Publications by authors named "Zubair Ahmed"

315 Publications

Impact of Customized and Sustained Physiotherapy in Charcot-Marie-Tooth Disease.

Cureus 2021 Aug 15;13(8):e17201. Epub 2021 Aug 15.

Musculoskeletal Physiotherapy, Tilak Maharashtra Vidyapeeth Jayantrao Tilak College of Physiotherapy, Pune, IND.

Charcot-Marie-Tooth (CMT) disease is the most inherited form of peripheral neuropathy. This condition is also known as hereditary motor and sensory neuropathy (HMSN), which is a slowly progressive neuropathy affecting peripheral nerves and causes sensory loss, weakness and muscle wasting. This primarily involves distal muscles of feet, lower legs, hands and forearm. CMT is the most frequently inherited peripheral neuropathy known to affect 1 in 2500 individuals. There are four types: CMT1, CMT2, CMT3 and CMT4, depending upon the involvement of specific gene deficit, inheritance pattern, age of onset and whether the primary defect results in an abnormality of the myelin or axon of the nerve. Diagnosis of CMT is done based on physical examination, genetic testing, and electromyography (EMG) and nerve conduction velocity (NCV) test results. Symptoms of weakness progress from distal to proximal, i.e., it begins from feet and ankles. CMT is a known length dependent neuropathy which results in foot drop and later weakness of hands and forearm becomes evident. Due to the involvement of sensory nerve fibres, sensations like heat, touch, pain and most prominently vibration is also present distally. Long standing effects of CMT leads to the development of deformity and/or contractures which may involve forefoot, hindfoot, toes and/or long finger flexors. As physiotherapy is a means to maintain and/or gain maximum possible functional independence, consistency of the treatment becomes the most important factor. This case report intends to show that consistency in performing physiotherapeutic exercises helps in gaining maximum possible functional independence. This case report is a discussion of a 25-year-old male patient referred to the physiotherapy department with the polyneuropathy type symptoms with his history and investigation reports being consistent with that of Charcot-Marie-Tooth disease.
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http://dx.doi.org/10.7759/cureus.17201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439527PMC
August 2021

Thermosensitive collagen/fibrinogen gels loaded with decorin suppress lesion site cavitation and promote functional recovery after spinal cord injury.

Sci Rep 2021 Sep 13;11(1):18124. Epub 2021 Sep 13.

Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

The treatment of spinal cord injury (SCI) is a complex challenge in regenerative medicine, complicated by the low intrinsic capacity of CNS neurons to regenerate their axons and the heterogeneity in size, shape and extent of human injuries. For example, some contusion injuries do not compromise the dura mater and in such cases implantation of preformed scaffolds or drug delivery systems may cause further damage. Injectable in situ thermosensitive scaffolds are therefore a less invasive alternative. In this study, we report the development of a novel, flowable, thermosensitive, injectable drug delivery system comprising bovine collagen (BC) and fibrinogen (FB) that forms a solid BC/FB gel (Gel) immediately upon exposure to physiological conditions and can be used to deliver reparative drugs, such as the naturally occurring anti-inflammatory, anti-scarring agent Decorin, into adult rat spinal cord lesion sites. In dorsal column lesions of adult rats treated with the Gel + Decorin, cavitation was completely suppressed and instead lesion sites became filled with injury-responsive cells and extracellular matrix materials, including collagen and laminin. Decorin increased the intrinsic potential of dorsal root ganglion neurons (DRGN) by increasing their expression of regeneration associated genes (RAGs), enhanced local axon regeneration/sprouting, as evidenced both histologically and by improved electrophysiological, locomotor and sensory function recovery. These results suggest that this drug formulated, injectable hydrogel has the potential to be further studied and translated into the clinic.
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http://dx.doi.org/10.1038/s41598-021-97604-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438067PMC
September 2021

Generation of Multipotential NG2 Progenitors From Mouse Embryonic Stem Cell-Derived Neural Stem Cells.

Front Cell Dev Biol 2021 24;9:688283. Epub 2021 Aug 24.

Neuroscience and Ophthalmology Research Group, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

Embryonic stem cells (ESC) have the potential to generate homogeneous immature cells like stem/progenitor cells, which appear to be difficult to isolate and expand from primary tissue samples. In this study, we developed a simple method to generate homogeneous immature oligodendrocyte (OL) lineage cells from mouse ESC-derived neural stem cell (NSC). NSC converted to NG2/OLIG2double positive progenitors (NOP) after culturing in serum-free media for a week. NOP expressed , but not gene, highlighting their immature phenotype. Interestingly, FACS analysis revealed that NOP expressed proteins for NG2, but not PDGFRɑ, distinguishing them from primary OL progenitor cells (OPC). Nevertheless, NOP expressed various OL lineage marker genes including , α, , and , but not genes, and, when cultured in OL differentiation conditions, initiated transcription of and genes, and expression of PDGFRα proteins, implying that NOP converted into a matured OPC phenotype. Unexpectedly, NOP remained multipotential, being able to differentiate into neurons as well as astrocytes under appropriate conditions. Moreover, NOP-derived OPC myelinated axons with a lower efficiency when compared with primary OPC. Taken together, these data demonstrate that NOP are an intermediate progenitor cell distinguishable from both NSC and primary OPC. Based on this profile, NOP may be useful for modeling mechanisms influencing the earliest stages of oligogenesis, and exploring the cellular and molecular responses of the earliest OL progenitors to conditions that impair myelination in the developing nervous system.
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http://dx.doi.org/10.3389/fcell.2021.688283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423355PMC
August 2021

Overexpression of Reticulon 3 Enhances CNS Axon Regeneration and Functional Recovery after Traumatic Injury.

