An in silico approach to elucidate the pathways leading to primary osteoporosis: age-related vs. postmenopausal.

Numerical models of bone remodelling have traditionally been used to perform in silico tests of bone loss in postmenopausal women and also to simulate the response to different drug treatments. These models simulate the menopausal oestrogen decline by altering certain signalling pathways. However, they do not consider the simultaneous effect that ageing can have on cell function and bone remodelling, and thus on bone loss. Considering ageing and oestrogen decline together is important for designing osteoporosis treatments that can selectively counteract one or the other disease mechanism. A previously developed bone cell population model was adapted to consider the effect of ageing through: (1) the decrease of TGF- ß contained in the bone matrix and (2) an increased production of sclerostin by non-skeletal cells. Oestrogen deficiency is simulated in three different ways: (a) an increase in RANKL expression, (b) a decrease in OPG production, and (c) an increase in the responsiveness of osteoclasts to RANKL. The effect of ageing was validated using the cross-sectional study of (Riggs et al. in J Bone Miner Res 19: 1945-1954, 2004) on BMD of trabecular bone of the vertebral body of men. The joint effect of ageing and oestrogen deficiency was validated using these same clinical results but in women. In ageing, the effect of the increasing production of sclerostin is more important than the decrease of TGF- ß , while the three mechanisms used to simulate the effect of oestrogen deficiency produce almost identical responses. The results show that an early menopause leads to a lower average density in the fifth decade, but after the sixth decade the average density is independent of the age at menopause. Treatment of osteoporosis with denosumab was also simulated to conclude that the drug is not very effective if started before 10 years after menopause or before age 60.

Periodontal index and salivary Ph in first trimester´s pregnant women: A cross-sectional study.

Background: Recent reviews have suggested a possible association between periodontal disease and increasing risks during pregnancy, such as newborn low weight, premature birth, gestational diabetes mellitus and preeclampsia. Besides, being saliva a valuable source of information on general and buccal health, it is necessary to know its parameters associated with periodontal diseases; in order to help odontologists to better understand this disease, and provide a sound clinical treatment. Therefore, this research sought to assess the correlation between periodontal index, and salivary pH on first trimester pregnant women. Material and Methods: 71 pregnant women were evaluated by observational, transversal and correlational study, using the community periodontal index and salivary pH-meter. The Spearman coefficient was employed, considering a p value of 0.05. Results: A correlation was found between periodontal index and salivary pH in first trimester pregnant women (p=0.039). According to age, correlations were found to be very weak in age group 18 to 24 years (p=0.605), and age group 25 to 35 years (p=0.071). Similarly, no strong correlation was found when pairing based on number of pregnancies (primiparous p=0.239 and multi pregnancy p=0.114). Also, 36.6% of pregnant women showed periodontal pockets smaller than 5 mm. Conclusions: With lower salivary pH, the periodontal index in pregnant women gets lower; however, no correlation could be found between age group and number of pregnancies. Key words:Periodontal index, periodontal pocket, periodontal diseases, saliva, pregnancy, pregnant women.

Chronological pattern of venous thromboembolism (VTE) occurrence impacts in survival of pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND: Limited data exist on the prognostic significance of the chronology of VTE in patients with PDAC. METHODS: Medical data and survival characteristics of patients treated for PDAC from 2019 to 2021 were retrospectively reviewed. Early VTE was defined as occurring within the three months of PDAC diagnosis. RESULTS: 197 patients were included, 54 (27.4%) developed a VTE. Early appearance of VTE was associated with worse prognosis: median overall survival (mOS) VTE < 3 months 8.5 months (HR 1.65, 95% CI 1.11-2.46; p = 0.014), mOS VTE > 3 months 12.8 months (HR 0.78, 95% CI 0.39-1.54; p = 0.5) and mOS patients without VTE 11.4 months (95% CI 10.1-15.4). There was no significant association between the patient's VTE risk according to the Khorana risk score (KRS) (chi2 test p-value = 0.9). CONCLUSION: Early VTE is a prognostic factor in PDAC, which may identify a more aggressive subtype.

