 kg, human immunodeficiency virus-infected vs. control, respectively; P < 0.0001). In univariate regression analysis, muscle mass (r = 0.53; P = 0.004) and estrogen (r = 0.51; P = 0.008), but not free testosterone (r = -0.05, P = 0.81), were strongly associated with lumbar spine bone density in the human immunodeficiency virus-infected patients. The association between muscle mass and bone density remained significant, controlling for body mass index, hormonal status, and age (P = 0.048) in multivariate regression analysis. These data indicate that both hormonal and body composition factors contribute to reduced bone density in women with acquired immune deficiency syndrome wasting. Anabolic strategies to increase muscle mass may be useful to increase bone density among osteopenic women with acquired immune deficiency syndrome wasting.

Penile urethral compression-release maneuver as a non-invasive screening test for diagnosing prostatic obstruction.

The purpose of this study was to evaluate the feasibility of using a penile urethral compression and quick release maneuver during urination as a potential non-invasive clinical screening tool in the evaluation of patients with voiding dysfunction and the diagnosis of prostatic obstruction. The penile compression-release maneuver was performed in adult men with symptomatic voiding dysfunction and in asymptomatic normal men by compressing the penile urethra for 2-3 seconds after the initiation of flow and quickly releasing the compression. The penile compression-release index, calculated from the resulting flow rate surge (Q(surge)) and the steady flow rate (Q(surg)-Q(s)/Q(s)), was analyzed with respect to the type of voiding dysfunction. A comprehensive urodynamic study was performed in each patient to determine the presence and severity of prostatic obstruction and to measure detrusor contractility. The penile compression-release indices measured with this maneuver in patients with bladder outlet obstruction (183+/-76%, n = 43) or detrusor instability (157+/-65%, n = 13) were significantly greater than the index observed in non-obstructed patients with normal contractility (67+/-37%, n = 24) or in non-obstructed patients with impaired detrusor contractility (70+/- 32%, n = 10). In asymptomatic younger men who had normal free flow rates (>15 mL/s), the penile compression-release index (55+/-29%, n = 20) was significantly less than that observed in patients with outlet obstruction or detrusor instability. These findings suggest that the magnitude of the flow rate change generated after the penile compression-release maneuver depends on the magnitude of the isometric detrusor contraction developed during penile urethral compression and on the conduit status of the outlet. In patients determined to have poor urinary flow rates, this non-invasive maneuver has been able to differentiate prostatic obstruction associated with normal detrusor contractility from other causes of low urinary flow rates. Despite these encouraging trends, further studies in a larger cohort are required to determine its potential clinical utility as a screening tool for diagnosing prostatic obstruction.

Combination of symptom score, flow rate and prostate volume for predicting bladder outflow obstruction in men with lower urinary tract symptoms.

PURPOSE: The severity of lower urinary tract symptoms associated with benign prostatic enlargement correlates poorly with bladder outlet obstruction. Since urodynamic studies are presumed to be relatively complex, invasive and not cost-effective, they are not routinely performed by physicians treating men with lower urinary tract symptoms. As a result, a large number of patients are treated for bladder outlet obstruction when in fact obstruction may not be present. Since other noninvasive methods have not been effective for predicting bladder outlet obstruction, we investigated whether a combination of prostate volume, uroflowmetry and the American Urological Association (AUA) symptom index would be reliable for predicting this condition. MATERIALS AND METHODS: We prospectively evaluated 204 men with a mean age plus or minus standard deviation of 66.7 +/- 7.5 years who presented with lower urinary tract symptoms. Each patient completed an AUA symptom index questionnaire and underwent uroflowmetry, post-void residual urine volume measurement, pressure flow study and transrectal ultrasound of the prostate to estimate prostatic volume. We constructed receiver operating characteristics curves using various threshold values for maximum urine flow and prostate volume. Threshold values for maximum urine flow and prostate volume were used alone and combined with the AUA symptom index for predicting bladder outlet obstruction. We selected a cutoff value for maximum urine flow of 10 or less ml. per second and prostate volume of 40 gm. or greater, and used these values with an AUA symptom index of greater than 20 to predict bladder outlet obstruction in the group overall. RESULTS: Differences in the mean symptom index score in men with and without bladder outlet obstruction were not statistically significant. There was no obstruction in 19%, 28.9% and 35% of those with severe, moderate and mild symptoms, respectively. The selected cutoff values of maximum urine flow, prostate volume and symptom score combined correctly predicted obstruction in all 39 patients. Therefore, our combination of cutoff values proved to be highly accurate for predicting bladder outlet obstruction. Sensitivity, specificity, and positive and negative predictive values were 26%, 100%, 100% and 32%, respectively. CONCLUSIONS: Our study showed that combining the AUA symptom index, maximum urine flow and prostate volume reliably predicted bladder outlet obstruction in a small subset of patients only. Although bladder outlet obstruction was correctly predicted by our threshold values of AUA symptom index, maximum urine flow and prostate volume in only 39 men (26%) with obstruction, these patients represent a substantial group in any large urological practice treating male lower urinary tract symptoms.

