Rapidly restoring vitamin D levels to normal might be desirable in certain clinical situations. Larger doses of supplementation, have been shown to increase bone loss and the risk of falls. The ...optimal way to perform vitamin D loading safely and effectively is still not well elucidated. Our study was aimed to assess the safety and efficacy of two oral vitamin D loading protocols. Sixty-nine subjects with vitamin D deficiency (25OH-vitamin D (25(OH)D) < 20 ng/ml) were included. Thirty-five participants received 30 000 IU of vitamin D3 per week for 10 weeks (group Slower Loading Dose (SLD)) and thirty-four received 30 000 IU twice weekly for 5 weeks (group Moderate Loading Dose (MLD)) resulting in a loading dose of 300 000 IU for all subjects. Following this initial loading phase, both groups received 30 000 IU biweekly for 4 weeks to test whether the recommended daily vitamin D supplementation in range of 2000 IU dose-equivalent could maintain the achieved levels. Seventy-nine percent of those subjects treated in group SLD and everyone in group MLD achieved a 25(OH)D level of 30 ng/ml, which is the lower limit of the recommended normal range in Hungary. The mean increase in 25(OH)D was significantly higher in group MLD than in group SLD (38.6 ± 1.80 ng/ml vs 46,6 ± 1.80 ng/ml). No significant decrease was observed with the administration of the maintenance dose. There were no clinically significant changes in serum or urine calcium, and bone biomarkers in either group. Both protocols were found to be safe and effective, but the five-week dosing caused a significantly greater increase in 25(OH)D. A maintenance dose applied for four weeks after the loading protocol did not raise 25(OH)D levels further but maintained the achieved increase. The administration of 30 000 IU of vitamin D3 twice weekly for five weeks is a rapid, effective and safe way to treat vitamin D deficiency in vitamin D deficient patients.
•Twice weekly 30 000 IUs vitamin D3 for five weeks are effective and safe treatment of vitamin D deficiency.•The same cumulative dose in shorter loading protocol resulted in more prominent increase in 25(OH)D levels.•Biweekly supplementation of 30 000 IUs after a successful loading maintains the previously achieved vitamin D sufficiency.
Background
To preserve the benefit of atrial sensing without the implantation of an additional lead, a single‐lead ICD system with a floating atrial dipole (DX ICD) has been developed. The purpose of ...this nationwide survey was to provide an overview of the current key influences of device selection focusing on DX ICD and to test the applicability of a previously published decision‐making flowchart of ICD‐type selection.
Methods
An online questionnaire was sent to all implanting centers in Hungary. Eleven centers reported data from 361 DX ICD and 10 CRT‐DX systems implantations between February 2021 and May 2023.
Results
The most important influencing clinical factors indicated by the participating doctors were elevated risk of atrial fibrillation (AF)/stroke (56%), risk of sinus/supraventricular tachycardias (SVT) (42%), and a potential need for CRT upgrade in the future (36%). The DX ICD was considered in the majority of cases instead of the VVI system (87%), and only in a small proportion instead of a DDD ICD (13%). 60% of the patients with DX ICDs were also included into remote monitoring‐based follow‐up. In 83% of the cases, good (>2 mV) or excellent (>5) atrial signal amplitude was recorded within 6 weeks after the implantation.
Conclusion
In the current national survey, the most important influencing factors indicated by the implanters for selecting a DX ICD were the elevated risk of stroke or sinus/SVT and a potential need for CRT upgrade in the future. These findings support the use of a previously published decision‐making flowchart.
The benefit of using gelatin solution in cardiac surgery is still controversial. Previous data suggested adverse interactions of gelatin infusion with acute kidney injury (AKI) or coagulopathy. The ...purpose of this study was to evaluate the association between perioperative gelatin use and fluid overload (FO), hemodynamic stability, and outcomes compared to crystalloid-based fluid management.
A retrospective study design.
At a single-center tertiary university setting.
Propensity score-matched cohort study of 191 pairs of patients scheduled for cardiac surgery.
