Adaptive behaviour deficits in individuals with 3q29 deletion syndrome.

BACKGROUND: 3q29 deletion syndrome (3q29del) is associated with a significantly increased risk for neurodevelopmental and neuropsychiatric phenotypes. Mild to moderate intellectual disability (ID) is common in this population, and previous work by our team identified substantial deficits in adaptive behaviour. However, the full profile of adaptive function in 3q29del has not been described nor has it been compared with other genomic syndromes associated with elevated risk for neurodevelopmental and neuropsychiatric phenotypes. METHODS: Individuals with 3q29del (n = 32, 62.5% male) were evaluated using the Vineland Adaptive Behaviour Scales, Third Edition, Comprehensive Parent/Caregiver Form (Vineland-3). We explored the relationship between adaptive behaviour and cognitive function, executive function, and neurodevelopmental and neuropsychiatric comorbidities in our 3q29del study sample, and we compared subjects with 3q29del with published data on fragile X syndrome, 22q11.2 deletion syndrome and 16p11.2 deletion and duplication syndromes. RESULTS: Individuals with 3q29del had global deficits in adaptive behaviour that were not driven by specific weaknesses in any given domain. Individual neurodevelopmental and neuropsychiatric diagnoses had a small effect on adaptive behaviour, and the cumulative number of comorbid diagnoses was significantly negatively associated with Vineland-3 performance. Both cognitive ability and executive function were significantly associated with adaptive behaviour, and executive function was a better predictor of Vineland-3 performance than cognitive ability. Finally, the severity of adaptive behaviour deficits in 3q29del was distinct from previously published data on comparable genomic disorders. CONCLUSIONS: Individuals with 3q29del have significant deficits in adaptive behaviour, affecting all domains assessed by the Vineland-3. Executive function is a better predictor of adaptive behaviour than cognitive ability in this population and suggests that interventions targeting executive function may be an effective therapeutic strategy.

A distinct cognitive profile in individuals with 3q29 deletion syndrome.

BACKGROUND: 3q29 deletion syndrome is associated with mild to moderate intellectual disability as well as comorbid psychopathology such as ADHD, anxiety, ASD and schizophrenia. A greater understanding of specific profiles that could increase risk for psychopathology is necessary in order to best understand and support individuals with 3q29 deletion syndrome. The goal of this study was to thus carefully outline the strengths and weaknesses of these individuals. A second goal was to ask whether the cognitive impact of the deletion predicted psychopathology in other domains. METHODS: We systematically evaluated cognitive ability, adaptive behaviour and psychopathology in 32 individuals with the canonical 3q29 deletion using gold-standard instruments and a standardised phenotyping protocol. RESULTS: Mean full scale IQ was 73 (range 40-99). Verbal subtest score (mean 80, range 31-106) was slightly higher and had a greater range than non-verbal subtest score (mean 75, range 53-98). Spatial ability was evaluated in a subset (n = 24) and was lower than verbal and non-verbal ability (mean 71, range 34-108). There was an average 14-point difference between verbal and non-verbal subset scores; 60% of the time the verbal subset score was higher than the non-verbal subset score. Study subjects with a verbal ability subtest score lower than the non-verbal subtest score were four times more likely to have a diagnosis of intellectual disability (suggestive, P value 0.07). The age at which a child first spoke two-word phrases was strongly associated with measures of verbal ability (P value 2.56e-07). Cognitive ability was correlated with adaptive behaviour measures (correlation 0.42, P value 0.02). However, although group means found equivalent scores, there was, on average, a 10-point gap between these skills (range -33 to 33), in either direction, in about 50% of the sample, suggesting that cognitive measures only partially inform adaptive ability. Cognitive ability scores did not have any significant relationship to cumulative burden of psychopathology nor to individual neurodevelopmental or psychiatric diagnoses. CONCLUSIONS: Individuals with 3q29 deletion syndrome have a complex pattern of cognitive disability. Two-thirds of individuals with the deletion will exhibit significant strength in verbal ability; this may mask deficits in non-verbal reasoning, leading to an overestimation of overall ability. Deficits in verbal ability may be the driver of intellectual disability diagnosis. Cognitive ability is not a strong indicator of other neurodevelopmental or psychiatric impairment; thus, individuals with 3q29 deletion syndrome who exhibit IQ scores within the normal range should receive all recommended behavioural evaluations.

