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Background and Objective : The complexity of antiretroviral therapy (ART) regimens in people living with HIV (PLHIV) poses significant challenges for medication management, impacting adherence and overall health outcomes. The Medication Regimen Complexity Index (MRCI) is a tool that quantifies regimen complexity, yet its correlation with hospitalization rates and adverse drug reactions (ADRs) in PLHIV remains underexplored. Materials and Methods : This prospective study, which was conducted at a government-funded antiretroviral treatment center, investigated the relationships among MRCI scores, hospitalization due to ADRs, and the ADR rates in 285 PLHIV participants over 18 months. Results : The study revealed a significant association between higher baseline MRCI scores and hospitalization due to ADRs, with a threshold MRCI score of 8 indicating increased risk. There was no significant association between average MRCI scores and overall ADR rates or non-ADR-related hospitalizations. Conclusions : These findings emphasize the importance of monitoring medication regimen complexity in PLHIV, particularly in the context of preventing hospitalizations related to ADRs. Further research is needed to understand the multifactorial influences on ADR occurrence and to optimize ART regimens for better patient outcomes.

Objectives: Chronic periodontitis and type 2 diabetes mellitus (T2DM) are associated with cognitive decline when examined individually. To gain deeper insight into the combined effects of these conditions on cognitive decline, the present study aimed to examine the cognitive status of individuals with co-occurring T2DM and chronic periodontitis., Methods: We recruited 220 participants categorized into four groups: Group I, healthy subjects; Group II, individuals with chronic periodontitis; Group III, individuals with T2DM; and Group IV, individuals with both T2DM and chronic periodontitis. Medical histories were recorded for all participants, followed by periodontal examination and evaluation of cognitive status using the Montreal Cognitive Assessment (MoCA) scale. Finger dexterity was assessed using the nine-hole peg test., Results: A statistically significant increase in the proportion of mild cognitive impairment (MCI) was observed between groups I and IV (p < 0.001). Logistic regression analysis revealed that, among the parameters assessed in this study, the adjusted odds ratio (OR) was significant for age, finger dexterity scores, and co-occurrence of T2DM and periodontitis., Conclusions: The findings of this study suggest that the co-occurrence of chronic periodontitis and T2DM can have a detrimental effect on the cognitive abilities of an individual. Subsequent research should include longitudinal monitoring of the cognitive status in patients with concurrent conditions during treatment to gain deeper prognostic insights into the relationship between these co-occurring conditions and cognitive decline., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest in this study., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Pineal cysts are frequently encountered as incidental findings in magnetic resonance imaging, usually devoid of symptoms, yet some patients exhibit symptomatic manifestations possibly associated with the cyst, even in the absence of hydrocephalus. The etiology of these symptoms remains contentious. This study aims to investigate the presence of lymphatic endothelial cell (LEC) markers and indications of inflammation or immune response within the pineal cysts of patients experiencing symptomatic non-hydrocephalic presentations. Eight patients who underwent surgical excision of their cysts were included in the study. Immunohistochemistry was utilized to assess the expression of LYVE-1, PDPN, and VEGFR3 as LEC markers, alongside IL-6 and CD3 for indications of inflammation or immune activity. Our analysis revealed an absence of inflammatory markers or immune response. However, a distinct expression of VEGFR3 was observed, likely localized to neurons within the pineal cyst tissue. We propose that these VEGFR3+ neurons within the pineal cyst may contribute to the headache symptoms reported by these patients. Further investigations are warranted to substantiate this hypothesis., Competing Interests: Declaration of competing interest The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting brain microvessels. There is a rich literature on the role of AQP4 in experimental stroke. While its role in oedema formation following middle cerebral artery occlusion (MCAO) has been studied extensively, its specific impact on infarct volume remains unclear. This study investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery (dMCAO) occlusion. Compared to MCAO, this model induces smaller infarcts confined to neocortex, and less oedema. We show that AQP4 deletion significantly reduced infarct volume as assessed 1 week after dMCAO, suggesting that the role of AQP4 in stroke goes beyond its effect on oedema formation and dissolution. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas. No significant differences were observed in the number of microglia among the genotypes. These findings provide new insights in the role of AQP4 in ischaemic injury indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone. KEY POINTS: Aquaporin-4 (AQP4) is the main water channel in brain and is enriched in perivascular astrocyte processes abutting microvessels. A rich literature exists on the role of AQP4 in oedema formation following middle cerebral artery occlusion (MCAO). We investigated the effects of total and partial AQP4 deletion on infarct volume in mice subjected to distal medial cerebral artery occlusion (dMCAO), a model inducing smaller infarcts confined to neocortex and less oedema compared to MCAO. AQP4 deletion significantly reduced infarct volume 1 week after dMCAO, suggesting a broader role for AQP4 in stroke beyond oedema formation. The reduction in infarct volume was associated with increased astrocyte reactivity in the peri-infarct areas, while no significant differences were observed in the number of microglia among the genotypes. These findings provide new insights into the role of AQP4 in stroke, indicating that AQP4 affects both infarct volume and astrocyte reactivity in the peri-infarct zone., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC., Methods: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m 2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m 2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB., Results: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively)., Conclusions: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.B. reports advisory roles with AbbVie, AstraZeneca, Bayer, BMS, Causalis, Merck Serono, MSD, Novartis, Roche, and Takeda and receiving research funding from Immunai, OncoHost, MSD, and AstraZeneca. D.R.A. reports personal fees/honoraria for consultancy or advisory roles and lectures from Roche, Genentech, AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; and travel expenses from Roche, Bristol Myers Squibb, MSD, Sanofi, Regeneron, and Novartis. E.F. reports personal fees or honoraria for advisory roles from Abbvie, Amgen, AstraZeneca, Bayer, Bergen Bio, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point; speaker’s bureau fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and independent board membership with Grifols. M.P. reports lecture fees, honoraria, or other fees from Bristol Myers Squibb, Roche, MSD, AstraZeneca, Takeda, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, and Pfizer; and research funds from MSD, AstraZeneca, Roche, Boehringer Ingleheim, and Bristol Myers Squibb. D.R.C. reports lecture fees, honoraria or other fees from Roche and AstraZeneca. S.M.T, J.K., and E.J.D. report employment with MSD. M.A. reports employment and stock ownership with MSD. N.H. reports advisory or consultancy roles and stock ownership with Curve Biosciences. R.Mc. and B.J. report employment with Grail LLC. R.Ma reports employment with Grail LLC and stock ownership with Illumina. D.B. reports employment with GRAIL LLC and stock ownership with Illumina. E.E., S.P.A., M.G., A.R., A.F., S.B.R., G.S., T.C. have no conflicts of interest to disclose., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and purpose: Previous experimental studies have shown that meningeal lymphatic vessels are located primarily along the walls of the dural sinus veins. Whether they are more widespread throughout human dura mater has presently not been characterized. The present study explored in humans whether meningeal lymphatic vessels may be identified remote from the sinus veins and whether they differ in the various location of dura mater. Methods: We included 15 patients who underwent neurosurgery, in whom dura mater was removed as part of the planned procedure. Tissue was prepared for immunohistochemistry using the lymphatic endothelial cell markers lymphatic vessel endothelial hyaluronan receptor 1 protein (LYVE-1), podoplanin and vascular endothelial growth factor receptor 3 (VEGFR3). Results: Lymphatic endothelial cell positive cells were found in dura mater at the posterior fossa (n = 8), temporal skull base (n = 5), frontal convexity (n = 1), and cranio-cervical junction (n = 1). They were most commonly seen remote from blood vessels, but also occurred along blood vessels, and seemed to be most abundant at the skull base. Conclusion: The present observations show that human lymphatic vessels are widespread in dura mater, not solely lining the dural sinuses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vera Quesada, Rao, Torp and Eide.)