Cells 2021 Aug 6;10(8). Epub 2021 Aug 6.

Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK.

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-A. Here, we focused on RTN3 as its contribution to CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a well-characterised model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin, however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury.
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http://dx.doi.org/10.3390/cells10082015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395006PMC
August 2021

Effects of intravitreal injection of siRNA against caspase-2 on retinal and optic nerve degeneration in air blast induced ocular trauma.

Sci Rep 2021 Aug 19;11(1):16839. Epub 2021 Aug 19.

Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Ocular repeated air blast injuries occur from low overpressure blast wave exposure, which are often repeated and in quick succession. We have shown that caspase-2 caused the death of retinal ganglion cells (RGC) after blunt ocular trauma. Here, we investigated if caspase-2 also mediates RGC apoptosis in a mouse model of air blast induced indirect traumatic optic neuropathy (b-ITON). C57BL/6 mice were exposed to repeated blasts of overpressure air (3 × 2 × 15 psi) and intravitreal injections of siRNA against caspase-2 (siCASP2) or against a control enhanced green fluorescent protein (siEGFP) at either 5 h after the first 2 × 15 psi ("post-blast") or 48 h before the first blast exposure ("pre-blast") and repeated every 7 days. RGC counts were unaffected by the b-ITON or intravitreal injections, despite increased degenerating ON axons, even in siCASP2 "post-blast" injection groups. Degenerating ON axons remained at sham levels after b-ITON and intravitreal siCASP2 "pre-blast" injections, but with less degenerating axons in siCASP2 compared to siEGFP-treated eyes. Intravitreal injections "post-blast" caused greater vitreous inflammation, potentiated by siCASP2, with less in "pre-blast" injected eyes, which was abrogated by siCASP2. We conclude that intravitreal injection timing after ocular trauma induced variable retinal and ON pathology, undermining our candidate neuroprotective therapy, siCASP2.
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http://dx.doi.org/10.1038/s41598-021-96107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377143PMC
August 2021

Tolerability and Safety of Lasmiditan Treatment in Elderly Patients With Migraine: Post Hoc Analyses From Randomized Studies.

Clin Ther 2021 06 6;43(6):1066-1078. Epub 2021 Aug 6.

Eli Lilly and Company, Indianapolis, Indiana.

Purpose: Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population.

Methods: These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing).

Findings: Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period.

Implications: The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).
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http://dx.doi.org/10.1016/j.clinthera.2021.04.004DOI Listing
June 2021

Efficacy of tracheal tube introducers and stylets for endotracheal intubation in the prehospital setting: a systematic review and meta-analysis.

Eur J Trauma Emerg Surg 2021 Jul 31. Epub 2021 Jul 31.

Institute of Inflammation and Ageing, College of Medical and Dental Science, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.

Purpose: Tracheal tube introducers and stylets remain some of the most widely used devices for aiding practitioners in performing endotracheal intubation (ETI). The purpose of this systematic review is to evaluate the efficacy of tracheal tube introducers and stylets for ETI in the prehospital setting.

Methods: A literature search was conducted on the 2nd of March 2021 across PubMed, Embase (Ovid) and the Cochrane Central Register of Controlled Trials (CENTRAL) to identify relevant studies. Included studies had their data extracted and both a quality assessment and statistical analysis were performed.

Results: The summary estimate of prehospital studies with video technology showed a statistically significant increase in first pass ETI success in favour of bougies (RR 1.15, CI 1.10-1.21, p < 0.0001). The summary estimates of prehospital studies without video technology and simulation studies with and without video technology showed no statistical difference between methods for first pass or overall ETI success. Some of the highest success rates were recorded by devices that incorporated video technology. Stylets lead to a shorter time to ETI while bougies were easier to use. Neither device was associated with a higher rate of ETI complications than the other.

Conclusion: Both tracheal tube introducers and stylets function as efficacious aids to intubation in the prehospital environment. Where video technology is available, bougies could offer a statistically significant advantage in terms of first pass ETI success. Where video technology is unavailable, a combination of clinical scenario, practitioner expertise and personal preference might ultimately guide the choice of device.
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http://dx.doi.org/10.1007/s00068-021-01762-5DOI Listing
July 2021

The role of CDHR3 in susceptibility to otitis media.

J Mol Med (Berl) 2021 Jul 28. Epub 2021 Jul 28.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus (CU-AMC), 12700 E. 19th Ave, Aurora, CO, 80045, USA.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility. KEY MESSAGES: • Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media. • Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media. • CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens. • Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear. • Cdhr3 was downregulated 3 h after infection of mouse middle ear.
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http://dx.doi.org/10.1007/s00109-021-02118-7DOI Listing
July 2021

Gut integrity and duodenal enteropathogen burden in undernourished children with environmental enteric dysfunction.

