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Local cell therapy has recently gained attention for the treatment of joint diseases and fractures. Mesenchymal stem cells (MSCs) are not only involved in osteogenesis and angiogenesis, but they also have immunomodulatory functions, such as inducing macrophage migration during bone regeneration via macrophage crosstalk. C-C motif chemokine ligand 2 (CCL2), a known inflammatory mediator, is associated with the migration of macrophages during inflammation. This study examined the utility of CCL2 as a therapeutic target for local cell therapy. Using lentiviral vectors for rabbit MSCs, genetically modified CCL2 overexpressing MSCs were generated. Osteogenic differentiation assays were performed using MSCs with or without macrophages in co-culture, and cell migration assays were also performed. Additionally, co-cultures were performed with endothelial cells (ECs), and angiogenesis was evaluated using a tube formation assay. Overexpression of CCL2 did not affect bone formation under monoculture conditions but promoted chemotaxis and osteogenesis when co-cultured with macrophages. Furthermore, CCL2-overexpression promoted tube formation in co-culture with ECs. These results suggest that CCL2 induces macrophage chemotaxis and osteogenesis by promoting crosstalk between MSCs and macrophages; CCL2 also stimulates ECs to induce angiogenesis. These findings indicate that CCL2 may be a useful therapeutic target for local cell therapy in areas of bone loss. [ABSTRACT FROM AUTHOR]

Nanomedicines designed for enhanced pulmonary barriers penetration based on physicochemical characteristics of nanocarriers. [Display omitted] The lack of effective treatments for pulmonary diseases presents a significant global health burden, primarily due to the challenges posed by the pulmonary barrier that hinders drug delivery to the lungs. Inhaled nanomedicines, with their capacity for localized and precise drug delivery to specific pulmonary pathologies through the respiratory route, hold tremendous promise as a solution to these challenges. Nevertheless, the realization of efficient and safe pulmonary drug delivery remains fraught with multifaceted challenges. This review summarizes the delivery barriers associated with major pulmonary diseases, the physicochemical properties and drug formulations affecting these barriers, and emphasizes the design advantages and functional integration of nanomedicine in overcoming pulmonary barriers for efficient and safe local drug delivery. The review also deliberates on established nanocarriers and explores drug formulation strategies rooted in these nanocarriers, thereby furnishing essential guidance for the rational design and implementation of pulmonary nanotherapeutics. Finally, this review cast a forward-looking perspective, contemplating the clinical prospects and challenges inherent in the application of inhaled nanomedicines for respiratory diseases. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alveolar cleft repair is an important step in the sequence of treatments for cleft lip and palate. Intrinsically osteoinductive materials have been the subject of research interest. OBJECTIVE: The aim of this study was to explore the use of osteoinductive biphasic calcium phosphate (BCP) ceramics to repair alveolar cleft defects in dogs. METHODS: We prepared two kinds of BCP ceramic with different physical characteristics: osteoinductive BCP (OBCP) and non-osteoinductive BCP (NBCP). Bilateral alveolar cleft models were surgically established in dogs. On one side, OBCP was implanted in the defect; on the opposite side NBCP was implanted as a control. The materials were also implanted in the femoral muscles to test their properties at non-osseous sites. The osteogenic ability of materials was evaluated with imaging, spiral CT, histology and fluorescent dye tests. RESULTS: At the muscular implantation sites, new bone formed in all of the OBCP samples, but none in the NBCP samples. Imaging and spiral CT revealed good appearance and continuity of the alveolar cleft postoeration, with normal eruption of the bilateral permanent teeth in the groups. Histological and fluorescent dye testing revealed new bone formation in both groups in situ. However, earlier osteogenesis initiation and bone remodeling were superior with OBCP. Osteogenic process in the intramuscular samples with OBCP was similar to that seen in situ. CONCLUSIONS: Our findings indicated that osteoinductive biphasic calcium phosphate ceramics (OBCP) have superior characteristics in alveolar cleft repair compared with non-osteoinductive calcium phosphate ceramics (NBCP). [ABSTRACT FROM AUTHOR]