Unexpected complication after reverse shoulder arthroplasty: Brachial artery pseudoaneurysm: A case report.

Pseudoaneurysm should be acknowledged as a possible but infrequent postoperative complication after shoulder arthroplasty which could be easily misdiagnosed. It is important that the upper-extremity surgeon suspects this problem in the follow-up assessment for appropriate management. In this paper, we present an unusual case of brachial artery pseudoaneurysm in the early postoperative period after reverse shoulder arthroplasty.

Use of Ozone Therapy in Diabetic Foot Ulcers.

INTRODUCTION: ozone therapy is a therapy composed of ozone. This gas is in the atmosphere with various general effects: direct disinfectant and trophic effects and a systemic antibacterial and antiviral effect. This gas also improves blood circulation, makes glucose metabolism more effective, improves erythrocyte metabolism, and improves fatty acid metabolism. OBJECTIVE: Provide evidence of the effectiveness of ozone therapy in wounds of patients with diabetic foot. Analyze the effectiveness of ozone therapy compared to other treatments to achieve good wound healing in patients with diabetic foot. To study the benefits of the use of ozone therapy in ulcers of patients. Analyze the management of ozone therapy and other treatments to achieve healing of ulcers in patients. METHODOLOGY: A bibliographic review focused on articles published between November 2014 and June 2023 was carried out. The following databases were consulted: Pubmed (Medline), Dialnet, Google Scholar, Web of Science (WOS), Scielo, and Scopus. RESULTS: After applying the article selection criteria and evaluating the quality of the methodology, a total of 17 articles were obtained. The results affirm ozone therapy as promising for the treatment of wounds in patients with diabetic foot. CONCLUSIONS: the evidence has been able to determine that ozone therapy is adequate for the treatment of diabetic foot ulcers. In addition, the therapy has been shown to be effective, safe, and beneficial, with few adverse effects for the treatment of diabetic foot ulcers.

Analysis of the Factors Intervening in the Prehospital Time in a Stroke Code.

INTRODUCTION: Strokes continue to be considered public health problems due to the great social and health impact they entail. They are the second cause of death in the world, with a high incidence and prevalence. They are time-dependent diseases, and more than 80% of cases could be avoidable with greater management of risk factors. OBJECTIVE: to analyze the factors that influence prehospital time in a stroke code. Assess the population's knowledge of stroke symptoms and teach them how to act when a case is suspected. Document the continued training of health professionals for the early identification of patients with a suspected stroke. Demonstrate the importance of calling EMS as the first contact to reduce delays in prehospital time in a stroke. METHODOLOGY: A bibliographic review was carried out focusing on articles published between December 2014 and August 2023. The following databases were consulted: Pubmed (Medline), Dialnet, Google Scholar, Web of Science (WOS), Scielo, Scopus, and ScienceDirect. RESULTS: After applying the article selection criteria and evaluating the quality of the methodology, a total of 18 articles were obtained. The results affirm that the importance of achieving a reduction in prehospital time is based mainly on knowledge of the symptoms and the use of new technologies. CONCLUSIONS: The evidence supports that the prehospital time of action in the stroke code is affected by numerous factors. These factors are determining factors in the time of action to achieve good effectiveness in the treatment of the pathology.

Trends in prevalence and implant types in the Nova Scotia Joint Database Registry between 2005 and 2021.

