Identification of proximal 1p36 deletions using array-CGH: a possible new syndrome

Monosomy 1p36 is the most common terminal deletion syndrome with an estimated occurrence of 1:5000 live births. Typically, the deletions span <10 Mb of 1pter-1p36.23 and result in mental retardation, developmental delay, sensorineural hearing loss, seizures, cardiomyopathy and cardiovascular malformations, and distinct facies including large anterior fontanel, deep-set eyes, straight eyebrows, flat nasal bridge, asymmetric ears, and pointed chin. We report five patients with 'atypical' proximal interstitial deletions from 1p36.23-1p36.11 using array-comparative genomic hybridization. Four patients carry large overlapping deletions of approximately 9.38-14.69 Mb in size, and one patient carries a small 2.97 Mb deletion. Interestingly, these patients manifest many clinical characteristics that are different from those seen in 'classical' monosomy 1p36 syndrome. The clinical presentation in our patients included: pre- and post-natal growth deficiency (mostly post-natal), feeding difficulties, seizures, developmental delay, cardiovascular malformations, microcephaly, limb anomalies, and dysmorphic features including frontal and parietal bossing, abnormally shaped and posteriorly rotated ears, hypertelorism, arched eyebrows, and prominent and broad nose. Most children also displayed hirsutism. Based on the analysis of the clinical and molecular data from our patients and those reported in the literature, we suggest that this chromosomal abnormality may constitute yet another deletion syndrome distinct from the classical distal 1p36 deletion syndrome.     

Photochemical cross-linking for collagen-based scaffolds: a study on optical properties, mechanical properties, stability, and hematocompatibility

Collagen presents an attractive biomaterial for tissue engineering because of its excellent biocompatibility and negligible immunogenicity. However, some intrinsic features related to the mechanical stability and thrombogenicity limit its applications in orthopedic and vascular tissue engineering. Photochemical cross-linking is an emerging technique able to stabilize tissue grafts and improve the physicochemical properties of collagen-based structures. However, other important properties of collagen-based structures and the effect of processing parameters on these properties have not been explored. In this study, we aim to investigate the dose dependence of tensile and swelling properties on two parameters, namely, laser energy fluence and rose Bengal photosensitizer concentration. We also study the compression properties using cyclic compression test, long-term stability using subcutaneous implantation, and hematocompatibility using platelets adhesion test, of cross-linked collagen structures. Moreover, because limited optical penetration in turbid media is the major obstacle for light-based techniques, we also characterize the optical properties, which partially determine the effective optical penetration depth in collagen gel samples, during photochemical cross-linking. Laser energy fluence and rose Bengal concentration are important parameters affecting the cross-linking efficiency, which was characterized as the mechanical and the swelling properties, in a dose-dependent manner. Under the experimental conditions in this study, the peak fluence was 12.5 J/cm2 and the minimal rose Bengal concentration for effective cross-linking was >0.00008% (0.786 micromol). Photochemical cross-linking also enhanced the compression strength and long-term stability of collagen structures without compromising the tissue compatibility. Furthermore, photochemical cross-linking reduced platelet adhesion and abolished fibrin mesh formation, thereby improving the hematocompatibility of collagen structures. These results suggest the feasibility of using the photochemically cross-linked collagen structures for orthopedic and vascular tissue engineering. Finally, the effective optical penetration depth in collagen gel samples is wavelength and rose Bengal concentration dependent, and was approximately 12 mm at 514 nm at 0.001% (9.825 micromol), the rose Bengal concentration mostly used in this study.     

Effect of Cardiorespiratory Fitness on Academic Achievement is Stronger in High‐SES Elementary Schools Compared to Low

BACKGROUND

Academic achievement is influenced by factors at the student, school, and community levels. We estimated the effect of cardiorespiratory fitness performance on academic performance at the school level in Georgia elementary schools and examined effect modification by sociodemographic factors.