Patients received either gelatin + crystalloid or pure crystalloid-based perioperative fluid management. The primary outcomes were the frequency of FO and hemodynamic stability defined by the vasoactive-inotropic score. Postoperative complications and 3-year survival were analyzed also.
Patients who received gelatin experienced more frequent postoperative FO than controls (11.0% v 3.1%, p = 0.006) despite comparable hemodynamic stability in both groups. Gelatin administration was linked with a higher rate of postoperative complications, including blood loss, AKI, and new-onset postoperative atrial fibrillation. Use of gelatin infusion resulted in an adjusted odds ratio of 1.982 (95% CI 1.051-3.736, p = 0.035) for developing early postoperative AKI. This study confirmed a dose-dependent relationship between gelatin infusion and AKI. Thirty-day mortality and 3-year survival were similar in the groups.
Gelatin administration versus crystalloid fluid management showed a significant association with a higher rate of FO and an increased risk for early postoperative AKI in a dose-dependent manner.
The tumor microenvironment (TME) has gained considerable scientific attention by playing a role in immunosuppression and tumorigenesis. Besides tumor cells, TME is composed of various other cell ...types, including cancer-associated fibroblasts (CAFs or MAFs when referring to melanoma-derived CAFs) and tumor-infiltrating lymphocytes (TILs), a subpopulation of which is labeled as γδ T cells. Since the current anti-cancer therapies using γδ T cells in various cancers have exhibited mixed treatment responses, to better understand the γδ T cell biology in melanoma, our research group aimed to investigate whether activated γδ T cells are capable of killing MAFs. To answer this question, we set up an in vitro platform using freshly isolated Vδ2-type γδ T cells and cultured MAFs that were biobanked from our melanoma patients. This study proved that the addition of zoledronic acid (1–2.5 µM) to the γδ T cells was necessary to drive MAFs into apoptosis. The MAF cytotoxicity of γδ T cells was further enhanced by using the stimulatory clone 20.1 of anti-BTN3A1 antibody but was reduced when anti-TCR γδ or anti-BTN2A1 antibodies were used. Since the administration of zoledronic acid is safe and tolerable in humans, our results provide further data for future clinical studies on the treatment of melanoma.
Vascular graft maturation is associated with blood flow characteristics, such as velocity, pressure, vorticity, and wall shear stress (WSS). Many studies examined these factors separately. We aimed ...to examine the remodeling of arterio-venous fistulas (AVFs) and loop-shaped venous interposition grafts, together with 3D flow simulation. Thirty male Wistar rats were randomly and equally divided into sham-operated, AVF, and loop-shaped venous graft (Loop) groups, using the femoral and superficial inferior epigastric vessels for anastomoses. Five weeks after surgery, the vessels were removed for histological evaluation, or plastic castings were made and scanned for 3D flow simulation. Remodeling of AVF and looped grafts was complete in 5 weeks. Histology showed heterogeneous morphology depending on the distribution of intraluminal pressure and WSS. In the Loop group, an asymmetrical WSS distribution coincided with the intima hyperplasia spots. The tunica media was enlarged only when both pressure and WSS were high. The 3D flow simulation correlated with the histological findings, identifying “hotspots” for intimal hyperplasia formation, suggesting a predictive value. These observations can be useful for microvascular research and for quality control in microsurgical training.
Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be ...suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with
gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III-IV than stage I-II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.
The importance of measuring aortic pulse wave velocity (PWVao), aortic augmentation index (Aix) and central systolic blood pressure (SBPao) has been shown under different clinical conditions; ...however, information on these parameters is hard to obtain. The aim of this study was to evaluate the accuracy of a new, easily applicable oscillometric device (Arteriograph), determining these parameters simultaneously, against invasive measurements.
Aortic Aix, SBPao and PWVao were measured invasively during cardiac catheterization in 16, 55 and 22 cases, respectively, and compared with the values measured by the Arteriograph.