Aims: The aim of this study is to evaluate the change in incidence rate of shoulder arthroplasty, indications, and surgeon volume trends associated with these procedures between January 2003 and April 2021 in the province of Nova Scotia, Canada. Methods: A total of 1,545 patients between 2005 and 2021 were analyzed. Patients operated on between 2003 and 2004 were excluded due to a lack of electronic records. Overall, 84.1% of the surgeries (n = 1,299) were performed by two fellowship-trained upper limb surgeons, with the remainder performed by one of the 14 orthopaedic surgeons working in the province. Results: Total shoulder arthroplasty (TSA) was the most frequent procedure (32.17%; n = 497), followed by stemmed hemiarthroplasty (SHA) (27.7%; n = 428). The most frequent indication for primary shoulder arthroplasty was degenerative osteoarthritis (58.1%; n = 882), followed by acute proximal humerus fracture in 15.11% (n = 245), and rotator cuff arthropathy in 14.18% (n = 220). The overall rate of revision was 7.7% (2.8% to 11.2%). The number of TSAs and reverse shoulder arthroplasties (RSAs) has been increasing since 2016. The amount of revision cases is proportional to the number of operations performed in the same year throughout the study period. Conclusion: The incidence of shoulder arthroplasty in the Maritime Provinces has increased over the last 16 years. Revision rates are similar the those found in other large database registries. Reverse shoulder arthroplasty prevalence has increased since 2016.

Mechanistic PK-PD model of alendronate treatment of postmenopausal osteoporosis predicts bone site-specific response.

Alendronate is the most widely used drug for postmenopausal osteoporosis (PMO). It inhibits bone resorption, affecting osteoclasts. Pharmacokinetics (PK) and pharmacodynamics (PD) of alendronate have been widely studied, but few mathematical models exist to simulate its effect. In this work, we have developed a PK model for alendronate, valid for short- and long-term treatments, and a mechanistic PK-PD model for the treatment of PMO to predict bone density gain (BDG) at the hip and lumbar spine. According to our results, at least three compartments are required in the PK model to predict the effect of alendronate in both the short and long terms. Clinical data of a 2-year treatment of alendronate, reproduced by our PK-PD model, demonstrate that bone response is site specific (hip: 7% BDG, lumbar spine: 4% BDG). We identified that this BDG is mainly due to an increase in tissue mineralization and a decrease in porosity. The difference in BDG between sites is linked to the different loading and dependence of the released alendronate on the bone-specific surface and porosity. Osteoclast population diminishes quickly within the first month of alendronate treatment. Osteoblast population lags behind but also falls due to coupling of resorption and formation. Two dosing regimens were studied (70 mg weekly and 10 mg daily), and both showed very similar BDG evolution, indicating that alendronate accumulates quickly in bone and saturates. The proposed PK-PD model could provide a valuable tool to analyze the effect of alendronate and to design patient-specific treatments, including drug combinations.

Implant placement accuracy in total knee arthroplasty: validation of a CT-based measurement technique.

BACKGROUND: The primary goal of many computer-assisted surgical systems like robotics for total knee arthroplasty (TKA) is to accurately execute a preoperative plan. To assess whether the preoperative plan was executed accurately in 3D, one option is to compare the planned and postoperative implant placement using a preoperative and postoperative CT scan of the patient's limb. This comparison requires a 3D-to-3D surface registration between the preoperative and postoperative 3D bone models and between the planned and postoperative 3D implants. Hence, the present study aimed at validating this measurement technique by determining (I) the anatomical regions that result in the lowest 6-degree of freedom (DoF) errors for 3D-to-3D surface registration of bone models, (II) the 6-DoF errors for 3D-to-3D surface registration of the implant models, and (III) the 6-DoF of the complete measurement technique. METHODS: Four different regions of the femur were tested to determine which one would result in the most accurate 3D-to-3D registration of the bone models using 12 cadaveric lower limb specimens. Next, total knee arthroplasties were performed on six specimens, and the accuracy of the 3D-to-3D implant registration was evaluated against a gold standard registration performed using fiducial markers. RESULTS: The most accurate 3D-to-3D bone registration was obtained when using the largest anatomical regions available after TKA, being the full 3D femur model or the femur model without the distal femur which resulted in root mean square errors within 0.2 mm for translations and 0.2° for rotation. The accuracy of the 3D-to-3D femoral and tibial implant registration was within 0.7 mm for translations and 0.4°-0.6° for rotations, respectively. The accuracy for the overall procedure was within 0.9 mm and 0.6° for both femur and tibia when using femoral regions resulting in accurate 3D-to-3D bone registration. CONCLUSIONS: In conclusion, this measurement technique can be used in applications where measurement errors up to 0.9 mm in translations and up to 0.6° in rotations in component placement are acceptable.

