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Objectives: Dysregulation of lipid homeostasis pathway causes many liver diseases, including hepatic steatosis. One of the primary factors contributing to lipid accumulation is fatty acid uptake by the liver. Transmembrane protein 135 (TMEM135), which exists in mitochondria and peroxisomes, participates in intracellular lipid metabolism. This study aims to investigate the role of TMEM135 on regulating cellular lipid import in the liver., Methods: We used in vivo, ex vivo, and in vitro models of steatosis. TMEM135 knockout (TMEM135KO) and wild type (WT) mice were fed a high-fat diet (HFD) to induce hepatic steatosis. Primary mouse hepatocytes and AML12 cells were treated with free fatty acid (FFA). Additionally, TMEM135-deficient stable cells and overexpressed cells were established using AML12 cells., Results: TMEM135 deficiency mitigated lipid accumulation in the liver of HFD-fed TMEM135KO mice. TMEM135-depleted primary hepatocytes and AML12 cells exhibited less lipid accumulation when treated with FFA compared to control cells, as shown as lipid droplets. Consistently, the effect of TMEM135 depletion on lipid accumulation was completely reversed under TMEM135 overexpression conditions. CD36 expression was markedly induced by HFD or FFA, which was reduced by TMEM135 depletion. Among the SIRT family proteins, only SIRT1 expression definitely increased in the liver of HFD-fed TMEM135KO mice along with a significant increase in NAD + /NADH ratio. However, inhibition of SIRT1 in TMEM135-depleted cells using siSIRT1 or the SIRT1 inhibitor EX-527 resulted in an increase of CD36 expression and consequent TG levels., Conclusions: TMEM135 depletion attenuates CD36 expression in a SIRT1-dependent manner, thereby reducing cellular lipid uptake and hepatic steatosis., Competing Interests: Declaration of competing interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript., (Copyright © 2024. Published by Elsevier GmbH.)

Background: Calcium is a ubiquitous intracellular messenger that regulates the expression of various genes involved in cell proliferation, differentiation, and motility. The involvement of calcium in diverse metabolic pathways has been suggested. However, the effect of calcium in peroxisomes, which are involved in fatty acid oxidation and scavenges the result reactive oxygen species (ROS), remains elusive. In addition, impaired peroxisomal ROS inhibit the mammalian target of rapamycin complex 1 (mTORC1) and promote autophagy. Under stress, autophagy serves as a protective mechanism to avoid cell death. In response to oxidative stress, lysosomal calcium mediates transcription factor EB (TFEB) activation. However, the impact of calcium on peroxisome function and the mechanisms governing cellular homeostasis to prevent diseases caused by calcium deficiency are currently unknown., Methods: To investigate the significance of calcium in peroxisomes and their roles in preserving cellular homeostasis, we established an in-vitro scenario of calcium depletion., Results: This study demonstrated that calcium deficiency reduces catalase activity, resulting in increased ROS accumulation in peroxisomes. This, in turn, inhibits mTORC1 and induces pexophagy through TFEB activation. However, treatment with the antioxidant N-acetyl-l-cysteine (NAC) and the autophagy inhibitor chloroquine impeded the nuclear translocation of TFEB and attenuated peroxisome degradation., Conclusions: Collectively, our study revealed that ROS-mediated TFEB activation triggers pexophagy during calcium deficiency, primarily because of attenuated catalase activity. We posit that calcium plays a significant role in the proper functioning of peroxisomes, critical for fatty-acid oxidation and ROS scavenging in maintaining cellular homeostasis. These findings have important implications for signaling mechanisms in various pathologies, including Zellweger's syndrome and ageing., (© 2024. The Author(s).)

