Tumor homing peptide modified liposomes of capecitabine for improved apoptotic activity and HER2 targeted therapy in breast cancer: in vitro studies

In the present study, we have formulated a liposomal formulation of cytotoxic agent capecitabine (CAP) to overcome its bioavailability issues. Then we have surface modified CAP loaded liposomes (CAP-LPs) with a tumour homing peptide (THP-CAP-LPs) to achieve site specific delivery to breast cancer cells. We found a significant cellular internalization of THP-CAP-LPs when compared to unmodified CAP-LPs. The cytotoxic effect of CAP was also significantly improved with THP-CAP-LPs by downregulating anti-apoptotic proteins and upregulating pro-apoptotic proteins as observed by Western blot analysis. THP-CAP-LPs mediated delivery of CAP can be, therefore, a promising approach for improving antitumor activity and reducing off-target effects.

Tumor homing peptide modified liposomes loaded with capecitabine (CAP) were prepared in the present study. The in vitro efficacy was tested in breast cancer cells.     

Pre-intervention Predictors for Acquisition of Adaptive Behavior Among Children with Intellectual Disability

Type 2 diabetes mellitus (T2DM) is a chronic progressive disease with high morbidity and mortality rates. Previously an adult onset disease, it is now being diagnosed more and more in childhood and adolescence. Lately, Asia has become the epicenter of this epidemic. Childhood T2DM is a new challenge for the pediatrician. Due to similarities in presentation, children may initially be misdiagnosed with Type 1 diabetes mellitus (T1DM). Most oral anti-diabetic agents have not been approved for use in adolescents, and there is a concern for safety of their use. Lifestyle intervention is difficult to conduct, and adherence to recommendations is lower in adolescents than in adults with T2DM. Higher incidence and early onset of co-morbidities, with lack of long term outcomes data make the management problematic. In many communities, due to a shortage of specialists, general practitioners will treat children with T2DM. Guidelines cited in this review are designed to help with the diagnostic process and management.     

Reversibility of brainstem evoked response audiometry abnormalities at 3 months in term newborns with hyperbilirubinemia

Background

High bilirubin level is toxic to developing brain and auditory system but the current debate surrounds the toxicity of bilirubin in healthy term infants.

Methods

Longitudinal observational study to find BERA abnormalities in term newborns with isolated hyperbilirubinemia of 20 mg/dL and more and to follow up babies at 3 months to find out about the reversibility in BERA abnormalities noted at birth.

Results

BERA abnormalities were present in 17.64% of babies with isolated hyperbilirubinemia at discharge. There was a reversibility of BERA abnormalities in 61.61% during follow up.

Conclusion

BERA abnormalities are reversible in term neonates with hyperbilirubinemia.     

Development of pattern vision following early and extended blindness

Visual plasticity peaks during early critical periods of normal visual development. Studies in animals and humans provide converging evidence that gains in visual function are minimal and deficits are most severe when visual deprivation persists beyond the critical period. Here we demonstrate visual development in a unique sample of patients who experienced extended early-onset blindness (beginning before 1 y of age and lasting 8–17 y) before removal of bilateral cataracts. These patients show surprising improvements in contrast sensitivity, an assay of basic spatial vision. We find that contrast sensitivity development is independent of the age of sight onset and that individual rates of improvement can exceed those exhibited by normally developing infants. These results reveal that the visual system can retain considerable plasticity, even after early blindness that extends beyond critical periods.Early visual experience is crucial to the normal development of the neural substrates of vision. Abnormal early experience results in dramatic changes in visual cortices, as well as corresponding behavioral deficits in visual abilities (1–7). Neurophysiological studies in animals following early binocular visual deprivation demonstrate reductions in the responsiveness, orientation selectivity, resolution, and contrast sensitivity of neurons in visual cortex (1–4) that persist when sight is restored later in life (8). Given their vulnerability to deprivation, can these neural mechanisms recover functionality after extended periods of deprivation?To investigate this question, we examined the development of contrast sensitivity in a unique group of sight restoration patients. Contrast sensitivity is a fundamental metric of visual performance that describes the sensitivity of neurons and observers. It is the primary visual limitation in a variety of tasks, including mobility, reading, and face and object recognition (9). The neural underpinnings of contrast sensitivity are found in early visual cortex (10–12). In both brain and behavior, contrast sensitivity functions (CSFs) exhibit a characteristic shape: a band-pass function with peak contrast sensitivity and a falloff at relatively lower and higher spatial frequencies. There is a direct relationship between behavioral and neural contrast sensitivity: the peak frequency of behavioral contrast sensitivity is the mode of the distribution of peak frequencies of neural CSFs (12). Contrast sensitivity therefore provides a valuable assay for visual development (3) and examination of its change following deprivation can provide fundamental insights into the critical periods of neural plasticity.Two factors are thought to influence the extent of visual ability after blindness: the age of onset and the duration of blindness. We define “early-onset” blindness as occurring before 1 y of age. We define “extended” blindness as lasting at least until early childhood, when many visual abilities in normally developing children reach adult levels. Contrast sensitivity in particular develops until approximately age 7 in normally sighted humans (13–15). Previous studies of sight restoration in humans have examined patients after either early-onset blindness or extended blindness, but not with both. Following early-onset blindness lasting a short duration (from birth to 6 mo of age), contrast sensitivity is deficient at high spatial frequencies and does not improve after age 7 (16). Improvement in contrast sensitivity is even more limited after extended blindness with delayed onset. In Fine et al.''s study (17), patient MM, blind from age 3 to 43, did not exhibit contrast sensitivity improvement for the 2 y following sight restoration surgery. He has continued to exhibit impaired vision and an abnormal receptive field map in V1 with reduced foveal representation and increased receptive field sizes (18). These findings suggest that the neural mechanisms supporting contrast sensitivity only develop during a specific age-defined window and cannot develop if the period of binocular deprivation extends beyond this window. Without exposure to the normal range of spatial frequency information, these neural substrates may lose plasticity after critical periods of development have passed.Contrary to these predictions, we report marked improvements in the CSFs of a unique sample of sight restoration patients who experienced early-onset visual deprivation that remained untreated for an extended duration (the minimum age at treatment was 8 y). These patients exhibited extremely poor presurgical acuity of, at most, finger counting at a distance of 1 m. According to the standards adopted by the World Health Organization (19), this level of vision is equivalent to an acuity of 20/1,200 (1/60) and is categorized as the third most severe level of blindness (after light perception and no light perception). This study was conducted as part of Project Prakash, a joint scientific and humanitarian effort to treat curable blindness in India and to investigate the resulting course of visual development (20). Access to this population allowed us to examine contrast sensitivity across a large sample of sight restoration patients compared with previous reports (16–18, 21–23). Consequently, we could also explore individual differences in contrast sensitivity development.     