We found strong correlation between the invasively measured aortic Aix and the oscillometrically measured brachial Aix on either beat-to-beat or mean value per patient basis (r = 0.9, P < 0.001; r = 0.94, P < 0.001), which allowed the noninvasive calculation of the aortic Aix without using generalized transfer function. Similarly strong correlation (r = 0.95, P < 0.001) was found between the invasively measured and the noninvasively calculated central SBPao; furthermore, the BHS assessment of the paired differences fulfilled the 'B' grading. The PWVao values measured invasively and by Arteriograph were 9.41 ± 1.8 m/s and 9.46 ± 1.8 m/s, respectively (mean ± SD); furthermore, the Pearson's correlation was 0.91 (P < 0.001). The limits of agreement were 11.4% for aortic Aix and 1.59 m/s for PWVao.
Aix, SBPao and PWVao, measured oscillometrically, showed strong correlation with the invasively obtained values. The observed limits of agreement are encouragingly low for accepting the method for clinical use. Our results suggest that the PWVao values, measured by Arteriograph, are close to the true aortic PWV, determined invasively.
The extracellular concentrations of adenosine are increased during sepsis, and adenosine receptors regulate the host's response to sepsis. In this study, we investigated the role of the ...adenosine-generating ectoenzyme, ecto-5'-nucleotidase (CD73), in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury, as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased cleavage of caspase-3 and poly(ADP-ribose) polymerase and increased activation of NF-κB. Septic CD73 KO mice had higher blood urea nitrogen levels and increased cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using α, β-methylene ADP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis.
Summary
In the article a method which is able to provide the required performance level of a system is proposed. Its principle is to combine the results of conventional control methods with those of ...methods based on nonconventional, for example, machine‐learning‐based ones. In more detail, it designs a robust linear parameter varying (LPV) control in a predefined form, whose output is equivalent to the output of a machine‐learning‐based control inside a predefined operational range. Outside of the operation range the output of the machine‐learning‐based control is overridden, while the intervention with the performance level is guaranteed. The efficiency of the proposed method is illustrated through an example on the semiactive suspension control design. The nonlinearities in the dynamics of the magneto‐rheological damper are considered through a nonlinear parameter varying (NLPV) model. It designs an NLPV model‐based LPV control, which is combined with a neural network to achieve preview capability.
Sepsis remains the leading cause of morbidity and mortality in critically ill patients. Excessive inflammation is a major cause of organ failure and mortality in sepsis. Ectonucleoside triphosphate ...diphosphohydrolase 1, ENTPDase1 (CD39) is a cell surface nucleotide‐metabolizing enzyme, which degrades the extracellular purines ATP and ADP, thereby regulating purinergic receptor signaling. Although the role of purinergic receptor signaling in regulating inflammation and sepsis has been addressed previously, the role of CD39 in regulating the host's response to sepsis is unknown. We found that the CD39 mimic apyrase (250 U/kg) decreased and knockout or pharmacologic blockade with sodium polyoxotungstate (5 mg/kg; IC50 ã 10 μM) of CD39 increased mortality of mice with polymicrobial sepsis induced by cecal ligation and puncture. CD39 decreased inflammation, organ damage, immune cell apoptosis, and bacterial load. Use of bone marrow chimeric mice revealed that CD39 expression on myeloid cells decreases inflammation in septic mice. CD39 expression is upregulated during sepsis in mice, as well as in both murine and human macrophages stimulated with Escherichia coli. Moreover, E. coli increases CD39 promoter activity in macrophages. Altogether, these data indicate CD39 as an evolutionarily conserved inducible protective pathway during sepsis. We propose CD39 as a novel therapeutic target in the management of sepsis—Csóka, B., Németh, Z. H., Törő, G., Koscsó, B., Kókai, E., Robson, S. C., Enjyoji, K., Rolandelli, R. H., Erdélyi, K., Pacher, P., Haskó, G., CD39 improves survival in microbial sepsis by attenuating systemic inflammation. FASEB J. 29, 25–36 (2015). www.fasebj.org
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