Thermoregulation, scratch, itch and sleep deficits in children with eczema.

Successful sleep onset and maintenance is associated with a reduction in core temperature, facilitated by heat loss at the distal periphery. Problems with initiating and maintaining sleep in children with eczema may relate to impaired thermoregulatory mechanisms, which also contribute to itching and scratching. Our hypothesis was that nocturnal distal skin temperature in eczematous children would be lower than controls, and would also be related to poor sleep quality. We compared overnight polysomnography and distal (finger) and proximal (clavicle) skin temperature in 18 children with eczema and 15 controls (6-16 years). Children with eczema had longer periods of nocturnal wakefulness (mean [SD] = 88.8 [25.8] vs. 44.3 [35.6] min) and lower distal temperatures (34.1 [0.6] °C vs. 34.7 [0.4] °C) than controls, whereas proximal temperature and the distal-proximal gradient were not significantly different. In children with eczema, a higher distal temperature was associated with indicators of poor sleep quality, whereas lower distal temperature was related to more scratching events during sleep. In conclusion, our findings indicate complex interrelationships among eczema, thermoregulation and sleep, and further, that deficits in thermoregulatory mechanisms may contribute to sleep disturbances in children with eczema.

Experimental design and reporting standards for improving the internal validity of pre-clinical studies in the field of pain: Consensus of the IMI-Europain consortium.

Background and aims Pain is a subjective experience, and as such, pre-clinical models of human pain are highly simplified representations of clinical features. These models are nevertheless critical for the delivery of novel analgesics for human pain, providing pharmacodynamic measurements of activity and, where possible, on-target confirmation of that activity. It has, however, been suggested that at least 50% of all pre-clinical data, independent of discipline, cannot be replicated. Additionally, the paucity of "negative" data in the public domain indicates a publication bias, and significantly impacts the interpretation of failed attempts to replicate published findings. Evidence suggests that systematic biases in experimental design and conduct and insufficiencies in reporting play significant roles in poor reproducibility across pre-clinical studies. It then follows that recommendations on how to improve these factors are warranted. Methods Members of Europain, a pain research consortium funded by the European Innovative Medicines Initiative (IMI), developed internal recommendations on how to improve the reliability of pre-clinical studies between laboratories. This guidance is focused on two aspects: experimental design and conduct, and study reporting. Results Minimum requirements for experimental design and conduct were agreed upon across the dimensions of animal characteristics, sample size calculations, inclusion and exclusion criteria, random allocation to groups, allocation concealment, and blinded assessment of outcome. Building upon the Animals in Research: Reportingin vivo Experiments (ARRIVE) guidelines, reporting standards were developed for pre-clinical studies of pain. These include specific recommendations for reporting on ethical issues, experimental design and conduct, and data analysis and interpretation. Key principles such as sample size calculation, a priori definition of a primary efficacy measure, randomization, allocation concealments, and blinding are discussed. In addition, considerations of how stress and normal rodent physiology impact outcome of analgesic drug studies are considered. Flow diagrams are standard requirements in all clinical trials, and flow diagrams for preclinical trials, which describe number of animals included/excluded, and reasons for exclusion are proposed. Creation of a trial registry for pre-clinical studies focused on drug development in order to estimate possible publication bias is discussed. Conclusions More systematic research is needed to analyze how inadequate internal validity and/or experimental bias may impact reproducibility across pre-clinical pain studies. Addressing the potential threats to internal validity and the sources of experimental biases, as well as increasing the transparency in reporting, are likely to improve preclinical research broadly by ensuring relevant progress is made in advancing the knowledge of chronic pain pathophysiology and identifying novel analgesics. Implications We are now disseminating these Europain processes for discussion in the wider pain research community. Any benefit from these guidelines will be dependent on acceptance and disciplined implementation across pre-clinical laboratories, funding agencies and journal editors, but it is anticipated that these guidelines will be a first step towards improving scientific rigor across the field of pre-clinical pain research.

Development and pharmacological characterization of a model of sleep disruption-induced hypersensitivity in the rat.