PLoS Negl Trop Dis 2021 Jul 15;15(7):e0009584. Epub 2021 Jul 15.

Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.

Environmental enteric dysfunction (EED) is a subclinical condition of intestinal inflammation, barrier dysfunction and malabsorption associated with growth faltering in children living in poverty. This study explores association of altered duodenal permeability (lactulose, rhamnose and their ratio) with higher burden of enteropathogen in the duodenal aspirate, altered histopathological findings and higher morbidity (diarrhea) that is collectively associated with linear growth faltering in children living in EED endemic setting. In a longitudinal birth cohort, 51 controls (WHZ > 0, HAZ > -1.0) and 63 cases (WHZ< -2.0, refractory to nutritional intervention) were recruited. Anthropometry and morbidity were recorded on monthly bases up to 24 months of age. Dual sugar assay of urine collected after oral administration of lactulose and rhamnose was assessed in 96 children from both the groups. Duodenal histopathology (n = 63) and enteropathogen analysis of aspirate via Taqman array card (n = 60) was assessed in only cases. Giardia was the most frequent pathogen and was associated with raised L:R ratio (p = 0.068). Gastric microscopy was more sensitive than duodenal aspirate in H. pylori detection. Microscopically confirmed H. pylori negatively correlated with HAZ at 24 months (r = -0.313, p = 0.013). Regarding histopathological parameters, goblet cell reduction significantly correlated with decline in dual sugar excretion (p< 0.05). Between cases and controls, there were no significant differences in the median (25th, 75th percentile) of urinary concentrations (μg/ml) of lactulose [27.0 (11.50, 59.50) for cases vs. 38.0 (12.0, 61.0) for controls], rhamnose [66.0 (28.0, 178.0) vs. 86.5 (29.5, 190.5)] and L:R ratio [0.47 (0.24, 0.90) vs. 0.51 (0.31, 0.71)] respectively. In multivariable regression model, 31% of variability in HAZ at 24 months of age among cases and controls was explained by final model including dual sugars. In conclusion, enteropathogen burden is associated with altered histopathological features and intestinal permeability. In cases and controls living in settings of endemic enteropathy, intestinal permeability test may predict linear growth. However, for adoption as a screening tool for EED, further validation is required due to its complex intestinal pathophysiology.
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http://dx.doi.org/10.1371/journal.pntd.0009584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352064PMC
July 2021

Outcome of early short-course corticosteroids in hospitalized patients with coronavirus disease-2019 (COVID-19): A report from a Saudi Arabian hospital.

J Family Community Med 2021 May-Aug;28(2):125-128. Epub 2021 May 8.

Department of Internal Medicine, King Fahad Military Medical Complex, Dhahran, Saudi Arabia.

Background: The efficacy of corticosteroid use in patients with acute respiratory illness due to coronavirus disease-2019 (COVID-19) is unclear. In this study, we describe the clinical course of COVID-19 patients who received early course of corticosteroid treatment in patients with severe respiratory distress secondary to COVID-19.

Materials And Methods: The clinical course of 30 COVID-19 patients admitted to King Fahad Military Medical Complex in Dhahran from the period of late March 2020 till June 2020 was assessed and described. All the 30 patients received steroids. Data on demographics, medical history, laboratory findings, chest radiology, medication use, and clinical outcomes were extracted from patients' records. Data was entered and analyzed with SPSS software.

Results: A total of 30 patients admitted with COVID-19 were included. The mean age 52.53 years (SD=16.31) with a range from 22-98 years; 73.3% were males. About two-thirds of the patients at least had comorbidities; most common were diabetes (46.7%) and hypertension (46.7%), and chronic heart disease (16.7%). About 57% patients had fever, cough, and shortness of breath. The median C-reactive protein (CRP) level was 87.5 mg/dL (IQR 45.0 - 165.65); 46.7% had CRP levels >120 mg/dL. The median white blood cell, lymphocytes, and platelet counts were 4.39, 1.05, and 212 K/μL, respectively. All the patients received corticosteroids; 17 (56.7%) patients were given IV methylprednisolone and 13 (43.3%) received dexamethasone tablets. Of the total patients, 13 (43.3%) patients developed acute respiratory distress syndrome (ARDS); 17 (56.7%) required oxygen, 10 (33.3%) were admitted to Intensive Care Unit (ICU), and 7 (23.3%) required mechanical ventilation. All the patients improved and were discharged home well.

Conclusion: Early use of oral corticosteroids in patients with higher CRP levels may lead to better outcomes and may lower risk of transfer to ICU and use of mechanical ventilation.
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http://dx.doi.org/10.4103/jfcm.jfcm_69_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213107PMC
May 2021

CIB2 regulates mTORC1 signaling and is essential for autophagy and visual function.

Nat Commun 2021 06 23;12(1):3906. Epub 2021 Jun 23.

Department of Otorhinolaryngology - Head & Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.

