Neutrophil and natural killer cell imbalances prevent muscle stem cell-mediated regeneration following murine volumetric muscle loss.

Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell­ and progenitor-mediated myogenic repair. However, how immune cell infiltration and intercellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in the fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observed the heightened infiltration of natural killer (NK) cells as well as the persistence of neutrophils beyond 2 wk postinjury. Functional validation of NK cells revealed an antagonistic role in neutrophil accumulation in part via inducing apoptosis and CCR1-mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFß1). Blocking TGFß signaling reduced neutrophil accumulation and fibrosis and improved muscle-specific force. Collectively, these results enhance our understanding of immune cell­stem cell cross talk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

Dynamic Regulation of Caveolin-1 Phosphorylation and Caveolae Formation by Mammalian Target of Rapamycin Complex 2 in Bladder Cancer Cells.

The mammalian target of rapamycin (mTOR) and associated phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway is commonly up-regulated in cancer, including bladder cancer. mTOR complex 2 (mTORC2) is a major regulator of bladder cancer cell migration and invasion, but the mechanisms by which mTORC2 regulates these processes are unclear. A discovery mass spectrometry and reverse-phase protein array-based proteomics dual approach was used to identify novel mTORC2 phosphoprotein targets in actively invading cancer cells. mTORC2 targets included focal adhesion kinase, proto-oncogene tyrosine-protein kinase Src, and caveolin-1 (Cav-1), among others. Functional testing shows that mTORC2 regulates Cav-1 localization and dynamic phosphorylation of Cav-1 on Y14. Regulation of Cav-1 activity by mTORC2 also alters the abundance of caveolae, which are specialized lipid raft invaginations of the plasma membrane associated with cell signaling and membrane compartmentalization. Our results demonstrate a unique role for mTORC2-mediated regulation of caveolae formation in actively migrating cancer cells.

Clinical, histopathological, and in silico pathogenicity analyses in a pedigree with familial amyloidosis of the Finnish type (Meretoja syndrome) caused by a novel gelsolin mutation.

Purpose: Familial amyloidosis of the Finnish type (FAF) is an inherited amyloidosis arising from mutations in the gelsolin protein (GSN). The disease includes facial paralysis, loose skin, and lattice corneal dystrophy. To date, FAF has been invariably associated with substitution of Asp214 in GSN. We describe the clinical, histopathological, and genetic features of a family with FAF due to a novel GSN mutation. Methods: Five affected adult individuals in a three-generation FAF pedigree were included in the study. Histopathological analysis was performed on an eyelid skin biopsy from one patient. Genetic analysis included next-generation sequencing (NGS) and Sanger sequencing for confirmation of the GSN variant. Several tools for in silico analysis of pathogenicity for the novel variant and to predict the effect of the amino acid replacement on protein stability were used. Results: Three older adult affected patients exhibited corneal lattice dystrophy, cutis laxa, and facultative peripheral neuropathy. Two younger adult individuals presented only with corneal amyloid deposits. NGS identified a heterozygous GSN c.1631T>G transversion, predicting a novel p.Met544Arg mutation. All in silico tools indicated that p.Met544Arg is deleterious for GSN functionality or stability. Conclusions: The results expand the molecular spectrum of GSN-linked systemic amyloidosis. The novel p.Met544Arg pathogenic variant is predicted to affect gelsolin function, presumably by impairing a potential calcium-sensitive, actin-binding region.

Prevalence of vertebral fracture and densitometric osteoporosis in Spanish adult men: The Camargo Cohort Study.

The aim of this study was to assess the prevalence of densitometric osteoporosis and vertebral fractures in Spanish men aged ≥50 years, and to study how the relationship between them may change depending on how osteoporosis is diagnosed. A community-based population of 1003 men aged ≥50 years was studied. Bone mineral density (BMD) was measured by DXA at the lumbar spine, femoral neck and total hip. Vertebral fractures were assessed by lateral thoracic and lumbar spine radiographs. The prevalence of osteoporosis was estimated with both the World Health Organization (WHO) (T-score of <-2.5 at the femoral neck, calculated using the young white female normal reference database) and the National Osteoporosis Foundation (NOF) criteria (T-score of <-2.5 at the femoral neck, total hip or lumbar spine, calculated using the young white male normal reference database). The prevalence of osteoporosis using the WHO criterion was 1.1% and using the NOF criterion was 13%, while that of vertebral fractures was 21.3%. The area under the curve (AUC) for the relationship between BMD and vertebral fracture prevalence was 0.64. The odds ratio for osteoporosis using the WHO definition was 2.57 (p = 0.13), and 1.78 (p = 0.007) using the NOF definition. Vertebral fracture prevalence rose with age. The prevalence of osteoporosis increased only moderately in men aged >70 years with the WHO criterion, and showed no change using the NOF definition. The prevalence of osteoporosis in Spanish men using the WHO definition is too small to have any meaningful clinical use. Although the figure is higher using the NOF definition, it would seem that population-based studies of BMD in men are of questionable value.