BACKGROUND: Sleep disturbance is a commonly reported co-morbidity in chronic pain patients, and conversely, disruption of sleep can cause acute and long-lasting hypersensitivity to painful stimuli. The underlying mechanisms of sleep disruption-induced pain hypersensitivity are poorly understood. Confounding factors of previous studies have been the sleep disruption protocols, such as the 'pedestal over water' or 'inverted flower pot' methods, that can cause large stress responses and therefore may significantly affect pain outcome measures. METHODS: Sleep disruption was induced by placing rats for 8 h in a slowly rotating cylindrical cage causing arousal via the righting reflex. Mechanical (Von Frey filaments) and thermal (Hargreaves) nociceptive thresholds were assessed, and plasma corticosterone levels were measured (mass spectroscopy). Sleep disruption-induced hypersensitivity was pharmacologically characterized with drugs relevant for pain treatment, including gabapentin (30 mg/kg and 50 mg/kg), Ica-6p (Kv7.2/7.3 potassium channel opener; 10 mg/kg), ibuprofen (30 mg/kg and 100 mg/kg) and amitriptyline (10 mg/kg). RESULTS: Eight hours of sleep disruption caused robust mechanical and heat hypersensitivity in the absence of a measurable change in plasma corticosterone levels. Gabapentin had no effect on reduced nociceptive thresholds. Ibuprofen attenuated mechanical thresholds, while Ica-6p and amitriptyline attenuated only reduced thermal nociceptive thresholds. CONCLUSIONS: These results show that acute and low-stress sleep disruption causes mechanical and heat hypersensitivity in rats. Mechanical and heat hypersensitivity exhibited differential sensitivity to pharmacological agents, thus suggesting dissociable mechanisms for those two modalities. Ultimately, this model could help identify underlying mechanisms linking sleep disruption and hypersensitivity.

Postnatal depression mediates the relationship between infant and maternal sleep disruption and family dysfunction.

BACKGROUND: Previous research has linked family sleep disruption and dysfunction in children; however, the mechanism is unknown. AIMS: This study examined whether maternal sleep and postnatal depression (PND) mediate the relationship between infant sleep disruption and family dysfunction. STUDY DESIGN AND PARTICIPANTS: Mothers of infants aged 12 months old (N=111; 48% male) completed infant and parent sleep surveys, the Edinburgh Postnatal Depression Scale and the Family Assessment Device. RESULTS: Poor infant sleep was related to poor maternal sleep, which was associated with higher PND and higher level of family dysfunction. CONCLUSIONS: Results are consistent with the proposition that identification of both infant and maternal sleep problems during infancy can be relevant to reduction of PND and improved family functioning.

Parent versus teacher report of daytime behavior in snoring children.

PURPOSE: Problematic behavior is widely reported in children with sleep-disordered breathing (SDB). Daytime behavior is an important component in the evaluation of clinical history in SDB; however, there is a reliance on parental report alone, and it is unclear whether reports by teachers will aid diagnosis. METHODS: We assessed sleep and behavior reported by both parents and teachers in 19 children with SDB and 27 non-snoring controls. All children were screened for prior diagnoses of other medical and/or behavior and learning disorders and underwent polysomnography and both parental and teacher assessment of behavior. RESULTS: Both parents and teachers report greater problematic behavior in SDB children, predominantly of an internalizing nature. Despite this consistency and moderate correlation between informants, the agreement between parent and teacher reports of individual child behavior was poor when assessed using Bland-Altman plots. CONCLUSIONS: Clinicians should be mindful that the behavioral history of a child being evaluated for SDB may vary depending on whether parent or teacher report is being discussed as this may influence clinical decision making.

The effect of posterior spinal fusion on respiratory function in Duchenne muscular dystrophy.