Effect of radical prostatectomy on sensory threshold and pressure transmission.

PURPOSE: The mechanisms involved in post-radical prostatectomy incontinence remain unclear despite previous anatomical and functional studies. In addition, the factors responsible for the restoration of continence are not well studied. To improve our understanding of the alterations in continence mechanisms, we prospectively investigated the temporal changes in urodynamic parameters after radical prostatectomy. MATERIALS AND METHODS: Cystometry, urethral pressure profilometry and posterior urethral sensory threshold measurements were performed in patients undergoing radical prostatectomy. Preoperative pressure transmission was determined by the maximal urethral pressure divided by the maximal abdominal pressure during cough maneuvers at a bladder volume of 200 ml. Postoperative sensory threshold, pressure transmission (% of pressure transmission), maximal urethral closure pressure and functional sphincter length were measured 6 weeks and 6 months after prostatectomy. These parameters were compared between continent and incontinent patients. RESULTS: Preoperative and postoperative urodynamic studies were completed in 34 patients. The continence rate after 6 weeks was 18% (6 patients) and improved to 82% (28) after 6 months. Preoperatively sensory threshold was 16 +/- 11 mA. After 6 weeks and 6 months, respectively, sensory threshold was significantly higher in incontinent (84 +/- 11 mA., 70 +/- 8 mA.) compared to continent (65 +/- 8 mA., 41 +/- 12 mA.) patients. Preoperative proximal urethral sensory threshold was not correlated with degree of postoperative incontinence determined by pad tests. Pressure transmission was not different in continent and incontinent patients postoperatively. After 6 weeks and 6 months, respectively, pressure transmission was 77% and 91% in continent, and 37% and 58% in incontinent patients (p = 0.04, p = 0.03). Maximal urethral closure pressure was significantly higher in continent patients (35 +/- 6 cm. H2O) compared to incontinent patients (11 +/- 9 cm. H2O). Sphincter length decreased from 50 mm. preoperatively to 24 mm. after 6 weeks and 25 mm. after 6 months. There was no difference in sphincter length between continent and incontinent patients. CONCLUSIONS: Posterior urethral sensitivity and pressure transmission are impaired immediately after prostatectomy. An improvement in these parameters after 6 months is associated with the restoration of continence. These observations suggest that urinary continence after radical prostatectomy depends on the integrity of posterior urethral sensation and the efficiency of pressure transmission.

Hemispheric differences in hippocampal volume predict verbal and spatial memory performance in patients with Alzheimer's disease.

Atrophy of the hippocampal formation, a region important for the acquisition of new declarative knowledge, has been well-documented in Alzheimer's disease (AD), although the relation of such atrophy to the extent of memory dysfunction in these patients has been less clear. In the present study, 18 patients with a clinical diagnosis of probable AD were studied with a high-resolution, quantitative magnetic resonance imaging (MRI) protocol, as well as the verbal and spatial versions of the Buschke controlled learning task. The volumes of the hippocampal formation and, as a control for generalized atrophy, parahippocampal gyrus and temporal neocortex were computed from gapless coronal slices taken perpendicular to the long axis of the hippocampus. To correct for individual differences in brain size, volumes of regions of interest were divided by total intracranial volume. Separate stepwise regression analyses (with age, right and left hippocampal, parahippocampal gyrus, and temporal lobe volumes as the independent variables) showed that left hippocampal volume was the best predictor of free recall and delayed free recall of verbal information (P = 0.0042 and P < 0.0001, respectively). Recall and delayed recall of the spatial location of verbal items were best predicted by right hippocampal volume (P = 0.0054 and P = 0.0118, respectively). Memory scores did not correlate either with parahippocampal gyrus or temporal lobe volume. Furthermore, the relation between hippocampal volume and memory function observed in cases with AD did not hold for healthy aged control subjects.

Characterization of ureteral dysfunction in an experimental model of congenital bladder outlet obstruction.