Relationship between spinal osteoarthritis and vertebral fractures in men older than 50 years: data from the Camargo Cohort Study.

Spinal osteoarthritis has been suggested as a risk factor for vertebral fractures. However, results are conflicting: most of the data are focused on the lumbar region, and referred to postmenopausal women, whereas data for men are scarce. The aim of this study is to assess the relationship between spinal osteoarthritis and vertebral fractures in men over 50 years of age. We conducted a cross-sectional study, nested in a prospective population-based cohort, including 507 community-dwelling men, 93 of them with at least one vertebral fracture. Vertebral fractures, osteophytosis, and disc space narrowing (DSN) were assessed by lateral thoracic and lumbar radiographs. Anthropometric, clinical, and densitometric variables were also analyzed. A multiple logistic regression model was performed. Eighty-five percent of vertebral fractures were located at the thoracic spine. Osteophytosis and DSN showed a bimodal distribution, with major frequency peaks at mid- and distal lumbar spine. The three distributions overlapped around the T9 vertebra. We did not find any relationship between lumbar osteoarthritis and vertebral fractures. Nevertheless, thoracic osteophytosis (OR, 1.84; 95 % CI, 1.05-3.17; p = 0.03) and DSN (OR, 2.52; 95 % CI, 1.43-4.46; p = 0.001) were found to be independently associated with prevalent vertebral fractures, after adjusting for confounders. Our results suggest a positive relationship between radiologic osteoarthritic changes at the thoracic spine and prevalent vertebral fractures in men more than 50 years of age. Osteoarthritis may act as a local risk factor, in addition to other mechanical factors, resulting in a greater propensity to fracture, especially at the mid-thoracic region.

Clinical and Genetic Findings in Mexican Patients with Duane Anomaly and Radial Ray Malformations/Okihiro Syndrome.

BACKGROUND: Okihiro syndrome is an autosomal-dominant condition characterized by radial ray malformations associated with Duane anomaly and other clinical characteristics. SALL4 mutations have been identified in 80-90% of patients with Duane- Radial ray defects/Okihiro syndrome. We report the clinical findings and results of SALL4 sequencing from a group of Mexican patients with this disorder. OBJECTIVE: Clinical description and identification of SALL4 mutations in Mexican subjects with radial defects and Duane anomaly. MATERIALS AND METHODS: Five unrelated index cases were studied. Complete ophthalmologic and general physical examination was performed in all patients. Polymerase chain reaction amplification and automated nucleotide sequencing of coding exons and intron-exon junctions of SALL4 gene were carried out in genomic DNA. RESULTS: A novel heterozygous deletion was identified in one patient. Intragenic heterozygous single nucleotide polymorphisms on SALL4 gene ruled out deletions of some exons in other affected patients in whom non-pathogenic variants were identified by Sanger sequencing. Likewise, multiplex ligation-dependent probe amplification analysis ruled out large deletions in this gene. CONCLUSION: We observed a low frequency of SALL4 mutations in Mexican patients with clinical criteria of Okihiro syndrome.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Bone mineral density in statin users: a population-based analysis from a Spanish cohort.