METHODS

This study is a repeat cross‐sectional analysis of Georgia elementary schools between 2011 and 2014 (approximately 1138 schools per year). Multivariable beta regression estimated the effect of the proportion of 4th and 5th graders meeting cardiorespiratory fitness standards on the proportion of 5th graders passing standardized tests for Reading, English and Language Arts, Mathematics, Science, and Social Studies and considered potential interaction by school‐level socioeconomic status (SES), racial composition, and urbanity.

RESULTS

There was a 0.15 higher estimated odds (OR: 1.15 (1.09, 1.22)) of passing the mathematics standardized test for every 10‐percentage‐point increase in school‐level cardiorespiratory fitness among high‐SES schools and 0.04 higher odds (OR: 1.04 (1.02, 1.05)) for low‐SES schools. This pattern was similar for other academic subjects. No effect modification by racial composition or urbanity was observed for any academic subject.

CONCLUSIONS

Promoting physical fitness may be effective in improving academic performance among high‐SES schools, but additional strategies may be needed among lower‐SES schools.

     

Cold-induced vasodilatation in the foot is not homogenous or trainable over repeated cold exposure

Cold-induced vasodilatation (CIVD) is proposed to be a protective response to preserve tissue integrity in the extremities during cold exposure, but little research exists on either the trainability or the spatial pattern of CIVD response in the foot. We investigated the thermal response across the foot with repeated cold exposure. Ten healthy subjects immersed their left foot to the ankle in 8°C water for 30 min 5 days/week for 3 weeks. Skin temperature was recorded on the medial side of the nail bed of the 5 toes and the dorsum of the foot. The presence of CIVD, defined as an increase of 1°C at any time during cooling, was rare with our protocol. While a CIVD response was observed at least once in 8 of the 10 subjects, only 122 instances of CIVD were observed out of a total of 900 possible observations (10 subjects × 6 sites × 15 trials). Furthermore, thermal habituation was not evident, with toe temperatures at the end of each immersion (8–11°C) remaining near water temperature throughout the 15 sessions. Even within the two subjects exhibiting the most incidence of CIVD, high variability existed in the occurrence, magnitude, and/or onset times. Synchronicity was often observed where more than one toe exhibited CIVD, though the magnitude varied greatly (range 1–9°C). We conclude that, under realistic conditions of whole-foot immersion in cold water, CIVD is not a common or trainable response.     

A 3D collagen microsphere culture system for GDNF-secreting HEK293 cells with enhanced protein productivity

Mammalian cell culture technology has been used for decades in mass production of therapeutic proteins. However, unrestricted cell proliferation usually results in low-protein productivity. Controlled proliferation technologies such as metabolism intervention and genetic manipulation are therefore applied to enhance the productivity. Nevertheless, these strategies induced growth arrest with reduced viability and increased apoptosis. In this study, we report a new controlled proliferation technology by encapsulating human embryonic kidney (HEK) 293 cells over-expressing glial-derived neurotrophic factor (GDNF) in 3D collagen microspheres for extended culture. We investigated the viability, proliferation, cell cycle and GDNF productivity of HEK293 cells in microspheres as compared to monolayer culture. This system provides a physiologically relevant tissue-like environment for cells to grow and exerts proliferation control throughout the culture period without compromising the viability. A significant increase in the production rate of GDNF was found in the 3D microsphere system comparing with the monolayer culture. GDNF productivity was also significantly affected by the initial cell number and the serum concentration. The secreted GDNF was still bioactive as it induced neurite extension in PC12 cells. In summary, the 3D collagen microsphere system presents a cost-effective controlled growth technology for protein production in pharmaceutical manufacturing.     

