Prion protein pathology in Ubiquilin 2 models of ALS.

Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrPC) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrPC with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrPC protein degradation and leads to mislocalization of PrPC in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrPC bind together in a complex. The abnormalities in PrPC caused by UBQLN2 mutations may be relevant in disease pathogenesis.

Gut microbiota derived short-chain fatty acids in physiology and pathology: An update.

Short-chain fatty acids (SCFAs) are essential molecules produced by gut bacteria that fuel intestinal cells and may also influence overall health. An imbalance of SCFAs can result in various acute and chronic diseases, including diabetes, obesity and colorectal cancer (CRC). This review delves into the multifaceted roles of SCFAs, including a brief discussion on their source and various gut-residing bacteria. Primary techniques used for detection of SCFAs, including gas chromatography, high-performance gas chromatography, nuclear magnetic resonance and capillary electrophoresis are also discussed through this article. This review study also compiles various synthesis pathways of SCFAs from diverse substrates such as sugar, acetone, ethanol and amino acids. The different pathways through which SCFAs enter cells for immune response regulation are also highlighted. A major emphasis is the discussion on diseases associated with SCFA dysregulation, such as anaemia, brain development, CRC, depression, obesity and diabetes. This includes exploring the relationship between SCFA levels across ethnicities and their connection with blood pressure and CRC. In conclusion, this review highlights the critical role of SCFAs in maintaining gut health and their implications in various diseases, emphasizing the need for further research on SCFA detection, synthesis and their potential as diagnostic biomarkers. Future studies of SCFAs will pave the way for the development of novel diagnostic tools and therapeutic strategies for optimizing gut health and preventing diseases associated with SCFA dysregulation.

Modified hydrophobic and oleophilic polyurethane sponge for oil absorption with MIL-53.

A hydrophobic composite sponge (HPCS) is developed for the first time using the dip coating and drying method in an effort to remove organic contaminants like toluene and various oils from water. We employed a polyurethane (PU) sponge, which is reasonably priced, easily accessible, high mechanical strength and a suitable porous substrate on which the hydrophobic composite of MIL-53(Al) along with PDMS was anchored. A crystalline metal organic framework (MOF), MIL-53(Al), with adjustable porosity, functionality, and hydrophobicity is used for oil absorption. Polydimethylsiloxane (PDMS) is utilized to increase the hydrophobicity of MIL-53(Al). The MIL-53(Al)@PDMS composite was used to the produce a sponge having high hydrophobicity and oleophilicity. In contrast to PU sponge, which has a low water contact angle (79.64°), the hydrophobic composite sponge showed a wide range of oil absorption capacity (12-50.5 g/g), a very low amount of water absorption (0.84 g/g), and water contact angle of 128.13°. This hydrophobic composite performed phenomenally by separating out various oils and solvents from water even in varying ionic strengths. Moreover, the recyclability of the formed composite was also performed resulting into 6-20 cycles for different oils and solvents. The synthesized hydrophobic composite sponge was characterized using FT-IR, XRD, TEM, surface area analysis, FESEM, XPS, TG analysis and contact angle measurement. Furthermore, the materials used in the synthesis of composite are non-toxic and do not harm the environment, resulting in no greenhouse gas emissions making our composite environmentally friendly.

Cerebrospinal fluid leaks secondary to dural tears: a review of etiology, clinical evaluation, and management.