We studied 2,315 subjects (1,422 women and 893 men) from the Camargo Cohort and analyzed the differences in BMD between statin or non-statin users. We also studied effects of the type of statin, dose, pharmacokinetic properties, and length of treatment on bone mineral density (BMD). Of the subjects, 478 (21 %) were taking statins (256 women and 222 men). Overall, they had higher BMD than non-users (p < 0.0001). In adjusted multivariate models, women taking statins had higher BMD at femoral neck (p = 0.002) and total hip (p = 0.04) than non- users. No differences were found in men. Women taking simvastatin had higher increases in BMD than non-statin users at femoral neck (p = 0.02) and total hip (p = 0.009), those taking fluvastatin had lower BMD values at lumbar spine (p = 0.028), and those receiving lovastatin had higher increases at femoral neck (p = 0.006). In men, only atorvastatin was associated with higher femoral neck BMD than non-statin use (p = 0.029). Comparing with non-statin users, only women receiving lipophilic statins had greater BMD at femoral neck (p = 0.003). According to drug potency, women on high- or lower-potency agents showed higher BMD values at femoral neck than non-users (p = 0.028 and 0.022, respectively). In men, only high-potency statins were associated with higher femoral neck BMD than non-use (p = 0.021). No differences between dose or length of statin therapy were noted regarding BMD in either sex. In summary, in a large population-based cohort, women on statins had higher BMD at the hip than non-users. Overall, this increase in BMD was more evident in subjects on lipophilic or high-potency statins.

Frailty, Sarcopenia and Osteoporosis. / Fragilidad, sarcopenia y osteoporosis.

Frailty, sarcopenia and osteoporosis are entities specific to the elderly, who share some risk factors. For this reason, their relationship has been studied in different works, which have provided disparate results, probably because these studies have not always focused on the same aspects. This article reviews the relationship of frailty and sarcopenia with osteoporosis.

Association study of multiple gene polymorphisms with the risk of adult-onset primary open-angle glaucoma in a Mexican population.

The aim of this study was to investigate the association of multiple primary open-angle glaucoma (POAG)-risk alleles in a Mexican population for the first time. Genotyping was performed for a total of 26 previously associated alleles located in 11 different genes, including MYOC, CYP1B1, OPTN, IL1A, TNF, OPA1, EDNRA, AGTR2, MTHFR, GSTM1, and GSTT1. The frequencies of these variants were compared in a group of 218 individuals (118 with POAG and 100 adult controls without the disease). Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. GSTM1 and GSTT1 deletion variants were screened by agarose gel analysis. Individual SNP analysis showed that no specific variants conferred an elevated risk for developing POAG. However, the CG genotype for rs5335 polymorphism in EDNRA showed a protective effect against the development of POAG, as it provides an estimated odds ratio of 0.5 (95% CI, 0.3-0.9; p = 0.03). Moreover, one haplotype consisting of rs1056827 and rs100012 in CYP1B1 gene was significantly associated with a protective effect against POAG (p = 0.0045; OR = 0.3; 95% CI, 0.1-0.7). This is the first case-control investigation of POAG-risk alleles in multiple genes in a Latino population. Although our results support that the analyzed variants are not major risk factors for POAG in this ethnic group, they also point toward a protective effect conferred by EDNRA rs5335, as well as by a CYP1B1 haplotype consisting of rs1056827 and rs100012. Our study emphasizes the importance of genotyping ethnic groups with a complex admixture of ancestral populations for contributing to dissecting the genetics of POAG.

Maresin 1 repletion improves muscle regeneration after volumetric muscle loss.

The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied, and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.

Long-Term Treatment and Effect of Discontinuation of Calcifediol in Postmenopausal Women with Vitamin D Deficiency: A Randomized Trial.

Vitamin D plays a major role in bone health and probably also in multiple extraskeletal acute and chronic diseases. Although supplementation with calcifediol, a vitamin D metabolite, has demonstrated efficacy and safety in short-term clinical trials, its effects after long-term monthly administration have been studied less extensively. This report describes the results of a 1-year, phase III-IV, double-blind, randomized, controlled, parallel, multicenter superiority clinical trial to assess the efficacy and safety of monthly calcifediol 0.266 mg versus cholecalciferol 25,000 IU (0.625 mg) in postmenopausal women with vitamin D deficiency (25(OH)D < 20 ng/mL). A total of 303 women were randomized and 298 evaluated. Patients were randomized 1:1:1 to calcifediol 0.266 mg/month for 12 months (Group A1), calcifediol 0.266 mg/month for 4 months followed by placebo for 8 months (Group A2), and cholecalciferol 25,000 IU/month (0.625 mg/month) for 12 months (Group B). By month 4, stable 25(OH)D levels were documented with both calcifediol and cholecalciferol (intention-to-treat population): 26.8 ± 8.5 ng/mL (Group A1) and 23.1 ± 5.4 ng/mL (Group B). By month 12, 25(OH)D levels were 23.9 ± 8.0 ng/mL (Group A1) and 22.4 ± 5.5 ng/mL (Group B). When calcifediol treatment was withdrawn in Group A2, 25(OH)D levels decreased to baseline levels (28.5 ± 8.7 ng/mL at month 4 versus 14.4 ± 6.0 ng/mL at month 12). No relevant treatment-related safety issues were reported in any of the groups. The results confirm that long-term treatment with monthly calcifediol in vitamin D-deficient patients is effective and safe. The withdrawal of treatment leads to a pronounced decrease of 25(OH)D levels. Calcifediol presented a faster onset of action compared to monthly cholecalciferol. Long-term treatment produces stable and sustained 25(OH)D concentrations with no associated safety concerns. © 2023 Faes Farma SA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Goodpasture antigen-binding protein (GPBP) directs myofibril formation: identification of intracellular downstream effector 130-kDa GPBP-interacting protein (GIP130).

