Diagnostic exome sequencing in children: A survey of parental understanding, experience and psychological impact.

Clinical exome sequencing (CES) is increasingly being used as an effective diagnostic tool in the field of pediatric genetics. We sought to evaluate the parental experience, understanding and psychological impact of CES by conducting a survey study of English-speaking parents of children who had diagnostic CES. Parents of 192 unique patients participated. The parent's interpretation of the child's result agreed with the clinician's interpretation in 79% of cases, with more frequent discordance when the clinician's interpretation was uncertain. The majority (79%) reported no regret with the decision to have CES. Most (65%) reported complete satisfaction with the genetic counseling experience, and satisfaction was positively associated with years of genetic counselor (GC) experience. The psychological impact of CES was greatest for parents of children with positive results and for parents with anxiety or depression. The results of this study are important for helping clinicians to prepare families for the possible results and variable psychological impact of CES. The frequency of parental misinterpretation of test results indicates the need for additional clarity in the communication of results. Finally, while the majority of patients were satisfied with their genetic counseling, satisfaction was lower for new GCs, suggesting a need for targeted GC training for genomic testing.

Collaborative Occupational Therapy: Teachers' Impressions of the Partnering for Change (P4C) Model.

AIMS: Occupational therapists (OTs) often face barriers when trying to collaborate with teachers in school-based settings. Partnering for change (P4C), a collaborative practice model designed to support children with developmental coordination disorder, could potentially support all students with special needs. Therefore, the aim of this study was to explore how teachers experience OT services delivered using the P4C model to support children with a variety of special needs. METHODS: P4C was implemented at one elementary school in Courtenay, British Columbia. Eleven teachers participated in two focus groups and a one-on-one interview to gather descriptive, qualitative data. Grounded theory techniques were used for data analysis. RESULTS: Four themes (collaborating in the thick of it all, learning and taking risks, managing limited time and resources, and appreciating responsive OT support) represented teachers' experiences of P4C. CONCLUSIONS: Teachers strongly preferred collaborative OT services based on the P4C model. Students with a variety of special needs were supported within their classrooms as teachers learned new strategies from the OT and found ways to embed these strategies into their daily routines.

Understanding the links between resilience and type-2 diabetes self-management: a qualitative study in South Australia.

BACKGROUND: Research conducted by Ward, Muller, Tsourtos, et al. (Soc Sci Med 72(7):1140-1148, 2011) has led to the development of the psycho-social interactive model of resilience, which reveals the interaction between individual resilience factors (i.e. coping, confidence and self esteem) and external resilience environments (i.e. employment, supportive family environments and health promoting policies) in facilitating the development of resilience. This present study explored the utility of this model of resilience for understanding how people self-manage type-2 diabetes. METHODS: Data were collected via 14 semi-structured life-history interviews with women and men living with type-2 diabetes mellitus (T2DM). Participants varied according to socio-demographics (gender, age, education level, income) and were recruited based on their self-reported management (or lack thereof) of T2DM. RESULTS: The inter-play of internal traits and external resources with additive and subtractive resilience strategies were consistent with the psycho-social interactive model of resilience. Self-management was influenced by life history. Differences in self-management and material disadvantage were also identified. Alongside increased disadvantage are higher levels of external barriers to self-management practices. CONCLUSIONS: This paper supports the concepts of additive and subtractive resilience strategies for use with diabetes populations; providing health professionals and policy makers with an increased understanding of how to recognize and foster patient resilience for the improvement of self-care, disease management and ultimately health outcomes.

Further evidence that de novo missense and truncating variants in ZBTB18 cause intellectual disability with variable features.

Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.

Breast cancer antiestrogen resistance 3-p130Cas interactions promote adhesion disassembly and invasion in breast cancer cells.

Adhesion turnover is critical for cell motility and invasion. We previously demonstrated that the adaptor molecule breast cancer antiestrogen resistance 3 (BCAR3) promotes adhesion disassembly and breast tumor cell invasion. One of two established binding partners of BCAR3 is the adaptor molecule, p130Cas. In this study, we sought to determine whether signaling through the BCAR3-Cas complex was responsible for the cellular functions of BCAR3. We show that the entire pool of BCAR3 is in complex with Cas in invasive breast tumor cells and that these proteins colocalize in dynamic cellular adhesions. Although accumulation of BCAR3 in adhesions did not require Cas binding, a direct interaction between BCAR3 and Cas was necessary for efficient dissociation of BCAR3 from adhesions. The dissociation rates of Cas and two other adhesion molecules, α-actinin and talin, were also significantly slower in the presence of a Cas-binding mutant of BCAR3, suggesting that turnover of the entire adhesion complex was delayed under these conditions. As was the case for adhesion turnover, BCAR3-Cas interactions were found to be important for BCAR3-mediated breast tumor cell chemotaxis toward serum and invasion in Matrigel. Previous work demonstrated that BCAR3 is a potent activator of Rac1, which in turn is an important regulator of adhesion dynamics and invasion. However, in contrast to wild-type BCAR3, ectopic expression of the Cas-binding mutant of BCAR3 failed to induce Rac1 activity in breast cancer cells. Together, these data show that the ability of BCAR3 to promote adhesion disassembly, tumor cell migration and invasion, and Rac1 activity is dependent on its ability to bind to Cas. The activity of BCAR3-Cas complexes as a functional unit in breast cancer is further supported by the co-expression of these molecules in multiple subtypes of human breast tumors.

