Adults with Down syndrome: a comprehensive approach to manage complexity.

BACKGROUND: Down syndrome (DS) is characterised by premature ageing that affects selected organ systems, and persons with this condition can present patterns of co-morbidities and deficits often observed in the older population without DS. However, information on the characteristics of adult persons with DS is limited. The objective of the study is to describe characteristics of adults with DS collected with a standardised, comprehensive assessment instrument. METHODS: Cross-sectional study. Four hundred thirty adults with DS (age range 18/75 years) from three countries (Italy, n = 95; USA, n = 175; and Canada, n = 160). A standardised assessment instrument (interRAI intellectual disability) was used to assess sample characteristics. RESULTS: Mean age ranged from 35.2 (standard deviation 12.0) years in the US sample to 48.8 (standard deviation 9.0) years in the Canadian sample. Most participants in the Italian and US sample were living in private homes, while more than half of those in the Canadian sample were institutionalised. Prevalences of geriatric conditions, including cognitive deficits, disability in the common activities of daily living, symptoms of withdrawal or anhedonia, aggressive behaviour, communication problems, falls and hearing problems were high in the study sample. Gastrointestinal symptoms, skin and dental problems and obesity were also frequently observed. CONCLUSIONS: Adults with DS present with a high level of complexity, which may suggest the need for an approach based on a comprehensive assessment and management that can provide adequate care. Further research is needed to understand better the effectiveness of such an approach in the DS population.

Bone mineral density in adults with Down syndrome.

This study analyzed data of bone mineral density (BMD) from a large cohort of adults with Down syndrome (DS). BMD was found to decrease with age more rapidly in these subjects than in the general population, exposing adults with DS to an increased risk of osteoporosis and bone fracture. INTRODUCTION: Down syndrome (DS) in adulthood presents with a high prevalence of osteoporosis. However, in DS, bone mineral density (BMD) can be underestimated due to short stature. Furthermore, the rate of age-related decline in BMD and its association with gender in DS has been rarely evaluated or compared with the general population. The present study is aimed at assessing the variation of BMD with age and gender in a sample of adults with DS and to compare these data with those of the general population, after adjusting for anthropometric differences. METHODS: Adults with DS, aged 18 or older, were assessed dual-energy-X-ray-absorptiometry (DXA) at the femoral neck and at the lumbar spine. They were compared with the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 2009-2010 dataset. Bone mineral apparent density (BMAD) was calculated for each individual. RESULTS: DXA was evaluated in 234 subjects with DS (mean age 36.93 ± 11.83 years, ranging from 20 to 69 years; 50.4% females). In the lumbar spine both mean BMD (DS 0.880 ± 0.141 vs. NHANES 1.062 ± 0.167, p < 0.001) and BMAD (DS 0.138 ± 0.020 vs. NHANES 0.152 ± 0.020, p < 0.001) were significantly lower in the DS sample than in the NAHNES cohort. The same trend was observed at the femoral neck in both BMD (DS 0.658 ± 0.128 vs. NHANES 0.835 ± 0.137, p < 0.001) and BMAD (DS 0.151 ± 0.030 vs. NHANES 0.159 ± 0.028, p<0.001). Age was associated with lower femoral neck BMAD in both samples; importantly, this association was significantly stronger in the DS sample. In the lumbar spine region, no significant association between BMAD and age could be observed in both samples. CONCLUSIONS: Adults with DS have lower bone mineral density compared to the general population and they experience a steeper decline with age. Early screening programs are needed in DS population.

Synergistic enhancement of the acoustic startle reflex by dopamine D1 and 5-HT1A agonists and corresponding changes in c-Fos expression in the dorsal raphe of rats.

RATIONALE AND OBJECTIVES: Several studies have reported an increase in dopamine (DA)-stimulated behavioral responses after manipulations that reduce brain serotonin (5-hydroxytryptamine, 5-HT) levels. Because others have shown that systemic administration of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) reduces 5-HT levels throughout the brain, we tested the effects of 8-OH-DPAT on the enhancement of the acoustic startle reflex by the dopamine D1 receptor agonist SKF 82958. In addition, we used the expression of the c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes within the dorsal raphe (DR). METHODS AND RESULTS: Male Sprague-Dawley rats pretreated (10 min) with 8-OH-DPAT (0.5 mg/kg) showed a marked potentiation of the enhancement of startle by SKF 82958 (0.1 mg/kg). Furthermore, SKF 82958 produced a dramatic induction of c-Fos in the DR, an effect that was blocked by 8-OH-DPAT. Double-labeling immunohistochemistry for c-Fos and 5-HT showed that SKF 82958-induced expression of c-Fos, and its blockade by 8-OH-DPAT, occurred in a percentage of 5-HT-containing cells of the DR. CONCLUSIONS: These data suggest the possibility that inhibition of the DR by 8-OH-DPAT mediates the potentiation of startle by SKF 82958, perhaps through a reduction in 5-HT release in the striatum. Such an interpretation is consistent with the hypothesis of an inhibitory role of the 5-HT system on DA-mediated behaviors.