The impact of mild synovitis on the chondrogenic environment in the joint pertaining to cartilage repair is often neglected. In this study, 21 synovial samples were collected from foot surgeries for histology and isolation of fibroblast-like synoviocytes (FLSs). Of the 21 samples, 13 were normal and eight were mild synovitis, according to their synovitis scores. In mild synovitis, CD3+ lymphocytes were increased in the sublining layer. When chondrocytes were cultured and treated with the conditioned medium produced by FLSs, their glycosaminoglycan production was negatively correlated with the synovitis scores of the synovium, from which FLSs were isolated. In conclusion, mild synovitis in common joint conditions compromises the process of chondrogenesis, via inhibiting chondrocyte matrix production by FLSs. The results suggest that the concomitant synovitis, even being mild, could significantly alter the joint environment for chondrogenesis and impair the outcome of cartilage repair., (© 2023 S. Karger AG, Basel.)

Acute postoperative sialadenitis is a rare complication usually after surgery involving extreme head and neck rotation, such as posterior fossa surgery. It is characterized by the development of swelling in the submandibular region, usually contralateral to the surgical side, either immediately or within hours post-operatively. We report a case of a 43-year-old woman who developed sialadenitis leading to upper airway obstruction in the postoperative period. Further, she developed bilateral neck and face swelling. Dexmedetomidine used as an infusion throughout the surgery could be an additional cause. Swelling without signs of inflammation is rapidly progressive and may cause airway obstruction. Therefore, awareness and recognition are important, as a delay in airway securement can cause a complete collapse of the airway., Keywords: airway obstruction; case reports; sialadenitis.

Objective: Joint destruction in Charcot neuroarthropathy (CNA) is accompanied with abundant hyperplastic synovium. This study aimed to characterize the expression patterns of a group of neuropeptides in the CNA synovium., Methods: Synovial specimens were collected during surgery from the CNA (n = 6) and non-CNA joints (n = 14). Tissue samples were processed for protein extraction and western blot for vasoactive intestinal peptide (VIP), galanin, and calcitonin gene-related peptide (CGRP). Immunohistochemistry was performed to localize CGRP in the CNA synovium. Additionally, CGRP was applied to fibroblast-like synoviocytes (FLS) isolated from CNA synovium for its effects on cell proliferation and collagenolysis in vitro., Results: Western blot detected light bands of VIP in the CNA samples but abundant galanin in both CNA and non-CNA samples. Most of the CNA samples (5/6) increased expression of CGRP, with an average band density about 2 times that in the non-CNA group (p < .05). Immunohistochemistry of CGRP demonstrated intense staining in the intimal layer of the CNA synovium. In tissue culture, adding CGRP (10 nM) in the medium promoted FLS proliferation. In combination with TNF-α, CGRP enhanced FLS-mediated collagenolysis in vitro., Conclusion: This study revealed an increased expression of CGRP in the CNA synovium and demonstrated that CGRP regulates FLS proliferation and collagenolytic activity, suggesting CGRP may contribute to the bone and cartilage destruction in CNA., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Monoclonal gammopathy of renal significance (MGRS) is a rare disorder in which monoclonal immunoglobulin secreted by nonmalignant B cell or plasma cell clone causes kidney damage. Although MGRS is a premalignant condition, it can cause severe kidney disease and end-stage renal disease (ESRD) at any age. Herein, we present a 31-year-old female with past medical history of lupus nephritis who presented with signs of volume overload and worsening renal function despite adequate immunosuppressive therapy. Renal biopsy revealed heavy and light chain deposition consistent with MGRS. This case report demonstrates the importance of including MGRS in the differential diagnosis of worsening renal function despite adequate treatment, raising awareness of this premalignant yet morbid condition., Competing Interests: The authors declare that they have no conflicts of interests., (Copyright © 2022 Ayrton Bangolo et al.)

Bile cast nephropathy (BCN) is a rare form of acute kidney injury (AKI) that occurs in the setting of hyperbilirubinemia. We present the case of a 67 year-old male with severe kidney injury who was found to have obstructive cholestasis. By way of this report, we aim to expand upon the existing literature and showcase the importance of timely endoscopic retrograde cholangio-pancreatography (ERCP) in this setting, in order to prevent irreversible kidney damage., Competing Interests: No potential conflict of interest was reported by the authors., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.)

Aims: Femoroacetabular impingement (FAI) is a potential cause of hip osteoarthritis (OA). The purpose of this study was to investigate the expression profile of matrix metalloproteinases (MMPs) in the labral tissue with FAI pathology., Methods: In this study, labral tissues were collected from four FAI patients arthroscopically and from three normal hips of deceased donors. Proteins extracted from the FAI and normal labrums were separately applied for MMP array to screen the expression of seven MMPs and three tissue inhibitors of metalloproteinases (TIMPs). The expression of individual MMPs and TIMPs was quantified by densitometry and compared between the FAI and normal labral groups. The expression of selected MMPs and TIMPs was validated and localized in the labrum with immunohistochemistry., Results: On MMP arrays, most of the targeted MMPs and TIMPs were detected in the FAI and normal labral proteins. After data normalization, in comparison with the normal labral proteins, expression of MMP-1 and MMP-2 in the FAI group was increased and expression of TIMP-1 reduced. The histology of the FAI labrum showed disorderly cell distribution and altered composition of thick and thin collagen fibres. The labral cells expressing MMP-1 and MMP-2 were localized and their percentages were increased in the FAI labrum. Immunohistochemistry confirmed that the percentage of TIMP-1 positive cells was reduced in the FAI labrum., Conclusion: This study established an expression profile of MMPs and TIMPs in the FAI labrum. The increased expression of MMP-1 and MMP-2 and reduced expression of TIMP-1 in the FAI labrum are indicative of a pathogenic role of FAI in hip OA development. Cite this article: Bone Joint Res. 2020;9(4):173-181., Competing Interests: Conflict of interest statement: None declared, (© 2020 Author(s) et al.)

Background Several studies have found skin conductance a good indicator for detection of sympathetic response. But, valid and reliable tool for detection of sympathetic outflow in health and disease is still a quest. Thereby, comparison of superficial and, at core sympathetic effluence induced by deliberately supplied discrete external stimuli has been attempted in this study. Objective To assess the degree of sympathetic outflow for discrete cognitive and physical stimuli through perturbations in skin conductance and variations in heart rate in healthy adults. Method Quantitative and cross-sectional study was performed in 104 healthy subjects following random sampling method. Induction of sympathetic activity was realized by providing separate time bound cognitive exercises intervened with change in posture. Recordings to detect sympathetic responses at rest and, for supplied stimuli were made by electrocardiogram and galvanic skin response. Result Cognitive performance and postural change shifts baseline effluence and increases the sympathetic outflow significantly (p=0.000). There occurs no detectable rise in sympathetic effluence at the core (p=0.362) but, eventuate significantly appreciable sympathetic outflow to sweat glands in skin (p=0.000), when compared cognitive versus physical stimuli. Conclusion Sympathetic outflow induced by cognitive challenge and physical change in posture is readily assessable through sympathetic skin response yet core sympathetic effluence for latter stimuli is steady and unwavering. Differential effluence for sympathetic response called upon by discrete stimuli is operational for maintenance of steady state in healthy subjects.

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at -80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.

The calcineurin inhibitor cyclosporine A (CsA) suppresses the immune system but promotes hypertension, vascular dysfunction, and renal damage. CsA decreases regulatory T cells and this contributes to the development of hypertension. However, CsA's effects on another important regulatory immune cell subset, myeloid-derived suppressor cells (MDSCs), is unknown. We hypothesized that augmenting MDSCs would ameliorate the CsA-induced hypertension and vascular and renal injury and dysfunction and that CsA reduces MDSCs in mice. Daily interleukin-33 treatment, which increased MDSC levels, completely prevented CsA-induced hypertension and vascular and renal toxicity. Adoptive transfer of MDSCs from control mice into CsA-treated mice after hypertension was established dose-dependently reduced blood pressure and vascular and glomerular injury. CsA treatment of aortas and kidneys isolated from control mice for 24 hours decreased relaxation responses and increased inflammation, respectively, and these effects were prevented by the presence of MDSCs. MDSCs also prevented the CsA-induced increase in fibronectin in microvascular and glomerular endothelial cells. Last, CsA dose-dependently reduced the number of MDSCs by inhibiting calcineurin and preventing cell proliferation, as other direct calcineurin signaling pathway inhibitors had the same dose-dependent effect. These data suggest that augmenting MDSCs can reduce the cardiovascular and renal toxicity and hypertension caused by CsA., (© 2017 American Heart Association, Inc.)

Research question. This paper was done to answer the question on whether patients with IBS require higher analgesic or anxiolytic doses during colonoscopy. Setting. Gastroenterology practice in Michigan, USA. Methods. We reviewed the charts of patients following up with a US based gastroenterology practice. We collected data on whether or not they had IBS, and collected data on analgesic and anxiolytic requirement during colonoscopy. Results. 336 patients were included in the trial. 206 did not have IBS while 130 had a previous diagnosis of IBS. 234 were female (67.2%). When comparing patients who have IBS to those without IBS, we identified no statistically significant difference in midazolam dose (5.5 mg versus 5.5 mg), fentanyl dose ( 117 mg versus 112 mg) or meperidine dose (69 mg versus 69 mg). The lack of differences in medication doses used remained when we controlled for sex, prior analgesic use, and prior abdominal surgery. Conclusion. Dose of analgesic or anxiolytic used during colonoscopy cannot be used to identify patients with IBS.

Introduction: Isolated facial nerve palsy usually manifests as Bell's palsy. Lacunar infarct involving the lower pons is a rare cause of solitary infranuclear facial paralysis. The present unusual case is one in which the patient appeared to have Bell's palsy but turned out to have a pontine infarct., Case Presentation: A 47-year-old Asian Indian man with a medical history of hypertension presented to our institution with nausea, vomiting, generalized weakness, facial droop, and slurred speech of 14 hours' duration. His physical examination revealed that he was conscious, lethargic, and had mildly slurred speech. His blood pressure was 216/142 mmHg. His neurologic examination showed that he had loss of left-sided forehead creases, inability to close his left eye, left facial muscle weakness, rightward deviation of the angle of the mouth on smiling, and loss of the left nasolabial fold. Afferent corneal reflexes were present bilaterally. MRI of the head was initially read as negative for acute stroke. Bell's palsy appeared less likely because of the acuity of his presentation, encephalopathy-like imaging, and hypertension. The MRI was re-evaluated with a neurologist's assistance, which revealed a tiny 4 mm infarct involving the left dorsal aspect of the pons. The final diagnosis was isolated facial nerve palsy due to lacunar infarct of dorsal pons and hypertensive encephalopathy., Conclusion: The facial nerve has a predominant motor component which supplies all muscles concerned with unilateral facial expression. Anatomic knowledge is crucial for clinical localization. Bell's palsy accounts for around 72% of facial palsies. Other causes such as tumors and pontine infarcts can also present as facial palsy. Isolated dorsal infarct presenting as isolated facial palsy is very rare. Our case emphasizes that isolated facial palsy should not always be attributed to Bell's palsy. It can be a presentation of a rare dorsal pontine infarct as observed in our patient.

Pyruvate,orthophosphate dikinase (PPDK) plays a controlling role in the PEP-regeneration phase of the C(4) photosynthetic pathway. Earlier studies have fully documented its biochemical properties and its post-translational regulation by the PPDK regulatory protein (PDRP). However, the question of its evolution into the C(4) pathway has, until recently, received little attention. One assumption concerning this evolution is that changes in catalytic and regulatory properties of PPDK were necessary for the enzyme to fulfil its role in the C(4) pathway. In this study, the functional evolution of PPDK from its ancient origins in the Archaea to its ascension as a photosynthetic enzyme in modern C(4) angiosperms is reviewed. This analysis is accompanied by a comparative investigation into key catalytic and regulatory properties of a C(3) PPDK isoform from Arabidopsis and the C(4) PPDK isoform from Zea mays. From these analyses, it is proposed that PPDK first became functionally seated in C(3) plants as an ancillary glycolytic enzyme and that its transition into a C(4) pathway enzyme involved only minor changes in enzyme properties per se.