Purpose: We present a retrospective study of 15 cases with severe posttuberculous kyphosis of thoracolumbar region that underwent posterior vertebral column resection. Methods: From 2004 to 2009, 15 consecutive patients with posttubercular kyphotic deformity underwent posterior vertebral resection osteotomy. Six subjects were females and nine were males with an average age of 35.8 years (range 20-60 years) at the time of surgery. None of the patients had neurological deficits. The mean preoperative visual analogue scale was 8.7 (range 3-9), and the average preoperative Oswestry Disability Index was 46.5 (range 40-56). Results: The average duration of postoperative follow-up was 36.1 ± 10.7 months (range 24-62 months). The number of vertebra resected was 1.3 (range 1-2) on average. There were ten patients with one-level osteotomy and five patients with two-level osteotomy. The average operation time was 446.0 ± 92.5 min (range 300-640 min) with an average blood loss of 1,653.3 ± 777.9 ml (range 800-3000 ml). The focal kyphosis before surgery averaged 92.3 ± 8.9° (range 74-105°), and the kyphotic angle decreased to 34.5 ± 8.7° on average after the surgical correction. The average kyphotic angle at the last follow-up was 36.9 ± 8.5°, loss of correction was 2.4 ± 1.4° on average. All patients postoperatively received bony fusion within 6-9 months. Conclusions: Our results showed that although posterior vertebral resection is a highly technical procedure, it can be used safely and effectively in the management of severe posttuberculous kyphosis. It is imperative that operations be performed by an experienced surgical team to prevent operation-related complications. [ABSTRACT FROM AUTHOR]

Purpose: To compare the clinical outcomes of surgical management by posterior only and combined posterior and anterior approaches for thoracic spinal tuberculosis in the elderly. Materials and methods: This was a retrospective cohort study. Thirty-six cases of thoracic spinal tuberculosis treated by two different surgical procedures in our center from January 2004 to June 2009 were studied. All the cases were divided into two groups: 20 cases in Group A underwent single-stage posterior debridement, transforaminal fusion and instrumentation, and 16 cases in Group B underwent posterior instrumentation, anterior debridement and bone graft in a single- or two-stage procedure. The operation time, blood loss, correction rate, recovery of neurological function, fusion time and complications were, respectively, compared between Group A and Group B. Results: All patients were followed up for an average of 35.1 ± 5.8 months (range 26-45 months). It was obviously that the average operative duration, blood loss, hospitalization and complication rate of Group A was less than those of Group B. Spinal tuberculosis was completely cured and the grafted bones were fused in 10 months in all patients. There was no persistence or recurrence of infection and no differences in the radiological results in both groups. The kyphosis was significantly corrected after surgical management. However, loss of correction also occurred in both groups. Conclusion: Our study showed that the posterior approach only procedure obtained better clinical outcomes than combined posterior and anterior surgeries. It might be a better surgical treatment for thoracic spinal tuberculosis in aged patients with poor health status, especially for cases in early phase of bone destruction and/or mild and moderate kyphosis. [ABSTRACT FROM AUTHOR]

Purpose: Various surgical methods have been described for the management of lumbar tuberculous spondylitis in the literature. However, there were few reports on the two-stage surgical treatment of lumbar tuberculosis in children of elementary school age. We present a retrospective clinical study of 14 patients with lumbar and lumbosacral tuberculous spondylitis treated by two-stage surgery (first stage: posterior instrumentation; second stage: anterior debridement and allografting). The purpose is to determine the clinical efficacy of such surgical treatment for lumbar tuberculosis in children. Method: Our series was comprised 9 males and 5 females with an average age of 7.5 years treated with the abovementioned surgical procedure. All patients had lumbar and lumbosacral involvement with one patient having spondylitis at L2-3, three at L3-4, seven at L4-5, and three at L5-S1. All patients had single motion segment involvement. The Frankel scoring system was used to assess the neurological deficits. Frankel's grade B in two patients, grade C in four and grade D in eight. The following data were followed-up for an average period of 50.1 months (42-64 months) in these patients: healing of disease, deformity correction and its maintenance, neurologic function, and spinal bony fusion. Results: The average preoperative local deformity angle was −13.8°, correcting to 3.4° postoperatively and 1.5° at the final follow-up. With the exception of one patient who received a D at the final follow-up, all cases obtained complete neurological recovery. No breakage and looseness of internal fixation was found. Bony fusion was achieved in all cases within 6 months postoperatively. There was no recurrent tuberculous infection. Conclusion: Two-stage (posterior and anterior) surgery is a safe and effective procedure for the patient of elementary school age suffering from lumbar and lumbosacral tuberculous spondylitis, especially for the patients in poor general condition. The procedure has the advantage of minor surgical invasion, effective kyphosis correction and less complications. [ABSTRACT FROM AUTHOR]