Repeatability, reproducibility, and agreement of three computational methods to approximate the functional flexion-extension axis of the tibiofemoral joint using 3D bone models of the femur.

Background: Closely approximating the functional flexion-extension (FE) axis of the tibiofemoral joint in 3D models of the femur is important when computing joint motions which are physiologic. The objectives were to 1) develop methods to approximate the functional FE axis based on fitting circles, a tapered cylinder, and spheres to the posterior condyles, 2) determine the repeatability and reproducibility of each method, and 3) determine limits of agreement between pairs of axes. Methods: For each method, the respective axis was determined in forty 3D bone models of the distal femur. Varus-valgus angles and internal-external axial angles were computed relative to standard planes. Results: Repeatability and reproducibility were comparable for the tapered cylinder-based and sphere-based methods and better than that for the circle-based method. Limits of agreement were tightest when comparing the sphere-based and tapered cylinder-based axes. However, limits of agreement for the internal-external axial angle were wide at +3.6° to -3.9° whereas limits of agreement were tighter at +1.4° to -0.7° for the varus-valgus angle. Conclusion: The tapered cylinder-based and sphere-based methods offer advantages of better repeatability and reproducibility over the circle-based method. However, the sphere-based and tapered cylinder-based axes are not interchangeable owing to wide limits of agreement for the internal-external axial angle. The tapered cylinder-based axis is preferred intuitively over the sphere-based axis because the spheres require fitting in both the sagittal and coronal planes whereas the tapered cylinder requires fitting in the sagittal plane only which is the plane of motion in flexion-extension.

Kinematic alignment more closely restores the groove location and the sulcus angle of the native trochlea than mechanical alignment: implications for prosthetic design.

PURPOSE: Kinematic alignment (KA) and mechanical alignment (MA) position the prosthetic trochlea that guides patellar tracking differently. The present study determined whether KA or MA more closely restores the groove location and sulcus angle of the prosthetic trochlea to the native trochlea for three femoral component designs. METHODS: Ten 3D femur-cartilage models were created by combining computer tomographic (CT) and laser scans of native human cadaveric femurs. Three femoral component designs were positioned using KA and MA. Measurements of the prosthetic and native trochlea were made along the arc length of the native trochlear groove. The alignment technique with the smaller absolute difference between prosthetic and native for the medial-lateral and radial locations of the groove and sulcus angle of the trochlea more closely restored the native trochlea. RESULTS: For three femoral component designs, KA more closely restored to native the mean medial-lateral location (p = 0.0033 to < 0.0001) and mean radial location (p = 0.0150 to < 0.0001) than MA. For two femoral component designs, KA more closely restored to native the mean sulcus angle (p = 0.0326 to 0.0006) than MA. However, the differences in the mean sulcus angles between KA and MA were less than 2° for all three designs. CONCLUSION: KA more closely restored the native trochlea, which explains why the reported risk of patellofemoral complications for KA is not higher than MA according to five randomized clinical trials. Small design modifications of the medial-lateral and radial locations and sulcus angle are strategies for restoring the native trochlea. Such modifications might further reduce the risk of patellofemoral complications. LEVEL OF EVIDENCE: II.

Adrenocorticotropin induces mitogen-activated protein kinase phosphatase 1 in Y1 mouse adrenocortical tumor cells.

