Comparison of Physicochemical Characteristics and Biostimulatory Functions in Two Calcium Hydroxyapatite-Based Dermal Fillers.

BACKGROUND:   Dermal fillers containing calcium hydroxyapatite (CaHA) are categorized as biostimulatory. However, differences in CaHA biomaterial likely affect the resultant induction of collagen synthesis, and variability in microsphere shape and size likely influences a patient’s immune response. This study compares 2 CaHA based fillers: one suspended in carboxymethylcellulose (denoted "CaHA/CMC"), and one crosslinked with 1,4-butanediol diglycidyl ether to hyaluronic acid (denoted "CaHA/HA"). OBJECTIVE: To characterize CaHA/CMC and CaHA/HA fillers to stimulate in vitro collagen biosynthesis. METHODS: Physicochemical evaluations included G′ and extrusion force. Scanning electron microscopy (SEM) was used to characterize isolated CaHA microspheres and freeze-dried formulations. Collagen I and III expression were evaluated using immunofluorescence. RESULTS: CaHA/CMC showed higher G′ (P<0.001) and lower extrusion force (P=0.0003), with uniform polymeric-matrix interactions, compared with CaHA/HA. On SEM, isolated microspheres and freeze-dried CaHA/CMC showed round and smooth surfaced microspheres of similar size. Isolated microspheres and freeze-dried CaHA/HA showed nonhomogeneous, broken microspheres, of various sizes, with fragments embedded in the polymer matrix. Although both fillers induced collagen III expression, only CaHA/CMC induced longer-lasting collagen I expression, with increases of 123% (P=0.007) and 164% (P<0.0001) at 2 and 5 mg/mL, respectively, compared with control. CaHA/CMC also increased collagen I expression at equivalent CaHA microsphere concentrations at 2 (P=0.0052) and 5 mg/mL (P<0.0001), compared with CaHA/HA. CONCLUSION: The physicochemical characteristics selected for evaluation were more favorable for CaHA/CMC than CaHA/HA. When compared with CaHA/HA, the smooth, homogeneous microsphere composition of CaHA/CMC promoted significantly more collagen I biosynthesis, an essential process for tissue augmentation and long-lasting aesthetic improvement. Citation: Kunzler C, Hartmann C, Nowag B, et al. Comparison of physicochemical characteristics and biostimulatory functions in two calcium hydroxyapatite-based dermal fillers. J Drugs Dermatol. 2023;22(9):910-916. doi:10.36849/JDD.7684.

Sex differences in heart rate variability: a longitudinal study in international elite cross-country skiers.

PURPOSE: Exercise-related sudden cardiac deaths (SCD) occur with a striking male predominance. A higher sympathetic tone in men has been suggested as risk factor for SCD. Elite athletes have the highest risk for exercise-related SCD. We aimed to analyze the autonomic nervous system of elite cross-country skiers from Norway, Russia and Switzerland in supine position and after orthostatic challenge in various training periods (TP). METHOD: Measurements of heart rate variability (HRV) were performed on a weekly basis over 1 year using an orthostatic challenge test with controlled breathing. Main outcome parameters were the high-frequency power in supine position (HFsupine) as marker of cardiac parasympathetic activity and the low-frequency/high-frequency power ratio after orthostatic challenge (LF/HFstand) as marker of cardiac sympathetic activation. Training intensity and duration were recorded daily and expressed as training strain. The training year was divided into three TPs. An average of weekly HRV measurements was calculated for each TP. RESULT: Female (n = 19, VO2max 62.0 ± 4.6 ml kg(-1) min(-1), age 25.8 ± 4.3 years) and male (n = 16, VO2max 74.3 ± 6.3 ml kg(-1) min(-1), age 24.4 ± 4.2 years) athletes were included. Training strain was comparable between sexes (all p > 0.05) and changed between TPs (all p < 0.05) while no HRV parameters changed over time. There were no sex differences in HFsupine while the LF/HFstand was significantly higher in male athletes in all TPs. CONCLUSION: For a comparable amount of training, male athletes showed constantly higher markers of sympathetic activity after a provocation maneuver. This may explain part of the male predominance in sports-related SCD.

Good reproducibility of heart rate variability after orthostatic challenge in patients with a history of acute coronary syndrome.

BACKGROUND: Several parameters of heart rate variability (HRV) have been shown to predict the risk of sudden cardiac death (SCD) in cardiac patients. There is consensus that risk prediction is increased when measuring HRV during specific provocations such as orthostatic challenge. For the first time, we provide data on reproducibility of such a test in patients with a history of acute coronary syndrome. METHODS: Sixty male patients (65 ± 8 years) with a history of acute coronary syndrome on stable medication were included. HRV was measured in supine (5 min) and standing (5 min) position on 2 occasions separated by two weeks. For risk assessment relevant time-domain [standard deviation of all R-R intervals (SDNN) and root mean squared standard differences between adjacent R-R intervals (RMSSD)], frequency domain [low-frequency power (LF), high-frequency power (HF) and LF/HF power ratio] and short-term fractal scaling component (DF1) were computed. Absolute reproducibility was assessed with the standard errors of the mean (SEM) and 95% limits of random variation, and relative reproducibility by the intraclass correlation coefficient (ICC). RESULTS: We found comparable SEMs and ICCs in supine position and after an orthostatic challenge test. All ICCs were good to excellent (ICCs between 0.636 and 0.869). CONCLUSIONS: Reproducibility of HRV parameters during orthostatic challenge is good and comparable with supine position.

