Association of Intrinsic Capacity with Frailty, Physical Fitness and Adverse Health Outcomes in Community-Dwelling Older Adults.

BACKGROUND: Intrinsic capacity (IC) and frailty are complementary in advancing disability prevention through maintaining functionality. OBJECTIVES: We examined the relationship between IC and frailty status at baseline and 1-year, and evaluated if IC decline predicts frailty onset among robust older adults. The secondary objectives investigated associations between IC, physical fitness and health-related outcomes. DESIGN: Prospective cohort study. SETTING: Community-based assessments. PARTICIPANTS: Older adults aged>55 years, who were independent in ambulation (walking aids permitted). MEASUREMENTS: 5 domains of IC were assessed at baseline: locomotion (Short Physical Performance Battery, 6-minute walk test), vitality (nutritional status, muscle mass), sensory (self-reported hearing and vision), cognition (self-reported memory, age- and education adjusted cognitive performance), psychological (Geriatric Depression Scale-15, self-reported anxiety/ depression). Composite IC (0-10) was calculated, with higher scores representing greater IC. Frailty status was based on modified Fried criteria, with frailty progression defined as incremental Fried score at 1-year. RESULTS: 809 participants (67.6+6.8 years) had complete data for all 5 IC domains. 489 (60.4%) participants were robust but only 213 (26.3%) had no decline in any IC domain. Pre-frail and frail participants were more likely to exhibit decline in all 5 IC domains (p<0.05), with decremental composite IC [9 (8-9), 8 (6-9), 5.5 (4-7.5), p<0.001] across robust, prefrail and frail. IC was significantly associated with fitness performance, independent of age and gender. Higher composite IC reduced risk for frailty progression (OR=0.62, 95% CI 0.48-0.80), and reduced frailty onset among robust older adults (OR=0.53, 95% CI 0.37-0.77), independent of age, comorbidities and social vulnerability. Participants with higher IC were less likely to experience health deterioration (OR=0.70, 95% CI 0.58-0.83), falls (OR=0.76, 95% CI 0.65-0.90) and functional decline (OR=0.64, 95% CI 0.50-0.83) at 1-year. CONCLUSION: Declining IC may present before frailty becomes clinically manifest, increasing risk for poor outcomes. Monitoring of IC domains potentially facilitates personalized interventions to avoid progressive frailty.

A Non-Controlled Study of a Multi-Factorial Exercise and Nutritional Intervention to Improve Functional Performance and Prevent Frailty Progression in Community-Dwelling Pre-Frail Older Adults.

Background: Preventing frailty is important to avoid adverse health outcomes. Intervention studies have largely focused on frail elderly, although the intermediate pre-frail state may be more amenable to improvement. Objectives: This study aims to assess how physical performance may change among pre-frail elderly enrolled in a pragmatic non-controlled exercise and nutritional intervention programme. Methods: This is a non-controlled study involving a 4-month exercise and nutritional intervention for community dwelling pre-frail older adults. Pre-frailty was defined as the presence of 1 or 2 positive responses on the FRAIL questionnaire, or evidence of weak grip strength (<26kg for males; <18kg for females) or slow gait speed (<0.8m/s) amongst participants who were asymptomatic on FRAIL. Physical performance in flexibility, grip and lower limb strength, endurance, balance, and Short Physical Performance Battery were measured at 3 time-points: baseline, 3-month from recruitment (without intervention), and immediate post-intervention. Repeated measures mixed model analysis was performed to compare physical performance measures across the 3 time-points. Results: 94 pre-frail participants were eligible for intervention, of whom 59 (mean age = 70.9±7.2 years) were ready for the post-intervention review. 21 (35.6%) transitioned to robust phenotype while 32 (54.2%) remained as pre-frail. Significant improvement post-intervention was observed in lower limb strength and power, evident on reduction in time taken for 5 sit-to-stand repetitions (0.46±0.20s, p=0.03). There was no significant change to the other physical performance measures examined. Conclusion: We observed reversibility of pre-frailty, and the benefit of multi-component intervention in improving physical performance of pre-frail older adults. The findings in this non-controlled study will need to be corroborated with future controlled trials.