Providing a definitive diagnostic test in a disease emergency is critical to limit pathogen spread, develop and deploy medical countermeasures, and mitigate the social and economic harms of a serious epidemic. While major accomplishments have accelerated test development, expanded laboratory testing capacity, and established widespread point-of-care testing, the United States does not have a plan to rapidly respond, to develop, manufacture, deploy, and sustain diagnostic testing at a national scale. To address this gap, we are proposing a National Diagnostics Action Plan that describes the steps that are urgently needed to prepare for future infectious disease emergencies, as well as the actions we must take at the first signs of such' events. These recommendations require substantial collaboration between the US government (USG) and the private sector to solve a series of challenges now, as well as to prepare for the massive and rapid scale-up of laboratory and point-of-care test development and testing capacity in future emergencies. The recommendations include establishing pre-event contracts; ensuring rapid access to clinical samples; creating a permanent public-private testing coordinating body to allow for rapid information sharing and improved cooperation among the USG, test developers, and clinical laboratories; and accelerating testing rollout at the beginning of an event-and thus, the effective public health management of a disease crisis., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gigi Gronvall, Sujeet Rao, and Tom Inglesby declare no conflicts of interest. Mr. Borden is a shareholder in Siemens Healthineers, and he and Susan Van Meter work for ACLA, an organization which represents clinical laboratories., (© 2023 The Authors. Published by Elsevier B.V.)

Background: Despite greatly renewed interest concerning meningeal lymphatic function over recent years, the lymphatic structures of human dura mater have been less characterized. The available information derives exclusively from autopsy specimens. This study addressed methodological aspects of immunohistochemistry for visualization and characterization of lymphatic vessels in the dura of patients., Methods: Dura biopsies were obtained from the right frontal region of the patients with idiopathic normal pressure hydrocephalus (iNPH) who underwent shunt surgery as part of treatment. The dura specimens were prepared using three different methods: Paraformaldehyde (PFA) 4% (Method #1), paraformaldehyde (PFA) 0.5% (Method #2), and freeze-fixation (Method #3). They were further examined with immunohistochemistry using the lymphatic cell marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and as validation marker we used podoplanin (PDPN)., Results: The study included 30 iNPH patients who underwent shunt surgery. The dura specimens were obtained average 16.1 ± 4.5 mm lateral to the superior sagittal sinus in the right frontal region (about 12 cm posterior to glabella). While lymphatic structures were seen in 0/7 patients using Method #1, it was found in 4/6 subjects (67%) with Method #2, while in 16/17 subjects (94%) using Method #3. To this end, we characterized three types of meningeal lymphatic vessels: (1) Lymphatic vessels in intimate contact with blood vessels. (2) Lymphatic vessels without nearby blood vessels. (3) Clusters of LYVE-1-expressing cells interspersed with blood vessels. In general, highest density of lymphatic vessels were observed towards the arachnoid membrane rather than towards the skull., Conclusions: The visualization of meningeal lymphatic vessels in humans seems to be highly sensitive to the tissue processing method. Our observations disclosed most abundant lymphatic vessels towards the arachnoid membrane, and were seen either in close association with blood vessels or remote from blood vessels., (© 2023. The Author(s).)

Background: Long term outcomes of lung transplantation are impacted by the occurrence of chronic lung allograft dysfunction (CLAD). Recent evidence suggests a role for the lung microbiome in the occurrence of CLAD, but the exact mechanisms are not well defined. We hypothesize that the lung microbiome inhibits epithelial autophagic clearance of pro-fibrotic proteins in an IL-33 dependent manner, thereby augmenting fibrogenesis and risk for CLAD., Methods: Autopsy derived CLAD and non-CLAD lungs were collected. IL-33, P62 and LC3 immunofluorescence was performed and assessed using confocal microscopy. Pseudomonas aeruginosa (PsA), Streptococcus Pneumoniae (SP), Prevotella Melaninogenica (PM), recombinant IL-33 or PsA-lipopolysaccharide was co-cultured with primary human bronchial epithelial cells (PBEC) and lung fibroblasts in the presence or absence of IL-33 blockade. Western blot analysis and quantitative reverse transcription (qRT) PCR was performed to evaluate IL-33 expression, autophagy, cytokines and fibroblast differentiation markers. These experiments were repeated after siRNA silencing and upregulation (plasmid vector) of Beclin-1., Results: Human CLAD lungs demonstrated markedly increased expression of IL-33 and reduced basal autophagy compared to non-CLAD lungs. Exposure of co-cultured PBECs to PsA, SP induced IL-33, and inhibited PBEC autophagy, while PM elicited no significant response. Further, PsA exposure increased myofibroblast differentiation and collagen formation. IL-33 blockade in these co-cultures recovered Beclin-1, cellular autophagy and attenuated myofibroblast activation in a Beclin-1 dependent manner., Conclusion: CLAD is associated with increased airway IL-33 expression and reduced basal autophagy. PsA induces a fibrogenic response by inhibiting airway epithelial autophagy in an IL-33 dependent manner., Competing Interests: Conflict of interest None., (Published by Elsevier Inc.)