Reproducibility of peripheral arterial tonometry measurements in male cardiovascular patients.

BACKGROUND: Assessment of endothelial function of the microvasculature by peripheral arterial tonometry (EndoPAT(®)) has gained increasing popularity in patients with cardiovascular risk factors. Only limited knowledge about its reproducibility in patients with coronary artery disease (CAD) is available. We therefore aimed to quantify reproducibility of EndoPAT(®) parameters in patients with stable CAD. DESIGN: EndoPAT(®) measurements were performed repeatedly in 78 male patients (age 66 ± 8 years) with CAD on stable medication. We calculated overall mean, standard deviation (SD), coefficient of variation (CV) and intraclass correlation coefficient (ICC) of the following parameters: reactive hyperemic index (RHI), PAT ratio of the postocclusion period 90-150 s as used for calculation of the RHI (PAT ratio90-150 s) and 90-120 s (PAT ratio90-120 s) as used for the often employed Framingham RHI (F-RHI), as well as PAT ratio of the peak hyperemic response (PAT ratiopeak response). Additionally, least significant changes (LSC) for individual subjects and minimum sample sizes for parallel and cross-over design studies were calculated. RESULTS: Mean RHI was 1·84 (SD 0·36). For RHI, PAT ratio90-150 s , PAT ratio90-120 s , and PAT ratiopeak response the CVs were 17·0%, 25·4%, 26·1%, and 25·0%, respectively. The ICCs were 0·45, 0·49, 0·48 and 0·51, respectively, and LSC for RHI was 47·2%. CONCLUSIONS: CV of RHI in our population was moderate; however, we consider this precision insufficient to monitor changes in individual patients, as they would need to exceed 47% to show a significant change. Further, the poor ICCs reflect the difficulty of detecting treatment effects in homogenous populations, such as patients with stable CAD.

Ultra-endurance sports have no negative impact on indices of arterial stiffness.

PURPOSE: Marathon running has been linked with higher arterial stiffness. Blood pressure is a major contributor to pulse wave velocity (PWV). We examined indices of arterial stiffness with a blood pressure-independent method in marathon runners and ultra-endurance athletes. METHODS: Male normotensive amateur runners were allocated to three groups according to former participation in competitions: group I (recreational athletes), group II (marathon runners) and group III (ultra-endurance athletes). Indices of arterial stiffness were measured with a non-invasive device (VaSera VS-1500N, Fukuda Denshi, Japan) to determine the cardio-ankle vascular index (CAVI, primary endpoint) and brachial-ankle PWV (baPWV). Lifetime training hours were calculated. Cumulative competitions were expressed as marathon equivalents. Linear regression analysis was performed to determine predictors for CAVI and baPWV. RESULTS: Measurements of arterial stiffness were performed in 51 subjects (mean age 44.6 ± 1.2 years): group I (n = 16), group II (n = 19) and group III (n = 16). No between-group differences existed in age, anthropometric characteristics and resting BP. CAVI and baPWV were comparable between all groups (P = 0.604 and P = 0.947, respectively). In linear regression analysis, age was the only independent predictor for CAVI (R(2) = 0.239, ß = 0.455, P = 0.001). Systolic BP was significantly associated with baPWV (R(2) = 0.225, ß = 0.403, P = 0.004). CONCLUSIONS: In middle-aged normotensive athletes marathon running and ultra-endurance sports had no negative impact on arterial stiffness.

Biostimulating fillers and induction of inflammatory pathways: A preclinical investigation of macrophage response to calcium hydroxylapatite and poly-L lactic acid.

INTRODUCTION: Initial macrophage response to biostimulatory substances is key in determining the subsequent behavior of fibroblasts and the organization of newly synthesized collagen. Though histological studies suggest that calcium hydroxylapatite (CaHA) filler initiates a regenerative healing response with collagen and elastin deposition similar to natural, healthy tissue rather than an inflammatory response with fibrosis, the relative activity of macrophages stimulated by CaHA, as well as how this activity compares to that induced by other biostimulatory fillers, has not been explored. The aim of the study is to characterize the in vitro macrophage response to two biostimulory fillers, CaHA and PLLA (poly-L lactic acid), and to evaluate their inflammatory potential. METHODS: Primary human macrophages were incubated with two dilutions (1:50 and 1:100) of commercially available CaHA or PLLA. After 24 h incubation, an inflammation array was used to screen for the expression of 40 cytokines, released by macrophages. ELISA was used to confirm array results. RESULTS: Four cytokines were significantly upregulated in M1 macrophages incubated with PLLA compared to both unstimulated controls and CaHA: CCL1 (p < 0.001), TNFRII (p < 0.01), MIP-1α (p < 0.05), and IL-8 (p < 0.001). In M2 macrophages, MIP-1α (p < 0.01) and MIP-1ß (p < 0.01) were significantly upregulated by PLLA compared to CaHA and unstimulated controls. CONCLUSION: Together, these findings indicate that the CaHA mode of action is a non-inflammatory response while PLLA initiates expression of several cytokines known to play a role in inflammation. Our study supports the concept that these two "biostimulatory" fillers follow distinct pathways and should be considered individually with regard to mechanism of action.

Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition.

It has been proposed that activation of metabotropic glutamate receptor subtype 2/3 (mGluR2/3) may induce both antipsychotic and anxiolytic effects. The aim of this study was to evaluate further the effect of the mGluR2/3 agonist, LY354740 [(+)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylate monohydrate] in animal models relevant to both psychotic and cognitive impairment in schizophrenia. The elevated plus maze was used to select the doses for further experiments, LY354740 induced anxiolytic-like effects at doses of 3 and 10 mg/kg but not 1 mg/kg. At a dose of 10 mg/kg. LY354740 attenuated phencyclidine (PCP)-induced locomotor activity. Administered alone, it had no effect on horizontal activity, but at doses of 3 and 10 mg/kg, slightly decreased vertical activity (rearings). LY354740 (1-10 mg/kg intraperitoneally) affected neither prepulse inhibition in normal rats nor reversed the disruption of prepulse inhibition produced by PCP (2 mg/kg subcutaneously). Moreover, LY354740 (3-10 mg/kg) did not modify PCP-induced working memory deficits assessed in a spontaneous alternation task and had no effect on PCP-evoked amnesia in the passive avoidance test. LY354740 alone (3 and 10 mg/kg) induced working memory deficits, but had no effect on acquisition of passive avoidance. In conclusion, LY354740 was effective in models for anxiety and positive symptoms of schizophrenia but not in models for sensorimotor gating and cognitive impairment.

Effect of a Tibetan herbal mixture on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation.

In this 6-week prospective, randomized, placebo-controlled and double-blind study, we investigated the effects of a natural herbal remedy based on a recipe from Tibet (Padma® 28), on microvascular endothelial function, heart rate variability and biomarkers of inflammation, clotting and coagulation in 80 coronary artery disease (CAD) patients (age 66 ± 8 years) on guideline-based medication for secondary prevention. We found no significant effects of Padma 28 and conclude that the addition of Padma 28 to guideline-based secondary prevention treatment of CAD did not lead to significant effects on important surrogate markers in elderly male CAD patients.

Exercise economy in skiing and running.

Substantial inter-individual variations in exercise economy exist even in highly trained endurance athletes. The variation is believed to be determined partly by intrinsic factors. Therefore, in the present study, we compared exercise economy in V2-skating, double poling, and uphill running. Ten highly trained male cross-country skiers (23 ± 3 years, 180 ± 6 cm, 75 ± 8 kg, VO2peak running: 76.3 ± 5.6 mL·kg(-1)·min(-1)) participated in the study. Exercise economy and VO2peak during treadmill running, ski skating (V2 technique) and double poling were compared based on correlation analysis. There was a very large correlation in exercise economy between V2-skating and double poling (r = 0.81) and large correlations between V2-skating and running (r = 0.53) and double poling and running (r = 0.58). There were trivial to moderate correlations between exercise economy and the intrinsic factors VO2peak (r = 0.00-0.23), cycle rate (r = 0.03-0.46), body mass (r = -0.09-0.46) and body height (r = 0.11-0.36). In conclusion, the inter-individual variation in exercise economy could be explained only moderately by differences in VO2peak, body mass and body height. Apparently other intrinsic factors contribute to the variation in exercise economy between highly trained subjects.

Contaminação bacteriológica de águas subterrâneas da região oeste de Santa Catarina, Brasil / Bacteriological contamination of groundwater of the western area of Santa Catarina, Brazil

O objetivo do estudo foi avaliar a qualidade bacteriológica de águas subterrâneas da região oeste do Estado de Santa Catarina, onde é comum a utilização de poços comunitários ou particulares. As amostras foram avaliadas pela técnica de fermentação em tubos múltiplos de acordo com a metodologia descrita no American Public Health Association e segundo a instrução normativa 62 de 26 de agosto de 2003, do Ministério da Agricultura Pecuária e Abastecimento. Além disso, foi realizado levantamento de dados por meio de um questionário, cujas questões foram respondidas pelo responsável pelo respectivo poço. Das 212 amostras de água analisadas, 161 (75,94%) estavam impróprias para o consumo humano, conforme a Portaria 518/2004 do Ministério da Saúde. Apesar dos altos índices de contaminação bacteriológica nas amostras avaliadas, a maioria dos consumidores julga essa água de boa qualidade e por isso, apenas 10% dos usuários costumam filtrar e 8% fervem a água antes do consumo. Portanto, torna-se necessário a adoção de medidas preventivas e o tratamento das águas já comprometidas.