Goodpasture antigen-binding protein-1 (GPBP-1) is an exportable non-conventional Ser/Thr kinase that regulates glomerular basement membrane collagen organization. Here we provide evidence that GPBP-1 accumulates in the cytoplasm of differentiating mouse myoblasts prior to myosin synthesis. Myoblasts deficient in GPBP-1 display defective myofibril formation, whereas myofibrils assemble with enhanced efficiency in those overexpressing GPBP-1. We also show that GPBP-1 targets the previously unidentified GIP130 (GPBP-interacting protein of 130 kDa), which binds to myosin and promotes its myofibrillar assembly. This report reveals that GPBP-1 directs myofibril formation, an observation that expands its reported role in supramolecular organization of structural proteins to the intracellular compartment.

Aminobisphosphonates: Reconsideration 25 years after their approval for the treatment of osteoporosis. / Aminobisfosfonatos: reconsideración a los 25 años de su aprobación para el tratamiento de la osteoporosis.

Aminobisphosphonates are widely used in the treatment of osteoporosis. They have a high affinity for hydroxyapatite, binding primarily to resorbing surfaces, but also to forming surfaces and to some extent to resting surfaces. They inhibit osteoclasts, thereby decreasing remodelling units. Consequently, they increase bone mass and reduce stress risers. This decreases the risk of fractures. If this decrease is sufficient, they can be temporarily withdrawn (drug holidays), which prevents serious complications (atypical femoral fracture). They probably reduce mortality. Virtually all patients with osteoporosis can benefit from them at some point in the course of their disease (at the beginning of treatment or after the administration of anabolics, selective estrogen receptor modulators or denosumab). If well tolerated orally, alendronate and risedronate are preferable. Otherwise, zoledronate is preferred. Their efficacy vs. cost-safety-convenience ratio makes aminobisphosphonates reference drugs in the field of osteoporosis.

Sarcopenic osteoporosis, sarcopenic obesity, and sarcopenic osteoporotic obesity in the Camargo cohort (Cantabria, Spain).

The associations of sarcopenia with osteoporosis or obesity have a very low prevalence. No trend towards an association between osteoporosis and sarcopenia is observed. Sarcopenia and obesity tend not to coincide, as if they were antagonistic disorders. PURPOSE: To know (a) the prevalence in our region of sarcopenic osteoporosis (association of sarcopenia and osteoporosis (T-score < - 2.5)), sarcopenic obesity, and the association of osteoporosis, sarcopenia, and obesity; (b) the tendency of osteoporosis, sarcopenia, and obesity to associate with each other; and (c) the bone mineral density (BMD), the components of sarcopenia, and the prevalence of fragility fractures in these associations. METHODS: The study was performed in the Camargo cohort. Osteoporosis was diagnosed by DXA, sarcopenia by the EWGSOP-1 criteria, and obesity by body mass index (BMI) and fat percentage. Fractures were verified radiographically or by consulting the medical records. RESULTS: The prevalence of sarcopenic osteoporosis was 2.8% and the OR for this association 1.03 (p = 0.89). The prevalence of sarcopenic obesity by BMI was 1.4% and by fat percentage 5.9% (corresponding ORs: 0.18 (p < 0.0001) and 0.58 (p < 0.003) respectively). The prevalence of the association of osteoporosis, sarcopenia, and obesity was 0.0% when assessed by BMI and 0.8% when assessed by fat percentage. Patients with sarcopenic osteoporosis have less muscle mass and more fragility fractures than sarcopenic patients overall. In patients with sarcopenic obesity by fat percentage, muscle mass and strength, as well as physical performance, were similar to those of sarcopenic patients overall. Neither BMD nor fracture prevalence showed differences between patients with sarcopenic obesity and patients with sarcopenia or obesity in general. CONCLUSION: Our study supports the idea that the prevalence of the mixed disorders studied is low. No significant association between osteoporosis and sarcopenia was found. Sarcopenia and obesity seem to tend to occur in different people, as if suffering from one of them hinders suffering from the other.