Combining 2 Commonly Adopted Nutrition Instruments in the Critical Care Setting Is Superior to Administering Either One Alone

Background: This study aimed to determine the agreement between the modified Nutrition Risk in Critically ill Score (mNUTRIC) and the Subjective Global Assessment (SGA) and compare their ability in discriminating and quantifying mortality risk independently and in combination. Methods: Between August 2015 and October 2016, all patients in a Singaporean hospital received the SGA within 48 hours of intensive care unit admission. Nutrition status was dichotomized into presence or absence of malnutrition. The mNUTRIC of patients was retrospectively calculated at the end of the study, and high mNUTRIC was defined as scores ≥5. Results: There were 439 patients and 67.9% had high mNUTRIC, whereas only 28% were malnourished. Hospital mortality was 29.6%, and none was lost to follow‐up. Although both tools had poor agreement (κ statistics: 0.13, P < .001), they had similar discriminative value for hospital mortality (C‐statistics [95% confidence interval (CI)], 0.66 [0.62–0.70] for high mNUTRIC and 0.61 [0.56–0.66] for malnutrition, P = .12). However, a high mNUTRIC was associated with higher adjusted odds for hospital mortality compared with malnutrition (adjusted odds ratio [95% CI], 5.32 [2.15–13.17], P < .001, and 4.27 [1.03–17.71], P = .046, respectively). Combination of both tools showed malnutrition and high mNUTRIC were associated with the highest adjusted odds for hospital mortality (14.43 [5.38–38.78], P < .001). Conclusion: The mNUTRIC and SGA had poor agreement. Although they individually provided a fair discriminative value for hospital mortality, the combination of these approaches is a better discriminator to quantify mortality risk.     

Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics

Somatic chromosomal mosaicism is a well-established cause for birth defects, mental retardation, and, in some instances, specific genetic syndromes. We have developed a clinically validated, targeted BAC clone array as a platform for comparative genomic hybridization (aCGH) to enable detection of a wide range of pathologic copy number changes in DNA. It is designed to provide high sensitivity to detect well-characterized submicroscopic micro-deletion and duplication disorders while at the same time minimizing detection of variation of uncertain clinical significance. In the course of studying 2,585 samples submitted to our clinical laboratory, chromosomal mosaicism was detected in 12 patient samples; 10 of these cases were reported to have had a normal blood chromosome analysis. This enhanced ability of aCGH to detect mosaicism missed by routine chromosome analysis may be due to some combination of testing multiple cell lineages and/or failure of cytogenetically abnormal T lymphocytes to respond to mitogens. This suggests that aCGH may detect somatic chromosomal mosaicism that would be missed by conventional cytogenetics.     

Mammographic Surveillance in Older Women With Breast Cancer in Canada and the United States: Are We Choosing Wisely?

PurposeGuidelines on mammographic surveillance after breast cancer treatment have been disseminated internationally and incorporated into Choosing Wisely recommendations to reduce low-value care. However, adherence within different countries before their publication is unknown.Methods and MaterialsLow-value mammography, defined as “short-interval” (within 6 months of radiation) or “high-frequency” (>1 within 12 months of radiation), was compared in Medicare fee-for-service in the United States and Ontario, Canada. Women ≥65 years diagnosed with breast cancer who underwent breast-conserving therapy with a minimum of 24 months of follow-up were included (n = 19,715 United States; 6479 Ontario). Secondary outcomes were patient and physician characteristics associated with discordance.ResultsShort-interval mammography was higher in the United States than in Ontario (55.9% vs 38.0%, P < .001), as was high-frequency (39.6% vs 7.9%, P < .001). In Ontario, younger age (42% ≥85 vs 58% <74 years, P < .001) and chemotherapy (69% vs 51%, P < .001) were associated with short-interval mammography; in the United States, age, earlier diagnosis year, stage, chemotherapy, rurality, and academic center treatment were associated with greater use. Chemotherapy was associated with high-frequency mammography in both countries (13% vs 7% in Ontario, P < .001; 69% vs 51% in United States, P = .02); younger age, earlier diagnosis year, stage, and nonacademic center treatment were associated in the United States. In both countries, radiation oncologists had the highest proportion of providers ordering low-value mammograms.ConclusionsDespite significant evidence guiding surveillance mammography recommendations, there are high rates of short-interval mammography in both the United States and Ontario, and high rates of high-frequency mammography in the United States. Further international efforts, such as Choosing Wisely, are needed to reduce low-value mammography.