Frailty Assessment in Community-Dwelling Older Adults: A Comparison of 3 Diagnostic Instruments.

OBJECTIVES: Compare the diagnostic performance of FRAIL against Fried Phenotype and Frailty Index (FI), and identify clinical factors associated with pre-frailty/frailty. DESIGN: Cross-sectional analysis. SETTING: Community-based screenings in Senior Activity Centres, Residents' Corners and Community Centres in northeast Singapore. PARTICIPANTS: 517 community dwelling participants aged >55 years and ambulant independently (with/ without walking aids) were included in this study. Residents of sheltered or nursing homes, and seniors unable to ambulate at least four meters independently were excluded. MEASUREMENTS: The multidomain geriatric screen included assessments for social vulnerability, mood, cognition, sarcopenia and nutrition. Participants completed a battery of physical fitness tests for grip strength, gait speed, lower limb strength and power, flexibility, balance and endurance, with overall physical performance represented by Short Physical Performance Battery (SPPB). Frailty status was assigned on FRAIL, Fried and 35-item FI. RESULTS: Prevalence of frailty was 1.3% (FRAIL) to 3.1% (FI). Pre-frailty prevalence ranged from 17.0% (FRAIL) to 51.2% (FI). FRAIL demonstrated poor agreement with FI (kappa=0.171, p<0.0001), and Fried (kappa=0.194, p<0.0001). A lower FRAIL cut-off ≥1 yielded significantly improved AUC of 0.70 (95%CI 0.55 to 0.86, p=0.009) against Fried, and 0.71 (95%CI 0.55 to 0.86, p=0.008) against FI. All 3 frailty measures were diagnostic of impaired physical performance on SPPB, with AUCs ranging from 0.69 on FRAIL to 0.77 on Fried (all p values <0.01). Prevalence of low socio-economic status, depression, malnutrition and sarcopenia increased significantly, while fitness measures of gait speed, balance, and endurance declined progressively across robust, pre-frail and frail on all 3 frailty instruments (p <0.05). CONCLUSIONS: Our results suggest that different frailty instruments may capture over-lapping albeit distinct constructs, and thus may not be used interchangeably. FRAIL has utility for quick screening, and any positive response should trigger further assessment, including evaluation for depression, social vulnerability and malnutrition.

A forgetful and angry old lady.

Dementia is typically characterized by the deterioration of cognitive abilities and is a common disorder among the elderly in Malaysia. However, behavioral and psychological symptoms are also present in approximately 90% of dementia patients.1 We report the manifestation of these symptoms in an elderly woman with dementia and the treatment thereof.

100 años de gloria y el horizonte por venir / 100 Years of Glory and the Next

Mientras celebramos los 100 años de la siembra comercial de palma de aceite en nuestro país, tenemos también tiempo para reflexionar. Un análisis oportuno 100 años de gloria y el horizonte por venir nos permite reafirmar algunos de los planes en curso y, quizá, retomar algunos caminos que habíamos iniciado. A medida que retomamos conversaciones con los malasios mediante la iniciativa gubernamental de Transformación Nacional TN50, quizá es también momento de incorporar a la industria del aceite de palma a este proyecto para trazar una hoja de ruta conjunta para 2050

While we celebrate the 100th anniversary of the commercial sowing of oil palm in our country, we also have time to reflect. A timely analysis 100 years of glory and the horizon to come allows us to reaffirm some of the plans underway and, perhaps, resume some of the paths we had started. As we resume conversations with Malaysians through the government's National Transformation TN50 initiative, perhaps it is also time to incorporate the palm oil industry into this project to draw a joint roadmap for 2050

Does parental support influence children's active school travel?