Osteocyte deficiency in hip fractures.

Osteocytes play a central role in the regulation of bone remodeling. The aim of this study was to explore osteocyte function, and particularly the expression of SOST, a Wnt inhibitor, in patients with hip fractures. Serum sclerostin levels were measured by ELISA. The expression of several osteocytic genes was studied by quantitative PCR in trabecular samples of the femoral head of patients with hip fractures, hip osteoarthritis and control subjects. The presence of sclerostin protein and activated caspase 3 was revealed by immunostaining. There were no significant differences in serum sclerostin between the three groups. Patients with fractures have fewer lacunae occupied by osteocytes (60 ± 5% vs. 64 ± 6% in control subjects, P = 0.014) and higher numbers of osteocytes expressing activated caspase 3, a marker of apoptosis. The proportion of sclerostin-positive lacunae was lower in patients with fractures than in control subjects (34 ± 11% vs. 69 ± 10%, P = 2 × 10(-8)). The proportion of sclerostin-positive osteocytes was also lower in patients. RNA transcripts of SOST, FGF23 and PHEX were also less abundant in fractures than in control bones (P = 0.002, 5 × 10(-6), and 0.04, respectively). On the contrary, in patients with osteoarthritis, there was a decreased expression of SOST and FGF23, without differences in PHEX transcripts or osteocyte numbers. Osteocyte activity is altered in patients with hip fractures, with increased osteocyte apoptosis and reduced osteocyte numbers, as well as decreased transcription of osteocytic genes. Therefore, these results suggest that an osteocyte deficiency may play a role in the propensity to hip fractures.

Vascular cognitive impairment in small vessel disease: clinical and neuropsychological features of lacunar state and Binswanger's disease.

BACKGROUND: ischaemic cerebrovascular small vessel disease (SVD) is a prevalent and under-diagnosed condition that triggers vascular cognitive impairment (VCI). OBJECTIVE: to describe the neuropsychological and clinical profiles in SVD (Binswanger's disease, BD; lacunar state, LS) from the clinician's perspective at the VCI stage. METHODS: a total of 1257 patients admitted to a tertiary center with a diagnosis of stroke, neuroradiological vascular disease, cognitive impairment/dementia, during a 13-year period were investigated. We prospectively assessed cognition in a subset of 141 patients with VCI (LS n = 28, BD n = 69, large vessel disease-LVD-n = 44) with MMSE, CAMDEX-H, WAIS-R, EXIT-25 and Trail making test. RESULTS: executive dysfunction (ECD) (n = 89, 91.7% versus n = 10, 22.7%; P < 0.001) and gait disturbances (n = 74, 76.3% versus n = 15, 34.1%; P < 0.001) characterized SVD. Prior strokes (n = 9, 9.3% versus n = 23, 52.3%; P < 0.001) and embologenous cardiopathy (n = 39, 40.2% versus n = 28, 63.6%; P < 0.04) featured LVD cases. BD was defined by hypertension (n = 52, 75.4% versus n = 30, 44.1%; P < 0.001), ECD (n = 65, 94.2% versus n = 34, 47.2%; P < 0.001) and VCI onset with cognitive impairment but not strokes (n = 44, 63.8% versus n = 34, 50%; P < 0.01). CONCLUSIONS: ECD and a frontal gait are SVD's clinical landmarks in our sample. LS and BD cases share a similar cognitive profile.

3D analysis of bone mineral density in a cohort: age- and sex-related differences.