OBJECTIVE: Damage to the dura mater often occurs in trauma cases of the head and spine, surgical procedures, lumbar punctures, and meningeal diseases. The resulting damage from dural tears, or durotomy, causes cerebrospinal fluid (CSF) to leak out into the surrounding space. The CSF leak induces intracranial hypotension, which can clinically present with a range of symptoms not limited to positional headaches which can confound accurate diagnosis. Current methods of evaluation and management of dural tears are discussed herewith, as well as the present understanding of its etiology, which may be classified as related to surgery, procedure, trauma, or connective tissue disorder. METHODS: We piloted a MEDLINE® database search of literature, with emphasis on the previous five years, combining keywords such as "cerebrospinal fluid leak," "surgery," "procedure," and "trauma" to yield original research articles and case reports for building a clinical profile. RESULTS: Patients with suspected dural tears should be evaluated based on criteria set by the International Headache Society, radiological findings, and a differential diagnosis to accurately identify the tear and its potential secondary complications. Afflicted patients may be treated promptly with epidural blood patches, epidural infusions, epidural fibrin glue, or surgical repair. At this time, epidural blood patches are the first line of treatment. Dural tears can be prevented to an extent by utilizing minimally invasive techniques and certain positions for lumbar puncture. Surgical, trauma, lumbar puncture, and epidural injection patients should be observed very carefully for dural tears and CSF leaks as the presenting clinical manifestations can be highly individualized and misguiding. CONCLUSION: Because studies have demonstrated a high frequency of dural tears, particularly in spinal surgery patients, there is a need for prospective studies so that clinicians can develop an elaborate prevention strategy and response to avoid serious, unseen complications.

Revisiting the pineal gland: a review of calcification, masses, precocious puberty, and melatonin functions.

Introduction: The pineal gland, an endocrine organ of the posterior cranial fossa famously involved in sleep and wakefulness, has continually been a topic of scientific advancement and curiosity. Methods: We review present an up-to-date review including the anatomy, embryology, and physiology of the pineal gland and its ability to secrete hormones including melatonin, pathophysiology of pineal gland tumors, cysts, and calcifications, their clinical presentation including their association with parkinsonism and precocious puberty, and various treatment approaches. Results: Exploring the biochemistry of melatonin, various calcification morphologies, and pineal tumors may uncover a wider role and the exhaustive case study consolidation allows clinicians to carefully review the literature and aid their treatment approaches. Conclusion: It is imperative that clinicians and diagnosticians are able to distinguish manifestations of an overlooked gland.

Neurological and neuropsychiatric manifestations of porphyria.

Porphyrias are inherited disorders of the heme biosynthetic pathway, usually characterized by dermatological changes due to the accumulation of byproducts in the pathway. Select porphyrias also affect the nervous system, namely hereditary coproporphyria, acute intermittent porphyria and variegate porphyria. Complications include paralysis, hyponatremia which can risk central pontine myelinolysis, seizures and coma. Neurological complications usually result from severe episodes of acute attacks. Acute attacks may also elicit neuropsychiatric symptoms such as confusion, hallucinations, anxiety and psychosis. However, these manifestations are generally self-limiting. Due to the generally low incidence of porphyria and full knowledge the associated neurological and psychiatric manifestations, we review the relevant porphyrias along with their clinical manifestations, evaluation, and management to raise its awareness in the clinical picture and to prevent misdiagnosis. Porphyria should be considered within the differential diagnosis for unexplained neurological symptoms.

Neuro-urological sequelae of lumbar spinal stenosis.

PURPOSE: Lumbar spinal stenosis is characterized by the narrowing of the spinal canal, which subsequently induces impingement of neural elements in the lumbar spine. Thus, symptoms of lumbar spinal stenosis are typically associated with damage to those neural elements. Herewith, we target the genitourinary symptoms of lumbar spinal stenosis and the importance of differentiating these symptoms from other genitourinary pathologies, namely benign prostatic hyperplasia. MATERIALS AND METHODS: MeSH and keywords relevant to lumbar spinal stenosis and the organs of the urinary tract were used to a guide a literature search on MEDLINE. RESULTS: Bladder dysfunction, lower urinary tract symptoms (e.g. urinary incontinence, detrusor overactivity and underactivity, as well as frequent urinary tract infections), renal osteodystrophy and sexual dysfunction (e.g. erectile dysfunction and priapism) are implicated in lumbar spinal stenosis. CONCLUSIONS: It is imperative for urologists to conduct a thorough history and physical examination so that they will not misdiagnose secondary genitourinary manifestations of lumbar spinal stenosis as primary problems or misunderstand secondary problems. Urological consultations are also integral to prioritizing patients with the highest risk of bladder damage for corrective spinal surgery.