Impaired pancreatic beta cell function in the fetal GK rat. Impact of diabetic inheritance.

The Goto-Kakisaki (GK) rat is a genetic model of non-insulin-dependent diabetes. At 21.5 d of age we found that GK fetuses had an increased plasma glucose concentration, a decreased plasma insulin level, and a reduced pancreatic beta cell mass. To investigate the beta cell function during fetal life we used a hyperglycemic clamp protocol applied to the mothers, which allowed us to obtain a steady-state hyperglycemia in the corresponding fetuses. At variance, with Wistar (W) fetuses, plasma insulin concentration in GK fetuses did not rise in response to hyperglycemia. In contrast, GK fetal pancreas released insulin in response to glucose in vitro to the same extent as W fetal pancreas. Such a discrepancy between the in vivo and in vitro results suggests that the lack of pancreatic reactivity to glucose as seen in vivo is extrinsic to the fetal GK beta cell. Finally, the importance of gestational hyperglycemia was investigated by performing crosses between GK and W rats. Fetuses issued from crosses between W mother and GK father or GK mother and W father had a beta cell mass close to normal values and were still able to increase their plasma insulin levels in response to hyperglycemia in vivo. Our data suggest that hyperglycemia in utero does not influence the severity of the decrease of the beta cell mass or the lack of the insulin secretory response to glucose in the fetal GK rat. Moreover they indicate that conjunction of GK genes originating from both parents is necessary in order for these defects to be fully expressed.

Insulin administration enhances growth of the beta-cell mass in streptozotocin-treated newborn rats.

We have previously reported that the damage caused by streptozotocin (STZ) administration to the beta-cells in newborn rats was followed by spontaneous recovery from neonatal diabetes. Our present data indicate that STZ administration on the day of birth (day 1) reduced the total beta-cell mass on day 4 to only 10% of the normal value and that after such damage, 27% of the corresponding normal beta-cell mass was spontaneously regained on day 7. During days 4-7, the contribution of the predicted beta-cell growth (due to the replication of preexisting differentiated beta-cells) to the total beta-cell growth represented only 56%. Therefore, recruitment of new beta-cells from a precursor pool indeed represents a significant mechanism for beta-cell regeneration after STZ during this period of life. Here, we report for the first time that 1) insulin therapy from days 2 to 4 did not significantly influence the occurrence of beta-cell damage after STZ administration (total beta-cell mass on day 4 was reduced to 12% of the normal value) and 2) insulin therapy from days 2 to 6 did improve the otherwise spontaneous beta-cell regeneration, since on day 7 total beta-cell mass was 44% of the corresponding normal beta-cell mass. During days 4-7, the contribution of the predicted beta-cell growth to the total beta-cell growth represented only 32% in the insulin-treated STZ group. Finally the insulin-favored regeneration of the beta-cells reflects both an increased replication from differentiated beta-cells and an increased neogenesis from precursor/stem cells, with this last pathway being preferentially activated.

Pancreatic beta-cell regeneration after 48-h glucose infusion in mildly diabetic rats is not correlated with functional improvement.

We investigated the effect of glucose infusion on beta-cell regeneration in rats made mildly diabetic by a single injection of low dosage (35 mg/kg) streptozotocin (STZ). Nondiabetic (ND) and STZ rats were submitted to a 48-h glucose infusion (hyperglycemia approximately 22 mmol/l in both groups: ND and STZ hyperglycemic-hyperinsulinemic [ND HG-HI and STZ HG-HI rats]). Before infusion, beta-cell mass was 65% lower in STZ rats than in ND rats (2.0 +/- 0.02 vs. 5.5 +/- 0.6 mg), 1.6-fold increased in ND HG-HI rats (8.7 +/- 1.7 mg), and 2.7-fold increased in STZ HG-HI rats (5.4 +/- 0.9 mg). In ND HG-HI rats, beta-cell enlargement was related to an increase in beta-cell responsiveness to nutrient secretagogues both in vivo and in vitro, whereas in STZ HG-HI rats, no significant improvement in insulin secretion could be noticed. To determine the respective role of hyperglycemia and hyperinsulinemia on beta-cell area changes, ND and STZ rats were submitted to a 48-h hyperinsulinemic-euglycemic clamp. No modification of beta-cell mass was detected in either group. In conclusion, 48-h superimposed hyperglycemia was enough to restore beta-cell mass previously reduced by STZ injection. This effect seemed to be due to hyperglycemia rather than hyperinsulinemia alone. The data stress the dissociation between beta-cell regeneration and improvement in islet function in diabetic rats. Our model seems suitable for studying factors that can improve the plasticity and function of the pancreas in NIDDM.