Enhancement of the acoustic startle response by dopamine agonists after 6-hydroxydopamine lesions of the substantia nigra pars compacta: corresponding changes in c-Fos expression in the caudate-putamen.

Rats with 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway show enhanced locomotor and stereotyped behaviors when challenged with direct and indirect dopamine (DA) agonists due to the development of postsynaptic supersensitivity. To determine if this phenomenon generalizes to other motor behaviors, we have used this rat model of Parkinson's disease to examine the effects of the direct dopamine D(1) receptor agonist SKF 82958 and the indirect DA agonist L-3,4-dihydroxyphenylalanine (L-DOPA) on the acoustic startle response. In addition, we used the expression of c-Fos protein as a marker of neuronal activity to assess any corresponding drug-induced changes in the caudate-putamen (CPu) after L-DOPA administration. Male Sprague-Dawley rats received bilateral injections of 6-OHDA into the substantia nigra pars compacta and 1 week later were tested for startle after systemic administration of SKF 82958 (0.05 mg/kg) or L-DOPA (1, 5, 10 mg/kg). SKF 82958 produced a marked enhancement of startle with a rapid onset in 6-OHDA-lesioned but not SHAM animals. L-DOPA produced a dose- and time-dependent enhancement of startle in 6-OHDA-lesioned rats that had no effect in SHAM animals even at the highest dose (10 mg/kg). Furthermore, L-DOPA produced a dramatic induction of c-Fos in the CPu in 6-OHDA-lesioned animals. Consistent with other literature, these data suggest that neurons in the CPu become supersensitive to the effects of DA agonists after 6-OHDA-induced denervation of the nigrostriatal pathway and that supersensitive dopamine D(1) receptors may mediate the enhancement of startle seen in the present study.

GABA in the deep layers of the superior Colliculus/Mesencephalic reticular formation mediates the enhancement of startle by the dopamine D1 receptor agonist SKF 82958 in rats.

GABA transmission in the deep layers of the superior colliculus/deep mesencephalic reticular formation (deep SC/Me) mediates several motor responses, including those expressed after systemic administration of dopamine agonists. In the present study we examined the role of the deep SC/Me in the modulation of the acoustic startle reflex and its enhancement by the dopamine D(1) agonist SKF 82958. Rats were implanted with bilateral cannulas into the deep SC/Me or superficial layers of the SC (super SC) and 1 week later were infused with various compounds. The GABA(A) antagonist bicuculline (0, 5, and 10 ng) produced a dose- and time-dependent enhancement of startle after infusion into the deep SC/Me, but not the super SC. Infusion of the GABA(A) agonist muscimol (0.1 microg) into the deep SC/Me, but not the super SC, blocked the enhancement of startle by systemic SKF 82958 (1 mg/kg) but had no effect on baseline startle by itself. This effect was not produced by infusion of the D(1) antagonist SCH 23390(1 microg) or the glutamate antagonist NBQX (0.1 microg). Deposits of FluoroGold into the deep SC/Me, combined with immunohistochemistry for glutamic acid decarboxylase (GAD), confirmed a direct GABAergic input from the substantia nigra pars reticulata (SNr) to the deep SC/Me. These results suggest that GABA tone in the deep SC/Me modulates the expression of startle as well as the enhancement of startle by dopamine D(1) agonists. On the basis of these data and previous work, we have proposed a striatonigral-tectal-reticular neural pathway mediating the effects of dopamine D(1) agonists on startle.

Enhancement of the acoustic startle response in rats by the dopamine D1 receptor agonist SKF 82958.