Golgi defects enhance APP amyloidogenic processing in Alzheimer's disease.

Increased amyloid beta (Aß) production by sequential cleavage of the amyloid precursor protein (APP) by the ß- and γ-secretases contributes to the etiological basis of Alzheimer's disease (AD). This process requires APP and the secretases to be in the same subcellular compartments, such as the endosomes. Since all membrane organelles in the endomembrane system are kinetically and functionally linked, any defects in the trafficking and sorting machinery would be expected to change the functional properties of the whole system. The Golgi is a primary organelle for protein trafficking, sorting and modifications, and Golgi defects have been reported in AD. Here we hypothesize that Golgi fragmentation in AD accelerates APP trafficking and Aß production. Furthermore, Golgi defects may perturb the proper trafficking and processing of many essential neuronal proteins, resulting in compromised neuronal function. Therefore, molecular tools that can restore Golgi structure and function could prove useful as potential drugs for AD treatment.

Aß-induced Golgi fragmentation in Alzheimer's disease enhances Aß production.

Golgi fragmentation occurs in neurons of patients with Alzheimer's disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1E9 transgenic mouse and tissue culture models. Our results show that accumulation of amyloid beta peptides (Aß) leads to Golgi fragmentation. Further biochemistry and cell biology studies revealed that Golgi fragmentation in AD is caused by phosphorylation of Golgi structural proteins, such as GRASP65, which is induced by Aß-triggered cyclin-dependent kinase-5 activation. Significantly, both inhibition of cyclin-dependent kinase-5 and expression of nonphosphorylatable GRASP65 mutants rescued the Golgi structure and reduced Aß secretion by elevating α-cleavage of the amyloid precursor protein. Our study demonstrates a molecular mechanism for Golgi fragmentation and its effects on amyloid precursor protein trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.

Generation and nuclear translocation of sumoylated transmembrane fragment of cell adhesion molecule L1.

The functions of the cell adhesion molecule L1 in the developing and adult nervous system are triggered by homophilic and heterophilic interactions that stimulate signal transductions that activate cellular responses. Here, we show that stimulation of signaling by function-triggering L1 antibodies or L1-Fc leads to serine protease-dependent cleavage of full-length L1 at the plasma membrane and generation of a sumoylated transmembrane 70-kDa fragment comprising the intracellular and transmembrane domains and part of the extracellular domain. The 70-kDa transmembrane fragment is transported from the plasma membrane to a late endosomal compartment, released from endosomal membranes into the cytoplasm, and transferred from there into the nucleus by a pathway that depends on importin and chromatin-modifying protein 1. Mutation of the sumoylation site at Lys(1172) or of the nuclear localization signal at Lys(1147) abolished L1-stimulated generation or nuclear import of the 70-kDa fragment, respectively. Nuclear import of the 70-kDa fragment may activate cellular responses in parallel or in association with phosphorylation-dependent signaling pathways. Alterations in the levels of the 70-kDa fragment during development and in the adult after spinal cord injury or in a mouse model of Alzheimer disease suggest that this fragment is functionally implicated in development, regeneration, neurodegeneration, tumorigenesis, and possibly synaptic plasticity in the mature nervous system.

Clinical utility of ozone therapy and hyperbaric oxygen therapy in degenerative disc disease.

Ozone can be medically useful concerning healing wounds and relieving pain in various conditions, such as disc disease. The aspects of human blood ozonation have been reviewed, as well as potential complications that may arise. The mechanisms of ozone therapy are discussed in detail. It is imperative to recognize ozone as a useful proxy in oxidative-stress related diseases, consolidating other medical gases recognized for their therapeutic importance. The utility of hyperbaric oxygen therapy is also discussed. Disc herniation is very common, as more than 3 million cases are treated per year. Herein we review the medical, surgical, and gene-based therapies that ozone therapy can provide regarding disc disease.

Clinical profile and outcome of early surgery in neonatal-onset glaucoma presenting over a 5-year period.

