Effects and mechanotransduction pathways of therapeutic ultrasound on healthy and osteoarthritic chondrocytes: a systematic review of in vitro studies.

OBJECTIVE: To investigate the effects and mechanotransduction pathways of therapeutic ultrasound on chondrocytes. METHOD: PubMed, EMBASE and Web of Science databases were searched up to 19th September 2021 to identify in vitro studies exploring ultrasound to stimulate chondrocytes for osteoarthritis (OA) treatment. Study characteristics, ultrasound parameters, in vitro setup, and mechanotransduction pathways were collected. Risk of bias was judged using the Risk of Bias Assessment for Non-randomized Studies (RoBANS) tool. RESULTS: Thirty-one studies were included comprising healthy and OA chondrocytes and explants. Most studies had high risk of performance, detection and pseudoreplication bias due to lack of temperature control, setup calibration, inadequate semi-quantitatively analyzes and independent experiments. Ultrasound was applied to the culture plate via acoustic gel, water bath or culture media. Regardless of the setup used, ultrasound stimulated the cartilage production and suppressed its degradation, although the effect size was nonsignificant. Ultrasound inhibited p38, c-Jun N-terminal kinases (JNK) and factor nuclear kappa B (NFκB) pathways in OA chondrocytes to reduce apoptosis, inflammation and matrix degradation, while triggered phosphoinositide-3-kinase/akt (PI3K/Akt), extracellular signal-regulated kinase (ERK), p38 and JNK pathways in healthy chondrocytes to promote matrix synthesis. CONCLUSION: The included studies suggest that ultrasound application induces therapeutic effects on chondrocytes. However, these results should be interpreted with caution because high risk of performance, detection and pseudoreplication bias were identified. Future studies should explore the application of ultrasound on human OA chondrocytes cultures to potentiate the applicability of ultrasound towards cartilage regeneration of knee with OA.

Outcome of neoadjuvant treatment for pancreatic cancer in elderly patients: comparative, observational cohort study.

BACKGROUND: Use of neoadjuvant therapy for elderly patients with pancreatic cancer has been debatable. With FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, oxaliplatin) or gemcitabine plus nab-paclitaxel (GnP) showing tremendous effects in improving the overall survival of patients with borderline resectable and locally advanced pancreatic cancer, there is no definitive consensus regarding the use of this regimen in the elderly. METHODS: This study evaluated the eligibility of elderly patients with borderline resectable or locally advanced pancreatic cancer for neoadjuvant therapy. Patients registered in the database of pancreatic cancer at the University of Colorado Cancer Center, who underwent neoadjuvant treatment between January 2011 and March 2019, were separated into three age groups (less than 70, 70-74, 75 or more years) and respective treatment outcomes were compared. RESULTS: The study included 246 patients with pancreatic cancer who underwent neoadjuvant treatment, of whom 154 and 71 received chemotherapy with FOLFIRINOX and GnP respectively. Among these 225 patients, 155 were younger than 70 years, 36 were aged 70-74 years, and 34 were aged 75 years or older. Patients under 70 years old received FOLFIRINOX most frequently (124 of 155 versus 18 of 36 aged 70-74 years, and 12 of 34 aged 75 years or more; P < 0.001). Resectability was similar among the three groups (60.0, 58.3, and 55.9 per cent respectively; P = 0.919). Trends towards shorter survival were observed in the elderly (median overall survival time 23.6, 18.0, and 17.6 months for patients aged less than 70, 70-74, and 75 or more years respectively; P = 0.090). After adjusting for co-variables, age was not a significant predictive factor. CONCLUSION: The safety and efficacy of multiagent chemotherapy in patients aged 75 years or over were similar to those in younger patients. Modern multiagent regimens could be a safe and viable treatment option for clinically fit patients aged at least 75 years.

Immune profiling of lupus miliaris disseminatus faciei and successful management with anti-tumour necrosis factor therapy.