Women have lower areal BMD (g/cm2) than men; however, the women have smaller-size bones. Our study showed that women ≤ 59 years have a hip volumetric BMD by DXA 3D similar to that of men of the same age. This makes us think about the importance of taking into account bone size at the time of analyzing the sex-related differences in bone mass. PURPOSE: Women have lower areal BMD (g/cm2) than men; however, these studies do not take into account that women have smaller-size bones. Recently, three-dimensional (3D) modeling methods were proposed to analyze volumetric BMD (vBMD). We want to determine the values of vBMD at the hip by DXA-based 3D modeling in a cohort of people in order to know the age- and sex-related differences. METHODS: A total of 2647 people of both sexes (65% women) were recruited from a large cohort (Camargo cohort, Santander, Spain). 3D-SHAPER® software (version 2.8, Galgo Medical, Barcelona, Spain) was used to derive 3D analysis from the hip DXA scans at baseline RESULTS: The differences were less pronounced for vBMD (cortical sBMD 9.3%, trabecular vBMD 6.4%, integral vBMD 2.2%) compared to aBMD (FN aBMD 11.4% and TH aBMD 13.3%). After stratifying by age (≤ 59 years, 60-69 years, 70-79 years, and ≥ 80 years), we observed in ≤ 59 years that aBMD was lower in women compared to men, at FN (0.758 [0.114] g/cm2 vs. 0.833 [0.117] g/cm2; p = 1.4 × 10-20) and TH (0.878 [0.117] g/cm2 vs. 0.990 [0.119] g/cm2; p = 4.1 × 10-40). Nevertheless, no statistically significant difference was observed for integral vBMD (331 [58] mg/cm3 in women and 326 [51] mg/cm3 in men; p = 0.19) and trabecular vBMD (190 [41] mg/cm3 in women and 195 [39] mg/cm3 in men; p = 0.20). CONCLUSION: Our results make us think about the importance of taking into account bone size at the time of analyzing the sex-related differences in bone mass.

Combined Bacterial and Herpes Simplex Virus Keratitis following Small-Incision Lenticule Extraction for the Correction of Myopia.

A 28-year-old male presented unilateral visual loss, intense ocular pain, redness and intraocular hypertension in his right eye 2 days after undergoing small-incision lenticule extraction (SMILE) in both eyes. Initial examination of the affected eye revealed the presence of white infiltrates within the corneal interface, as well as a central epithelial defect. The patient was diagnosed with infectious keratitis, posteriorly the eye was irrigated with balanced saline solution and treatment was initiated with hourly moxifloxacin 0.5%. Since this approach failed to resolve symptoms, a sample from the interface was obtained for PCR assay, which revealed the presence of herpes simplex virus DNA, confirming the cause of the infection. The patient was prescribed a regimen of oral acyclovir, topical ganciclovir and prednisolone. Clinical improvement following resolution of the epithelial defect was observed. Although rare, herpetic keratitis following SMILE is best managed via early diagnosis and initiation of appropriate anti-herpetic treatment.

Metabolipidomic profiling reveals an age-related deficiency of skeletal muscle pro-resolving mediators that contributes to maladaptive tissue remodeling.

Specialized pro-resolving mediators actively limit inflammation and support tissue regeneration, but their role in age-related muscle dysfunction has not been explored. We profiled the mediator lipidome of aging muscle via liquid chromatography-tandem mass spectrometry and tested whether treatment with the pro-resolving mediator resolvin D1 (RvD1) could rejuvenate the regenerative ability of aged muscle. Aged mice displayed chronic muscle inflammation and this was associated with a basal deficiency of pro-resolving mediators 8-oxo-RvD1, resolvin E3, and maresin 1, as well as many anti-inflammatory cytochrome P450-derived lipid epoxides. Following muscle injury, young and aged mice produced similar amounts of most pro-inflammatory eicosanoid metabolites of cyclooxygenase (e.g., prostaglandin E2 ) and 12-lipoxygenase (e.g., 12-hydroxy-eicosatetraenoic acid), but aged mice produced fewer markers of pro-resolving mediators including the lipoxins (15-hydroxy-eicosatetraenoic acid), D-resolvins/protectins (17-hydroxy-docosahexaenoic acid), E-resolvins (18-hydroxy-eicosapentaenoic acid), and maresins (14-hydroxy-docosahexaenoic acid). Similar absences of downstream pro-resolving mediators including lipoxin A4 , resolvin D6, protectin D1/DX, and maresin 1 in aged muscle were associated with greater inflammation, impaired myofiber regeneration, and delayed recovery of strength. Daily intraperitoneal injection of RvD1 had minimal impact on intramuscular leukocyte infiltration and myofiber regeneration but suppressed inflammatory cytokine expression, limited fibrosis, and improved recovery of muscle function. We conclude that aging results in deficient local biosynthesis of specialized pro-resolving mediators in muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on tissue regeneration of non-steroidal anti-inflammatory drugs.