Background:The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental ...retardation.Aim:We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome.Results:We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729–41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10−5).Conclusion:Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.
Chemotherapy-induced hand-foot syndrome and nail changes are common complications of many classic chemotherapeutic agents and the newer molecular targeted therapies. They significantly impact patient ...quality of life, and frequently necessitate chemotherapy dose intensity modification or reduction. We aim to describe the epidemiology, pathogenesis, clinical presentation, and current evidence-based treatment options for these entities.
In order to characterize fentanyl-related deaths in the province of Ontario, Canada, a retrospective study of all cases in which fentanyl was quantitaled in blood was conducted for the time period ...between 2002 and 2004. A total of 112 fentanyl-related deaths were identified. Decedents ranged in age from 4 to 93 years and comprised 63 men and 49 women. A variety of routes of administration of the drug were identified: lransdermal application of Duragesic® patches, intravenous injection of patch contents or fentanyl citrate solution, oral/transmucosal administration, and volatilization and inhalation of Duragesic systems. Blood fentanyl concentrations were determined for all modes of drug administration and are provided. There were 54 cases in which death was attributed solely to fentanyl intoxication; the mean blood concentration was 25 µg/L (range: 3.0–383 µg/L). This concentration range overlapped with blood fentanyl concentrations measured among cases where the presence of the drug was considered incidental. For example, a mean blood concentration of 12 µg/L was observed among 12 cases of natural death (range: 2.7–33 µg/L). Detailed case reports of six individuals are also included and provide additional insight into the use of this drug for both therapeutic and illicit means.
The nuclear spin gyromagnetic ratio can be enhanced by hyperfine coupling to the electronic spin. Here we show wide tunability of this enhancement on a 15N nuclear spin intrinsic to a single ...nitrogen-vacancy center in diamond. We perform control of the nuclear spin near the ground state level anti-crossing (GSLAC), where the enhancement of the gyromagnetic ratio from the ground state hyperfine coupling is maximized. We demonstrate a two order of magnitude enhancement of the effective nuclear gyromagnetic ratio compared to the value obtained at 500 G, a typical operating field that is suitable for nuclear spin polarization. Finally, we show that with strong enhancements, the nuclear spin ultimately suffers dephasing from the inhomogeneous broadening of the NMR transition frequency at the GSLAC.
The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.
We sought to determine the causative mutation in a family with AF, atrial septal defects, ...and ventricular septal defects.
We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset <66 years, for mutations in GATA6. Variants were functionally characterized using reporter assays in a mammalian cell line.
Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6. In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P < .0001; P91S: 2.5-fold, P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity.
Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.
Objective: To develop a behavioural assessment based on observations of patients recovering after severe head injury whereby data could be collected by observation and by testing everyday tasks.
...Design: A prospective observational study of a cohort of 88 consecutive hospital admissions with severe head injury.
Setting: Two district general hospitals in the UK.
Patients: Eighty-eight consecutive admissions with severe traumatic head injury. Ages ranged from 14 to 67 years, mean coma duration was 14 days and mean duration of post traumatic amnesia (PTA) was 56 days.
Results: Fifty-eight items of behaviour were identified. Paired preference analysis was used to identify a sequence of recovery of these behaviours. The sequence began with arousal and led on to behaviours signalling recovery of social interaction and communication. Subsequent behaviours indicated increasing cognitive organization and return of orientation and memory. The behaviours on the scale are hierarchical and range from coma to emergence from PTA.
Conclusions: A scale to assess patients and monitor cognitive recovery after severe head injury has been developed. While individual patients will show some departures from the sequence identified, the scale helps to make explicit the earliest stages of natural recovery patterns after head injury.
Purpose
Compare capillary and venous blood in the analysis of concentration and function of leucocyte sub-populations. This study hypothesised that capillary samples may be used in a site-specific ...manner as an alternative source of blood samples for assays of leucocyte concentration and neutrophilic phagocytic function and reactive oxygen species (ROS) production, allowing acquisition of multiple samples to better monitor transient but significant post-exercise immune modulation.