Inhibition of urease activity in the urinary tract pathogen Staphylococcus saprophyticus.

UNLABELLED: Urease is a virulence factor for the Gram-positive urinary tract pathogen Staphylococcus saprophyticus. The susceptibility of this enzyme to chemical inhibition was determined using soluble extracts of Staph. saprophyticus strain ATCC 15305. Acetohydroxamic acid (Ki = 8.2 µg ml(-1) = 0.106 mmol l(-1) ) and DL-phenylalanine hydroxamic acid (Ki = 21 µg ml(-1) = 0.116 mmol l(-1) ) inhibited urease activity competitively. The phosphorodiamidate fluorofamide also caused competitive inhibition (Ki = 0.12 µg ml(-1) = 0.553 µmol l(-1) = 0.000553 mmol l(-1) ), but the imidazole omeprazole had no effect. Two flavonoids found in green tea extract [(+)-catechin hydrate (Ki = 357 µg ml(-1) = 1.23 mmol l(-1) ) and (-)-epigallocatechin gallate (Ki = 210 µg ml(-1) = 0.460 mmol l(-1) )] gave mixed inhibition. Acetohydroxamic acid, DL-phenylalanine hydroxamic acid, fluorofamide, (+)-catechin hydrate and (-)-epigallocatechin gallate also inhibited urease activity in whole cells of strains ATCC 15305, ATCC 35552 and ATCC 49907 grown in a rich medium or an artificial urine medium. Addition of acetohydroxamic acid or fluorofamide to cultures of Staph. saprophyticus in an artificial urine medium delayed the increase in pH that normally occurs during growth. These results suggest that urease inhibitors may be useful for treating urinary tract infections caused by Staph. saprophyticus. SIGNIFICANCE AND IMPACT OF THE STUDY: The enzyme urease is a virulence factor for the Gram-positive urinary tract pathogen Staphylococcus saprophyticus. We have shown that urease activity in cell-free extracts and whole bacterial cells is susceptible to inhibition by hydroxamates, phosphorodiamidates and flavonoids, but not by imidazoles. Acetohydroxamic acid and fluorofamide in particular can temporarily delay the increase in pH that occurs when Staph. saprophyticus is grown in an artificial urine medium. These results suggest that urease inhibitors may be useful as chemotherapeutic agents for the treatment of urinary tract infections caused by this micro-organism.

Depression predicts self-reported disease activity in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can significantly impact both physiological and psychological functioning. In order to examine the relationship between psychological functioning and disease activity in SLE, we administered instruments that collected sociodemographic information and measured indices of disease activity and psychosocial functioning from 125 adult Hispanic and White patients with SLE. Patients were recruited from four healthcare settings in the greater Southern California area. Both cross-sectional and longitudinal relationships between depression and disease activity were evaluated. Cross-sectional findings revealed that depression and ethnicity were independently correlated with self-reported disease activity. Longitudinally, depression alone predicted self-reported disease activity. These data suggest that depression may play a significant role in the health status of SLE patients and serve as an important target for clinical intervention.

Miniature eye-safe laser system for high-resolution three-dimensional lidar.

A microchip-laser-pumped optical parametric amplifier produces 35-microJ, 1.537-microm pulses of 190-ps duration at 8 kHz, in a near-diffraction-limited output beam with a Fourier-transform-limited spectrum. The flight-ready laser head is pumped by 20 W of optical power from two fiber-coupled laser-diode arrays, occupies a volume of 0.14 liters, and has a mass of 0.34 kg.

Differential expression of photoreceptor-specific genes in the retina of a zebrafish cadherin2 mutant glass onion and zebrafish cadherin4 morphants.