Effect of 5'-flanking sequence deletions on expression of the human insulin gene in transgenic mice.

Expression of the human insulin gene was examined in transgenic mouse lines carrying the gene with various lengths of DNA sequences 5' to the transcription start site (+1). Expression of the transgene was demonstrated by 1) the presence of human C-peptide in urine, 2) the presence of specific transcripts in pancreas, but not in other tissues, 3) the specific immunofluorescence staining of pancreatic islets for human C-peptide, and 4) the synthesis and accumulation of human (pro)insulin in isolated islets. Deletions in the injected DNA fragment of sequences upstream from positions -353, -258, and -168 allowed correct initiation of the transcripts and cell specificity of expression, while quantitative expression gradually decreased. Deletion to -58 completely abolished the expression of the gene. The amount of human product that in mice harboring the longest fragment contributes up to 50% of the total insulin does not alter the normal proportion of mice insulins I and II. These results suggest that expression of the human insulin gene in vivo results from the cooperation of several cis-regulatory elements present in the various deleted fragments. With none of the deletions used, expression of the transgene was observed in cell types other than beta-islet cells.

Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of noninsulin-dependent diabetes.

Considerable interest has recently been focused on the putative role of mutations in the mitochondrial genome for the development of noninsulin-dependent diabetes. The Goto-Kakizaki (GK) rat, a genetic model of defective insulin secretion and hyperglycemia, is characterized by partial maternal inheritance. Because the mitochondrial genome is known to be maternally transmitted, the aim of this study was to investigate whether the GK syndrome can be explained in terms of alterations of the mitochondrial DNA (mtDNA). For this purpose, pancreatic islets were isolated from adult and fetal control Wistar and diabetic GK rats. Using electron microscopy, the ultrastructural morphology of beta-cell mitochondria was analyzed in control and GK islets. It was found that the beta-cells of adult GK rats had a significantly smaller mitochondrial volume and an increased number of mitochondria per unit tissue volume as compared with the beta-cells of corresponding control islets. Moreover, mtDNA and mtRNA were isolated from the islets and, as a control tissue, from liver, and subsequently analyzed using Southern and Northern blot techniques. No major deletions or restriction fragment polymorphism could be detected in mtDNA from both GK liver and GK islets. The mtDNA sequence of the transfer RNAleu(UUS) gene was identical in both strains of rats. mtDNA contents of fetal GK islets and fetal GK liver were not different from those of fetal Wistar rats. However, adult GK islets contained markedly less mtDNA than the corresponding control islets, contrary to the mtDNA contents of adult liver, which were similar in the two strains. The lower islet mtDNA contents were paralleled by a decreased content of islet mtRNA (12S ribosomal RNA and cytochrome b messenger RNA). Islet insulin messenger RNA contents were similar in GK and Wistar rats. In conclusion, our results do not support a role of a genetic defect in mtDNA as a cause of the GK syndrome. Instead, mtDNA damage may occur specifically in islet cells as a consequence of the disturbed metabolic environment of the adult GK rat. It is speculated that a long-lasting metabolic dysfunction may induce mtDNA damage and/or inhibition of mtDNA replication leading to a gradual and late decrease in the mitochondrial volume fraction and subsequently an impaired capacity for oxidative metabolism.

The effects of donor and recipient endotoxemia on TNF alpha production and mortality in the rat model of syngenic orthotopic liver transplantation.