Age-related macular degeneration (AMD) is a multifactorial neurodegenerative disorder. Although molecular mechanisms remain elusive, deficits in autophagy have been associated with AMD. Here we show that deficiency of calcium and integrin binding protein 2 (CIB2) in mice, leads to age-related pathologies, including sub-retinal pigment epithelium (RPE) deposits, marked accumulation of drusen markers APOE, C3, Aβ, and esterified cholesterol, and impaired visual function, which can be rescued using exogenous retinoids. Cib2 mutant mice exhibit reduced lysosomal capacity and autophagic clearance, and increased mTORC1 signaling-a negative regulator of autophagy. We observe concordant molecular deficits in dry-AMD RPE/choroid post-mortem human tissues. Mechanistically, CIB2 negatively regulates mTORC1 by preferentially binding to 'nucleotide empty' or inactive GDP-loaded Rheb. Upregulated mTORC1 signaling has been implicated in lymphangioleiomyomatosis (LAM) cancer. Over-expressing CIB2 in LAM patient-derived fibroblasts downregulates hyperactive mTORC1 signaling. Thus, our findings have significant implications for treatment of AMD and other mTORC1 hyperactivity-associated disorders.
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http://dx.doi.org/10.1038/s41467-021-24056-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222345PMC
June 2021

ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment.

Eur J Hum Genet 2021 Jun 16. Epub 2021 Jun 16.

Center for Statistical Genetics, Gertrude H. Sergievsky Center, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA.

Hearing impairment (HI) is a common disorder of sensorineural function with a highly heterogeneous genetic background. Although substantial progress has been made in the understanding of the genetic etiology of hereditary HI, many genes implicated in HI remain undiscovered. Via exome and Sanger sequencing of DNA samples obtained from consanguineous Pakistani families that segregate profound prelingual sensorineural HI, we identified rare homozygous missense variants in four genes (ADAMTS1, MPDZ, MVD, and SEZ6) that are likely the underlying cause of HI. Linkage analysis provided statistical evidence that these variants are associated with autosomal recessive nonsyndromic HI. In silico analysis of the mutant proteins encoded by these genes predicted structural, conformational or interaction changes. RNAseq data analysis revealed expression of these genes in the sensory epithelium of the mouse inner ear during embryonic, postnatal, and adult stages. Immunohistochemistry of the mouse cochlear tissue, further confirmed the expression of ADAMTS1, SEZ6, and MPDZ in the neurosensory hair cells of the organ of Corti, while MVD expression was more prominent in the spiral ganglion cells. Overall, supported by in silico mutant protein analysis, animal models, linkage analysis, and spatiotemporal expression profiling in the mouse inner ear, we propose four new candidate genes for HI and expand our understanding of the etiology of HI.
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http://dx.doi.org/10.1038/s41431-021-00913-xDOI Listing
June 2021

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.

Am J Hum Genet 2021 07 7;108(7):1330-1341. Epub 2021 Jun 7.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys11], c.399_400del [p.Glu133Aspfs37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322935PMC
July 2021

The influence mechanism of dissolved organic matter on the adsorption of Cd (II) by calcite.

Environ Sci Pollut Res Int 2021 Jul 1;28(28):37120-37129. Epub 2021 Jun 1.

School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China.

Dissolved organic matter (DOM) has been widely existed in the soil, which has great influence on the adsorption of heavy metals by minerals. In this paper, the effects of DOM on Cd (II) adsorption by calcite were studied. In the presence of DOM (5 mg/L, 10 mg/L, and 20 mg/L), the maximum sorption of Cd (II) by calcite reduced from 48.94 mg/g to 44.14 mg/g, 28.11 mg/g, and 22.30 mg/g, respectively. The characterizations (XRD, SEM, XPS, FTIR, 3D-EEM, and UHPLC-Q-Orbitrap) were used to further study the mechanism about the effects of DOM on the adsorption of Cd (II) by calcite. These results showed calcite exhibited a significant adsorption capacity for Cd (II) at pH = 6.0, and CdCO was formed on the surface of calcite after calcite reaction with Cd (II). Meanwhile, the fractionation of DOM by calcite could change the binding characteristics of DOM to calcite, which would increase the migration of Cd (II) in the solution. After the reaction of DOM with Cd (II) and calcite, Cd (II)-DOM complex was formed, and part of calcite was dissolved in the solution which would further increase the migration of Cd (II) and decrease the adsorption of Cd (II) by calcite. This paper might help further understand the effect of calcite and DOM on the environmental behavior of Cd (II) in the soil environment.
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http://dx.doi.org/10.1007/s11356-021-14585-zDOI Listing
July 2021

Identification of Hearing Loss-Associated Variants of , , and in Pakistani Families.

Biomed Res Int 2021 24;2021:5584788. Epub 2021 Apr 24.

Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The inner ear is an essential part of a well-developed and well-coordinated hearing system. However, hearing loss can make communication and interaction more difficult. Inherited hearing loss (HL) can occur from pathogenic genetic variants that negatively alter the intricate inner ear sensory mechanism. Recessively inherited forms of HL are highly heterogeneous and account for a majority of prelingual deafness. The current study is designed to investigate genetic causes of HL in three consanguineous Pakistani families. After IRB approval, the clinical history and pure tone audiometric data was obtained for the clinical diagnosis of HL segregating in these three Pakistani families. We performed whole exome sequencing (WES) followed by Sanger sequencing in order to identify and validate the HL-associated pathogenic variants, respectively. The 3-D molecular modeling and the Ramachandran analysis of the identified missense variants were compiled to evaluate the impact of the variants on the encoded proteins. Clinical evaluation revealed prelingual severe to profound sensorineural HL segregating among the affected individuals in all three families. Genetic analysis revealed segregation of several novel variants associated with HL, including a canonical splice-site variant (c.55-2A>G) of in family GCFHL-01, a missense variant [c.1079G>A; p.(Arg360Gln)] of in family LUHL-01, and an insertion variant (c.10208-10211insCCACCAGGCCCGTGCCTC) within in family LUHL-011. All the identified variants had very low frequencies in the control databases. The molecular modeling of p.Arg360Gln missense variant also predicted impaired folding of SERPINB6 protein. This study reports the identification of novel disease-causing variants in three known deafness genes and further highlights the genetic heterogeneity of HL in Pakistani population.
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http://dx.doi.org/10.1155/2021/5584788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080868PMC
May 2021