Cadherins are Ca2+ -dependent transmembrane molecules that mediate cell-cell adhesion through homophilic interactions. Cadherin2 (also called N-cadherin) and cadherin4 (also called R-cadherin), members of the classic cadherin subfamily, have been shown to be involved in development of a variety of tissues and organs including the visual system. To gain insight into cadherin2 and cadherin4 function in differentiation of zebrafish photoreceptors, we have analyzed expression patterns of several photoreceptor-specific genes (crx, gnat1, gnat2, irbp, otx5, rod opsin, rx1, and uv opsin) and/or a cone photoreceptor marker (zpr-1) in the retina of a zebrafish cadherin2 mutant, glass onion (glo) and in zebrafish embryos injected with a cadherin4 specific antisense morpholino oligonucleotide (cdh4MO). We find that expression of all these genes, and of zpr-1, is greatly reduced in the retina of both the glo and cadherin4 morphants. Moreover, in these embryos, expression of some genes (e.g. gnat1, gnat2 and irbp) is more affected than others (e.g. rod opsin and uv opsin). In embryos with both cadherins functions blocked (glo embryos injected with the cdh4MO), the eye initially formed, but became severely and progressively disintegrated and expressed little or no crx and otx5 as development proceeded. Our results suggest that cadherin2 and cadherin4 play important roles in the differentiation of zebrafish retinal photoreceptors.

Energy-scavenging amplifiers for miniature solid-state lasers.

Longitudinally pumped miniature lasers are inefficient, partly because of their inefficient absorption of the pump light. Scavenging the unabsorbed pump light to pump an in-line amplifier can greatly enhance the efficiency of the system, with minimal added cost, size, or complexity.

Cadherin-2 and cadherin-4 in developing, adult and regenerating zebrafish cerebellum.

Cadherins are cell adhesion molecules that regulate development of a variety of tissues and maintenance of adult structures. In this study, we examined expression of two zebrafish classical cadherins, cadherin-2 and cadherin-4, in the cerebellum of developing, normal adult, and regenerating adult zebrafish using in situ hybridization and immunohistochemical methods. Cadherin-2 was widely expressed by the cerebellum of embryonic (24-50-h post fertilization) and larval zebrafish (3-14 days). Cadherin-2 expression became much reduced in the adult cerebellum, but it was greatly up-regulated in the regenerating adult cerebellum. Cadherin-4 was not detected in the embryonic cerebellum, but it was expressed in the Purkinje cells of the larval and adult cerebellum. To gain insight into cadherin-2 role in the formation of the cerebellum, we analyzed embryos injected with a specific cadherin-2 antisense morpholino oligonucleotide (cdh2MO1), and found that the cerebellar development of the cdh2MO1-injected embryos was severely disrupted. This phenotype was confirmed by examining a cadherin-2 mutant, glass onion. Our results suggest that cadherins are crucial for the normal development of the zebrafish cerebellum, and they may also be involved in the regeneration of injured fish cerebellum.

The epidemiology of glycopeptide-resistant enterococci on a haematology unit--analysis by pulsed-field gel electrophoresis.

As part of an interventional study to determine glycopeptide-resistant enterococci (GRE) acquisition on a three-ward haematology unit, rectal swabs were taken weekly from 293 patients recruited to the study between June 1995 and December 1996. The GRE isolates obtained from the first positive rectal swab from 120 colonized patients, the isolates from 7 patients with clinical infection and 43 isolates obtained from the ward environment were compared by pulsed-field gel electrophoresis (PFGE). Sixty-three of 120 patients were colonized by one of strains A-H, while 49 were colonized by unique strains. The first 18 weeks were associated with the highest prevalence of GRE by rectal swab, with a single strain A responsible for 52% of acquisitions on ward 2, 22% on ward 3 and 36% on ward 4. Other smaller ward associated clusters were evident. Environmental sampling of ward 2 during this time showed that all but 2 of 30 isolates were indistinguishable from strain A. As the GRE prevalence fell, rectal swab and environmental isolates became more heterogeneous, and strain A disappeared after week 55. GRE prevalence rose again in the final 15 weeks of the study, and a new predominant strain B emerged on ward 2 responsible for 50% of new acquisitions. In the seven patients with clinical infection with GRE, the clinical isolates were compared with the contemporaneous rectal swab isolate, and were found to be the same in only two cases. An analysis of five long-term carriers colonized for a median of 19 weeks (range 11-34) showed colonization with at least two and in one case six distinct strains, raising the question of how many strains may be colonizing a patient at any one time, and suggesting that multiple colonies should be analysed. These data suggest that cross-infection was an important factor in the spread of GRE when the colonization rate was high.

Membrane targeting of a Rab GTPase that fails to associate with Rab escort protein (REP) or guanine nucleotide dissociation inhibitor (GDI).