Increased astrocytic Ca 2+ signaling has been shown in Alzheimer's disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca 2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca 2+ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca 2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca 2+ signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRAB NE , we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca 2+ responses. Our data points to a dysfunction in the norepinephrine-astrocyte Ca 2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer's disease., Competing Interests: KÅ, GS, CC, DB, KB, LB, VJ, LN, SR, WT, GH, EN, OO, RT, RE No competing interests declared, (© 2022, Åbjørsbråten, Skaaraas et al.)

Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization. We utilized MoNNets for quantitative in vitro modelling of schizophrenia-related network dysfunctions caused by highly penetrant mutations in SETD1A and 22q11.2 risk loci. Furthermore, we demonstrate its utility for drug discovery by performing pharmacological rescue of alterations in neuronal ensembles stability and global network synchrony. MoNNets allow in vitro modelling of brain diseases for investigating the underlying neuronal network mechanisms and systematic drug discovery., (© 2022. The Author(s).)

Pediatric lung transplantation is a highly specialized treatment option at a select few hospitals caring for children. Advancements in surgical and medical approaches in the care of these children have improved their care with only minimal improvement in outcomes which remain the lowest of all solid organ transplants. A crucial time period in the management of these children is in the perioperative period after performance of the lung transplant. Supporting allograft function, preventing infection, maintaining fluid balance, achieving pain control, and providing optimal respiratory support are all key factors required for this highly complex pediatric patient population. We review commonly encountered complications that these patients often experience and provide strategies for management., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest and has no relevant disclosures regarding this manuscript., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Livestock plays a significant role in the socio-economic development of developing countries by providing livelihood and nutritional security, transport, contingency during crop failure and day-to-day earning to the farm family. The human population is projected to reach 9.9 billion by 2050, which along with increasing urbanization and growing income is expected to increase the demand for livestock products. Global livestock feed demand will be almost doubled, and 1.3 billion tons of grain will be required for feeding farm animals alone. To increase the livestock production efficiency, feed additives have been used to improve the production and growth of high-quality livestock products. Even though feed additives have a pertinent role in animal growth performance, disadvantages like endo toxin production and reduced absorption of nutrients by interaction of additives with naturally occurring nutrients limits the use of feed additives. A majority of the macronutrients in the rumen are metabolized or transformed by microbes, hence nutrients should be preserved and made available in the small intestine. Encapsulation technology, which has been employed in a broad range of applications in various fields of science, can address this challenge and rejuvenate livestock nutrition research. The present review explores the importance of encapsulated nano material in livestock and poultry production., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Aquaporin-4 (AQP4) water channels and gap junction proteins (connexins) are two classes of astrocytic membrane proteins critically involved in brain water and ion homeostasis. AQP4 channels are anchored by α1-syntrophin to the perivascular astrocytic endfoot membrane domains where they control water flux at the blood-brain interface while connexins cluster at the lateral aspects of the astrocytic endfeet forming gap junctions that allow water and ions to dissipate through the astrocyte syncytium. Recent studies have pointed to an interdependence between astrocytic AQP4 and astrocytic gap junctions but the underlying mechanism remains to be explored. Here we use a novel transgenic mouse line to unravel whether β1-syntrophin (coexpressed with α1-syntrophin in astrocytic plasma membranes) is implicated in the expression of AQP4 isoforms and formation of gap junctions in brain. Our results show that while the effect of β1-syntrophin deletion is rather limited, double knockout of α1- and β1-syntrophin causes a downregulation of the novel AQP4 isoform AQP4ex and an increase in the number of astrocytic gap junctions. The present study highlight the importance of syntrophins in orchestrating specialized functional domains of brain astrocytes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Vascular pathology is a common feature in patients with advanced Alzheimer's disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer's disease and Down's syndrome., Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and vessel density., Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques., Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density., Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors.