Symptomatic dermographism (SD) is the most common form of physical urticaria. So far no promising serum biomarkers for SD have been reported. Recently, microRNAs (miRNAs) have been reported to be serum biomarkers for chronic spontaneous urticaria. However, association of miRNAs with SD remains unclear. We enrolled 55 SD patients and 52 healthy controls in this study. We found that serum expressions of miR-126-3p and miR-16-5p were significantly downregulated in active SD patients and upregulated in remission. The area under the curve values of miR-126-3p (0.769) and miR-16-5p (0.789) showed significant ability to diagnostic SD. Serum level of vascular endothelial growth factor (VEGF)-A, a known target of the two miRNAs, was significantly increased in active SD patients and decreased in remission. Moreover, serum VEGF-A level was inversely correlated with expressions of miR-126-3p and miR-16-5p. Our findings indicate that miR-126-3p and miR-16-5p can serve as potential serum biomarkers for SD. • Serum expressions of miR-126-3p and miR-16-5p are downregulated in active SD. • Either miR-126-3p or miR-16-5p shows good diagnostic performance for SD. • Serum expressions of miR-126-3p and miR-16-5p are upregulated in remission SD. • Serum VEGF-A level is increased in active SD and decreased in remission. • Serum VEGF-A level is inversely related to expressions of miR-126-3p and miR-16-5p. [ABSTRACT FROM AUTHOR]

Novel compounds and more efficient treatment options are urgently needed for the treatment of cystic echinococcosis (CE), which is caused by Echinococcus granulosus. The decoction of Sophora moorcroftiana (Fabaceae) has been used to treat parasitosis for years in traditional Tibetan medicine. The aim of this study was to screen insecticidal water-soluble alkaloids from S. moorcroftiana seeds and evaluate the therapeutic effects against CE and the immune response induced by the alkaloidal fraction. Low polarity compounds (E2-a) were isolated from water-soluble alkaloid (E2) and matrine and sophocarpine were identified as major components. The E2-a fraction was more effective against protoscoleces than other constituents from S. moorcroftiana. After 20 weeks of secondary infection with protoscoleces, mice were orally treated with E2-a (100 mg/kg/day) for 6 weeks to evaluate therapeutic and immunoregulatory activities. Compared with the untreated group, E2-a treatment induced a significant reduction in cyst weight (mean 2.93 g) (p < 0.05) and an impaired ultrastructural modification of the cyst. Interestingly, the application of E2-a resulted in a significant increased frequency of CD3+CD4+ T-cell subsets and decreased frequency of CD3+PD-1+ T-cell subsets, compared with protoscolece-infected mice without treatment. The E2-a fraction of S. moorcroftiana can inhibit the cyst development of CE and boost the specific immune response by reducing the expression of PD-1 and accelerate the cytokine secretion of antigen-specific T-cells. All data suggest the E2-a fraction from S. moorcroftiana seeds may be used as a new potential therapeutic option against E. granulosus infection. [ABSTRACT FROM AUTHOR]

A versatile strategy for the synthesis of 6″-functionalized α-GalCers by using NAP ether group for permanent hydroxyl protection was developed, which provide the flexibility necessary for the incorporation of a wide range of functional groups in target molecules including alkyne, azide, thiol that are intolerant to Pd-catalyzed hydrogenolysis as well as other functionalities like carboxylic acid and amine. This strategy is also adaptable to other glycoconjugate synthesis especially those containing clickable tags and unsaturated functionalities. [ABSTRACT FROM AUTHOR]