The targeting of various Rab proteins to different subcellular compartments appears to be determined by variable amino acid sequences located upstream from geranylgeranylated cysteine residues in the C-terminal tail. All nascent Rab proteins are prenylated by geranylgeranyltransferase II, which recognizes the Rab substrate only when it is bound to Rab escort protein (REP). After prenylation, REP remains associated with the modified Rab until it is delivered to the appropriate subcellular membrane. It remains unclear whether docking of the Rab with the correct membrane is solely a function of features contained within the prenylated Rab itself (with REP serving as a "passive" carrier) or whether REP actively participates in the targeting process. To address this issue, we took advantage of a mutation in the alpha2 helix of Rab1B (i.e. Y78D) that abolishes REP and GDI interaction without disrupting nucleotide binding or hydrolysis. These studies demonstrate that replacing the C-terminal GGCC residues of Rab1B(Y78D) with a CLLL motif permits this protein to be prenylated by geranylgeranyltransferase I but not II both in cell-free enzyme assays and in transfected cells. Subcellular fractionation and immunofluorescence studies reveal that the prenylated Rab1B(Y78D)CLLL, which remains deficient in REP and GDI association is, nonetheless, delivered to the Golgi and endoplasmic reticulum (ER) membranes. When the dominant-negative S22N mutation was inserted into Rab1B-CLLL, the resulting monoprenylated construct suppressed ER --> Golgi protein transport. However, when the Y78D mutation was added to the latter construct, its inhibitory effect on protein trafficking was lost despite the fact that it was localized to the ER/Golgi membrane. Therefore, protein interactions mediated by the alpha2 helical domain of Rab1B(S22N) appear to be essential for its functional interaction with components of the ER --> Golgi transport machinery.

State of South Dakota's child: 2000.

For the second consecutive year, 1999 brought an increase in the total number of births in South Dakota. Low birth weight newborns also increased during this year to 5.9%, representing the highest rate observed since 1974. Although the total percent of low birth weight increased, the percent of very low birth weight slightly decreased. Also observed is an increase in the use of prenatal care in the first trimester of pregnancy. The infant mortality rate for the state decreased slightly but remains higher than what is noted nationally. The rate of neonatal mortality is also slightly higher than the national rate. South Dakota's rate of post neonatal mortality remains considerably higher than the national rate but did decrease in 1999. The special topic of this year's report is brain development and the role of early experience. The state's new Bright Start program for pregnant women and their infants is described.

The Balanced Budget Act: potential implications for the practice of vascular surgery.

PURPOSE: Previous study results have shown a favorable impact on stroke rate with an increasing hospital volume of carotid endarterectomies (CEAs). This is not only the most frequently performed peripheral vascular procedure in the United States but also perhaps the most widely dispersed procedure relative to hospital type. Medical centers have adopted various strategies to lower the cost of hospitalization by reducing the length of stay (LOS), the major component of hospital cost. By 2002, the Balanced Budget Act is projected to reduce Medicare provider payments to academic medical centers (AMCs) by 15.5%, a reduction that is twice that for minor or nonteaching hospitals. We assessed the relationships between hospital costs, CEA volume, and stroke-mortality rates in AMCs and non-AMCs in Massachusetts. METHODS: With patient level data from the Massachusetts Division of Health Care Finance and Policy and with hospital cost and charge reports from the Health Care Financing Administration, HealthShare Technology provided data for all the patients discharged from a Massachusetts hospital who underwent CEA (n = 10,211) during the fiscal years 1995, 1996, and 1997, including cost, LOS, and disposition. The outcomes were further defined with in-hospital stroke and mortality rates. Five high volume AMCs (HVAMCs) were compared with all other nonacademic hospitals, which were further subdivided by annual volume into high volume non-AMCs (> or =50 cases), medium volume non-AMCs (24-49 cases), and low volume non-AMCs (12-23 cases). Statistical analysis was performed with analysis of variance to compare the means of all the cost and LOS data, and chi(2) test was used for comparison of incidence (significance assumed for P < or =. 05). RESULTS: Hospital costs were comparable among the four hospital types during individual years and averaged $6200, but HVAMCs were significantly more expensive overall, with a mean cost of $7882. The only centers to decrease their costs during the years evaluated were the HVAMCs, from $8706 to $6784. Length of stay did not differ among the groups in any year or overall, with a mean of 3.8 days, but did decrease between years at HVAMCs from 3.9 to 2.5 days. The combined stroke-mortality rates were significantly less at the HVAMCs (0.9%) than at either the high volume non-AMCs (1.9%) or the medium volume non-AMCs (2.5%). There was no significance in the analysis results of all the data within the low volume non-AMCs. CONCLUSION: Patients in HVAMCs have the best outcomes after CEA. Despite the achievement of significant efficiencies, AMCs have a small cushion to reduce further either LOS or resources to maintain a competitive cost position and to compensate for the fixed expenses of academic medicine. The Balanced Budget Act raises an equity concern for AMCs because it differentially affects the centers with the best outcomes. The financial implication of this may be a direct incentive for procedures to be done in centers with less optimal outcomes.