ACTH signaling pathway includes the action of both protein kinases, mainly cAMP-dependent protein kinase (protein kinase A, PKA), and serine/threonine and tyrosine phosphatases. MAPK phosphatase-1 (MKP-1) is a dual activity protein phosphatase involved in the dephosphorylation of MAPK. To determine whether MKP-1 is a component of ACTH cascade, here we investigate the expression levels of MKP-1 gene in Y1 mouse adrenocortical tumor cells under ACTH stimulation. ACTH transiently increased MKP-1 mRNA and protein levels. MKP-1 mRNA increase occurred at 30 min, peaked at 1 h (6-fold), and returned to basal levels thereafter. The ACTH-mediated mRNA increase was blunted by actinomycin D and enhanced by cycloheximide. A cell permeable cAMP analog, 8-bromo-cAMP, also transiently induced MKP-1 mRNA (4-fold) and the PKA inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid abolished this effect. In contrast, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamid only partially reduced the effect of ACTH, suggesting the participation of PKA-independent mechanisms in the hormone-induced MKP-1 expression. In addition, we show that the rise in intracellular Ca(2+) and protein kinase C activation had a potent synergic effect on ACTH- and 8-bromo-cAMP-mediated MKP-1 induction. In summary, our findings demonstrate that MKP-1 is another component of ACTH signaling cascade and indicate that this hormone may potentially down-regulate MAPKs.

Concerted regulation of free arachidonic acid and hormone-induced steroid synthesis by acyl-CoA thioesterases and acyl-CoA synthetases in adrenal cells.

Although the role of arachidonic acid (AA) in the regulation of steroidogenesis is well documented, the mechanism for AA release is not clear. Therefore, the aim of this study was to characterize the role of an acyl-CoA thioesterase (ARTISt) and an acyl-CoA synthetase as members of an alternative pathway in the regulation of the intracellular levels of AA in steroidogenesis. Purified recombinant ARTISt releases AA from arachidonoyl-CoA (AA-CoA) with a Km of 2 micro m. Antibodies raised against recombinant acyl-CoA thioesterase recognize the endogenous protein in both adrenal tissue and Y1 adrenal tumor cells by immunohistochemistry and immunocytochemistry and Western blot. Stimulation of Y1 cells with ACTH significantly stimulated endogenous mitochondrial thioesterases activity (1.8-fold). Nordihydroguaiaretic acid (NDGA), an inhibitor of AA release known to affect steroidogenesis, affects the in vitro activity of recombinant ARTISt and also the endogenous mitochondrial acyl-CoA thioesterases. ACTH-stimulated steroid synthesis in Y1 cells was significantly inhibited by a synergistic effect of NDGA and triacsin C an inhibitor of the AA-CoA synthetase. The apparent IC50 for NDGA was reduced from 50 micro m to 25, 7.5 and 4.5 micro m in the presence of 0.1, 0.5 and 2 micro m triacsin C, respectively. Our results strongly support the existence of a new pathway of AA release that operates in the regulation of steroid synthesis in adrenal cells.

ACTH regulation of mitochondrial acyl-CoA thioesterase activity in Y1 adrenocortical tumour cells.

We have previously purified and cloned a phosphoprotein, Arachidonic acid-Related Thioesterase Involved in Steroidogenesis (ARTISt), involved in steroid synthesis through Arachidonic Acid (AA) release. Arachidonic acid-related thioesterase involved in steroidogenesis resulted to be a member of a new family of acyl-CoA thioesterases. The protein was identified by its biocapacity to increase mitochondrial steroidogenesis in a cell free bioassay. In the present study we measure the activity of ARTISt using arachidonoyl-CoA (AA-CoA) as substrate. We demonstrate that ACTH significantly stimulates endogenous mitochondrial thioesterase activity as early as 5 min after ACTH stimulation of Y1 cells. Nordihydroguaiaretic acid (NDGA), an inhibitor of AA release known to affect steroidogenesis, affects the in vitro activity of recombinant ARTISt and also the endogenous mitochondrial acyl-CoA thioesterases. ACTH activation of the enzyme protected ARTISt to the inhibitory effect of NDGA. These results show that an enzyme that release AA from AA-CoA can be regulated in intact cells by steroidogenic hormones.