Retinal Müller cells are highly polarized macroglial cells with accumulation of the aquaporin-4 (AQP4) water channel and the inwardly rectifying potassium channel K ir 4.1 at specialized endfoot membrane domains abutting microvessels and corpus vitreum. Proper water and potassium homeostasis in retina depends on these membrane specializations. Here we show that targeted deletion of β1-syntrophin leads to a partial loss of AQP4 from perivascular Müller cell endfeet and that a concomitant deletion of both α1- and β1-syntrophin causes a near complete loss of AQP4 from both perivascular and subvitreal endfoot membranes. α1-syntrophin is normally very weakly expressed in Müller cell endfeet but β1-syntrophin knockout mice display an increased amount of α1-syntrophin at these sites. We suggest that upregulation of perivascular α1-syntrophin restricts the effect of β1-syntrophin deletion. The present findings indicate that β1-syntrophin plays an important role in maintaining the functional polarity of Müller cells and that α1-syntrophin can partially substitute for β1-syntrophin in AQP4 anchoring. Functional polarization of Müller cells thus depends on an interplay between two syntrophin isoforms.

Evidence suggests that extracellular matrix molecules of perivascular basal laminae help orchestrate the molecular assemblies at the gliovascular interface. Specifically, laminin and agrin are thought to tether the dystrophin-associated protein (DAP) complex to the astrocytic basal lamina. This complex includes α-syntrophin (α-Syn), which is believed to anchor aquaporin-4 (AQP4) to astrocytic endfoot membrane domains. We have previously shown that the size of the perivascular AQP4 pool differs considerably between brain regions in an α-Syn-dependent manner. Also, both AQP4 and α-Syn occur at higher densities in endfoot membrane domains facing pericytes than in endfoot membrane domains facing endothelial cells. The heterogeneous distribution of AQP4 at the regional and capillary level has been attributed to a direct interaction between AQP4 and α-Syn. This would be challenged (1) if the microdistributions of laminin and agrin fail to align with those of DAP and AQP4 and (2) if targeted deletion of α-Syn leads to a loss of laminin and/or agrin. Here, we provide the first detailed and quantitative analysis of laminin and agrin in brain basal laminae of mice. We show that the microdistributions of these molecules vary in a fashion that is well aligned with the previously reported microdistribution of AQP4. We also demonstrate that the expression patterns of laminin and agrin are insensitive to targeted deletion of α-Syn, suggesting that α-Syn deletion affects AQP4 directly and not indirectly via laminin or agrin. These data fill remaining voids in the current model of how key molecules are assembled and tethered at the gliovascular interface.

Competing Interests: There are no conflicts of interest

Proper function of the retina depends heavily on a specialized form of retinal glia called Müller cells. These cells carry out important homeostatic functions that are contingent on their polarized nature. Specifically, the Müller cell endfeet that contact retinal microvessels and the corpus vitreum show a tenfold higher concentration of the inwardly rectifying potassium channel K ir 4.1 than other Müller cell plasma membrane domains. This highly selective enrichment of K ir 4.1 allows K+ to be siphoned through endfoot membranes in a special form of spatial buffering. Here, we show that K ir 4.1 is enriched in endfoot membranes through an interaction with β1-syntrophin. Targeted disruption of this syntrophin caused a loss of K ir 4.1 from Müller cell endfeet without affecting the total level of K ir 4.1 expression in the retina. Targeted disruption of α1-syntrophin had no effect on K ir 4.1 localization. Our findings show that the K ir 4.1 aggregation that forms the basis for K+ siphoning depends on a specific syntrophin isoform that colocalizes with K ir 4.1 in Müller endfoot membranes., (© 2019 Wiley Periodicals, Inc.)

Body temperature monitoring in most healthcare institutions is limited to checking the presence or absence of fever. Our present study evaluated the 24h continuous tympanic temperature pattern in patients with fever in order to detect typical patterns seen in tuberculosis (TB). This observational study was conducted on 81 undifferentiated fever patients whose recordings were stored using the TherCom device. Unique temperature patterns were analysed and compared. TB patients exhibited a unique temperature pattern, namely a slow temperature elevation followed by slow temperature fall seen in 78.5% (22/28) compared to 24.52% (13/53) of non-TB patients. Recognition of this pattern may therefore be useful as a valuable diagnostic aid in the early diagnosis of TB.