BACKGROUND: Neonatal-onset glaucoma (NOG) is a severe form of childhood glaucoma and is not always due to primary congenital glaucoma (PCG). Due to advances in neonatal care, the incidence of NOG is rising, but it remains an under-reported entity. The objective of the paper was to study the clinical profiles, surgical and visual outcomes of NOG at least 1 year following early surgery. METHODS: Prospective interventional cohort study at a tertiary care referral centre. Babies with NOG, who presented between January 2013 and December 2017, had a history suggestive of disease onset within 1 month of birth, and underwent surgery by 3 months of age, were prospectively enrolled. Those who completed a 1-year follow-up after surgery were analysed. RESULTS: 94 eyes of 53 babies were analysed. 35 (66%) had PCG. Neonatal congenital ectropion uveae, congenital rubella syndrome, Peter's anomaly and Sturge-Weber syndrome comprised the non-PCG group. The mean age at presentation and surgery was 24.8±21.9, and 36.7±29.9 days. Additional glaucoma surgery was required in 43 of the 94 eyes (45.7%). PCG had significantly better outcomes than other glaucomas at all time points. 28.3% of eyes had good vision (LogMar (0-0.5)), 34.7% had moderate visual impairment (LogMar 0.7-1.0) and 16% were blind (LogMar <1.62) . CONCLUSION: Our study shows that NOG does not always have a dismal prognosis. A small but significant proportion could have other underlying conditions than PCG. Timely surgery and rigorous amblyopia therapy resulted in good outcomes in terms of intraocular pressure control and vision in this cohort.

NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments.

The neural cell adhesion molecule NCAM plays important functional roles not only during nervous system development, but also in the adult after injury and in synaptic plasticity. Homophilic binding of NCAM triggers intracellular signaling events resulting in cellular responses such as neurite outgrowth that require NCAM palmitoylation-dependent raft localization and activation of the nonreceptor tyrosine kinases fyn and fak. In this study, we show that stimulation of NCAM by a function-triggering NCAM antibody results in proteolytic processing of NCAM and fak. The C-terminal fragment of NCAM, consisting of the intracellular domain, the transmembrane domain, and a stub of the extracellular domain, and the N-terminal fragment of fak are imported into the nucleus. NCAM-stimulated fak activation, generation, and nuclear import of NCAM and fak fragments as well as neurite outgrowth are abolished by mutation of the calmodulin binding motif in the intracellular domain of NCAM that is responsible for the calcium-dependent binding of calmodulin to NCAM. This mutation interferes neither with NCAM cell surface expression, palmitoylation, and raft localization nor with fyn activation. The way by which the transmembrane NCAM fragment reaches the nucleus in a calmodulin- and calcium-dependent manner is by endocytotic transport via the endoplasmic reticulum and the cytoplasm. The generation and nuclear import of NCAM and phosphorylated fak fragments resulting from NCAM stimulation may represent a signal pathway activating cellular responses in parallel or in association with classical kinase- and phosphorylation-dependent signaling cascades.

Surfer's myelopathy: A review of etiology, pathogenesis, evaluation, and management.

Context: Surfer's myelopathy (SM) is an acute syndrome identified by nontraumatic paraparesis or paraplegia. Though traditionally tied to first-time surfers, the condition encompasses any activity involving hyperextension of the back such as gymnastics, yoga, and Pilates.Methods: MEDLINE® and Google Scholar literature searches were gathered to identify relevant case reports for determining the etiology, pathogenesis, evaluation, and management of SM.Results: While the rare nature of SM limits its full understanding, studies have pinpointed that hyperextension in the back leads to vasculature insufficiency secondary to dynamic compression of the artery of Adamkiewicz. In surfing, this hyperextension combined with the execution of the Valsalva maneuver while trying to stand up on the surfboard likely increases intraspinal pressure. Due to its nontraumatic origin, the presence of SM is not immediately clear. Moreover, its similarity in clinical and radiological presentations with other entities can further complicate diagnosis. Seemingly, idiopathic urological symptoms can be explained by the physician if they conduct a thorough history.Conclusion: In an effort to raise awareness for the practicing physician, we presently review the etiology, diagnosis, treatment, and prolonged effects of SM. With the surging popularity of surfing as well as the advent of children participating in precarious sports and activities at an earlier age, we can expect a rising incidence of traumatic and nontraumatic spinal cord injuries. Neurologists, urologists, emergency medicine and sports medicine physicians alike can utilize this review to build a high index of suspicion for SM. The risk factors for SM should be conveyed to those participating in novices in surfing, yoga, gymnastics, ballet, and any activity enabling sustained or repeated spinal extension. Increased general awareness will facilitate increased symptom recognition in order to arrest aggravation of injury.