Methods
Resting blood samples were simultaneously obtained from vein, finger and earlobe of healthy subjects (
n
= 10, age: 25.1 ± 3.1 years). Leucocyte concentrations were measured using a five-part differential haematological analyser. Leucocyte sub-populations (CD3, CD4, CD8, CD19, CD56, CD14) and granulocytic functional-related (CD11b, CD18, CD16b, CD66b) surface antigen markers, neutrophil phagocytosis (FITC-labelled
Escherichia coli
) and stimulated ROS production (DHR) were quantified utilizing flow cytometry. A MANOVA (
α
< 0.05 significance) analysed the effects of the different sampling sites in the concentrations of leucocyte populations, their surface antigen expression and granulocytic functions.
Results
Leucocyte concentration and neutrophilic ROS production yielded non-significant differences between sampling sites. Expression of granulocytic surface antigens was increased in both capillary sites compared to venous site (
p
= 0.008), particularly for adhesion markers CD11b/CD18. The percentage of neutrophils performing phagocytosis was higher in venous samples compared to finger (
p
= 0.025). Increased number of
E. coli
ingested was observed in venous sample compared to finger (
p
= 0.001) and to earlobe (
p
= 0.006).
Conclusion
Whilst attention must be paid for varying neutrophilic surface antigen expression and further studies are needed to establish appropriate reference ranges, this study supports the use of capillary blood samples in a site-specific manner to enhance sampling capabilities field-based research.
Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and ...whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 19 samples worldwide. Healthy brain aging was estimated by predicting chronological age (18-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 952 male and 1236 female controls from the ENIGMA MDD working group. The learned model coefficients were applied to 927 male controls and 986 depressed males, and 1199 female controls and 1689 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain-predicted age difference (brain-PAD). On average, MDD patients showed a higher brain-PAD of +1.08 (SE 0.22) years (Cohen's d = 0.14, 95% CI: 0.08-0.20) compared with controls. However, this difference did not seem to be driven by specific clinical characteristics (recurrent status, remission status, antidepressant medication use, age of onset, or symptom severity). This highly powered collaborative effort showed subtle patterns of age-related structural brain abnormalities in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the clinical value of these brain-PAD estimates.
We evaluated physical activity changes resulting from a six-month public health model intervention that encouraged seniors (N = 89) 62-91 years of age (mean = 76) living in two low-income congregate ...housing facilities to increase their physical activity by participating in existing community-based physical activity classes and programs of their choice. The program was offered to everyone regardless of their health problems. Enrollees were encouraged to adopt activities tailored to their preferences, physical abilities, health status, income, and transportation resources. Using a comparison-group design, the intervention group was more active for all comparison months of the intervention period (p values < .05). The intervention also was associated with improvements in self-esteem (p < .05), though not with an array of other measures of health-related quality-of-life. Those who adopted and maintained a new physical activity over the six-month intervention period experienced improvements in anxiety, depression, and overall psychological well-being relative to those who did not. The intervention was subsequently replicated through a senior center (N = 22). A much larger proportion of the senior center sample adopted and maintained a new activity for six months (68%) compared to the congregate facilities sample (35%), which may have been due to differences in recruitment methods and sample characteristics in the two settings. An intervention promoting increased physical activity through the use of existing community resources may help increase physical activity in older adults.
Objective: The objective was to investigate the effect of increased intensity of rehabilitation therapy provided to brain-injured subjects on the rate at which independence was regained and the ...duration of hospital admission.
Design: A two-centre, prospective, controlled study with random allocation to groups.
Setting: Two district general hospitals on the south coast of England.
Subjects: Fifty-six people with moderate and severe head injury consecutively admitted to Southampton and Poole hospitals between June 1995 and September 1997.
Interventions: Increased intensity of rehabilitation therapy input without change in content.
Results: Subjects receiving more intensive therapy made more rapid progress and were discharged home sooner. The different intensities of therapy employed in this study showed no evidence of a ‘ceiling’ effect and the ‘intervention group’ made significantly more rapid progress on tests of dependency during the period of admission. A clear response to increased therapy input was seen in one of the centres with more rapid functional improvement and a shorter length of hospital stay. This centre already had more therapy and better community facilities. No such benefits were seen at the other centre where the intervention group had a longer hospital stay than the routine group.
Conclusion: Increasing the hours per week of therapy given to adults recovering from brain injury in hospital can accelerate the rate of recovery of personal independence and result in their being discharged from hospital sooner. Increased rehabilitation therapy after brain injury is associated with enhanced functional recovery and shorter hospital stay if provided in the context of an integrated service that can provide ongoing community support. There is no evidence of any ceiling effect of therapeutic intensity beyond which no further response is observed.
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