Abstract: Cyclopentylamine 4 was identified as a potent dual NK1R antagonist–SERT inhibitor. This compound demonstrated significant oral activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists–SERT inhibitors may be useful in treating depression disorders. [Copyright &y& Elsevier]

Abstract: Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET. [Copyright &y& Elsevier]

Acacetin, a O -methylated bioflavonoid isolated from the traditional Chinese medicine Xuelianhua ( Saussurea tridactyla ), is a promising orally effective atrium-selective antiarrhythmic agent for the treatment of atrial fibrillation (AF). Here we describe an efficient two-component method for the synthesis of acacetin and its derivatives. [ABSTRACT FROM AUTHOR]

The article presents the study about the artemisinin-resistant strain of Plasmodium falciparum in Africa as treatment of malaria in a case of a 48-year-old man. Topics discussed include the unknown date and therapeutic regimen of the patient which were associated with each episode, the findings of the microscopy which revealed P. falciparum parasites in the peripheral blood of the patient and the data of artemisinin resistance associated with M5791 mutation in Africa.

Abstract: A series of N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines were prepared and evaluated as potential CRF1R PET imaging agents. Optimization of their CRF1R binding potencies and octanol–phosphate buffer phase distribution coefficients resulted in discovery of analog 7e (IC50 =6.5nM, log D =3.5). [Copyright &y& Elsevier]

Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethylphosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole. [Copyright &y& Elsevier]

Background: We aimed to describe the relationship between changes in high-sensitivity cardiac troponin I (hsTnI) and cardiovascular outcomes.Methods: The EXAMINE trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care) was a phase IIIb clinical outcomes trial designed to evaluate the cardiovascular safety of alogliptin, a nonselective dipeptidyl peptidase 4 inhibitor. Patients with type 2 diabetes mellitus, glycohemoglobin between 6.5% and 11% (or between 7% and 11% if they were on insulin), and a recent acute coronary syndrome (between 15 and 90 days before randomization) were eligible for the trial. hsTnI was measured using the Abbott ARCHITECT assay at baseline and 6 months in patients randomized in the EXAMINE trial. This analysis was restricted to patients randomized ≥30 days after qualifying acute coronary syndrome to mitigate the potential for persistent hsTnI elevation after acute coronary syndrome (n=3808). The primary end point of the trial was cardiovascular death, myocardial infarction, or stroke. Cardiovascular death or heart failure was a prespecified, adjudicated secondary end point.Results: At baseline, hsTnI was detectable (≥1.9 ng/L) in 93% of patients and >99th percentile upper reference limit in 16%. There was a strong relationship between increasing hsTnI, both at baseline and 6 months, and the incidence of cardiovascular events through 24 months (P<0.001 for each). Patients with undetectable hsTnI at baseline and 6 months were at the lowest risk of future cardiovascular events. Stable patients with hsTnI ≥99th percentile upper reference limit at 6 months were at increased risk of cardiovascular death, myocardial infarction, or stroke compared with patients with hsTnI <99 percentile upper reference limit irrespective of whether hsTnI was newly elevated (28.1% versus 8.8%; adjusted hazard ratio, 2.65; 95% confidence interval, 1.64-4.28; P<0.001) or persistently so (22.5% versus 8.8%; adjusted hazard ratio, 1.90; 95% confidence interval, 1.33-2.70; P<0.001). Alogliptin neither increased nor decreased the risk of cardiovascular events compared with placebo in patients with high baseline hsTnI (22.3% versus 23.0%; hazard ratio, 0.87; 95% confidence interval, 0.60-1.25; P=0.44).Conclusions: Serial assessment of hsTnI revealed a substantial proportion of patients with type 2 diabetes mellitus without clinically recognized events had dynamic or persistently elevated values and were at high risk of recurrent events. hsTnI may have a role in personalizing preventive strategies in patients with diabetes mellitus based on risk.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00968708. [ABSTRACT FROM AUTHOR]