Grand rounds education in neurology, with a focus on headache medicine.

Headache 2021 Jul 15;61(7):1077-1085. Epub 2021 May 15.

Department of Neurology, Mayo Clinic Arizona, Scottsdale, AZ, USA.

Objective: To quantify the proportion of headache-related grand rounds in academic neurology programs and to compare this with adult neurology residency director views on the need for an increase in headache-related grand rounds.

Background: Although headache are among the most prevalent and most burdensome neurologic conditions, headache medicine is often considered underrepresented in neurology departments. Additionally, prior studies have shown that many neurology residency directors feel that training programs do not include an adequate amount of exposure to headache clinics or headache-related didactics. One important aspect of didactic education in neurology departments is adult neurology grand rounds. Previous publications have evaluated neither the proportion of headache-related grand rounds in academic neurology departments nor the residency program directors' views on appropriate amount of headache-related grand rounds. Our study has attempted to quantify this information to elucidate opportunities to improve practice educational gaps.

Methods: In this cross-sectional study, we surveyed adult neurology residency directors (from the Accreditation Council for Graduate Medical Education [ACGME] listing of academic adult neurology residency programs) between October 2018 and September 2019. In addition, we used two methods to obtain the proportion of headache-related grand rounds in neurology: (1) emailing residency directors a questionnaire asking for a list of prior grand rounds topics and (2) an online search for each academic neurology program.

Results: First, for our grand rounds analysis, headache medicine consisted of 3.7% of the lectures in 2017-2018 and 6.3% of the lectures in 2018-2019 (average of each institution; 17 institutions and 411 total lectures in 2017-2018, 21 institutions and 463 total lectures in 2018-2019). The most common number of lectures on headache medicine for each grand rounds series was zero (for 7 of 17 grand rounds series in 2017-2018 and 7 of 21 in 2018-2019), followed closely by one lecture (for 6 of 17 grand rounds series in 2017-2018 and 6 of 21 in 2018-2019). Second, for our survey, the response rate was 19.3% (29/150). No residency director thought their institution had too many grand rounds dedicated to headache medicine, and 62.1% (18/29) thought they had an adequate amount of headache grand rounds. Within the survey responders, 75.9% (22/29) of adult neurology residency programs have a board-certified headache specialist at their institution.

Conclusions: Although most adult neurology residency directors believe that headache is adequately represented in adult neurology grand rounds, headache medicine makes up 4%-6% of all neurology grand rounds. Compared with other neurology subspecialties and the other core ACGME milestones, headache makes up the fewest grand rounds lectures that were assessed in this study.
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http://dx.doi.org/10.1111/head.14116DOI Listing
July 2021

Determinants of pain interference and headache impact in patients who have chronic migraine with medication overuse: Results from the MOTS trial.

Cephalalgia 2021 Sep 2;41(10):1053-1064. Epub 2021 May 2.

Mayo Clinic, Department of Neurology, Phoenix, AZ, USA.

Objective: "Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse.

Methods: Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model.

Results: PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact.

Conclusions: Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.
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http://dx.doi.org/10.1177/03331024211006903DOI Listing
September 2021

Adsorption of lead and antimony in the presence and absence of EDTA by a new vermiculite product with potential recyclability.

Environ Sci Pollut Res Int 2021 Sep 1;28(35):49112-49124. Epub 2021 May 1.

School of Environment and Energy, South China University of Technology, Guangzhou, 510006, People's Republic of China.

A new two-step modification method has been proposed where 1.8% HCl and 3.1% HNO were applied to modify the interlayer of vermiculite (VMT). This product was given 90 °C of heat in 30% HSO solution that was used for Pb (II) and Sb (III) adsorption. The EDTA presence on the individual adsorption was assessed. X-ray diffraction revealed that the VMT inter-stratified reflection through acid intercalation within the interlayer decreased the parallel gaps between the atoms, witnessing on the outer-sphere adsorption. The driving force was found electrostatic, which fits well with pseudo-second-order kinetics and Langmuir isotherm. The Pb (II) and Sb (III) uptake followed descending order adsorption with increasing concentration of chelating EDTA. Three consecutive desorption cycles revealed that the prepared adsorbent was suitable that may be regarded as a good candidate for complex wastewaters.
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http://dx.doi.org/10.1007/s11356-021-13949-9DOI Listing
September 2021

Identification and Computational Analysis of Novel Pathogenic Variants in Pakistani Families with Diverse Epidermolysis Bullosa Phenotypes.