Comparison of nocturnal pulse oximetry with polysomnography in children with sleep disordered breathing

Purpose

Polysomnography (PSG) is the gold standard in the diagnosis of obstructive sleep apnea (OSA). However, due to high cost and limited availability, this is difficult to access and often delayed. To evaluate the reliability of overnight oximetry as a screening tool for OSA diagnosis.

Method

All children suspected of OSA who underwent an overnight oximetry and subsequent PSG between January 2014 and April 2016 were studied retrospectively. The “McGill oximetry scoring” was compared with OSA diagnosis as per the American Association of Sleep Medicine.

Results

A total of 110 patients had both oximetry and PSG. Sixty-one children (56%) had normal oximetry, whereas 30 (27%) had McGill grade 2 and 19 (17%) had McGill 3 and 4. Sixty-four percent (64%) of children with normal oximetry had a normal PSG. Seventy percent (70%) of children with McGill 2 had either a normal or mild OSA on PSG. All the children with McGill 3 and 4 had moderate/severe OSA by PSG. The overall sensitivity and specificity of oximetry in identifying OSA were 63% and 78%, respectively, and the positive and negative predictive values (PPV and NPV) were 78% and 64%, respectively. The sensitivity and specificity of McGill 3 and 4 in diagnosing moderate/severe OSA on PSG were 59% and 100%, respectively, and the PPV and NPV were 100% and 78%, respectively.

Conclusion

Overnight oximetry provides satisfactory diagnostic performance in detecting moderate and severe OSA; however, a normal or McGill 2 score does not rule out OSA and a PSG is required for diagnosis.

     

Early experience of implantation of the new CoreValve® Evolut™ in degenerated bioprosthetic aortic valves

Transcatheter aortic valve implantation (TAVI) is an established treatment for severe aortic stenosis in high‐risk patients. The PARTNER trial demonstrated equivalent 1‐year survival rates between patients randomized to TAVI versus conventional surgery (Leon et al., N Engl J Med 2010;363:1597–1607), with sustained benefit up to 2 years (Makkar et al., NEJM 2012;366:1696–1704). Recently, the ADVANCE registry cited all‐cause mortality rates of 4.5%, 12.8%, and 17.9% at 30‐days, 6 months, and 1‐year following TAVI in 1,015 high‐risk patients (Linke, TCT 2012, 2012). In addition, TAVI was demonstrated to be a feasible treatment for severe native valve regurgitation in a series of 31 high‐risk patients. The all‐cause 30‐day mortality rate was 6.4%, with a 30‐day major stroke rate of 6.4%. At 1‐year, the all‐cause mortality rate was 12.5% (Roy et al., J Am Coll Cardiol 2012;60(17S):B264). We report the successful transcatheter implantation of the new CoreValve^® Evolut^? in two patients with regurgitant aortic bioprostheses. © 2013 Wiley Periodicals, Inc.