Treatment outcomes and efficacy of pars plana vitrectomy-hyaloidotomy-zonulectomy-iridotomy in malignant glaucoma.

AIM: To study the treatment outcomes and efficacy of pars plana vitrectomy-hyaloidotomy-zonulectomy-iridotomy in malignant glaucoma. METHOD: A retrospective case series study of patients treated for malignant glaucoma between 2005 and 2017. The treatment included medical management as first-line in the form of cycloplegic with anti-glaucoma medications (AGM) or pars plana vitrectomy-hyaloidotomy-zonulectomy-iridotomy as second-line therapy. The resolution was defined as 'deepening of central anterior chamber' with intraocular pressure of ⩽ 21 mm Hg (minimum on two consecutive visits 1 week apart) with or without topical anti-glaucoma medications in the absence (complete success) or presence (qualified success) of systemic medications. RESULTS: Twenty-three eyes of 22 patients were included. At the time of diagnosis of malignant glaucoma preceding surgeries were cataract surgery (13 eyes) and trabeculectomy (4 eyes). One eye each had phacotrabeculectomy, Yag capsulotomy and optical keratoplasty. Eighteen eyes were pseudophakic and two eyes were phakic. At presentation, mean intraocular pressure was 26.25 ± 14.78 mmHg which was decreased to 15.90 ± 8.12 mmHg (p < 0.0001) at final follow-up (median follow-up was 15.50 months). Fifteen (75%) eyes had complete success, 3 (15%) eyes had qualified success and 2 (10%) eyes had treatment failure. Of 15 eyes that had achieved complete success, 3 eyes had undergone medical management and 12 eyes undergone second-line procedure. There was no significant difference in visual acuity or number of anti-glaucoma medication at presentation and final follow-up (p > 0.05). CONCLUSIONS: Though malignant glaucoma is highly refractory to treatment, appropriate management in the form of medical or vitrectomy-hyaloidotomy-zonulectomy-iridotomy could achieve 90% success in this series.

Safety and efficacy of oral Triclofos in the ophthalmic evaluation of children with pediatric glaucoma: An observational study.

Purpose: Oral Triclofos is widely used as a sedative agent in children. However, the role of Triclofos as a sedative agent in children undergoing ophthalmological procedures has not been adequately studied. The aim of this study was to determine the safety and efficacy of oral Triclofos in children suffering from pediatric glaucoma who were undergoing ocular examination. Methods: 80 children aged less than 5 years were assessed for eligibility for the trial after taking hospital ethical committee approval. The children were administered 80 mg/kg of oral Triclofos and Ramsay sedation score was measured every 5 min starting from 20 min after administration of the drug. If the child was not adequately sedated after 30 min, additional dose of 05 mg/kg was administered every 5 min till 60 min of drug administration. The procedure was considered a failure and general anesthesia (GA) administered if Ramsay sedation score was ≤4 after 60 min of initial drug administration. Heart rate and arterial oxygen saturation were measured throughout the period of sedation. The duration of sedation and incidence of side effects was also noted. Results: A total of 73 patients underwent the study. The mean age of children was 23.4 months (SD - 14.72) and mean weight was 12 kg (SD - 3.84). The mean dose of Pedicloryl (Triclofos) used was 83.8 mg/kg and the median duration of onset was 25 min. 64 children completed examination successfully, 2 children had to be administered GA during the procedure. There were no major side effects. Conclusion: Administration of oral Triclofos in a dose of 80 mg/kg body weight was safe and effective in children less than 5 years of age undergoing ocular examination.