PURPOSE: Posterior instrumented spinal fusion is indicated for progressive scoliosis that develops in Duchenne muscular dystrophy (DMD) patients. Whilst spinal fusion is known to improve quality of life, there is inconsistency amongst the literature regarding its specific effect on respiratory function. Our objective was to determine the effect of scoliosis correction by posterior spinal fusion on respiratory function in a large cohort of patients with DMD. Patients with DMD undergoing posterior spinal fusion were compared to patients with DMD not undergoing surgical intervention. METHODS: An observational study of 65 patients with DMD associated scoliosis, born between 1961 and 2001: 28 of which underwent correction of scoliosis via posterior spinal fusion (Surgical Group) and 37 of which did not undergo surgical intervention (Non-Surgical Group). Pulmonary function was assessed using traditional spirometry. Comparisons were made between groups at set times, and by way of rates of change over time. RESULTS: There was no correlation between the level of respiratory dysfunction and the severity of scoliosis (as measured by Cobb angle) for the whole cohort. The Surgical Group had significantly worse respiratory function at a comparable age pre-operatively compared to the Non-Surgical Group, as measured by per cent predicted forced vital capacity (p = 0.02) on spirometry. The rate of decline of forced vital capacity and per cent predicted forced vital capacity was not slowed following surgery compared to the non-operated cases. There was no significant difference in survival between the two groups. CONCLUSIONS: Severity of scoliosis was not a key determinant of respiratory dysfunction. Posterior spinal fusion did not reduce the rate of respiratory function decline. These two points suggest that intrinsic respiratory muscle weakness is the main determinant of decline in respiratory function in DMD.

Psychometric properties of an omnibus sleep problems questionnaire for school-aged children.

OBJECTIVE: There is a paucity of sleep questionnaires that have been psychometrically validated for use in school-aged children. Due to the limitation regarding the psychometric properties and the great variety in question design, there remains a need for a robust omnibus questionnaire that assesses sleep problems in community populations. This study aimed to develop such a questionnaire for school-aged children by assessing the construct validity and reliability of a questionnaire based on a combination of children's sleep domains from two frequently used and validated questionnaires (Habits Questionnaire and Sleep Disorders Scale for Children) and author devised questions. PATIENTS/METHODS: Parents of 1904 children aged 5-10 years (mean 7.7 ± 1.7 years) from 32 elementary schools in Adelaide, South Australia, completed the questionnaire. RESULTS: Principal axis factoring revealed six unique sub-scales--Sleep Routine, Bedtime Anxiety, Morning Tiredness, Night Arousals, Sleep Disordered Breathing, and Restless Sleep--containing a total of 26 items. Internal consistency for sub-scales were moderate to strong (range α = 0.6-0.8) and test-retest reliability was adequate (>0.4). T-score cut-offs were devised for age and sex. CONCLUSION: The new questionnaire provides a robust set of sleep problem sub-scales which can be used for assessment of sleep concerns in a community sample as well as provide for optimal analysis of associations with other measures of childhood daytime functioning such as neurocognition and behaviour.

Snoring and cognitive development in infancy.

OBJECTIVE: This study aimed to assess the influence of snoring and sleep duration on developmental outcomes in 6 month old infants. METHODS: As part of a longitudinal study of snoring in infancy, we identified 16 children (13 males) who commenced snoring shortly after birth and continued to snore frequently (≥ 3 nights/week) at 6 months of age and 88 healthy infant controls who were reported never to snore in the absence of a cold (36 males). Infants were assessed at 6 months of age with the Bayley Scales of Infant and Toddler Development Edition III, and parents completed demographic, sleep, and developmental surveys. RESULTS: Cognitive development was reduced in infants who snored frequently (mean=95.3; SD=4.3) from the first month of life compared to control infants (mean=100.6; SD=3.9) (F [1, 99]=23.8, p<.01; η(p)(2)=.21). CONCLUSION: Snoring during the first 6 months of life was associated with lower cognitive development scores. It is unknown whether these infants will continue to snore through childhood and, if so, whether the associated neurocognitive deficits will become worse with time.

Parental-reported snoring from the first month of life and cognitive development at 12 months of age.

OBJECTIVE: The aim of the present study was to evaluate the effect of persistent snoring in the first year of life on developmental outcomes. METHODS: As part of a longitudinal study of snoring and sleep in infancy, we identified 13 children (10 males) who commenced snoring shortly after birth and continued to snore frequently (≥ 3 nights/week) at 6 and 12 months of age and 78 controls (31 males) who were reported by parents to never snore in the absence of a cold. Infants were assessed with the Bayley Scales of Infant and Toddler Development Edition III and parents completed demographic and sleep questionnaires. RESULTS: Infants reported to snore frequently from the first month of life and who continued to snore frequently until 12 months of age had significantly lower cognitive development scores (mean=94.2; SD=3.9) compared to controls (mean=100.6; SD=3.7) (F (1, 96)=40 6, p<0.001; η(p)(2)=0.32). CONCLUSION: Persistent frequent snoring from the first month of life was associated with lower cognitive development scores at 12 months of age. It is possible that this deficit will become worse with age.