Today's 'backseat generation' of children is more often driven to school. Active school travel (AST) can contribute up to 30% of recommended daily physical activity. Although governed by a complex set of factors, parents are considered 'gatekeepers' of children's travel mode decisions. Therefore, we investigate the relationship between parental support and children's AST. Data were from Active Streets, Active People-Junior (British Columbia, Canada). Children self-reported travel mode to/from school for 1 week (10 trips). We assessed parental perceived neighborhood traffic and crime safety (Neighborhood Environmental Walkability Scale-Youth) and frequency of parental support for AST (0-5 ×/week). We investigated the association between daily AST behaviour and parental support using logistic regression (controlling for age, sex, distance to school and perceived neighborhood safety). In our sample (n = 179, 11.0 ± 1.0 years, 59% girls), 57% reported daily AST and 63% of parents provided daily support. Bivariate analyses showed AST behaviour was significantly associated with parental support frequency and parents' perceived safety. In adjusted analysis, daily parental support remained significantly associated with daily AST (OR 9.0, 95% CI 4.2, 19.7). The relationship between parental support and AST was independent of noted correlates of AST. Thus, interventions that focus solely on changes to the built environment may not be enough to encourage AST. Therefore, interventions that aim to increase AST should involve parents and children in the planning process.

Wnt signaling regulates homeostasis of the periodontal ligament.

BACKGROUND AND OBJECTIVE: In health, the periodontal ligament maintains a constant width throughout an organism's lifetime. The molecular signals responsible for maintaining homeostatic control over the periodontal ligament are unknown. The purpose of this study was to investigate the role of Wnt signaling in this process by removing an essential chaperone protein, Wntless (Wls), from odontoblasts and cementoblasts, and observing the effects of Wnt depletion on cells of the periodontal complex. MATERIAL AND METHODS: The Wnt responsive status of the periodontal complex was assessed using two strains of Wnt reporter mice: Axin2(LacZ/+) and Lgr5(LacZ/+) . The function of this endogenous Wnt signal was evaluated by conditionally eliminating the Wntless (Wls) gene using an osteocalcin Cre driver. The resulting OCN-Cre;Wls (fl/fl) mice were examined using micro-computed tomography and histology, immunohistochemical analyses for osteopontin, Runx2 and fibromodulin, in-situ hybridization for osterix and alkaline phosphatase activity. RESULTS: The adult periodontal ligament is Wnt responsive. Elimination of Wnt signaling in the periodontal complex of OCN-Cre;Wls(fl/fl) mice resulted in a wider periodontal ligament space. This pathologically increased periodontal width is caused by a reduction in the expression of osteogenic genes and proteins, which results in thinner alveolar bone. A concomitant increase in fibrous tissue occupying the periodontal space was observed, along with a disruption in the orientation of the periodontal ligament. CONCLUSION: The periodontal ligament is a Wnt-dependent tissue. Cells in the periodontal complex are Wnt responsive, and eliminating an essential component of the Wnt signaling network leads to a pathological widening of the periodontal ligament space. Osteogenic stimuli are reduced, and a disorganized fibrillary matrix results from the depletion of Wnt signaling. Collectively, these data underscore the importance of Wnt signaling in homeostasis of the periodontal ligament.

Magnetic resonance imaging-verified temporomandibular joint disk displacement in relation to sagittal and vertical jaw deformities.

This retrospective study was designed to analyze the relationships between temporomandibular joint (TMJ) disk displacement and skeletal deformities in orthodontic patients. Subjects consisted of 460 adult patients. Before treatment, lateral cephalograms and TMJ magnetic resonance imaging (MRI) were recorded. Subjects were divided into six groups based on TMJ MRI according to increasing severity of TMJ disk displacement, in the following order: bilateral normal TMJs, unilateral disk displacement with reduction (DDR) and contralateral normal, bilateral DDR, unilateral disk displacement without reduction (DDNR) and contralateral normal, unilateral DDR and contralateral DDNR, and bilateral DDNR. Subjects were subdivided sagittally into skeletal Class I, II, and III deformities based on the ANB (point A, nasion, point B) angle and subdivided vertically into hypodivergent, normodivergent, and hyperdivergent deformities based on the facial height ratio. Linear trends between severity of TMJ disk displacement and sagittal or vertical deformities were analyzed by Cochran-Mantel-Haenszel test. The severity of TMJ disk displacement increased as the sagittal skeletal classification changed from skeletal Class III to skeletal Class II and the vertical skeletal classification changed from hypodivergent to hyperdivergent. There were no significant differences in the linear trend of TMJ disk displacement severity between the sexes according to the skeletal deformities. This study suggests that subjects with skeletal Class II and/or hyperdivergent deformities have a high possibility of severe TMJ disk displacement, regardless of sex.