PURPOSE: Ureteral dysfunction is a significant sequela of congenital bladder outlet obstruction. However, the structural and functional alterations associated with ureteral dysfunction are not well defined. A model of fetal bladder obstruction in sheep was used to characterize the changes in ureteral smooth muscle, extracellular matrix (ECM) and functional properties in response to bladder outlet obstruction. MATERIALS AND METHODS: Partial bladder outlet obstruction was created in fetal sheep at gestational age 95 days via placement of a metal ring around the proximal urethra as well as ligation of the urachus. Ureters were harvested at 109 and 135 days (full term = 140 days) to determine the relative composition of smooth muscle, ECM and urothelium by morphometric analysis and to measure DNA and protein concentrations. Ureteral tissue from 135 day gestation obstructed and control sheep was harvested and immediately placed in Krebs solution. Smooth muscle strips (2-3 mm. x 7-8 mm.) were suspended in organ baths. The frequency and amplitude of spontaneous ureteral contractions was as well as the response to electric field stimulation (EFS) were determined. RESULTS: Bladder outlet obstruction caused a significant increase in ureteral weight, smooth muscle mass and total ECM at both 109 and 135 days gestation. Total ureteral DNA was greater in obstructed compared with sham ureters at 135 days gestation. Obstructed ureters demonstrated greater amplitude and frequency of spontaneous contractions as well as more pronounced response to EFS when compared to sham ureters. CONCLUSIONS: The fetal ureter responds to bladder obstruction with smooth muscle hyperplasia and hypertrophy which is associated with increased spontaneous activity and augmented response to EFS. ECM content is markedly increased indicating a shift in the balance of connective tissue synthesis and degradation. Congenital post-obstructive ureteral dysfunction therefore appears to be the result of dysregulated smooth muscle cell growth and altered ECM homeostasis producing abnormal ureteral contractility.

The functional interaction of visual-perceptual and response mechanisms during selective attention in young adults, young-old adults, and old-old adults.

A response compatibility paradigm was employed to address how the perceptual and response activation processes functionally interact during selective attention and how they may be influenced by aging. The results showed that increasing the visual similarity of targets within response sets reduced the magnitude of the interference effect, but only with a narrow interletter distance. In a dissimilar condition, the magnitude of the interference effect did not vary with age. However, in a similar condition, the magnitude of the interference effect was larger for both young (18-30 years) and young-old adults (55-79 years) than for old-old adults (> or = 80 years). In contrast, all three groups showed similar facilitation effects. These results failed to provide support for the notion that enhanced spatial filtering of the target from the flankers produces a corresponding decrease in response competition. Rather, the decrease in the interference effect can be attributed to a functional interaction between the perceptual availability of partial information and the magnitude of response competition. The results also suggest that age does not impair response activation but that advanced age diminishes the availability of local, but not global, feature information.

The flow regimes and the pressure-flow relationship in the canine urethra.

Classical fluid dynamics predicts that the pressure difference Deltap between any two points along a fully developed, viscous flow stream is linearly proportional to the flow rate Q (the Poiseuille relation). However, the passive urethral resistance relationship (PURR) widely used in modern urodynamics describes the pressure difference Deltap between two points along the urethra as linearly proportional to the flow rate squared (Q(2)). It is our hypothesis that this functional dependence may have its origins in the developing flow field within the urethra. That is, rather than being fully developed hydrodynamically, urethral flow is more likely representative of flow within the entry length of a rigid conduit. In our study, we used a canine model of the lower urinary tract to investigate the possibility of entrance effects. Although the most rigorous model of urethral fluid mechanics would include the elastic properties of the urethra into its configuration, the solutions from such a model would be unnecessarily complex and not readily lend themselves to the analysis of clinical data. Therefore, we chose to model the canine urethra at each instant in time as a rigid tube, and characterized its instantaneous flow using viscous flow theory for a rigid tube. All urodynamic analyses were performed on a surgically exposed urinary tract. Solid state pressure transducers were used to measure the intravesical and distal urethral pressures, whereas an ultrasonic flowmeter was used to obtain a simultaneous measure of the urinary flow rate. Detrusor contractions were induced using bilateral electrical stimulation of the pelvic nerves. Varying degrees of outlet obstruction were created using an inflatable sphincter cuff secured around the bladder outlet. The experimental data were evaluated using the well-known laminar entry length model of Atkinson and Goldstein. The peak Reynolds numbers under nonobstructed R(p)(e non-obs) and obstructed R(p)(e obs) outlet conditions ranged between 500 < R(p)(e non-obs) < 1,500 and 300 < R(p)(e obs) < 1,700, respectively. Under non-obstructed outlet conditions, the urethral diameters D and total lengths l(T) ranged between 1.5 mm < D < 2.5 mm and 75 mm < l(T) < 95 mm, respectively, whereas the peak entrance lengths L(p)(e non-obs) ranged between 55 mm < L(p)(e non-obs) < 215 mm. These data suggest that flow in the canine urethra under both non-obstructed and obstructed outlet conditions is typically laminar. The data further support the hypothesis that non-obstructed flows are predominantly entry length in nature. Entry length flows are fluid dynamically described by a quadratic pressure-flow relationship, thus suggesting a physiological basis for Schäfer's quadratic pressure-flow relationship, and therefore, for the PURR. Neurourol. Urodynam. 18:521-541, 1999.