Lupus miliaris disseminatus faciei (LMDF) is a chronic inflammatory dermatosis of unknown aetiology, most often seen in young adults. Although many treatments for LMDF exist, treatment guidelines have not been developed, and response to therapy is generally unpredictable. We present the results of transcriptomic analysis of LMDF lesional skin, which revealed a variety of differentially expressed genes linking LMDF to alterations in innate and adaptive T helper 1 immunity. Immunohistochemical analysis was also performed, identifying similar changes in T-cell immune responses. Given evidence for increased tumour necrosis factor (TNF) pathway activity, our patient, who had previously been refractory to multiple treatments, was initiated on TNF inhibitor therapy with excellent response. This characterization of the LMDF immune response may lead to improved treatment of this condition.

Induction of haem oxygenase-1 increases infection of dog macrophages by L. infantum.

We aimed to induce and inhibit HO-1, ascertaining its effect on infection rate, parasite load and the levels of superoxide, reactive oxygen species (ROS), nitric oxide (NO), TNF-alpha and IL-10 in cultured macrophages from healthy dogs infected by Leishmania infantum. Macrophages obtained from 15 healthy dogs were cultured alone or infected with L. infantum, with or without association of HO-1 inducer and inhibitor. The infection rate and the parasite load were determined by the number of infected macrophages and number of promastigotes per macrophage, respectively. HO-1 levels and gene expression, as well as IL-10 and TNF-alpha levels were also measured in these cultures. Superoxide, ROS and NO levels in macrophages were measured through flow cytometry. Induction of HO-1 increased the infection rate and parasite load, while its inhibition decreased the infection rate and IL-10 production. There was a positive correlation between HO-1 and infection rate or parasite load. Increased infection rate was associated with decreased superoxide, ROS and NO levels. Induction of HO-1 metabolism in dogs infected by L. infantum is possibly one of the mechanisms responsible for increasing the infection of macrophages, mainly through reduction in the oxidative and nitrosative metabolisms of these cells.

Monitoring the John Cunningham virus throughout natalizumab treatment in multiple sclerosis patients.

BACKGROUND AND PURPOSE: Progressive multifocal leukoencephalopathy (PML) cases have arisen amongst multiple sclerosis patients treated with natalizumab. Our objective was to gain a better understanding of the mechanisms that underlie the John Cunningham virus (JCV) infection which causes PML. METHODS: A study was made of (i) the quarterly JCV DNA levels in peripheral blood mononuclear cells (PBMCs), serum and urine samples in 100 multiple sclerosis patients during their natalizumab treatment (3-39 months), (ii) the association between human leukocyte antigen (HLA) class II and the previous viral detection and (iii) the identification of the JCV variants in those patients suspected of having PML. RESULTS: (i) JCV DNA in PBMCs and/or serum was detected in 23% of our cohort. Patients with an intermittent JCV excretion in urine had a significant increase of the viral load and prevalence in this compartment during natalizumab treatment. (ii) The frequency of the DRB1*07/DQA1*02:01/DQB1*02:02 haplotype tended to be higher in patients with detectable versus undetectable JCV DNA in PBMCs (P(corrected) = 0.108). (iii) The variants in PBMCs and serum of the non-PML patient matched the archetype. In the patient with non-fatal PML, the archetype and the same neurotropic variant in PBMCs, serum and cerebrospinal fluid was identified at the time PML was diagnosed, whereas in the patient with a worse PML prognosis, four neurotropic variants in the three previous compartments were found by the PML diagnosis. CONCLUSIONS: The detection of the neurotropic variant in blood during natalizumab treatment could be critical in the prevention of the development of severe PML, since this variant appears simultaneously with the clinical symptoms of PML and mutates quickly.

Effect of the combination of metformin hydrochloride and melatonin on oxidative stress before and during pregnancy, and biochemical and histopathological analysis of the livers of rats after treatment for polycystic ovary syndrome.