Ethanol alters calcium signaling in axonal growth cones.

Calcium (Ca2+) channels are sensitive to ethanol and Ca2+ signaling is a critical regulator of axonal growth and guidance. Effects of acute and chronic exposure to ethanol (22, 43, or 87 mM) on voltage-gated Ca2+ channels (VGCCs) in whole cells, and KCl-induced Ca2+ transients in axonal growth cones, were examined using dissociated hippocampal cultures. Whole-cell patch-clamp analysis in neurons with newly-formed axons (Stage 3) revealed that rapidly inactivating, low-voltage activated (LVA) and non-inactivating, high-voltage activated (HVA) currents were both inhibited in a dose-dependent manner by acute ethanol, with relatively greater inhibition of HVA currents. When assessed by Fluo-4-AM imaging, baseline fluorescence and Ca2+ response to ethanol in Stage 3 neurons was similar compared to neurons without axons, but peak Ca2+ transient amplitudes in response to bath-applied KCl were greater in Stage 3 neurons and were decreased by acute ethanol. The amplitude of Ca2+ transients elicited specifically in axonal growth cones by focal application of KCl was also inhibited by acute exposure to moderate-to-high concentrations of ethanol (43 or 87 mM), whereas a lower concentration (22 mM) had no effect. When 43 or 87 mM ethanol was present continuously in the medium, KCl-evoked Ca2+ transient amplitudes were also reduced in growth cones. In contrast, Ca2+ transients were increased by continuous exposure to 22 mM ethanol. Visualization using a fluorescent dihydropyridine analog revealed that neurons continuously exposed to ethanol expressed increased amounts of L-type Ca2+ channels, with greater increases in axonal growth cones than cell bodies. Thus, acute ethanol reduces Ca2+ current and KCl-induced Ca2+ responses in whole cells and axonal growth cones, respectively, and chronic exposure is also generally inhibitory despite apparent up-regulation of L-type channel expression. These results are consistent with a role for altered growth cone Ca2+ signaling in abnormal neuromorphogenesis associated with fetal alcohol spectrum disorders.

miRNA*: a passenger stranded in RNA-induced silencing complex?

Processing of the pre-microRNA (pre-miRNA) through Dicer1 generates a miRNA duplex, consisting of a miRNA and miRNA* strand (also termed guide strand and passenger strand, respectively). Despite the general consensus that miRNA*s have no regulatory activity, recent publications have provided evidence that the abundance, possible function, and physiological relevance of miRNA*s have been underestimated. This review provides an account of our current understanding of miRNA* origination and activity, mounting evidence for their unique functions and regulatory mechanisms, and examples of specific miRNA*s from the literature.

Effects of α-blocker 'add on' treatment on blood pressure in symptomatic BPH with or without concomitant hypertension.