Consolidated evidence indicates that astroglial cells are critical in the homeostatic regulation of cellular volume by means of ion channels and aquaporin-4. Volume-regulated anion channel (VRAC) is the chloride channel that is activated upon cell swelling and critically contributes to cell volume regulation in astrocytes. The molecular identity of VRAC has been recently defined, revealing that it belongs to the leucine-rich repeat-containing 8 (LRRC8) protein family. However, there is a lack of evidence demonstrating that LRRC8A underpins VRAC currents in astrocyte. Nonetheless, direct evidence of the role of LRRC8A in astrocytic regulatory volume decrease remains to be proved. Here, we aim to bridge this gap in knowledge by combining RNA interference specific for LRRC8A with patch-clamp analyses and a water-permeability assay. We demonstrated that LRRC8A molecular expression is essential for swelling-activated chloride current via VRAC in primary-cultured cortical astrocytes. The knockdown of LRRC8A with a specific short interference RNA abolished the recovery of the cell volume after swelling induced by hypotonic challenge. In addition, immunoblotting, immunofluorescence, confocal imaging, and immunogold electron microscopy demonstrated that LRRC8A is expressed in the plasma membrane of primary cortical astrocytes and in situ in astrocytes at the perivascular interface with endothelial cells. Collectively, our results suggest that LRRC8A is an essential subunit of VRAC and a key factor for astroglial volume homeostasis.-Formaggio, F., Saracino, E., Mola, M. G., Rao, S. B., Amiry-Moghaddam, M., Muccini, M., Zamboni, R., Nicchia, G. P., Caprini, M., Benfenati, V. LRRC8A is essential for swelling-activated chloride current and for regulatory volume decrease in astrocytes.

Dengue fever is an acute febrile illness with a duration of 2-12 days. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and compared this with 26 others with fever due to a non-dengue aetiology. A tri-phasic fever pattern was seen among two-thirds of dengue fever patients, but in only one with an inflammatory disease. One-third of dengue fever patients exhibited a single peak temperature. Continuous temperature monitoring and temperature pattern analysis in clinical settings can aid in the early differentiation of dengue fever from non-dengue aetiology.

Fever is one of the major clinical symptoms of undifferentiated fever cases. Early diagnosis of undifferentiated fever is a challenging task for the physician. The aim of this study was to classify infectious and noninfectious diseases from 24-hour continuous tympanic temperature recordings of patients with undifferentiated fever using a machine learning algorithm (artificial neural network). This was an observational study conducted in 103 patients who presented with undifferentiated fever. Twenty-four-hour continuous tympanic temperature was recorded from each patient. Features were extracted from temperature signals and classified into infectious and noninfectious diseases using an artificial neural network (ANN). The ANN classifier provided the highest accuracy at 91.3% for differentiating infectious and noninfectious diseases from undifferentiated fever cases. Significant kappa agreement (κ = 0.777) was found between the final diagnosis as determined by the physician and the classification obtained using an ANN classifier. Based on our results, we conclude that the continuous 24-hour temperature monitoring and application of an ANN classifier provides a simple noninvasive and inexpensive supplementary diagnostic method to differentiate infectious and noninfectious diseases.

Introduction: The widespread use of cell phone in recent years has raised many questions whether their use is safe to operator who is exposed to Electromagnetic Waves (EMV)., Aim: To find out the effect of cell phone emitted radiations on the orofacial structures., Materials and Methods: To identify suitable literature, an electronic search was performed using Medline, Pubmed and EBSCO host database in December 2016. The search was focused on effect of cell phone on orofacial structures. Among the literature available in English, the screening of the related titles and abstracts was done, and only those articles were selected for full text reading that fulfilled the inclusion criteria., Results: The initial literature search resulted in 360 articles out of which only 24 articles fulfilled the inclusion criteria and were included in this systematic review., Conclusion: Cell phone emitted radiations had their adverse effect on salivary glands and facial nerves. Studies showed that cell phone emitted radiations had effects on oral mucosal cells and causes changes in salivary flow rate. It was still unclear that cell phone radiations cause tumours of the salivary glands.