The aim of the present study was to analyze the effect of a combination of metformin hydrochloride and melatonin on oxidative stress together with a biochemical and histopathological analysis of the livers of Wistar rats induced with PCOS. The results indicated that a combination of the drugs was more effective in the reduction of plasmatic levels of liver enzyme alanine aminotransferase, nitric oxide and total glutathione, and decreased the inflammatory response and histopathological damage, producing results that were significantly similar to animals from the control group. A mixture of the drugs produced more effective results against liver toxicity caused by PCOS, encouraging the normalization of biochemical parameters. During pregnancy, there was reduced oxidative stress compared to monotherapeutic use of these drugs. Interestingly, the combination of the drugs caused a physiological reaction similar to responses identified in healthy rats without induction of the PCOS control group. However, the clinical and physiological effectiveness of the combination should be further explored, especially with respect to the possible side effects on offspring.

Toll-like receptor-9 in Spanish multiple sclerosis patients: an association with the gender.

BACKGROUND AND PURPOSE: Toll-like receptor-9 (TLR9) is a potent inducer of innate immune system triggered by infection with viruses, some of them previously related to multiple sclerosis (MS). The aim of this study was to analyze the possible association of two TLR9 single nucleotide polymorphisms (SNPs; rs352162 and rs187084) with susceptibility to MS. METHODS: Two independent cohorts of MS patients and controls were included: 574 clinically definite relapsing-remitting MS patients (367 females) and 807 healthy controls (418 females) for the first cohort; and 366 relapsing-remitting MS patients (238 females) and 224 healthy controls (160 females) for the second cohort. Genotyping was performed by TaqMan assays. RESULTS: The AT haplotype was found to be significantly higher in women than in men (P = 0.013 and P = 0.044). CONCLUSIONS: Here two possible genetic markers are proposed that could be also associated with the differences observed in the clinical course of MS in both genders. Further studies with larger cohorts should be performed to confirm these results.

Desorption dynamics of heavy alkali metal atoms (Rb, Cs) off the surface of helium nanodroplets.

We present a combined ion imaging and density functional theory study of the dynamics of the desorption process of rubidium and cesium atoms off the surface of helium nanodroplets upon excitation of the perturbed 6s and 7s states, respectively. Both experimental and theoretical results are well represented by the pseudodiatomic model for effective masses of the helium droplet in the desorption reaction of meff/mHe ≈ 10 (Rb) and 13 (Cs). Deviations from this model are found for Rb excited to the 6p state. Photoelectron spectra indicate that the dopant-droplet interaction induces relaxation into low-lying electronic states of the desorbed atoms in the course of the ejection process.

Fosaprepitant-induced phlebitis: a focus on patients receiving doxorubicin/cyclophosphamide therapy.

PURPOSE: The purpose of this study was to investigate the incidence of fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin/cyclophosphamide (AC) chemotherapy. METHODS: A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC from January 2011 to April 2012. Data collected included baseline demographics, antiemetic regimen, documentation of ISAEs, and type of intravenous (IV) access. Descriptive statistics (mean and standard deviation or percentages) were summarized overall, by type of IV access and initial antiemetic given. RESULTS: Among the 148 patients included in this analysis, 98 initially received fosaprepitant and 44 received aprepitant. The incidence of ISAEs associated with fosaprepitant administration was 34.7 % (n=34), while the incidence of aprepitant-associated ISAEs was 2.3 % (n=1). All ISAEs were associated with peripheral IV access. The most commonly reported ISAEs were infusion site pain (n=26), erythema (n=22), swelling (n=12), superficial thrombosis (n=8), infusion site hives (n=5), and phlebitis/thrombophlebitis (n=5). Twenty-six patients experienced more than one type of ISAE. CONCLUSIONS: The incidence and severity of ISAEs associated with fosaprepitant administration among a group of patients receiving AC chemotherapy are significant and appreciably higher than what has been previously reported.

Mechanical response of melt-spun amorphous filaments.