We investigated the effects of 'add on' treatment of α-blocker (AB) on blood pressure (BP) and the safety of ABs in men with symptomatic BPH with or without hypertension. We retrospectively reviewed 2,924 BPH outpatients who took ABs at our institution between 2005 and 2009. BPH symptom severity, prostate volume and BP were determined for 953 patients with their baseline data. BP level and International Prostate Symptom Score were measured within 2 months after AB treatment. Patients were assigned to four groups: group 1 had 272 normotensive patients on concomitant hypertensive medication; group 2 had 293 normotensive patients not on the medication; group 3 had 216 hypertensive patients on concomitant medication; and group 4 had 172 hypertensive patients not on the medication. The addition of AB lowered the mean systolic BP by 16.6 mm Hg for group 3 and by 8.6 mm Hg for group 4, and diastolic BP by 18.0 mm Hg for group 3 (P<0.05). However, normotensive groups on entry, irrespective of antihypertensive medication, showed no significant BP changes from baseline after AB medication. In the hypertensive groups on entry, the doxazosin gastrointestinal therapeutic system (GITS) resulted in significant reductions in systolic BP from 142.2 to 134.9 mm Hg and in diastolic BP from 97.6 to 84.6 mm Hg. When analyzed by AB regimen, the incidence of BP-related adverse events was comparable. AB therapy for BPH can have an appropriate and beneficial effect on BP, especially in baseline hypertensive patients. Doxazosin GITS treatment resulted in optimal management of BP within the normal range, especially in pharmacologically or physiologically hypertensive patients.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia.

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25,000 single-nucleotide polymorphisms (SNPs) located within approximately 14,000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case-control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Functional nicotinic acetylcholine receptor expression on stem and progenitor cells of the early embryonic nervous system.

Although the adult brain contains nicotinic acetylcholine (ACh) receptors vital to cortical function, little is known about the assembly of embryonic receptor subunits into functional receptors or their role in fetal brain development. We now report the first evidence of functional nicotinic ACh receptors on stem and progenitor cells of fetal mouse cerebral cortex as early as embryonic day 10.

Calcium transport proteins in active secretory zones: Na-Ca exchange isoforms and exchanger kinetic properties in chromaffin granules and plasma membranes.

We have found that Na-Ca exchange influences Ca(2+) efflux, signal decay, and the rate of secretion in chromaffin cells. We now report the presence of two distinct splicing variant isoforms of Na-Ca exchange proteins in bovine chromaffin cells and their transport properties in chromaffin granules and plasma membrane vesicles.

Functional nicotinic acetylcholine receptor expression in stem and progenitor cells of the early embryonic mouse cerebral cortex.

The adult cerebral cortex contains nicotinic acetylcholine (ACh) receptors vital to cortical function. However, little is known about the assembly of embryonic nicotinic receptor subunits into functional receptors or whether they play an active role in cortical development. We now report evidence of functional nicotinic acetylcholine receptor channels in fetal mouse cerebral cortex as early as embryonic day 10 (E10), when the cortex consists of dividing stem and progenitor cells. Patch-clamp electrophysiological measurements indicate that nicotine and ACh evoke sizable inward currents characteristic of nicotinic receptors, that are strongly rectifying with a reversal potential near 0 mV. Three different nicotinic agonists, ACh, nicotine, and dimethylphenylpiperazinium, evoked cytosolic Ca(2+) signals. Agonist-evoked Ca(2+) signals and electrophysiological responses were found in greater than 70% of all E10-E11 cells tested and were blocked by nicotinic receptor antagonists. The Ca(2+) response to nicotinic agonists was markedly prolonged in cells from early embryonic stages relative to later stages of development. alpha3, alpha4, and alpha7 receptor subunit proteins were detected immunocytochemically in cortical cells from E10 to birth. The incidence of each subunit declined with embryonic age, suggesting a role in early development. We discuss the possible function of nicotinic receptors in early cortical development and their role as a target for nicotine in the developmental pathologies associated with the fetal tobacco syndrome.

Kidney development in cadherin-6 mutants: delayed mesenchyme-to-epithelial conversion and loss of nephrons.

