The effect of docosahexaenoic acid on bone microstructure in young mice and bone fracture in neonates

Background

As low bone mineral density is a risk factor for fracture in childhood, optimizing age appropriate bone mass is recommended and might lower the impact of bone loss related to age. Consumption of omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic and docosahexaenoic (DHA) acids have been shown to beneficially modulate bone metabolism. The objective of this study was to determine the incidence of fracture in neonates receiving a fish compared with soybean oil–based intravenous lipid emulsion and evaluate the effect of varying dietary omega-3 PUFA consumption on growing bone in young mice.

Materials and methods

Eligibility criteria for the clinical study included gestational age ≤37 wk and parenteral nutrition–dependence for ≥4 wk. Radiographs were reviewed after lipid initiation to identify radiologic bone fracture. The animal study evaluated female C57/Bl6 mice randomized into one of five groups from age 3–12 wk, at which time femurs were harvested for micro–computed tomography and light microscopy analysis.

Results

A lower incidence of bone fracture was found in neonates maintained on fish compared with soybean oil. In the animal study, findings suggest the DHA diet provides the best protection against trabecular bone loss as evidenced by increased bone volume fraction, increased trabecular number, and decreased trabecular separation on micro–computed tomography. These protective effects appeared to affect the bone microstructure alone.

Conclusions

The lower fracture risk observed in fish oil fed neonates in combination with the protective effects of DHA observed in the femurs of young C57/BL6 mice suggest an important role for omega-3 PUFAs on bone growth.     

Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits

Background

Sunitinib (Sutent) is a Food and Drug Administration–approved receptor tyrosine kinase inhibitor found to reduce postoperative adhesion formation in animal models. The objective of the present study was to evaluate anastomotic healing and potential drug-related toxicities after short-term sunitinib administration in New Zealand White rabbits.

Materials and methods

Under an approved study protocol, 40 rabbits underwent a laparotomy followed by colonic transection and anastomosis. Animals were randomly assigned to treatment with oral sunitinib (10 mg/kg/d) or placebo, received one preoperative dose followed by 10 postoperative doses, and were divided into two groups following the procedure: group I animals were euthanized on completion of drug treatment and group II animals were euthanized 30 d after completion of treatment. Prior to study completion, animals underwent an echocardiogram and laboratory test results were obtained. At necropsy, intestinal bursting strength (in mmHg) was evaluated.

Results

All animals survived until designated euthanasia. There was no evidence of intra-abdominal sepsis or intestinal obstruction. Sunitinib-treated animals were found to have lower intestinal anastomotic strength compared with placebo-treated animals, as measured by bursting pressure at euthanasia, and a greater percentage of bursting at the anastomosis. On echocardiography, all ejection and shortening fractions were within established normal reference values. There were no significant differences in liver enzymes between animals. There were no wound infections, dehiscence, or delayed wound healing in any animal.

Conclusions

These results caution against the administration of sunitinib in cases involving intestinal anastomoses because of the elevated risk of anastomotic leak. No evidence of cardiotoxicity, hepatotoxicity, or detrimental effect on wound healing was found in any animal.     

The vaso-occlusive pain crisis in sickle cell disease: Definition,pathophysiology, and management

Early diagnosis, treatment, and prevention of a vaso-occlusive crisis (VOC) are critical to the management of patients with sickle cell disease. It is essential to differentiate between VOC-associated pain and chronic pain, hyperalgesia, neuropathy, and neuropathic pain. The pathophysiology of VOCs includes polymerization of abnormal sickle hemoglobin, inflammation, and adhesion. Hydroxyurea, L-glutamine, crizanlizumab, and voxelotor have been approved by the US Food and Drug Administration for reducing the frequency of VOCs; the European Medicines Agency has approved only hydroxyurea. Other novel treatments are in late-stage clinical development in both the United States and the European Union. The development of agents for prevention and treatment of VOCs should be driven by our understanding of its pathophysiology.     

Decreased white matter integrity in fronto-occipital fasciculus bundles: Relation to visual information processing in alcohol-dependent subjects

Chronic alcohol abuse is characterized by impaired cognitive abilities with a more severe deficit in visual than in verbal functions. Neuropathologically, it is associated with widespread brain structural compromise marked by gray matter shrinkage, ventricular enlargement, and white matter degradation. The present study sought to increase current understanding of the impairment of visual processing abilities in alcohol-dependent subjects, and its correlation with white matter microstructural alterations, using diffusion tensor imaging (DTI). To that end, a DTI study was carried out on 35 alcohol-dependent subjects and 30 healthy male control subjects. Neuropsychological tests were assessed for visual processing skills and deficits were reported as raw dysfunction scores (rDyS). Reduced FA (fractional anisotropy) and increased MD (mean diffusivity) were observed bilaterally in inferior and superior fronto-occipital fasciculus (FOF) fiber bundles. A significant inverse correlation in rDyS and FA values was observed in these fiber tracts whereas a positive correlation of these scores was found with the MD values. Our results suggest that FOF fiber bundles linking the frontal lobe to occipital lobe might be related to visual processing skills. This is the first report of an alteration of the white matter microstructure of FOF fiber bundles that might have functional consequences for visual processing in alcohol-dependent subjects who exhibit no neurological complications.     