Prevalence of snoring and associated factors in infancy.

INTRODUCTION: In children aged 3-12 years snoring is associated with significant neurocognitive and behavioural deficits; however, there are few studies that have considered both the prevalence of snoring in infants and associated factors that may influence the development of snoring. The goal of the present study was to examine sleep, snoring and associated factors in a community sample of 0-3 month olds. METHODS: Previously validated infant sleep and parent sleep questionnaires were completed by parents of 457 term infants aged 1-13.9 weeks old (mean age=4.6 weeks; SD=2.7; 45% males) during a home-based nurse visit. RESULTS: Approximately 9% of infants were reported to snore habitually (snoring ≥ 3 nights/week). Habitual snoring was significantly associated with exclusive formula feeding (OR: 28.87; p<.01), maternal concern about child's breathing during sleep (OR: 3.91; p=.01) and restless sleep ≥ 3 nights/week (OR: 17.76; p<.001). CONCLUSION: These results show that snoring is as common in infants as it is in older children. Given the known relationships between Sleep Disordered Breathing (SDB) and neurocognitive development, the effect of SDB developing early in childhood may have important consequences on future developmental outcomes.

WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression.

BACKGROUND AND PURPOSE: Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity. EXPERIMENTAL APPROACH: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one). KEY RESULTS: WAY-318068 is a potent and effective inhibitor of the NET with a K(i) of 8.7 nM in a binding assay, and an IC(50) of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits. CONCLUSIONS AND IMPLICATIONS: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.

Inhibition of osteoclasts prevents cartilage loss and pain in a rat model of degenerative joint disease.

OBJECTIVE: To investigate the relationship between efficacy of a bisphosphonate, pain and extent of joint damage in the monosodium iodoacetate (MIA) model of painful degenerative joint disease. METHODS: Zoledronate treatment was initiated prior to and at various times following model induction, including late time points representing advanced disease. Radiographic and histological structural parameters were correlated with pain as measured by weight bearing. RESULTS: Intraarticular (IA) MIA resulted in a progressive loss of bone mineral density (BMD) and chondrocytes, thinning of cartilage, loss of proteoglycan, resorption of calcified cartilage and subchondral bone, as well as pain. This was completely prevented by pre-emptive chronic zoledronate treatment with joint sections being histologically indistinguishable from saline-injected controls. When initiation of treatment was delayed efficacy was reduced. In animals with advanced joint degeneration, treatment partially restored BMD and had a significant, but limited, effect on pain. We confirmed these radiographic and behavioral findings in the medial meniscal tear model. To understand the mechanism-of-action of zoledronate we investigated an early time point 4 days post-model induction when chondrocytes were histologically viable, with minor loss of proteoglycan and generalized synovitis. Osteoclast-mediated resorption of the calcified cartilage was observed and was prevented by two doses of zoledronate. CONCLUSION: Subchondral bone remodeling plays an important role in nociception and the pathobiology of the MIA model with osteoclasts being implicated in both bone and cartilage resorption. Inhibition of osteoclastic activity when initiated early leads to improved efficacy.

Species-specific in vitro pharmacological effects of the cannabinoid receptor 2 (CB2) selective ligand AM1241 and its resolved enantiomers.

BACKGROUND AND PURPOSE: Racemic (R,S) AM1241 is a cannabinoid receptor 2 (CB(2))-selective aminoalkylindole with antinociceptive efficacy in animal pain models. The purpose of our studies was to provide a characterization of R,S-AM1241 and its resolved enantiomers in vitro and in vivo. EXPERIMENTAL APPROACH: Competition binding assays were performed using membranes from cell lines expressing recombinant human, rat, and mouse CB(2) receptors. Inhibition of cAMP was assayed using intact CB(2)-expressing cells. A mouse model of visceral pain (para-phenylquinone, PPQ) and a rat model of acute inflammatory pain (carrageenan) were employed to characterize the compounds in vivo. KEY RESULTS: In cAMP inhibition assays, R,S-AM1241 was found to be an agonist at human CB(2), but an inverse agonist at rat and mouse CB(2) receptors. R-AM1241 bound with more than 40-fold higher affinity than S-AM1241, to all three CB(2) receptors and displayed a functional profile similar to that of the racemate. In contrast, S-AM1241 was an agonist at all three CB(2) receptors. In pain models, S-AM1241 was more efficacious than either R-AM1241 or the racemate. Antagonist blockade demonstrated that the in vivo effects of S-AM1241 were mediated by CB(2) receptors. CONCLUSIONS AND IMPLICATIONS: These findings constitute the first in vitro functional assessment of R,S-AM1241 at rodent CB(2) receptors and the first characterization of the AM1241 enantiomers in recombinant cell systems and in vivo. The greater antinociceptive efficacy of S-AM1241, the functional CB(2) agonist enantiomer of AM1241, is consistent with previous observations that CB(2) agonists are effective in relief of pain.