During nephrogenesis, dynamic changes in the expression of cell adhesion molecules are evident as epithelial structures differentiate from the induced mesenchyme. The cadherins are thought to play an important role in the metanephric mesenchyme, when cells aggregate to form the renal vesicle, a polarized epithelial structure which eventually fuses with the ureteric bud to generate a continuous nascent nephron. We have generated and analyzed mice with a targeted mutation in the gene encoding cadherin-6 (Cad-6), a type II cadherin expressed during early stages of nephrogenesis. These mice are viable and fertile, and they complete both early and late aspects of nephrogenesis. However, upon closer examination in vitro and in vivo, a fraction of the induced metanephric mesenchyme in Cad-6 mutant kidneys fails to form a fully polarized epithelium on schedule. Moreover, a significant number of the renal vesicles in Cad-6 mutant kidneys apparently fail to fuse to the ureteric bud. These alterations in epithelialization and fusion apparently lead to a loss of nephrons in the adult. These studies support the idea that cadherins play an essential role in the formation of epithelial structures and underscore the importance of timing in orchestrating the morphogenesis of complex epithelial tissues.

Safety and efficacy study with various doses of SS-cream in patients with premature ejaculation in a double-blind, randomized, placebo controlled clinical study.

OBJECTIVES: SS-cream is a topical agent made from the extracts of natural products for treating premature ejaculation (PE). To determine the optimal clinical dosage of SS-cream on PE, we investigated the safety and efficacy of SS-cream with various doses. A double blind, randomized placebo controlled clinical study was performed. METHODS: Fifty patients completed the study. Mean age of the patients was 37.1+/-1.O y and mean ejaculatory latency was 1.35+/-0.07 min. Sexual satisfaction rate of both the partner and patient was 16.2%. Each patient was instructed to apply the different cream (placebo, SS-cream 0.05, 0.10, 0.15, 0.20 g) on glans penis 1 h before sexual intercourse in random fashion. The ejaculatory latency was measured by stop watch and the satisfaction rate of both partner and patient was also recorded two times in the screening period and after the application of each test drugs. Clinical efficacy was considered if ejaculatory latency was prolonged more than 2 min and sexual satisfaction rate increased more than 20% than that of pretest values. RESULTS: The mean ejaculatory latencies were significantly prolonged after using various test drugs (placebo 2.27+/-0.32, SS-cream 0.05 g 4.47+/-0.81, 0.10 g 5.34+/-0.79, 0.15 g 6.22+/-0.87, 0.20 g 11.06+/-1.17 min, respectively). Clinical efficacies evaluated by ejaculatory latency were placebo 18%, SS-cream 0.05 g 30%, 0.10 g 60%, 0.15 g 54%, 0.20 g 84%, respectively. The satisfaction rate was also significantly increased dose-dependently (placebo 26%, SS-cream 0.05 g 60%, 0.10 g 70%, 0.15 g 78%, 0.20 g 90%, respectively). A side effect such as local mild burning sensation was noted in 35/250 times (14%) and no adverse effect on sexual function and no systemic side effects were observed. From the result of logistic regression analysis on clinical efficacy, the ED50 of SS-cream was obtained as 0.10 g. SS-cream 0.20 g was effective in 84% without any serious systemic side effects. CONCLUSION: From the above results, our conclusions are that SS-cream is effective on the treatment of PE with a few local side effects and that clinical optimal dose of SS-cream is 0.20 g.

Ibogaine acts at the nicotinic acetylcholine receptor to inhibit catecholamine release.

In an effort to determine mechanisms of action of the putative anti-addictive agent ibogaine, we have measured its effects on catecholamine release in a model neuronal system, cultured bovine chromaffin cells. Various modes of stimulating catecholamine release were used including nicotinic ACh receptor activation, membrane depolarization with elevated K+ and Na+ channel activation with veratridine. In addition, because ibogaine has been reported to interact with kappa opioid receptors, we tested whether kappa receptor antagonists could reverse ibogaine's effects on catecholamine release. Ibogaine, at low concentration (<10 microM) was found to selectively inhibit nicotinic receptor-mediated catecholamine release, while having no significant effect on release evoked by either veratridine or membrane depolarization with elevated K+. The inhibitory actions of ibogaine and the kappa agonists were not reversed by preincubation with the opioid antagonists nor-binaltorphimine or naltrexone, suggesting that these inhibitory effects are not mediated by the kappa opioid receptor. The effects of low dose (10 microM) ibogaine were rapidly reversible, while the inhibitory effects of higher ibogaine doses persisted for at least 19 h following ibogaine washout. The results provide evidence for a mechanism of action ibogaine at the nicotinic ACh receptor. The results are consistent with a model in which the initial high transient brain concentrations (100 microM) of ibogaine act at multiple cellular sites and then have a selective action at the nicotinic ACh receptor cation channel following its metabolism to lower brain concentrations. The present findings are relevant to potential anti-addictive actions of ibogaine and to the development of drugs to combat nicotine addiction.