The effects of administration of endotoxin to donors or recipients on the mortality rate, evolution of endotoxin levels, and tumor necrosis factor alpha (TNF-alpha) release were investigated in a syngenic orthotopic liver transplantation model in Lewis rats with portal reperfusion only. No significant recipient endotoxemia, TNF-alpha release, or mortality occurred in control recipients following transplantation from normal donors. The doses of endotoxin needed to kill 50% and 100% of animals after hepatic artery ligation were, respectively, 4 mg/kg and 10 mg/kg. Transplantation of animals' livers with no preservation phase from donors who were administered a lethal dose of endotoxin for this combination (10 mg/kg) produced significant recipient endotoxemia at 10 min (6.9 +/- 2.5 x 10(3) endotoxin unit/ml (EU/ml), P < 0.01), 45 min (8.8 +/- 1.1 x 10(3) EU/ml, P < 0.001) and 8 hr (18.5 +/- 3.5 x 10(3) EU/ml, P < 0.001) after graft reperfusion. Significant levels of TNF-alpha were also detected in these animals at 45 min (280 +/- 70 pg/ml, P < 0.007) and 8 hr (80 +/- 40 pg/ml, P < 0.05) when compared with the controls. Mortalities in recipients of OLT from donor animals that had received endotoxin (2 mg/kg or 4 mg/kg) immediately prior to the harvesting procedure was 0% and 20%, respectively, compared with no death in the control group. When recipient animals were administered endotoxin immediately after graft reperfusion the resistance to endotoxin administration was significantly reduced compared with animals that had not received OLT (LD50 < 2 mg/kg versus 4 mg/kg; LD100 4 mg/kg versus 10 mg/kg, respectively). These results show that endotoxin and its effects can be transferred from the liver graft donor to the recipient and that OLT per se reduces the recipient resistance to endotoxin with subsequent increase in mortality.

Insulin secretion and glucose tolerance after islet transplantation in rats with noninsulin-dependent diabetes induced by neonatal streptozotocin.

The present study was designed to identify in a model of noninsulin-dependent diabetes induced by neonatal streptozotocin (n0-STZ), the long-term consequences of an islet graft upon 1) glucose handling of the recipient and, 2) glucose response of the residual beta cells in the recipient pancreas. We have examined, 4 and 8 wk after islet implantation under the kidney capsule of syngeneic diabetic n0-STZ rats, their tolerance to glucose administered in vivo, together with their insulin release in response to glucose in vivo (oral glucose tolerance test) as well as in vitro (perfused pancreas). The results in the islet-grafted n0-STZ rats, were compared to those obtained in nongrafted nondiabetic rats and nongrafted n0-STZ rats. Our study shows that transplanting a limited number (900) of adult islets under the kidney capsule reverses to normal, many parameters of the noninsulin-dependent diabetic state in the n0-STZ rat model: these include body weight, basal plasma glucose in both the nonfasted and postabsorptive states, and basal plasma insulin in the postabsorptive state. Furthermore, tolerance to oral glucose administration was greatly improved in the transplanted rats and it was correlated with restoration of a manifest glucose-induced insulin secretion in vivo as evaluated (delta 1) during an oral glucose tolerance test. Our data clearly show that the insulin response to glucose from the endogenous pancreas of n0-STZ diabetic rat was not really improved by long-term (8 wk) basal normoglycemia. More precisely, we were able to detect a slight but significant improvement of the early phase of insulin release in vitro in response to glucose; however, the overall insulin response remained 15 times lower than the normal one with no reappearance of the late phase of insulin release. After cessation of glucose stimulation in vivo, off-response of insulin, which is also a landmark of the impaired insulin release by the beta cells of n0-STZ rats, was still detectable in the perfused pancreas of the transplanted n0-STZ rats. Finally, because the reactivity to glucose of the endogenous residual beta cells was not regained, the insulin released in vivo during the oral glucose test in the graft-bearing n0-STZ rats can be attributed mainly to functioning of the grafted islets population.

Clinical evaluation of the Vital system compared with the Hémoline diphasic method for the detection of aerobic blood cultures.