Sleep-disordered breathing in Prader-Willi syndrome and its association with neurobehavioral abnormalities.

OBJECTIVES: To determine the prevalence and type of sleep-disordered breathing among patients with Prader-Willi syndrome (PWS) and its relationship to such neurobehavioral abnormalities as mental retardation, obsessive-compulsive behavior, and conduct disorders. STUDY DESIGN: Polysomnography (PSG) studies were conducted in 13 unselected subjects with PWS (age 1.5 to 28 years). PSG results were compared with tests of behavior and cognition (Development Behavior Checklist [DBC], Auditory Continuous Performance Test [ACPT], and Wechsler Intelligence Scale appropriate for age). RESULTS: Nine of 13 (69%) subjects had > 10 apneas and hypopneas per hour of sleep. Apart from a 2-year-old subject with normal body weight who demonstrated severe central hypopnea in rapid eye movement sleep, the sleep-breathing disturbance was due to upper airway obstruction. Age-adjusted body mass index was associated with more severe hypoxemia during sleep (min SaO2, r = -.87, P < .005) and more sleep disruption (arousals/hour of sleep, r = .62, P < .05; sleep efficiency, r = -.66, P < .05). Increasing severity of obstructive sleep apnea (OSA) or sleep disturbance was associated with daytime inactivity/sleepiness and autistic-relating behavior (DBC) and with impulsiveness (ACPT). Unexpectedly, sleep hypoxemia appeared to be predictive of increased performance IQ. CONCLUSIONS: OSA is prevalent among subjects with PWS and is associated with increased body mass, daytime inactivity/ sleepiness, and some behavioral disturbances.

Sirolimus-mediated prolongation of rat cardiac allograft survival is enhanced by beta1 integrin very late antigen-4 blockade.

The beta1 integrin very late antigen-4 (VLA-4) plays a key role in lymphocyte rolling and adhesion to endothelium, and in lymphocyte migration through fibronectin. Thus, VLA-4 blockade may modulate allograft rejection. Here, we examined the effect of WAY-279, a small molecule VLA-4 antagonist, combined with sirolimus in a model of vascularized heart allograft (BN --> LEW) in the rat. Recipients were treated with low doses of WAY-279 (10-50 mg/kg, bid) and/or sirolimus (0.04 mg/kg) for 14 days, starting on the day of transplantation. The median-effect principle and the combination index (CI) were used to assess the combined effect of WAY-279 and sirolimus (CI < 1: synergism; CI = 1: summation; CI > 1 antagonism). Low doses of WAY-279 or sirolimus alone slightly prolonged allograft survival as compared to control group (MST = 7 days). When recipients were treated with WAY-279 and sirolimus, the cardiac allograft survival was synergistically prolonged for up to 45 days (P < .001; CI = 0.174-0.970). We showed that a concomitant treatment of WAY-279 with sirolimus produced a synergistic effect in prolonging cardiac allograft survival in the rat.

Reduced neurocognition in children who snore.