Differential expression and function of cadherin-6 during renal epithelium development.

The cadherin gene family encodes calcium-dependent adhesion molecules that promote homophilic interactions among cells. During embryogenesis, differential expression of cadherins can drive morphogenesis by stimulating cell aggregation, defining boundaries between groups of cells and promoting cell migration. In this report, the expression patterns of cadherins were examined by immunocytochemistry and in situ hybridization in the embryonic kidney, during the time when mesenchymal cells are phenotypically converted to epithelium and the pattern of the developing nephrons is established. At the time of mesenchymal induction, cadherin-11 is expressed in the mesenchyme but not in the ureteric bud epithelium, which expresses E-cadherin. The newly formed epithelium of the renal vesicle expresses E-cadherin near the ureteric bud tips and cadherin-6 more distally, suggesting that this primitive epithelium is already patterned with respect to progenitor cell types. In the s-shaped body, the cadherin expression patterns reflect the developmental fate of each region. The proximal tubule progenitors express cadherin-6, the distal tubule cells express E-cadherin, whereas the glomeruli express P-cadherin. Ultimately, cadherin-6 is down-regulated whereas E-cadherin expression remains in most, if not all, of the tubular epithelium. Antibodies generated against the extracellular domain of cadherin-6 inhibit aggregation of induced mesenchyme and the formation of mesenchyme-derived epithelium but do not disrupt ureteric bud branching in vitro. These data suggest that cadherin-6 function is required for the early aggregation of induced mesenchymal cells and their subsequent conversion to epithelium.

Immunoreactivity of androgen receptor protein in sexually dimorphic spinal motonucleus in neonatal male rats.

The spinal motonucleus of the genitofemoral nerve regulating scrotal temperature can also be related to prenatal and neonatal testicular descent by gubernacular change in rats, and a sexually dimorphic-like bulbocavernosus/dorsolateral motonucleus. There is a hypothesis that neonatal androgen affects these motonuclei, and induces development of sexual organs through neural stimulation. Until now, the accumulation of isotope-labelled androgen and the immuno-reactivity of androgen receptor protein in each sexually-dimorphic spinal motonucleus have been revealed in adult rats but they have not been established in rats during neonatal periods. To investigate the presence of the androgen receptor in spinal sexually-dimorphic motonuclei in the neonatal period, we evaluated the androgen receptor immunoreactivity of these motonuclei. In Sprague-Dawley male rats, the lumbar spinal cords were resected at postnatal days 3, 10 and 30, and stained immunohistochemically using polyclonal antibody of androgen receptor protein. The immunoreactivity of androgen receptor protein was observed in the cells of the genitofemoral motonucleus from the 13th thoracic to the 2nd lumbar spinal cord and the bulbocavernosus/dorsolateral motonucleus was observed from the 4th to 5th lumbar spinal cord in all age groups. The proportional areas of both motonuclei at days 3 and 10 on cross-section were larger than at day 30. The motonuclei at days 3 and 10 were similar in all age groups. With the above results, the presence of androgen receptor protein was confirmed in the genitofemoral and bulbocavernosus/dorsolateral motonucleus from neonate to day 30. The larger proportional area of these motonuclei in neonates may indicate an active role for these motonuclei during the neonatal period. Although the immunoreactivity does not directly imply the presence of a functional receptor, neonatal androgen could be responsible for the development of sexual organs through the spinal motonucleus.