Mangiferin (MGN), a C-glucosylxanthone abundantly found in mango plants, was studied for its potential to ameliorate methylmercury (MeHg) induced mitochondrial damage in HepG2 (human hepatocarcinoma) cell line. Cell viability experiments performed using 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) showed protective property of MGN in annulling MeHg-induced cytotoxicity. Conditioning the cells with optimal dose of MGN (50 µM) lowered MeHg-induced oxidative stress, calcium influx/efflux, depletion of mitochondrial trans-membrane potential and prevented mitochondrial fission as observed by decrease in Mitotracker red fluorescence, expression of pDRP1 (serine 616), and DRP1 levels. MGN pre-treated cells demonstrated elevation in the activities of glutathione (GSH), Glutathione-S-transferase (GST), Glutathione peroxidase (GPx), Glutathione reductase (GR), reduced levels of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) and mitochondrial electron transport chain (ETC) enzyme complexes. In addition, the anti-apoptotic effect of MGN was clearly indicated by the reduction in MeHg-induced apoptotic cells analyzed by flowcytometric analysis after Annexin V-FITC/propidium iodide staining. In conclusion, the present work demonstrates the ability of a dietary polyphenol, MGN to ameliorate MeHg-mediated mitochondrial dysfunction in human hepatic cells in vitro. This hepatoprotective potential may be attributed predominantly to the free radical scavenging/antioxidant property of MGN, by facilitating the balancing of cellular Ca 2+ ions, maintenance of redox homeostasis and intracellular antioxidant activities, ultimately preserving the mitochondrial function and cell viability after MeHg intoxication. As MeHg intoxication occurs over a period of time, continuous consumption of such dietary compounds may prove to be very useful in promoting human health. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 630-644, 2017., (© 2016 Wiley Periodicals, Inc.)

Diagnosis of undifferentiated fever is a major challenging task to the physician which often remains undiagnosed and delays the treatment. The aim of the study was to record and analyze a 24-hour continuous tympanic temperature and evaluate its utility in the diagnosis of undifferentiated fevers. This was an observational study conducted in the Kasturba Medical College and Hospitals, Mangaluru, India. A total of ninety-six ( n = 96) patients were presented with undifferentiated fever. Their tympanic temperature was recorded continuously for 24 hours. Temperature data were preprocessed and various signal characteristic features were extracted and trained in classification machine learning algorithms using MATLAB software. The quadratic support vector machine algorithm yielded an overall accuracy of 71.9% in differentiating the fevers into four major categories, namely, tuberculosis, intracellular bacterial infections, dengue fever, and noninfectious diseases. The area under ROC curve for tuberculosis, intracellular bacterial infections, dengue fever, and noninfectious diseases was found to be 0.961, 0.801, 0.815, and 0.818, respectively. Good agreement was observed [kappa = 0.618 ( p < 0.001, 95% CI (0.498-0.737))] between the actual diagnosis of cases and the quadratic support vector machine learning algorithm. The 24-hour continuous tympanic temperature recording with supervised machine learning algorithm appears to be a promising noninvasive and reliable diagnostic tool.

This study demonstrates the protective potential of hydroxytyrosol (HT), an olive oil phenol, against methylmercury (MeHg)-induced neurotoxicity using IMR-32 human neuroblastoma cell line. HT inhibited MeHg-induced cytotoxicity and genotoxicity as confirmed by MTT, micronucleus, and comet assays. Cells preconditioned with HT showed reduction of MeHg-induced cellular oxidative stress along with the maintenance of glutathione, superoxide dismutase, glutathione-S-tranferase, and catalase. Fluorescence microscopy and DNA ladder assays indicated the inhibitory effect of HT against MeHg-induced apoptosis, which was further established by Western blotting. An effective concentration of 5 µM HT caused downregulation of p53, bax, cytochrome c, and caspase 3 and upregulation of prosurvival proteins including nuclear factor erythroid 2-related factor 2 (Nrf2) and metallothionein. This work indicates the cytoprotective potential of HT against MeHg-induced toxicity primarily by the lowering of oxidative stress, which may be endorsed to its antigenotoxic and antiapoptotic potential, in addition to its free radical scavenging ability. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1264-1275, 2016., (© 2015 Wiley Periodicals, Inc.)

Introduction: Detection of accurate body temperature fluctu-ations in hospitalized patients is crucial for appropriate clinical decision-making. The accuracy and reliability of body temperature assessment may significantly affect the proper treatment., Aim: To compare the conventional and continuous body temperature recordings in hospitalized patients., Materials and Methods: This cross-sectional study was carried out at a tertiary care centre and study included 55 patients aged between 18-65 years with a history of fever admitted to a tertiary care hospital. A noninvasive continuous temperature recording was done using TherCom ® device through tympanic temperature probe at tympanic site at one-minute intervals for 24 hours. The conventional temperatures were recorded in the axilla using mercury thermometer at specific time intervals at 12:00 noon, 8:00 PM and 5:00 AM. Peak temperature differences between continuous and conventional methods were compared by applying Independent sample t-test. Intra class Correlation Coefficient (ICC) test was performed to assess the reliability between two temperature-monitoring methods. A p<0.05 was considered as significant., Results: The average peak temperature by non-invasive continuous recording method was 39.07°C ±0.76°C while it was 37.55°C ±0.62°C by the conventional method. A significant temperature difference of 1.52°C [p<0.001;95% CI(1.26-1.78)] was observed between continuous and conventional temperature methods. Intra class Correlation Coefficient (ICC) between continuous and conventional temperature readings at 12:00 noon was α= 0.540, which had moderate reliability. The corresponding coefficients at 8:00 PM and 5:00 AM were α=0.425 and 0.435, respectively, which had poor reliability., Conclusion: The conventional recording of temperature is routinely practiced and does not reflect the true temperature fluctuations. However, the continuous non-invasive temperature recording is simple, inexpensive and a better tool for recording the actual temperature changes.

Purpose: To evaluate the influence of blur on ocular comfort while systematically manipulating vision using habitual refractive correction, induced spatial blur, dioptric defocus, and under the absence of visual structure., Methods: Twenty emmetropic subjects rated vision, ocular comfort, and other sensations (burning, itching, and warmth) under clear viewing condition, spatial blur, and dioptric defocus, each lasting for 5 min. During each condition, subjects viewed digital targets projected from a distance of 3 m, and vision and ocular sensations were rated using magnitude estimation. Dioptric defocus was induced using +6.00DS contact lens, and equivalent spatial blur was produced by spatially filtering the targets. In a separate study, 15 participants rated vision and comfort while viewing a ganzfeld and behind an occluding patch (each of which provided an absence of visual structure) in addition to the above experimental conditions. Repeated-measures analysis of variance was used to compare the ratings of vision and comfort under the different experimental conditions., Results: Vision under blurred conditions (both spatial blur and dioptric defocus) was rated significantly different (p < 0.001) from clear viewing condition. Vision was significantly different when targets were dioptrically defocused than when they were spatially blurred (p < 0.001). Ratings of comfort showed significant differences between clear and blurred conditions (p < 0.001). However, there was no significant difference in comfort ratings between dioptric defocus and spatial blur (p value at least 0.28). There were also no differences in comfort (p value at least 0.99) between clear vision, ganzfeld viewing, and occlusion despite the lack of visual structure in the latter two conditions., Conclusions: There does seem to be an association between clarity of vision and ocular comfort. Although the pathways for ocular surface pain and vision are perhaps exclusive, complex psychological influences such as nocebo or Hawthorne effects can subtly influence the participants to anticipate a change in comfort when vision is blurred.

Background: Micronutrients such as B12 and folic acid deficiencies are found in higher number in HIV-infected patients., Objective: We conducted a study to examine the effect of Vitamin B12 and folic acid supplementation on neuropsychiatric manifestations, CD4 count, and anthropometric measurements in HIV-positive patients., Materials and Methods: Three different groups of HIV patients, namely, HIV patients with tuberculosis, HIV patients with neuropsychiatric manifestations, and asymptomatic HIV patients with 50 patients in each group were included in the study. Baseline and follow-up CD4 count, anthropometric measurements, neuropsychiatric assessments, Vitamin B12, and folic acid estimation were done., Results: The prevalence of folic acid deficiency was 27.1% in Group I, 31.9% in Group II, and 23.4% in Group III. The prevalence of Vitamin B12 deficiency was 8.16% in Group I, 6.12% in Group II, and 4.16% in Group III. HIV patients with neuropsychiatric manifestations were noted to have the lowest mean mini-mental score. After the supplementation of vitamins, anthropometric measurements, MMSE as well as Hamilton depression scores, improved in all the three groups whereas Hamilton anxiety scores improved only in Group III. The CD4 count also improved in Groups I and II after the supplementation of vitamins., Conclusion: Folic acid deficiency was highest among neuropsychiatric patients. The majority of people who had a folic acid deficiency have shown improvement in their neuropsychiatric assessment scores as well as CD4 count after its supplementation.