RATIONALE: The present series of experiments was conducted in order to assess the nature of dopaminergic modulation of the acoustic startle response using agonists and antagonists specific for dopamine D1 and D2 receptors. OBJECTIVES: The objective of the present study was to demonstrate an enhancement of the acoustic startle response by dopamine D1 receptor agonists and to characterize this effect pharmacologically in terms of dose-response and selective antagonism at both the dopamine D1 and D2 receptor using a varied range of startle-eliciting intensities. METHODS: Male Sprague-Dawley rats were injected subcutaneously with the dopamine D1 receptor agonist SKF 82958 (0, 0.01, 0.1, 1, or 3 mg/kg) or SKF 81297 (3 mg/kg) and their startle response was measured across a range of startle-eliciting intensities. For testing with the dopamine D1 or D2 receptor antagonists, animals received injections of either SCH 23390 (0.01 and 0.1 mg/kg) or raclopride (0.1 and 1 mg/kg) 10 min before the challenge with SKF 82958 (1 mg/kg). RESULTS: Systemic administration of SKF 82958 produced a marked enhancement of startle over a wide range of startle intensities. This effect was dose-dependent, with a dose of 1 mg/kg producing the maximal amount of startle enhancement at each intensity. SKF 81297 (3 mg/kg) also produced a robust enhancement of startle. Pretreatment with SCH 23390 produced a dose-dependent blockade of the enhancement of startle by SKF 82958. Pretreatment with raclopride blocked the enhancement of startle by SKF 82958 at the low intensities and attenuated the enhancement at the high intensities. CONCLUSIONS: These data suggest that dopamine D1 receptor agonists enhance the acoustic startle response. Furthermore, this effect is dependent on a cooperative type of D1/D2 receptor interaction whereby D2 receptor activation is necessary for the full expression of the D1 receptor-mediated enhancement of startle.

Muscimol in the deep layers of the superior colliculus/mesencephalic reticular formation blocks expression but not acquisition of fear-potentiated startle in rats.

Deposits of the retrograde tracer Fluoro-Gold into the ventrolateral nucleus reticularis pontis caudalis labeled neurons in the deep layers of the superior colliculus/mesencephalic reticular formation (deep SC/Me). To test the involvement of this area in the fear-potentiated startle effect, rats were implanted with cannulas into the deep SC/Me and trained for fear-potentiated startle after infusion of the GABA(A) agonist muscimol (0.1 microg/0.5 microl). Two days later, they were tested for fear-potentiated startle. Rats then received a 2nd training session without any infusions, and 2 days later they were reinfused with muscimol (0.1 microg/0.5 microl) and tested for fear-potentiated startle. Local infusion of muscimol into the deep SC/Me completely blocked the expression but not the acquisition of fear-potentiated startle. These results indicate that a synapse in the midbrain is critical for the expression of fear-potentiated startle.

The dorsal cochlear nucleus contributes to a high intensity component of the acoustic startle reflex in rats.

The dorsal cochlear nucleus (DCN) has been shown to project to a region of the nucleus reticularis pontis caudalis (PnC) critical for the evocation of startle in rats, suggesting a possible modulatory influence of the DCN on startle. This study examined the involvement of the DCN in the acoustic startle reflex and various other forms of behavioral plasticity seen with this response. Animals received bilateral electrolytic lesions of the DCN and were tested for acoustic startle responses, background noise facilitation, short-term habituation, prepulse inhibition and facilitation, and fear conditioning. Compared to sham lesioned rats, DCN lesioned rats showed a significant reduction in startle amplitude at the two highest startle-eliciting intensities (110 and 115 dB SPL) and normal responses on all other measures. Hence, the DCN appears to contribute to a high intensity component of the acoustic startle response in rats.

Localization of the effector-specifying regions of Gi2alpha and Gqalpha.

Heterotrimeric G proteins transmit hormonal and sensory signals received by cell surface receptors to effector proteins that regulate cellular processes. Members of the highly conserved family of alpha subunits specifically modulate the activities of a diverse array of effector proteins. To investigate the determinants of alpha subunit-effector specificity, we localized the effector-specifying regions of alphai2, which inhibits adenylyl cyclase, and alphaq, which stimulates phosphoinositide phospholipase C using chimeric alpha subunits. The chimeras were generated using an in vivo recombination method in Escherichia coli. The effector-specifying regions of both alphai2 and alphaq were localized within the GTPase domain. An alphaq/alphai2/alphaq chimera containing only 78 alphai2 residues within the GTPase domain robustly inhibited adenylyl cyclase. This alphai2 segment includes regions corresponding to two of the three regions of alphas that activate adenylyl cyclase, but does not include any of the alpha subunit regions that switch conformation upon binding GTP. Replacement of the alphaq residues that comprise the helical domain with the homologous alphai2 residues resulted in a chimeric alpha subunit that activated phospholipase C. Combined with previous studies of the effector-specifying residues of alphas and alphat, our results suggest that the effector specificity of alpha subunits is generally determined by the GTPase and not the helical domain.