Biomolecules 2021 04 22;11(5). Epub 2021 Apr 22.

Medical Genetics Research Laboratory, Department of Biotechnology, Quaid-i-Azam University, Islamabad 45320, Pakistan.

Epidermolysis bullosa (EB) includes a group of rare gesnodermatoses that result in blistering and erosions of the skin and mucous membranes. Genetically, pathogenic variants in around 20 genes are known to alter the structural and functional integrity of intraepidermal adhesion and dermo-epidermal anchorage, leading to four different types of EB. Here we report the underlying genetic causes of EB phenotypes segregating in seven large consanguineous families, recruited from different regions of Pakistan. Whole exome sequencing, followed by segregation analysis of candidate variants through Sanger sequencing, identified eight pathogenic variants, including three novel ( c.1285G>T, and c.3373G>A; c.1828A>G) and five previously reported variants ( c.6209G>A, and c.1573C>T; c.676insC; c.151insG; c.1705C>T). All identified variants were either absent or had very low frequencies in the control databases. Our in-silico analyses and 3-dimensional (3D) molecular modeling support the deleterious impact of these variants on the encoded proteins. Intriguingly, we report the first case of a recessively inherited form of rare EBS-Ogna associated with a homozygous variant in the gene. Our study highlights the clinical and genetic diversity of EB in the Pakistani population and expands the mutation spectrum of EB; it could also be useful for prenatal diagnosis and genetic counseling of the affected families.
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http://dx.doi.org/10.3390/biom11050620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143555PMC
April 2021

Real-World Treatment Profiles, Clinical Outcomes, and Healthcare Resource Utilization of Patients with Migraine Prescribed Erenumab: A Multicenter Chart-Review Study of US Headache Centers.

Neurol Ther 2021 Jun 15;10(1):293-306. Epub 2021 Apr 15.

Amgen Inc., Thousand Oaks, CA, USA.

Introduction: Erenumab, a first-in-class monoclonal antibody targeting the calcitonin gene-related peptide pathway, was approved by the US Food and Drug Administration in 2018 for the prevention of migraine in adults. There is limited data available on its impact in real-world settings. The study aim was to characterize the real-world treatment profiles, clinical outcomes, and healthcare resource utilization of patients prescribed erenumab from select major US headache centers.

Methods: A retrospective chart review of patients with migraine treated with erenumab for at least 3 months across five major headache centers was conducted. Data was collected from patient charts between April 2019 and April 2020 and included patient and clinical characteristics, migraine medication use, and outpatient visits. The date of the first prescription fill of erenumab was defined as the index date. The baseline period comprised the 3 months prior to the index date and the study period comprised the at least 3 months on erenumab treatment.

Results: Data from a total of 1034 patients with chronic migraine with a mean of 9.3 months of erenumab treatment were analyzed. Patients were on average 48 years old, 86% were female, and 79% were white. Patients had a mean of 5 preventive treatment failures prior to erenumab initiation. Patients used a mean of 2 preventive treatments (excluding erenumab) and 2 acute treatments during baseline and study periods. Among patients with effectiveness data, 45% of patients had improvement in physician-reported migraine severity and 35% experienced at least 50% reduction in mean headache/migraine days per month. The average number of monthly outpatient visits was 0.43 and 0.30 before and after erenumab initiation, respectively.

Conclusion: In this predominantly refractory chronic migraine population treated in select headache centers, patients had fewer headache/migraine days per month and outpatient visits after initiating erenumab. However, patients largely continued to be managed via a polypharmacy approach after erenumab initiation.
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http://dx.doi.org/10.1007/s40120-021-00245-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140045PMC
June 2021

Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder.

Genet Med 2021 07 6;23(7):1246-1254. Epub 2021 Apr 6.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.

Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder.

Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization.

Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons.

Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
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http://dx.doi.org/10.1038/s41436-021-01133-wDOI Listing
July 2021

Genetic Causes of Oculocutaneous Albinism in Pakistani Population.

Genes (Basel) 2021 03 28;12(4). Epub 2021 Mar 28.

Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Melanin pigment helps protect our body from broad wavelength solar radiation and skin cancer. Among other pigmentation disorders in humans, albinism is reported to manifest in both syndromic and nonsyndromic forms as well as with varying inheritance patterns. Oculocutaneous albinism (OCA), an autosomal recessive nonsyndromic form of albinism, presents as partial to complete loss of melanin in the skin, hair, and iris. OCA has been known to be caused by pathogenic variants in seven different genes, so far, according to all the currently published population studies. However, the detection rate of alleles causing OCA varies from 50% to 90%. One of the significant challenges of uncovering the pathological variant underlying disease etiology is inter- and intra-familial locus heterogeneity. This problem is especially pertinent in highly inbred populations. As examples of such familial locus heterogeneity, we present nine consanguineous Pakistani families with segregating OCA due to variants in one or two different known albinism-associated genes. All of the identified variants are predicted to be pathogenic, which was corroborated by several in silico algorithms and association with diverse clinical phenotypes. We report an individual affected with OCA carries heterozygous, likely pathogenic variants in and , raising the question of a possible digenic inheritance. Altogether, our study highlights the significance of exome sequencing for the complete genetic diagnosis of inbred families and provides the ramifications of potential genetic interaction and digenic inheritance of variants in the and genes.
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http://dx.doi.org/10.3390/genes12040492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066997PMC
March 2021

Impact of device scaling on the electrical properties of MoS field-effect transistors.

