A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease.

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.

Elliptical metallic rings-shaped fractal metamaterial absorber in the visible regime.

Achieving the broadband response of metamaterial absorbers has been quite challenging due to the inherent bandwidth limitations. Herein, the investigation was made of a unique kind of visible light metamaterial absorber comprising elliptical rings-shaped fractal metasurface using tungsten metal. It was found that the proposed absorber exhibits average absorption of over 90% in the visible wavelength span of 400-750 nm. The features of perfect absorption could be observed because of the localized surface plasmon resonance that causes impedance matching. Moreover, in the context of optoelectronic applications, the absorber yields absorbance up to ~ 70% even with the incidence obliquity in the range of 0°-60° for transverse electric polarization. The theory of multiple reflections was employed to further verify the performance of the absorber. The obtained theoretical results were found to be in close agreement with the simulation results. In order to optimize the results, the performance was analyzed in terms of the figure of merit and operating bandwidth. Significant amount of absorption in the entire visible span, wide-angle stability, and utilization of low-cost metal make the proposed absorber suitable in varieties of photonics applications, in particular photovoltaics, thermal emitters and sensors.

Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel.

AIM: The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). BACKGROUND: The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. REVIEW RESULTS: The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. CONCLUSION: Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.

Fixed-dose combination in management of type 2 diabetes mellitus: Expert opinion from an international panel.

Type 2 diabetes mellitus (T2DM) is a progressive disease with multifactorial etiology. The first-line therapy includes monotherapy (with metformin), which often fails to provide effective glycemic control, necessitating the addition of add-on therapy. In this regard, multiple single-dose agents formulated as a single-dose form called fixed-dose combinations (FDCs) have been evaluated for their safety, efficacy, and tolerability. The primary objective of this review is to develop practice-based expert group opinion on the current status and the causes of concern regarding the irrational use of FDCs, in Indian settings. After due discussions, the expert group analyzed the results from several clinical evidence in which various fixed combinations were used in T2DM management. The panel opined that FDCs (double or triple) improve patient adherence, reduce cost, and provide effective glycemic control and, thereby, play an important role in the management of T2DM. The expert group strongly recommended that the irrational metformin FDC's, banned by Indian government, should be stopped and could be achieved through active participation from the government, regulatory bodies, and health ministry, and through continuous education of primary care physicians and pharmacists. In T2DM management, FDCs play a crucial role in achieving glycemic targets effectively. However, understanding the difference between rational and irrational FDC combinations is necessary from the safety, efficacy, and tolerability perspective. In this regard, primary care physicians will have to use a multistep approach so that they can take informed decisions.

Rapid tea catechins and caffeine determination by HPLC using microwave-assisted extraction and silica monolithic column.

A rapid reversed-phase high performance liquid chromatographic method using a monolithic column for the determination of eight catechin monomers and caffeine was developed. Using a mobile phase of water:acetonitrile:methanol (83:6:11) at a flow rate of 1.4 mL min(-1), the catechins and caffeine were isocratically separated in about 7 min. The limits of detection and quantification were in the range of 0.11-0.29 and 0.33-0.87 mg L(-1), respectively. Satisfactory recoveries were obtained (94.2-105.2 ± 1.8%) for all samples when spiked at three concentrations (5, 40 and 70 mg L(-1)). In combination with microwave-assisted extraction (MAE), the method was applied to the determination of the catechins and caffeine in eleven tea samples (6 green, 3 black and 2 oolong teas). Relatively high levels of caffeine were found in black tea, but higher levels of the catechins, especially epigallocatechin gallate (EGCG) were found in green teas.

Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems.

Correction of perinatally lethal neurogenetic diseases requires efficient transduction of several cell types within the relatively inaccessible CNS. Intravenous AAV9 delivery in mouse has achieved development stage-specific transduction of neuronal cell types, with superior neuron-targeting efficiency demonstrated in prenatal compared with postnatal recipients. Because of the clinical relevance of the non-human primate (NHP) model, we investigated the ability of AAV9 to transduce the NHP CNS following intrauterine gene therapy (IUGT). We injected two macaque fetuses at 0.9 G with 1 × 10(13) vg scAAV9-CMV-eGFP through the intrahepatic continuation of the umbilical vein. Robust green fluorescent protein (GFP) expression was observed for up to 14 weeks in the majority of neurons (including nestin-positive cells), motor neurons and oligodendrocytes throughout the CNS, with a significantly lower rate of transduction in astrocytes. Photoreceptors and neuronal cell bodies in the plexiform and ganglionic retinal layers were also transduced. In the peripheral nervous system (PNS), widespread transduction of neurons was observed. Tissues harvested at 14 weeks showed substantially lower vector copy number and GFP levels, although the percentage of GFP-expressing cells remained stable. Thus, AAV9-IUGT in late gestation efficiently transduces both the CNS and PNS with neuronal predilection, of translational relevance to hereditary disorders characterized by perinatal onset of neuropathology.