Obstructive sleep apnea syndrome (OSAS) has been associated with reduced neurocognitive performance in children, but the underlying etiology is unclear. The aim of this study was to evaluate the relationship between hypoxemia, respiratory arousals, and neurocognitive performance in snoring children referred for adenotonsillectomy. Thirteen snoring children who were referred for evaluation regarding the need for adenotonsillectomy to a children's hospital otolaryngology/respiratory department underwent detailed neurocognitive and polysomnographic (PSG) evaluation. PSGs were evaluated for respiratory abnormalities and compared with 13 nonsnoring control children of similar age who were studied in the same manner. The snoring children had an obstructive respiratory disturbance index within normal range (mean obstructive apnea/hypopnea index, 0.6/hr). Despite this, several domains of neurocognitive function were reduced in the snoring group. These included mean verbal IQ scores (snorers 92.6 vs. nonsnorers 110.2, P < 0.001), mean global IQ scores (snorers 96.7 vs. nonsnorers 110.2, P < 0.005), mean selective attention scores (snorers 46.4 vs. nonsnorers 11.8, P < 0.001), mean sustained attention scores (snorers 8.0 vs. nonsnorers 2.2, P = 0.001), and mean memory index (snorers 95.2 vs. nonsnorers 112.1, P = 0.001). There was a direct relationship between number of mild oxygen desaturations of > or = 3%, obstructive hypopneas with > or = 3% oxygen desaturations, and respiratory arousals and severity of neurocognitive deficits, with the greatest effect being on memory scores. The disruption of sleep in snoring children produced by relatively mild changes in oxygen saturation or by increases in respiratory arousals may have a greater effect on neurocognitive function than hitherto appreciated. A possible explanation for these neurocognitive deficits may be the combination of the chronicity of sleep disruption secondary to snoring which is occurring at a time of rapid neurological development in the first decade of life. Future studies need to confirm the reversal of these relatively mild neurocognitive decrements post adenotonsillectomy.

The nido-osmaboranes [2,2,2-(CO)(PPh(3))(2)-nido-2-OsB(5)H(9)] and [6,6,6-(CO)(PPh(3))(2)-nido-6-OsB(9)H(13)].

The structural characterization of the osmahexaborane 2-carbonyl-2,2-bis(triphenylphosphine)-nido-2-osmahexaborane(9), [Os(B(5)H(9))(C(18)H(15)P)(2)(CO)], (I), a metallaborane analogue of B(6)H(10), confirms the structure proposed from NMR spectroscopy. The structure of the osmadecaborane 6-carbonyl-6,6-bis(triphenylphosphine)-nido-6-osmadecaborane(13), [Os(B(9)H(13))(C(18)H(15)P)(2)(CO)], (IV), is similarly confirmed. The short basal B-B distance of 1.652 (8) A in (I), not bridged by an H atom, mirrors that in the parent hexaborane(10) [1.626 (4) A].

Isomeric icosaboranes B20H26: the synchrotron structure of 1,1'-bis(nido-decaboranyl).

An isomer of B20H26, isolated from the autolysis of nido-B10H14 in a silent electrical discharge, is shown to be the title compound 1,1'-bis(nido-decaboranyl). The molecule has crystallographic inversion symmetry and a long intercage B-B bond of 1.704 (3) A.

Ten-vertex rhodadithiaborane chemistry:.

Neutral 8-(5-iodo-n-pentyl)-3-(eta(5)-pentamethylcyclopentadienyl)-arachno-3-rhoda-7,8-dithiaundecaborane, [Rh(C(5)H(19)B(8)IS(2))(C(10)H(15))], obtained from the [arachno-7,8-S(2)B(9)H(10)](-) anion by treatment with I(CH(2))(5)I followed by [Rh(C(5)Me(5))Cl(2)](2) and N,N,N',N'-tetramethyl-1,8-diaminonaphthalene, has the 11-vertex cluster geometry of [arachno-7,8-S(2)B(9)H(10)](-), but with an [Rh(C(5)Me(5))] unit in the 3-position instead of a [BH] unit, and with a -(CH(2))(5)I chain attached exo to an S atom.

beta -Amyloid peptide-induced apoptosis regulated by a novel protein containing a g protein activation module.

Degeneration of neurons in Alzheimer's disease is mediated by beta-amyloid peptide by diverse mechanisms, which include a putative apoptotic component stimulated by unidentified signaling events. This report describes a novel beta-amyloid peptide-binding protein (denoted BBP) containing a G protein-coupling module. BBP is one member of a family of three proteins containing this conserved structure. The BBP subtype bound human beta-amyloid peptide in vitro with high affinity and specificity. Expression of BBP in cell culture induced caspase-dependent vulnerability to beta-amyloid peptide toxicity. Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to beta-amyloid peptide mediated toxicity. These findings suggest that BBP is a target of neurotoxic beta-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease.