Destabilization of ß Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes.

SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic ß cell LD biogenesis, which in turn induces ß cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of ß cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.

Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

AIMS/HYPOTHESIS: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility, which we explore here by focusing on the imprinted gene Nnat (encoding neuronatin [NNAT]), which is required for normal insulin synthesis and secretion. METHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing enhanced GFP under the control of the Nnat enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de novo methyltransferase DNA methyltransferase 3 alpha (DNMT3A) from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 AM and Cal-590 AM. Insulin secretion was measured using homogeneous time-resolved fluorescence imaging. RESULTS: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic datasets demonstrated the early establishment of Nnat-positive and -negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulation specialised for insulin production, and were diminished in db/db mice. 'Hub' cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialisation. CONCLUSIONS/INTERPRETATION: These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes. DATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465.

Investigation of the effects of Gamma Knife radiosurgery on optic pathways using diffusion tensor MRI within the first year after treatment.

PURPOSE: To investigate the radiation-induced effects of Gamma Knife radiosurgery (GKRS) for sellar-parasellar tumors on optic pathways using DTI parameters within the first year after treatment. METHODS: Twenty-five patients with sellar-parasellar tumors underwent MRI before and 3 months after GKRS, including T1WI, DTI, T2WI. Moreover, 21 patients underwent follow-up DTI 6-8 months after radiosurgery. ROIs were set on optic nerves, optic radiations, and control localizations; DTI parameters for each were calculated. Pre- and post-radiosurgery differences in DTI values were statistically compared and assessed with respect to tumor size changes. RESULTS: Following GKRS, DTI parameters, notably ADC, FA, and RD, showed statistically significant changes in optic nerves and anterior optic radiations. DTI changes were more significant in the group of cases with tumor shrinkage. In this group, DTI of the anterior optic radiations further deteriorated 3 months post-GKRS, whereas acute changes in DTI parameters of the optic nerves resolved within 6-8 months. DTI of central and posterior optic radiations did not differ significantly following radiosurgery; 6-8 months after radiosurgery, visual function was stable in 14 (56%) patients and improved in 11 (44%), showing no correlation with tumor size changes or DTI parameters. CONCLUSION: White Matter (WM) injury in the optic pathways can be induced by Gamma Knife radiosurgery targeted to sellar and parasellar tumors. Following GKRS, microstructural abnormalities occurred in the optic radiations as well as the optic nerves within the first post-treatment year. Our findings could support modifications to radiosurgical treatment strategies to minimize the risk of permanent WM injury.

Development of Somaliland national harmonised medical curriculum.

BACKGROUND AND OBJECTIVES: The rational for the Somaliland national harmonised curriculum (NHC) was driven by shared concern about the quality of medical education. PROCESS: The Ministry of Education and Science and the Ministry of Health Development produced a Medical Education Policy 2018. Policy objectives included the development of the NHC and accreditation for medical schools that met the standards of the World Federation for Medical Education (WFME). Two bodies were asked to oversee these aims: the National Health Professions' Commission (NHPC) and the National Commission of Higher Education (NCHE). Between 2018 and 2020, a collaborative approach between the Somaliland government, medical school stakeholders, King's Global Health Partnership's (KGHP) volunteers and the Tropical Health Education Trust (THET) team was used to design the 6-years NHC. The NHC structure, content and delivery were grounded by WFME standards, health needs of the local population, student focused and active learning methods, and feasibility of implementation in medical schools. OUTCOMES: The NHC comprises details about the educational outcomes, curriculum model and framework, educational principles, instructional and learning methods, core as well as optional content, and assessment strategy. CONCLUSIONS: The approach used to develop the NHC ensured it is bespoken for Somaliland. Ongoing evaluation of patient and population needs, each medical school's review of programme implementation and outcomes will inform continuous revision and renewal.

Comparative evaluation of brain perfusion with ASL and DSC MRI following intracranial vascular flow diverter stent replacement.

PURPOSE: The objective of this study was to asses brain perfusion parameters and ischemic changes following treatment of aneurysm with flow diverters with two different perfusion MRI technique (Arterial spin labeling and DSC MRI), and to compare the results and effectiveness of these two methods. METHODS: The prospective data was collected from patients with aneurysm who treated with flow diverters. MR examinations, including diffusion-weighted imaging (DWI), ASL, and DSC perfusion MRI, were conducted before and after treatment within the first week and at 6 months. Perfusion parameters of territory area and contralateral side were measured and analyzed by statistically. The relationships between ASL and DSC parameters were analyzed by using Sperman's correlation analysis. RESULTS: A total of 14 cases of aneurysms in 11 patients treated successfully with endovascular flow diverter stent placement. Pretreatment and post treatment (within first week and 6 months) MRI images were evaluated. Asymptomatic randomly distributed millimetric restricted diffusion foci were observed in 8 of all patients. There was no statistically difference between pre and post treatment perfusion parameters (p > 0.05). A statistically significant correlation was found between variable ASL CBF, and the variables of DSC CBF and TTP. CONCLUSIONS: Notwithstanding the fact that flow diverters change flow dynamics in aneurysm sac, there is no any perfusion abnormality in the territory area. Asymptomatic randomly distributed diffusion restricted foci in the both cerebral hemisphere can be observed. ASL and DSC MRI are effective for evaluation of brain perfusion.

The Influence of Chirality on the ß-Amino-Acid Naphthalenediimides/G-Quadruplex DNA Interaction.

G-quadruplexes (G4s) have been identified as a potential alternative chemotherapy target. A series of eight ß-amino acid derived naphthalenediimides (NDI) were screened against a series of oncogenic G4 sequences: c-KIT1, h-TELO, and TBA. Three sets of enantiomers were investigated to further our understanding of the effect of point chirality on G4 stabilisation. Enantioselective binding behaviour was observed with both c-KIT1 and h-TELO. Docking studies using GNINA and UV-vis titrations were employed to better understand this selective binding behaviour.

DWI-based MR thermometry: could it discriminate Alzheimer's disease from mild cognitive impairment and healthy subjects?

PURPOSE: The aim of this study is to compare lateral ventricular cerebrospinal fluid (CSF) temperature of the patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy subjects (HS) using diffusion-weighted imaging (DWI)-based magnetic resonance (MR) thermometry. METHODS: Seventy-two patients (37 AD, 19 MCI, 16 HS) who underwent 3-T MR examination from September 2018 to August 2019 were included in this study. Smoking habits, education level, disease duration, and comorbidity status were recorded. Patients were assessed using Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating (CDR) score. Brain temperatures were measured using DWI-based MR thermometry. Group comparisons of brain temperature were performed using the Pearson chi-square, Mann-Whitney, and Kruskal-Wallis tests. Further analysis was performed using the post hoc Bonferroni test. Receiver operating characteristic (ROC) analysis was also used. RESULTS: A CDR score of 0.5, 1, and 2 was 2 (5.4%), 14 (37.8%), and 21 (56.8%) in AD, respectively. The median MMSE score had significant differences among groups and also in pairwise comparisons. The median CSF temperature (°C) values showed statistically significant difference among groups (HS: 38.5 °C, MCI: 38.17 °C, AD: 38.0 °C). The post hoc Mann-Whitney U test indicated a significant difference between AD patients and HS (p = 0.009). There were no significant CSF temperature differences in other pairwise comparisons. CONCLUSION: Lower CSF temperatures were observed in AD patients than in HS, probably due to decreased brain metabolism in AD. DWI-based MR thermometry as a noninvasive imaging method enabling the measurement of CSF temperatures may contribute to the diagnosis of AD.

Perception and reaction of Nanyang Technological University (NTU) researchers to different forms of research integrity education modality.

BACKGROUND: Research and academic institutions use various delivery channels to deliver Research Integrity (RI) education in their communities. Yet there is no consensus on the best delivery method and the effectiveness of these channels in inculcating a positive RI culture varies across institutions. Hence, this study aimed to understand the preferences of the research community in Nanyang Technological University (NTU), Singapore. METHODS: An online survey was conducted on NTU research community to understand their experience with, and preference for each RI education mode offered in NTU. The RI education modes surveyed in the general ranking question are Data Management Plan (DMP) workshops, Epigeum e-Learning, Compass e-newsletter (email), and NTU policy on Research Integrity and Responsible Conduct of Research. There were 242 responses, comprising 50% research students, 32.2% research staff and 17.8% faculty members. Non-parametric statistical techniques were used to analyse preferences across different RI education modes and within sub-groups (i.e., fields, age, native language, roles in research community). RESULTS: More than 92% of respondents subscribed to the importance of RI education, but with different preferences for education modes. With respect to RI education in NTU, Compass e-newsletters were ranked the lowest (p < 0.05). Most felt that they were too wordy and unengaging, making it difficult to absorb information. Similarly, Epigeum e-Learning (p < 0.05) and 'policy' (p < 0.05) were found to be too lengthy in presentation. The compulsory NTU RI education modes (Epigeum e-learning and 'policy') enjoyed higher participation rates of 70-80% compared with 32-37% for the self-regulated modes (DMP workshop and e-newsletter). This suggests that regulatory mechanisms are still necessary to promote participation in RI education, and thus, core RI education content should be made compulsory in research/academic institutions. Although Epigeum is a compulsory course, some may not have participated in the programme due to technical issues or they might have forgotten to participate in the programme within the permissible timeframe. For all four RI education modes in NTU, the lack of awareness was among the top cited reasons for not participating. CONCLUSIONS: Most NTU researchers perceived RI education positively although they may have reservations for some approaches. Conversely, e-Learning is favored over all the other modes except for the mode of Policy. Findings from this study are useful for improving the design of RI education strategies to be more appealing to the research community by enhancing user experience in terms of user-friendliness, relevance to specialisation, providing concise information and better presentation of materials For institutions with similar modes of RI education as NTU, these results may be relevant in improving participation rates and presentation of RI education modes, such as the use of infographics and more concise information.

Ceramide Acyl Chain Length and Its Relevance to Intracellular Lipid Regulation.

Ceramides are a class of sphingolipids which are implicated in skin disorders, obesity, and other metabolic diseases. As a class with pleiotropic effects, recent efforts have centred on discerning specific ceramide species and their effects on atopic dermatitis, obesity, type 2 diabetes, and cardiovascular diseases. This delineation has allowed the identification of disease biomarkers, with long acyl chain ceramides such as C16- and C18-ceramides linked to metabolic dysfunction and cardiac function decline, while ultra-long acyl chain ceramides (>25 carbon acyl chain) were reported to be essential for maintaining a functional skin barrier. Given the intricate link between free fatty acids with ceramides, especially the de novo synthetic pathway, intracellular lipid droplet formation is increasingly viewed as an important mechanism for preventing accumulation of toxic ceramide species. Here, we review recent reports of various ceramide species involved in skin abnormalities and metabolic diseases, and we propose that promotion of lipid droplet biogenesis can be seen as a potential protective mechanism against deleterious ceramides.

Congenital defects of glycosylation: Novel presentations with mainly neurological involvement and variable dysmorphic features.

The pathophysiology of congenital defects of glycosylation (CDG) is complex and the diagnosis has been a challenge because of the overlapping clinical signs and symptoms as well as a large number of disorders. Isoelectric focusing of transferrin has been used as a screening method but has limitations. Individual enzyme or molecular genetic tests have been difficult to perform. In this study, we aimed to describe CDG patients who were referred to from different departments either without a preliminary diagnosis or suspected to have a genetic disorder other than CDG. The patients were diagnosed mainly with a 450 gene next-generation DNA sequencing panel for inborn errors of metabolism, which also included 25 genes for CDG. A total of 862 patients were investigated with the panel, whereby homozygous (10) or compound heterozygous (4) mutations were found in a total of 14 (1.6%) patients. A total of 13 different mutations were discovered, 10 of them being novel. Interestingly, none of the patients was suspected to have a CDG before referral. This report expands the clinical/laboratory findings in patients with CDG and stresses on the fact that CDG should be in the differential list for pediatric patients presented with nonspecific dysmorphic features and neurological delays/regression. Also, next-generation DNA sequencing with panel approach was noticed to have a significant diagnostic potential in patients presented with nonspecific neurologic and dysmorphic findings.

Effectiveness of data auditing as a tool to reinforce good research data management (RDM) practice: a Singapore study.

BACKGROUND: Institutions, funding agencies and publishers are placing increasing emphasis on good research data management (RDM). RDM lapses in medical science can result in questionable data and cause the public's confidence in the scientific community to crumble. A fledgling medical school in a young university in Singapore has mandated every funded research project to have a data management plan (DMP). However, researchers' adherence to their DMPs was unknown until the school embarked on routine data auditing. We hypothesize that research data auditing improves RDM awareness, compliance and reception in the school. METHODS: We conducted surveys with research PIs and researchers before and after data auditing to evaluate differences in self-reported RDM awareness, compliance and reception. As it is mandatory to deposit research data in a central data repository system in the school, we tracked data deposition by each laboratory from 2 weeks before to 3 months after data auditing as a marker of actual RDM compliance. RESULTS: Research data auditing had an overall positive effect on self-reported RDM awareness, compliance and reception for both research PIs and researchers. Research PIs agreed more that RDM was important to scientific reproducibility, were more aware of proper RDM, had higher RDM strength in their laboratories and were more compliant with the DMP. Both research PIs and researchers believed data auditing helped them to be more compliant with data deposition in the repository. However, data auditing had no significant impact on laboratories' data deposition rates over time, which could be due to the short sampling period. CONCLUSIONS: Research PIs and researchers generally felt that data auditing was effective in improving RDM practices. It helped to evaluate their RDM practices objectively, propose corrective actions for RDM lapses and spread awareness of the university's data management policies. Our findings corroborated other studies in medical research, geosciences, engineering and ethics that data auditing promotes good RDM practices. Hence, we recommend research institutions worldwide to adopt data auditing as a tool to reinforce research integrity.

Efficacy and Safety of Intravitreal Sirolimus for Noninfectious Uveitis of the Posterior Segment: Results from the Sirolimus Study Assessing Double-Masked Uveitis Treatment (SAKURA) Program.

PURPOSE: To evaluate the efficacy and safety of intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment (NIU-PS). DESIGN: Combined analysis of 2 phase 3, randomized, double-masked, multinational, 6-month studies. PARTICIPANTS: Adults with active NIU-PS (intermediate uveitis, posterior uveitis, or panuveitis; defined as vitreous haze [VH] ≥1.5+ on modified Standardization of Uveitis Nomenclature scale). METHODS: Patients were randomized 1:1:1 to receive intravitreal sirolimus 44 µg (n = 208), 440 µg (n = 208), or 880 µg (n = 177) on days 1, 60, and 120. Patients discontinued medications for NIU-PS except for systemic corticosteroids, which were tapered according to protocol. Enrollment in the 880-µg group was terminated after interim results found no significant difference in efficacy compared with the 440-µg dose. MAIN OUTCOME MEASURES: The primary efficacy end point was the percentage of patients with VH of 0 at month 5 in the study eye without the use of rescue therapy. Secondary efficacy end points included VH of 0 or 0.5+, corticosteroid-tapering success, and changes in best-corrected visual acuity (BCVA). Safety measures included ocular and nonocular adverse events. RESULTS: A total of 592 patients were randomized. Significantly higher proportions of patients treated with 440 µg compared with 44 µg intravitreal sirolimus achieved VH of 0 (21.2% vs. 13.5%; P = 0.038) and VH of 0 or 0.5+ (50.0% vs. 40.4%; P = 0.049) at month 5. Best-corrected visual acuity was stable (absolute change <5 ETDRS letters) or improved >5 letters in 80.1% and 80.2% of patients in the 440-µg and 44-µg groups, respectively. At month 5, corticosteroids were tapered successfully in 69.6% and 68.8% of patients in the 440-µg and 44-µg groups, and among these patients, VH of 0 or 0.5+ was achieved by 43.5% and 28.1% in the 440-µg and 44-µg groups. Both doses were generally well tolerated. Mean changes from baseline intraocular pressure (IOP) in the study eye at each analysis visit were minimal in all treatment groups. CONCLUSIONS: Intravitreal sirolimus 440 µg improved ocular inflammation, as measured by VH, compared with the 44-µg dose, with minimal impact on IOP, while preserving BCVA.

Correlation of language lateralization with resting state hippocampal connectivity in temporal lobe epilepsy patients

Background/aim: The main purpose of this study is to evaluate the resting state hippocampal connectivity with language areas and to correlate them with laterality index calculations on single subject basis, hence to present hippocampal lateralization for language with rs-fMRI. Materials and methods: Task based and rs-fMRI data were gathered from a total of 45 subjects in 3T scanner. BrainVoyager QX, SPM, and CONN softwares were used for data analysis. LI score of each subject was calculated and converted into normalized LI score (nLI). Intrahemispheric rs-connectivity analysis was performed between hippocampus and Broca's regions on both sides. Correlation between these variables was measured with SPSS software. Results: Right-TLE patients were found to have highest whereas left-TLE group were found to have lowest mean LI scores. Regarding hippocampal-lingual networks; left intrahemispheric connectivity values showed strong positive correlation with nLI values in left, right-TLE patients and healthy controls (P = 0.035, 0.014, 0.047). There were no significant correlation between right intrahemispheric connectivity values and nLI scores in all groups. Conclusions: This study seems to depict the existence of resting state hippocampal-lingual functional network which correlates well with lateralization of language function in the left hemisphere in both temporal lobe epilepsy patients and healthy controls.

Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes.

ß-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.

Clinical utility of arterial spin labeling imaging in disorders of the nervous system.

Neuroimaging is an indispensable tool in the workup and management of patients with neurological disorders. Arterial spin labeling (ASL) is an imaging modality that permits the examination of blood flow and perfusion without the need for contrast injection. Noninvasive in nature, ASL provides a feasible alternative to existing vascular imaging techniques, including angiography and perfusion imaging. While promising, ASL has yet to be fully incorporated into the diagnosis and management of neurological disorders. This article presents a review of the most recent literature on ASL, with a special focus on its use in moyamoya disease, brain neoplasms, seizures, and migraines and a commentary on recent advances in ASL that make the imaging technique more attractive as a clinically useful tool.

Treatment-related alterations of imaging findings in osteoid osteoma after percutaneous radiofrequency ablation.

OBJECTIVES: We aimed to report the long-term outcomes of osteoid osteoma patients and to determine CT and dynamic contrast-enhanced MR imaging characteristics of radiofrequency ablation (RFA) treatment related changes of osteoid osteoma between follow-up periods. MATERIALS AND METHODS: Thirty patients (seven female, 23 male) who underwent CT-guided RFA of osteoid osteoma were included. Follow-up imaging examinations were divided into two subgroups; first (1-3 months) and second (> 6 months) periods. Nidus size, calcification, cortical thickening, maximum signal intensity (SImax), time of SImax (Tmax), slope of signal intensity-time (SIT) curves were noted. CT and dynamic MR imaging findings were compared between follow-up periods. RESULTS: Clinical success rate was 100%. The mean of OO nidi size was 5.85 ± 1.98 mm before treatment. There was a significant difference for OO nidi sizes between pretreatment and second follow-up period examinations (p = 0.002). SImax and slope of SIT curves of all patients (100%) showed decrease on follow-up MRIs. There was a significant decrease for SImax values between pretreatment and second follow-up period. There was a significant decrease for slope of SIT curves between pretreatment and both follow-up periods. CONCLUSIONS: RFA is an effective and safe treatment choice for osteoid osteomas. On follow-up imaging, slope of SIT curve and Tmax have the most important positive predictive value for long-term outcomes and single dynamic contrast-enhanced MRI within first 3 months after treatment may be sufficient for symptom-free patients.

BNP as a Major Player in the Heart-Kidney Connection.

Brain natriuretic peptide (BNP) is an important biomarker for patients with heart failure, hypertension and cardiac hypertrophy. Although it is known that BNP levels are relatively higher in patients with chronic kidney disease and no heart disease, the mechanism remains unknown. Here, we review the functions and the roles of BNP in the heart-kidney interaction. In addition, we discuss the relevant molecular mechanisms that suggest BNP is protective against chronic kidney diseases and heart failure, especially in terms of the counterparts of the renin-angiotensin-aldosterone system (RAAS). The renal medulla has been reported to express depressor substances. The extract of the papillary tips from kidneys may induce the expression and secretion of BNP from cardiomyocytes. A better understanding of these processes will help accelerate pharmacological treatments for heart-kidney disease.

The relationship between patellofemoral arthritis and fat tissue volume, body mass index and popliteal artery intima-media thickness through 3T knee MRI

Background/aim: Evaluating the relationship of patellar chondromalacia with obesity, infrapatellar fat pad (IFP) volume and popliteal artery intima-media thickness (IMT). Materials and methods: A total of203 patients with different degree of patellar chondromalacia (103 male, 100 female) and 52 control subjects (19 male, 33 female) were included and grouped according to sex, age, body surface area (BSA), body mass index (BMI) and patellar chondromalacia classification. All measurements were completed with 3T magnetic resonance imaging (MRI). Articular cartilage and IFP volume were measured in saggital plane using double echo steady state (DESS) and DIXON sequences, respectively. Patellar cartilage damage was graded using modified outerbridge classification, and the relations among cartilage volume and BMI, BSA, IFP, IMT were statistically assessed. Results: Popliteal artery IMT showed an independent association with the prevalence of cartilage defects and IFP volumes (P ˂ 0.001). There was an association between BMI and IFP volumes (P ˂ 0.001). However, no differences were observed between IFP volume and different chondromalacia groups. When IFP measurements were corrected using individual BMI and BSA values, a positive correlation was found between control and advanced chondromalacia groups (P ˂ 0.001). Conclusion: This study demonstrates the relationship among obesity, IMT and chondromalacia and highlights this potential circle to develop effective treatments and inhibit the progression of chondromalacia.

The effectiveness of RENAL nephrometry score in ablated renal tumors via radiofrequency ablation or cryoablation

Background/aim: This study aimed to evaluate the clinical efficacy of radiofrequency ablation (RFA) and cryotherapy and to scrutinize the therapeutic success of the RENAL (radius, exophytic/endophytic, nearness to collecting system, anterior/posterior, and location) nephrometry score in terms of possible complications and the predictive status of oncological results. Materials and methods: Forty-five patients with biopsy-proven renal cell carcinomas (32 males, 13 females) treated with RFA and cryotherapy were included. Patients were 22­90 years old (average: 59.2 years). Statistical analyses were performed using SPSS for Windows. Results: A total of 79 lesions with dimensions varying between 0.9 and 4.5 cm (average: 2.2 cm) were ablated. Complete ablation was achieved for 72 (91.1%) lesions. Six repeat RFA sessions were applied for 4 (5%) lesions with residue/recurrence. The average RENAL nephrometry scores of lesions that underwent complete ablation and those that developed residue/recurrence were 6.3 and 7.7, respectively. The average recurrence-free survival time was 34.8 months (range: 3­55 months), while it was 44.6 months (range: 6­55 months) for cryotherapy and 28.6 months (range: 3­50 months) for RFA. Conclusion: Ablative therapies are minimally invasive and effective methods for treating small renal tumors. RENAL nephrometry scoring is a valuable system for standardizing renal tumors and evaluating the success of ablative therapies, possible complications, and oncological results.

Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from ß-cells.

Glucose stimulates insulin secretion from ß-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin-7 at serine-103, which enhances glucose- and Ca(2+)-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca(2+)-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca(2+)-triggered exocytosis by direct phosphorylation of a synaptotagmin.