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression.

The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

Fate and ultra-structural features of chicken skin mucosa around juvenile polyps.

OBJECTIVE: Chicken skin mucosa (CSM) is a common finding around juvenile polyps in children. Its ultrastructural features and fate after polypectomy are not yet clear. The aim was to study ultra-structural features and outcome of this CSM compared to that of the polyps and distant endoscopically normal mucosa. MATERIAL AND METHODS: From 240 children with juvenile polyps, 45 needed a second colonoscopy. Thirty six patients showing CSM represented the cohort of this study. One polyp only was studied in each patient. The histologic features of the CSM were compared to normal and polyp mucosa. The fate of CSM was evaluated in the second colonoscopy. RESULTS: The mean numbers of intraepithelial lymphocytes, as well as lamina propria inflammatory cellular infiltrates were significantly higher in polyp mucosa than in CSM. Goblet cells were significantly higher in CSM compared to normal mucosa with marked depletion in the polyp mucosa. The muscularis mucosae thickness was significantly higher in CSM compared to polyps (p<0.0001) and both showed higher values than the normal mucosa. The CSM almost disappeared within a month period following polypectomy. CONCLUSIONS: The polyp showed the most intense mucosal inflammatory reaction. CSM with the unique thickening of muscularis mucosae especially around larger polyps almost disappeared after polypectomy. So these results suggest that CSM is a benign compensatory reaction induced by the mechanical effect of the polyp.

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors.

Non-integrating lentiviral vectors show considerable promise for gene therapy applications as they persist as long-term episomes in non-dividing cells and diminish risks of insertional mutagenesis. In this study, non-integrating lentiviral vectors were evaluated for their use in the adult and fetal central nervous system of rodents. Vectors differentially pseudotyped with vesicular stomatitis virus, rabies and baculoviral envelope proteins allowed targeting of varied cell populations. Efficient gene delivery to discrete areas of the brain and spinal cord was observed following stereotactic administration. Furthermore, after direct in utero administration (E14), sustained and strong expression was observed 4 months into adulthood. Quantification of transduction and viral copy number was comparable when using non-integrating lentivirus and conventional integrating vector. These data support the use of non-integrating lentiviral vectors as an effective alternative to their integrating counterparts in gene therapy applications, and highlight their potential for treatment of inherited and acquired neurological disorders.

Respiratory complications after thyroidectomy and the need for tracheostomy in patients with a large goitre.

BACKGROUND: Thyroidectomy for a large goitre carries a relatively high risk of postoperative respiratory obstruction which may necessitate tracheostomy. METHODS: One hundred and three patients with a large goitre who underwent thyroidectomy were studied prospectively. The presence or absence of six preoperative predictive factors for the development of serious postoperative respiratory obstruction was recorded. These factors were: goitre for more than 5 years, preoperative recurrent laryngeal nerve palsy, significant tracheal narrowing and/or deviation, retrosternal extension, difficult endotracheal intubation and thyroid cancer. Tracheostomy was performed on the basis of clinical judgement. RESULTS: Postoperative respiratory complications occurred in 32 patients (31 per cent), and were obstructive in 24 patients and not obstructive in eight. Tracheostomy was necessary in 13 patients (13 per cent). Tracheomalacia was the most common indication (n = 5). There were no deaths. At least four of the six risk factors were present in nine of the 13 patients who underwent tracheostomy compared with two of the 90 patients who did not. CONCLUSION: Multiple preoperative risk factors in a patient with a large goitre may be useful in predicting the need for planned tracheostomy following thyroidectomy.

Significance of tumour markers in colorectal carcinoma associated with Schistosomiasis.

Schistosomiasis as well as Colorectal Carcinoma are equally prevalent in Egypt. However, the role of Schistosomiasis as a risk factor for Colorectal Carcinoma is not well established. Three tumour markers have been assessed in 69 patients with large bowel disease. They were classified into five groups. Group 1 (A) included 21 cases with Schistosomal hepatic fibrosis. Group 2 (B) included 6 cases of ulcerative colitis. Group 3 (C) included 10 cases of adenomatous polypi of which 12 cases had Schistosomiasis. Group 4 (D) consisted of 21 cases of colorectal carcinoma, 12 cases had schistosomiasis in association with colorectal carcinoma constituting group 5 (E). Elevated CEA was observed in benign tumours but showed non significant difference in G4 and G5. Significantly increased AFP levels were evident in G1, G4, and G5. Significant increase of B-HCG was observed only in G4 and G5 indicating its significance as diagnostic index in case of malignancy. It has been observed that Schistosomal hepatic fibrosis induced increased levels of some of the tumour markers. Therefore, the factor of Schistosomal hepatic fibrosis should be considered during the assessment of tumour markers in colorectal carcinoma cases.