A primary acoustic startle pathway: obligatory role of cochlear root neurons and the nucleus reticularis pontis caudalis.

Davis et al. (1982) proposed a primary acoustic startle circuit in rats consisting of the auditory nerve, posteroventral cochlear nucleus, an area near the ventrolateral lemniscus (VLL), nucleus reticularis pontis caudalis (PnC), and spinal motoneurons. Using fiber-sparing lesions, the present study reevaluated these and other structures together with the role of neurons embedded in the auditory nerve [cochlear root neurons (CRNs)], recently hypothesized to be involved in acoustic startle. Small electrolytic lesions of the VLL of ventrolateral tegmental nucleus (VLTg) failed to eliminate startle. Large electrolytic lesions including the rostral ventral nucleus of the trapezoid body (rVNTB) and ventrolateral parts of PnC or lesions of the entire PnC blocked startle. However, small NMDA-induced lesions of the rVNTB failed to block startle, making it unlikely that the rVNTB itself is part of the startle pathway. In contrast, NMDA lesions of the full extension of the ventrolateral part of the PnC blocked startle completely, suggesting that the ventrolateral part of the PnC is critically involved. Bilateral kainic acid lesions of CRNs also blocked the startle reflex completely, providing the first direct evidence for an involvement of CRNs in startle. This blockade probably was not caused by damage to the auditory nerve, because the lesioned animals showed intact compound action potentials recorded from the ventral cochlear nucleus. Hence, a primary acoustic startle pathway may involve three synapses onto (1) CRNs, (2) neurons in PnC, and (3) spinal motoneurons.

[Unusual location of hydatid cysts: clinical and therapeutic aspects]. / Localizzazioni non usuali della cisti da echinococco: aspetti clinici e terapeutici.

Among patients treated for hydatidosis, unusual sites are observed in 5-30% of cases, with highest rates in endemic areas; on these basis during the diagnostic work up of masses arising from peritoneum, spleen, mediastinum, kidney and muscle, this possibility should be always taken into account. In fact, only a preoperative diagnosis allows a correct therapeutic approach, especially when synchronous lesions coexist. In this paper the Authors report their experience in the treatment of 66 (5.2%) hydatid cysts developed in unusual sites, out of 1275 patients treated for hydatidosis from 1949 to 1993. They discuss the main pathogenetic and clinical features as well as the therapeutic management of these atypical lesions.

[Ectopic pancreas with gastric localization: a clinical case and review of the literature]. / Pancreas ectopico a localizzazione gastrica: caso clinico e revisione della letteratura.

Heterotopic pancreatic tissue localized in the upper gastrointestinal (UGI) tract rarely presents with symptoms unless it is complicated by bleeding or mucosal ulceration. The case of a 26 year old man who presented with a one year history of epigastric pain, dyspepsia and several episodes of vomiting, without signs of bleeding or ulceration is reported. Work-up, which included upper gastrointestinal endoscopy, abdominal ultrasound and UGI series, revealed an intramural mass on the lesser curvature of the stomach, with normal overlying mucosa. The patient underwent surgical excision of the lesion and histologic examination showed normal pancreatic tissue. Postoperatively the patient did well with marked clinical improvement. In reviewing the literature on aberrant pancreatic lesions of the stomach the Authors discuss the varying clinical presentation and differential diagnosis as well as treatment options: when the lesions present with disabling symptoms, surgical excision should always be performed.

[Papillomatous lesions of the biliary tract]. / Le lesioni papillomatose delle vie biliari.

Biliary papillomatosis is a rare entity, characterized by single or multiple lesions arising from the biliary epithelium, leading to relapsing attacks of obstructive jaundice and cholangitis. Usually considered a benign disease, progression to malignancy has though been reported. In this paper the case of a 72 year old patient, with a single papilloma of the left hepatic duct treated by left hepatectomy, is discussed. The main histological, clinical and therapeutic aspects of this unusual pathology are then examined, with a complete review of the Literature.