Sci Rep 2021 Mar 23;11(1):6610. Epub 2021 Mar 23.

IMEC, Leuven, Belgium.

Two-dimensional semiconducting materials are considered as ideal candidates for ultimate device scaling. However, a systematic study on the performance and variability impact of scaling the different device dimensions is still lacking. Here we investigate the scaling behavior across 1300 devices fabricated on large-area grown MoS material with channel length down to 30 nm, contact length down to 13 nm and capacitive effective oxide thickness (CET) down to 1.9 nm. These devices show best-in-class performance with transconductance of 185 μS/μm and a minimum subthreshold swing (SS) of 86 mV/dec. We find that scaling the top-contact length has no impact on the contact resistance and electrostatics of three monolayers MoS transistors, because edge injection is dominant. Further, we identify that SS degradation occurs at short channel length and can be mitigated by reducing the CET and lowering the Schottky barrier height. Finally, using a power performance area (PPA) analysis, we present a roadmap of material improvements to make 2D devices competitive with silicon gate-all-around devices.
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http://dx.doi.org/10.1038/s41598-021-85968-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987965PMC
March 2021

Green synthesis of ZnO nanoparticles for antimicrobial and vegetative growth applications: A novel approach for advancing efficient high quality health care to human wellbeing.

Saudi J Biol Sci 2021 Mar 19;28(3):1808-1815. Epub 2020 Dec 19.

Adhiyaman Arts and Science College for Women, Uthangarai, Tamil Nadu 635207, India.

The present work aims to synthesize zinc oxide (ZnO) nanoparticles via green approaches using leaf extract of . UV-vis and FT-IR tests confirmed the existence of biomolecules, active materials, and metal oxides. The X-ray diffraction structural study exposes the ZnO nanoparticles formation with hexagonal phase structures. SEM and TEM analysis reveal surface morphologies of ZnO nanoparticles and most of them are spherical with a size range of 10 nm. ZnO nanoparticles were revealed strong antimicrobial activity against both bacterial and fungal strains. The germination of seeds and vegetative growth of has been greatly improved.
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http://dx.doi.org/10.1016/j.sjbs.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938149PMC
March 2021

Dielectric-Loaded Waveguides as Advanced Platforms for Diagnostics and Application of Transparent Thin Films.

Langmuir 2021 Mar 8;37(11):3248-3260. Epub 2021 Mar 8.

Department of Physics, Pontifícia Universidade Católica do Rio de Janeiro, Rua Marques de São Vicente, 22451-900 Rio de Janeiro, Brazil.

An alternative approach to classical surface plasmon resonance spectroscopy is dielectric-loaded waveguide (DLWG) spectroscopy, widely used in the past decades to investigate bio-interaction kinetics. Despite their wide application, a successful and clear approach to use the DLWGs for the one-step simultaneous determination of both the thickness and refractive index of organic thin films is absent in the literature. We propose here, for the first time, an experimental protocol based on the multimodal nature of DLWGs to be followed in order to evaluate the optical constants and thickness of transparent thin films with a unique measurement. The proposed method is general and can be applied to every class of transparent organic materials, with a resolution and accuracy which depend on the nature of the external medium (gaseous or liquid), the geometrical characteristics of the DLWG, and the values of both the thickness and dielectric constant of the thin film. From the experimental point of view, the method is demonstrated in a nitrogen environment with an accuracy of about 3%, for the special case of electroluminescent thin films of Euβ-diketonate complexes, with an average thickness of about 20 nm. The high value of the refractive index measured for the thin film with the Eu(btfa)(t-bpete) complex was confirmed by the use of a spectroscopic model based on the Judd-Ofelt theory, in which the magnetic dipole transition D → F (Eu) for similar films containing Eu complexes is taken as a reference. The DLWGs are finally applied to control the refractive index changes of the organic thin films under UVA irradiation, with potential applications in dosimetry and monitoring light-induced transformation in organic thin films.
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http://dx.doi.org/10.1021/acs.langmuir.0c02862DOI Listing
March 2021

Penetration Enhancers for Topical Drug Delivery to the Ocular Posterior Segment-A Systematic Review.

Pharmaceutics 2021 Feb 18;13(2). Epub 2021 Feb 18.

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

There is an unmet clinical need for eye drop formulations to efficiently treat the diseases of the posterior ocular segment by non-invasive topical administration. Here, we systematically reviewed the literature on ocular penetration enhancers and their ability to transfer drugs to the posterior segment of the eye in experimental studies. Our aim was to assess which penetration enhancer is the most efficient at delivering drugs to the posterior segment of the eye, when topically applied. We conducted a comprehensive search in three electronic databases (Ovid Embase, Ovid MEDLINE, and PubMed) to identify all the relevant manuscripts reported on ocular penetration enhancers based on the PRISMA guidelines. We identified 6540 records from our primary database search and filtered them per our inclusion/exclusion criteria to select a final list of 14 articles for qualitative synthesis. Of these, 11 studies used cell penetrating peptides (CPPs), 2 used chitosan, and 1 used benzalkonium chloride (BAC) as the penetration enhancer. Cationic and amphipathic CPPs, transactivator of transcription (TAT), and penetratin can be inferred to be the best among all the identified penetration enhancers for drug delivery to the fundus oculi via topical eye drop instillation. Further high-quality experimental studies are required to ascertain their quantitative efficacy.
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http://dx.doi.org/10.3390/pharmaceutics13020276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922526PMC
February 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

An assessment of level of heavy metals pollution in the water, sediment and aquatic organisms: A perspective of tackling environmental threats for food security.