State of South Dakota's child: 1999.

The Surgeon General's Year 2000 health goals for the nation are presented and data from South Dakota and the United States that measure progress toward achieving them are discussed. The percentage of low-birth weight babies (LBW) in South Dakota is lower than observed nationally, but, similar to the national trend, has increased in the past few years. Between 1996-1998, 1.1% of all newborns in the state weighed less than 1500 grams, and 5.7% weighed less than 2500 grams. There has been continuing progress observed in the survival rate of the very low birth weight infant. In 1996 the state experienced a precipitous drop in its infant mortality rate (IMR) that has not been sustained in the past two years. The state's 1998 IMR of 9.0 per 1000 live births, however, is less than the mean rate of 10 that persisted over the previous decade. The IMR for white babies (5.7) has achieved the Year 2000 Goal. The rate of Sudden Infant Death in South Dakota is significantly higher (p < .001) than that observed nationally and speaks to the importance of placing babies on their backs to sleep and education regarding the risks associated with exposing a fetus and baby to smoking. The special topic of this year's report is breast-feeding. The benefits of breast-feeding to babies and mothers are described, as well as the need for it to be advocated by the health care community. This advocacy must emphasize breast-feeding's importance, how women can be assisted as they begin to nurse, and how community efforts can be taken to enable breast-feeding continuation when women return to work following delivery.

Acute and chronic toxicity of the herbicide benzofenap (Taipan 300) to Chironomus tepperi Skuse (Diptera: Chironomidae) and Isidorella newcombi (Adams and Angas) (Gastropoda: Planorbidae).

Acute and chronic toxicity tests were conducted on the herbicide benzofenap (Taipan 300) using two Australian freshwater invertebrates. The commercial formulation of benzofenap and a blank formulation containing only the adjuvants of Taipan 300 were tested against final instar larvae of the midge Chironomus tepperi and adults of the aquatic snail Isidorella newcombi. In 24-h acute bioassays the midge larvae did not show significant mortality at a nominal concentration of 1.2 mg/L active ingredient (AI), double the maximum notional concentration expected in rice fields after application of Taipan 300 at the permit rate of 2 L/ha. No significant snail mortality was recorded in acute bioassays (24-h exposure, 48-h recovery) at nominal concentrations up to 76 mg/L AI, which is over 120 times the maximum notional field concentration. In chronic assays, the pupation and emergence of C. tepperi was monitored after a 4-h pulse exposure of final instar larvae to Taipan 300 (nominal concentrations 0.001 to 0.1 mg/L AI) and adjuvant-only (0.1 mg/L equivalent) treatments. No statistically significant effects were observed, although emergence appeared to be delayed by higher benzofenap concentrations and by the adjuvant-only treatment. During snail bioassays, egg and feces production were monitored for 21 days after 24-h exposure to Taipan 300 (nominal concentrations 1.2 mg/L to 60 mg/L AI) and adjuvant-only treatments (60 mg/L equivalent). No significant chronic effects were proven against I. newcombi, despite a decline in egg mass production following exposure to all treatments and a reduction in the total numbers of eggs produced at the highest nominal concentrations tested (60 mg/L AI and adjuvant-only treatments). Similarly, feces production by snail pairs exposed to the majority of treatments declined, but these differences were not statistically significant. It is concluded that Taipan 300 does not represent a significant risk to mature C. tepperi larvae or adult I. newcombi in downstream environments when applied to rice fields at the permit rate of 2 L/ha.

State of South Dakota's child: 1998.

Births in South Dakota again decreased in 1997, continuing an ongoing trend that began in 1980. Progress in 1997 was noted in the use of first trimester prenatal care and the rate of low birth weight in the State remained lower than that observed nationally. The State's infant mortality rate for 1997 showed a continuation of the favorable shift in rates of the last decade that was initiated with the progress observed in 1996. Smoking and drinking during pregnancy is higher in South Dakota than noted nationally. How and why substance abuse prevention efforts must begin during childhood is discussed in this review. Currently, the rates of smoking and alcohol use are higher among South Dakota teens than noted nationally, and have increased over the past six years. Approaches to preventing substance abuse for the sake of the health and well being of youth and their potential future children are presented.