In a collaborative study at two university hospitals, the recovery of microorganisms and the speed of detection of microbial aerobic growth by the Vital system (bioMérieux) and a diphasic conventional blood culture system were compared. The Vital system monitors each blood culture bottle every 15 minutes to detect inactivation of fluorescent suspended in the broth medium due to microbial growth. A total of 1086 comparisons were made between the two systems, yielding a total of 117 isolates. Microorganisms were recovered more often from the Vital aerobic bottles (p < 0.05). The Vital system detected 43% of the microorganisms within the first 12 hours of incubation whereas in the same time the conventional system detected only 5% of the microorganisms. The results demonstrate that the Vital system is a reliable, continuous monitoring, fully automated system and an attractive alternative to conventional blood culture methods.

Women-specific alcohol use(r) intervention programs: a preliminary dimension analysis based on specialized services in Western New York State.

Women-specific models have been proposed as a means for achieving the best service user-treatment match for women who experience alcohol use related problems. To better understand how theoretical and empirical knowledge are being applied in real world programs, interviews were conducted at seven programs in Western New York State where specialized women's alcohol use(r) services have been developed. A preliminary analytical model of women's services is proposed, consisting of the following three dimensions: 1) level of orthodoxy, 2) population specificity, and 3) change target.

African-American women in an alcohol intervention group: addressing personal and political problems.

This paper describes a qualitative study in which African-American women met in a small group to discuss alcohol and drug problems. The goal was to expand the range of services available by creating an alternative intervention which provided a simultaneous focus on both the personal and the sociopolitical needs of Black women. Results suggest that the dual focus on individual and social issues, and the opportunity to simultaneously address racism, sexism, and classism in an African-American women-only alcohol recovery group was helpful.

[Variations of the loudness of a brief tone (20 ms) as a function of the rise and decay times at 1000 Hz]. / Variations de la sonie d'un son bref (20 ms) en fonction de la durée d'établissement et de déclin à 1000 Hz.

The loudness of brief tones have been studied in relation to rise and decay times, by reference a long tone of same frequency. Some differences appear, but they are different with the subjects and the sound pressure levels.

[Effects of duration on the equal loudness contours of short and brief tones: 40 phones equal loudness contours. Preliminary experiments (author's transl)]. / Effets de la durée sur les lignes isosoniques de sons courts ou brefs: Lignes isosoniques de 40 phones. Expériences préliminaires

Loudness balances have been obtained between 10-, 20-, 100- and 1,000-ms tones of different frequencies (62.5, 125, 250, 500, 1,000, 2,000, 4,000, 8,000 and 12,000 Hz), and a constant reference tone of 1,000 Hz and 1,000 ms duration at 40 dB SPL. The absolute thresholds were also measured on the same observers at each duration. Progressive shifts of the equal loudness contours appear when the durations become shorter, in the same direction as the corresponding shifts of the threshold curves; the shifts of the equal loudness contours and the corresponding shifts of the threshold curves do not however appear completely similar; some differences may also exist between tones of differing frequencies. These experiments were preliminary ones; some problems arise, in relation with the technique used; improvements appear necessary.

Beta-cell mass depletion precedes the onset of hyperglycaemia in the GK rat, a genetic model of non-insulin-dependent diabetes mellitus.

It is unclear whether reported histopathological changes in the endocrine pancreas of the GK rat (a spontaneous model of non-insulin-dependent diabetes) are related to the pathogenesis of hyperglycaemia or occur secondarily to metabolic alterations. We found that total pancreatic insulin stores in GK rats from the Paris colony were depleted by 62% (p < 0.01) in adult (4-month-old) overtly hyperglycaemic animals compared to those of normal Wistar control rats, and that beta-cell mass in GK pancreata was decreased to a similar extent (51%, p < 0.05). This indicates that decreased in vivo and in vitro insulin secretory response to glucose in GK rats could be due not only to impaired stimulus-secretion coupling for glucose in their beta cells but also to a reduced number of beta cells. Reduced total beta-cell mass in adult GK rats was associated with a noticeable alteration in the architecture of a subpopulation of islets: only large islets displayed signs of disorganization of the mantle-core relationship due to prominent fibrosis, with clusters of beta cells widely separated by strands of connective tissue. Our study also provides a first record of the pathophysiologic changes occurring in the GK rat from the neonatal period. Four-day-old GK pups demonstrated normal basal glycaemia compared to Wistar rats of the same age. GK islets displayed a well-preserved architecture, with normal staining of beta cells and no fibrosis. However, their total pancreatic insulin stores and total beta-cell mass were significantly lower [59% (p < 0.01) and 64% (p < 0.05) respectively] than those of controls. These data indicate that a reduction in islet tissue clearly predates the onset of diabetes (hyperglycaemia). Therefore, a reduction of total beta-cell mass should be considered as a primary feature in the pathological sequence leading to diabetes in GK rats, at least in those originating from the Paris colony.

Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat.

In the endocrine pancreas of the GK rat, a genetic model of non-insulin-dependent diabetes mellitus (NIDDM), it is not clear whether the histopathological changes reported up to now are related to the pathogenesis of hyperglycaemia or whether they occur secondarily to metabolic alterations. Using GK rats from the Paris colony, our study chronicles for the first time the pathophysiologic changes that occur in the GK pancreas from the late fetal period (day 21.5) until adult age (18 weeks). As compared to Wistar controls, GK fetuses exhibited higher plasma glucose level, lower plasma insulin level and normal plasma glucagon level. Their pancreatic insulin content and the relative volume and the total mass of their beta cells were sharply decreased, representing only 23, 38 and 23% of control values, respectively. During the period from 4 days to 14 days after birth, GK neonates exhibited normal basal plasma glucose and glucagon levels despite decreased plasma insulin level. Their pancreatic insulin content represented only 31-40% of values found in the age-related control pancreases and their total beta-cell mass was only 35% on day 4, 30% on day 7 and 37% on day 14. The adult diabetic GK rats exhibited higher basal plasma glucose and insulin levels while their basal plasma glucagon level remained normal. Their pancreatic insulin content and the total beta-cell mass remained decreased, representing only 32% and 47% of control values, respectively. Moreover, the adult GK pancreases exhibited noticeable alteration in the architecture of the large islet subpopulation which displayed considerable fibrosis with clusters of beta cells widely separated from each other by strands of connective tissue. Concerning the development of alpha cells in the GK rats, their relative volume was found to be normal during fetal and early neonatal periods. It was found to be moderately decreased (representing 64-67% of corresponding control values) in 14-day-old neonates and adult GK rats. Our findings demonstrate that in the GK rat, the deficit of total beta-cell mass as observed in the adult animal is related to impaired beta-cell development. The restriction of the beta-cell mass must be considered as a primary and crucial event in the sequence leading to overt diabetes in this NIDDM model.

Limits of commercial molecular tests for diagnosis of pulmonary tuberculosis.

Several studies report high specificity, but variable sensitivity, of Amplified Mycobacterium tuberculosis Direct Test (AMTDT, Gen-Probe) based on ribosomal ribonucleic acid (rRNA) amplification and Amplicor Mycobacterium tuberculosis test (Amplicor, Roche) based on deoxyribonucleic acid (DNA) amplification for diagnosis of pulmonary tuberculosis. We have retrospectively evaluated these assays on selected acid-fast bacilli (AFB)-positive and -negative smear specimens and compared the results obtained from nucleic acid amplification with those of AFB staining of semi-quantitative cultures as determined by radiometric Bactec and Löwenstein-Jensen cultures. In comparison to cultures, Amplicor and AMTDT assays exhibited identical overall sensitivities of 80%, while the staining had a lower sensitivity of 62%. The sensitivities of Amplicor and AMTDT were 98% and 100%, respectively, for the AFB-positive specimens, and 50 and 46%, respectively for the AFB-negative specimens in comparison to cultures. The sensitivities of both assays appeared similar, and were directly related to the number of bacilli in the specimens studied. The low sensitivity (50%) for smear-negative specimens showed that current amplification assays may be unsuitable to replace cultures for diagnosis of tuberculosis. The decision to perform these molecular techniques should result from close co-operation between clinicians and microbiologists, taking into account the sensitivity results reported here, as well as the expense of the assays.