Establishing postprandial bio-equivalency and IVIVC for generic metformin sustained release small sized tablets

The objective of current study was to develop metformin hydrochloride modified release small sized tablets, and to evaluate its bioequivalence when compared with the reference product (Glucophage^® SR). The physicochemical properties of the formulated and reference tablets were determined and compared. The in vitro dissolution profiles of formulated tablets were obtained using bio-relevant media and IVIVC was established. Bioequivalence investigation was carried out in 32 healthy male volunteers who received a single dose 1,000 mg of both test and reference products in a randomized two-way crossover design in postprandial conditions. After dosing, serial blood samples were collected for a period of 48 h. Metformin concentration was assayed by using a validated LC–MS/MS method. The log-transformed C_max and AUC were statistically compared by analysis of variance, and the 90 % confidence intervals (CI) of the ratio of the log-transformed C_max and AUC between the most promising developed formulation and the reference product were determined. It was deduced that the dissolution rate profile of the formulated modified release small sized tablets was similar to the reference product employed in the study. Their similarity and difference factors were found to be well within the established limits. In the bioequivalence study, the difference in C_max, AUC_last and AUC_inf between the test and reference product was not statistically significant, with the 90 % CI of 100.73–116.20, 86.16–97.37 and 87.12–96.99 %, respectively. The results suggested that the metformin small tablets formulated with reduced quantity of controlled release polymer were found to be bioequivalent in the postprandial state. For these small tablets, pH 5.5 acetate buffer as a bio-relevant dissolution media for the development of IVIVC.     

Sight-threatening intraocular infection in patients with COVID-19 in India

Purpose:Intraocular infection in patients with COVID-19 could be different in the presence of treatment with systemic corticosteroid and immunosuppressive agents. We describe the epidemiology and microbiological profile of intraocular infection in COVID-19 patients after their release from the hospital.Methods:We analyzed the clinical and microbiological data of laboratory-confirmed COVID-19 patients from April 2020 to January 2021 presenting with features of endogenous endophthalmitis within 12 weeks of their discharge from the hospital in two neighboring states in South India. The data included demography, systemic comorbidities, COVID-19 treatment details, time interval to visual symptoms, the microbiology of systemic and ocular findings, ophthalmic management, and outcomes.Results:The mean age of 24 patients (33 eyes) was 53.6 ± 13.5 (range: 5–72) years; 17 (70.83%) patients were male. Twenty-two (91.6%) patients had systemic comorbidities, and the median period of hospitalization for COVID-19 treatment was 14.5 ± 0.7 (range: 7–63) days. Infection was bilateral in nine patients. COVID-19 treatment included broad-spectrum systemic antibiotics (all), antiviral drugs (22, 91.66% of patients), systemic corticosteroid (21, 87.5% of patients), supplemental oxygen (18, 75% of patients), low molecular weight heparin (17, 70.8% of patients), admission in intensive care units (16, 66.6% of patients), and interleukin-6 inhibitor (tocilizumab) (14, 58.3% of patients). Five (20.8%) patients died of COVID-19-related complications during treatment for endophthalmitis; one eye progressed to pan ophthalmitis and orbital cellulitis; eight eyes regained vision >20/400. Fourteen of 19 (73.7%) vitreous biopsies were microbiologically positive (culture, PCR, and microscopy), and the majority (11 patients, 78.5%) were fungi.Conclusion:Intraocular infection in COVID-19 patients is predominantly caused by fungi. We suggest a routine eye examination be included as a standard of care of COVID-19.     

Modulation of flexo-rigid balance in photoresponsive thymine grafted copolymers towards designing smart healable coating

Efficacy and durability of the photovoltaic device mandates its protection against hot, humid weather condition, high energy of UV light and unwanted scratches. Such challenges can be mitigated by smart polymeric coating with inherent properties e.g. hydrophobicity to prevent moisture, optimal viscocity for better processibility and crack-healing. The hydrophobic polymers TP1–TP4 containing pendant photo-crosslinkable thymine moieties are designed that undergo [2 + 2] photocycloaddition upon UV_B irradiation and can be dynamically reverted back upon irradiation with UV_C light. A judicious control of solvent environment, chain length, functionality% and concentration of the polymers regulate the aspects of photodimerization thereby, rendering intra or inter-chain collapse to form diverse nanostructures. Photodimerization of the thymine moieties renders coil to globule transformation in dilute condition whereas irradiation performed at high macromolecular concentration regime exhibits higher order nanostructures. The photoresponsive chain collapse leads to the formation of rigid crosslinked domains within flexible polymer chains akin to the hard–soft phases of thermoplastic elastomers. Such rigidification of the crosslinked segments endows a tool to photomodulate the glass transition temperature (T_g) that can dynamically revert back upon decrosslinking. Further, the structural modulation of the polymers is explored towards autonomic and nonautonomic self-healing behaviour at ambient conditions. Moreover, the self-healing efficacy can be tuned with the film thickness and it remains unaltered upon using solar simulator or direct sunlight. Overall, such hydrophobic low T_g polymers display photo-regulated self-healing mechanism consisting of both autonomic and non-autonomic self-healing and may find applications in designing smart protective coatings for photovoltaic devices.

Photo-crosslinking using [2 + 2] cycloaddition in thymine grafted low viscosity polymer generates flexorigid domain to result self-healing polymer with increased hydrophobicity for potential use as smart coating material.     

Cerebroprotective Potential of Hesperidin Nanoparticles Against Bilateral Common Carotid Artery Occlusion Reperfusion Injury in Rats and In silico Approaches

Neurotoxicity Research - Cerebral ischemia-reperfusion (C I/R) accelerates neuronal injury through the overproduction of reactive oxygen species due to mitochondrial dysfunction. Hesperidin has...     

CEACAM-1 Induced CSF3-receptor Downregulation in Bone Marrow Associated With Refractory Neutropenia in Advanced Cirrhosis

Background and Aims: Cirrhosis patients exhibit cyto-penia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts th...