Saudi J Biol Sci 2021 Feb 2;28(2):1218-1225. Epub 2020 Dec 2.

Department of Zoology and Wildlife Biology A.V.C. College (Autonomous), Mannampandal, Mayiladuthurai - 609305, Tamil Nadu, India.

Pollution is severely threatening the wetland habitats. Heavy metals are one among of the major pollutants in wetland habitats. The cadmium (Cd), copper (Cu), chromium (Cr), cobalt (Co), lead (Pb), mercury (Hg), nickel (Ni) and zinc (Zn), were assessed in the water, sediment, benthic species (polychaetes, mollusc and crustaceans), prawn and fishes. The assessment of heavy metals was done by using double-beam Atomic Absorption Spectrophotometer (AAS). The Hg, Cr and Co were greater in sediment, Ni and Cd were higher in polychaetes and molluscs respectively. However, the Cu and Pb greater in crabs and the Zinc was greater in fishes. The concentration of metals showed significant differences among the various sources examined (P < 0.05) except Cr (P > 0.05). The inter-correlational analysis among the metals assessed from the various sources showed that the Cr and Pb not correlated among the eight metals examined. However, the Cu and Co were correlated with Hg (r = 0.307) and (r = 0.788) respectively. The nickel was correlated with Hg (r = 0.367), Cu (r = 0.362) and Co (r = 0.432). The Zinc was correlated with the Cd (r = 0.331) and Hg (r = 0.737). However, correlation of metals among the different sources shown that the metals of polychaetes correlated with sediment r = 0.637, the metals of crabs correlated with the sediment and polychaetes r = 0.630 and r = 842 respectively, the metals of molluscs was also correlated with sediment (r = 0.636), polychaetes (r = 0.889) and crabs (r = 0.894). In addition to that the metals of prawns was correlated with the polychaetes (r = 839), crabs (r = 0.628) and molluscs (r = 0.634). The metals of fishes correlated with polychaetes (r = 0.529), crabs (r = 0.710), molluscs (r = 0.493) and prawns (r = 0.593). Indeed the multiple regression model explained that the metals of sediments influence the accumulation of metals in biotic species such as polychaetes, molluscs, crustaceans, prawns and fishes with 84% (F = 21.079; p < 0.001).The order of the heavy metals in the water, sediment and biotic species was Hg > Pb > Ni > Cr > Zn > Co > Cu > Cd. The study found that the level of heavy metals at various sources in the sanctuary is showing considerable warning and the sanctuary is required intensive assessment on various aspects of pollution since the Point Calimere Wildlife Sanctuary is supporting several species of migratory and endangered shorebirds seasonally.
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http://dx.doi.org/10.1016/j.sjbs.2020.11.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878681PMC
February 2021

Reassessing the PFO-Migraine Trials: Are We Closer to Closure?

J Am Coll Cardiol 2021 02;77(6):677-679

Columbia University Medical Center, New York, New York, USA.

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http://dx.doi.org/10.1016/j.jacc.2020.12.017DOI Listing
February 2021

Safety and effectiveness of surgical fixation versus non-surgical methods for the treatment of flail chest in adult populations: a systematic review and meta-analysis.

Eur J Trauma Emerg Surg 2021 Feb 6. Epub 2021 Feb 6.

Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

Purpose: The objective of this systematic review is to compare the safety and efficacy of surgical fixation of rib fractures against non-surgical interventions for the treatment of flail chest in the adult population.

Methods: A search was performed on the 22nd of July 2020 to identify articles comparing surgical fixation versus clinical management for flail chest in adults, with a description of the outcome parameters (resource utility, mortality, adverse effects of the intervention and adverse progression in pulmonary status). Relevant randomised controlled trials were selected, their risk of bias assessed, and the data then extracted and analysed.

Results: 157 patients were included from four studies in the analyses, with 79 and 78 patients in the surgical and non-surgical groups, respectively. The pooled effects of all outcomes tended towards favouring surgical intervention. Surgical intervention was associated with lower rates of pneumonia (I = 46%, Tau = 0.16, p = 0.16), significantly lower rates of tracheostomy (I = 76%, Tau = 0.67, p = 0.02), and a significantly lower duration of mechanical ventilation (I = 88%, Tau = 33.7, p < 0.01) in comparison to the non-surgical management methods.

Conclusion: Our results suggest that surgical intervention reduces the need for tracheostomy, reduces the time spent in the intensive care unit following a traumatic flail chest injury and could reduce the risk of acquiring pneumonia after such an event. There is a need for further well-designed studies with sufficient sample sizes to confirm the results of this study and also detect other possible effects of surgical intervention in the treatment of traumatic flail chest in adults.
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http://dx.doi.org/10.1007/s00068-021-01606-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866961PMC
February 2021
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