Acute Hydrops in the Fellow Eye of Infants with Primary Congenital Glaucoma after Intraocular Pressure Reduction in 1 Eye.

PURPOSE: To demonstrate the occurrence of acute hydrops in the fellow eye of infants with primary congenital glaucoma (PCG) treated for glaucoma in 1 eye. DESIGN: Small, observational case series. PARTICIPANTS: Three infants with PCG who demonstrated acute hydrops in the fellow eye after treatment of the worse eye. METHODS: Intraocular pressure (IOP) was lowered surgically in 2 infants and medically in 1 infant with PCG. Two infants underwent combined trabeculotomy with trabeculectomy, and goniotomy was possible in 1 infant. MAIN OUTCOME MEASURES: Observation of the fellow eye after lowering IOP in an eye with acute hydrops. RESULTS: Two infants underwent glaucoma surgery in 1 eye and demonstrated acute hydrops in the fellow eye within 1 week. The third infant demonstrated acute hydrops after medically controlling IOP in 1 eye before the scheduled surgery. After surgical treatment, the stromal edema cleared completely in all 3 infants, leaving behind a small area of opacity where the Descemet's tear had healed. CONCLUSIONS: Our report demonstrates that the fellow eye of a patient with PCG may be at risk of sudden raised IOP resulting in acute hydrops, and early treatment may help to prevent this phenomenon in the fellow eye.

Impact of COVID-19 and lockdown on mental health of children and adolescents: A narrative review with recommendations.

BACKGROUND: COVID-19 pandemic and lockdown has brought about a sense of fear and anxiety around the globe. This phenomenon has led to short term as well as long term psychosocial and mental health implications for children and adolescents. The quality and magnitude of impact on minors is determined by many vulnerability factors like developmental age, educational status, pre-existing mental health condition, being economically underprivileged or being quarantined due to infection or fear of infection. AIMS: This paper is aimed at narratively reviewing various articles related to mental-health aspects of children and adolescents impacted by COVID-19 pandemic and enforcement of nationwide or regional lockdowns to prevent further spread of infection. METHODOLOGY: We conducted a review and collected articles and advisories on mental health aspects of children and adolescents during the COVID-19 pandemic. We selected articles and thematically organized them. We put up their major findings under the thematic areas of impact on young children, school and college going students, children and adolescents with mental health challenges, economically underprivileged children, impact due to quarantine and separation from parents and the advisories of international organizations. We have also provided recommendations to the above. CONCLUSION: There is a pressing need for planning longitudinal and developmental studies, and implementing evidence based elaborative plan of action to cater to the psycho social and mental health needs of the vulnerable children and adolescents during pandemic as well as post pandemic. There is a need to ameliorate children and adolescents' access to mental health support services geared towards providing measures for developing healthy coping mechanisms during the current crisis. For this innovative child and adolescent mental health policies policies with direct and digital collaborative networks of psychiatrists, psychologists, paediatricians, and community volunteers are deemed necessary.

The Role of Diabetes Mellitus in Diseases of the Gallbladder and Biliary Tract.

BACKGROUND: The increasing prevalence of diabetes mellitus worldwide continues to pose a heavy burden. Though its gastrointestinal impact is appropriately recognized, the lesser known associations may be overlooked. OBJECTIVE: We aim to review the negative implications of diabetes on the gallbladder and the biliary tract. METHODS: A MEDLINE® database search of literature was conducted with emphasis on the previous five years, combining keywords such as "diabetes," "gallbladder," and "biliary". RESULTS: The association of diabetes to the formation of gallstones, gallbladder cancer, and cancer of the biliary tract are discussed along with diagnosis and treatment. CONCLUSION: Though we uncover the role of diabetic neuropathy in gallbladder and biliary complications, the specific individual diabetic risk factors behind these developments is unclear. Also, in addition to diabetes control and surgical gallbladder management, the treatment approach also requires further focus.