High-speed melt spinning of a cyclo-olefin polymer (COP) and a copolyamide (CoPA) have been performed. Differential scanning calorimetry curves of the resulting monofilaments show that they remain in an amorphous state even after hot drawing. Wide angle x-ray diffraction patterns of undrawn and drawn COP filaments show that although the material remains in an amorphous state, a degree of orientation is induced in the polymer after drawing. The amorphous filaments show an enhanced bending recovery with respect to different semi-crystalline monofilaments commercially available. However, single fiber axial compressive testing indicates that the amorphous filaments exhibit a compressive modulus value which is 50% lower than what is observed for a reference semi-crystalline PET filament. Analysis of the compressive strains applied by the bending recovery test indicates that while the maximum applied strains remain well within the region of elastic deformation of the amorphous materials, the threshold between elastic and plastic deformation is reached for the semi-crystalline materials.

DNA as a perfect quantum computer based on the quantum physics principles.

DNA is a complex multi-resolution molecule whose theoretical study is a challenge. Its intrinsic multiscale nature requires chemistry and quantum physics to understand the structure and quantum informatics to explain its operation as a perfect quantum computer. Here, we present theoretical results of DNA that allow a better description of its structure and the operation process in the transmission, coding, and decoding of genetic information. Aromaticity is explained by the oscillatory resonant quantum state of correlated electron and hole pairs due to the quantized molecular vibrational energy acting as an attractive force. The correlated pairs form a supercurrent in the nitrogenous bases in a single band π -molecular orbital ( π -MO). The MO wave function ( Φ ) is assumed to be the linear combination of the n constituent atomic orbitals. The central Hydrogen bond between Adenine (A) and Thymine (T) or Guanine (G) and Cytosine (C) functions like an ideal Josephson Junction. The approach of a Josephson Effect between two superconductors is correctly described, as well as the condensation of the nitrogenous bases to obtain the two entangled quantum states that form the qubit. Combining the quantum state of the composite system with the classical information, RNA polymerase teleports one of the four Bell states. DNA is a perfect quantum computer.

Expression of human endogenous retrovirus HERV-K18 is associated with clinical severity in osteoarthritis patients.

OBJECTIVES: The aim of this study was to evaluate the involvement of human endogenous retrovirus K18 (HERV-K18) in osteoarthritis (OA), by genotyping the HERV-K18 env locus in OA patients and controls, and analysing HERV-K18 RNA expression and its association with OA risk and clinical variables. METHOD: We recruited 558 patients with symptomatic OA and 600 controls. We performed the genotyping by TaqMan assays and the analysis of expression by quantitative real-time polymerase chain reaction (qRT-PCR). Scores on the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), the Lequesne index, and the Stanford Health Assessment Questionnaire (HAQ) were analysed with regard to the expression levels of HERV-K18. RESULTS: The 18.3 haplotype tended towards an association with OA risk and concordantly this haplotype was associated with a higher HERV-K18 expression (p = 0.05). We found statistically significant differences when we compared the scores on the WOMAC, the Lequesne index for knee and hip, and the HAQ between OA patients with higher expression [normalization ratio (NR) > 10] and OA patients without HERV-K18 expression (p = 0.0003, 0.0005, 0.002, and 0.05, respectively), and also when the comparison was made between OA patients with higher expression (NR > 10) and OA patients with low expression of HERV-K18 (NR = 1) for the WOMAC and the Lequesne index for knee and hip (p = 0.002, 0.013, and 0.006, respectively). CONCLUSIONS: We found an association between health status measurement systems and severity index for OA and the levels of expression of HERV-K18. These results suggest the possible involvement of HERV-K18 in the aetiopathogenesis of the disease.

Mechanical bowel preparation for esophagocoloplasty in children: is it really necessary?

Esophagocoloplasty is a commonly performed procedure for esophageal replacement in children. Traditionally, mechanical bowel preparation (MBP) is performed before this operation. However, this practice has been questioned, initially in adults and now in children. The aim of this study was to evaluate the influence of MBP on esophagocoloplasty in a series of children. Data collected from 164 patients who underwent esophagocoloplasty in the Pediatric Surgery Division, University of São Paulo Medical School, from February 1978 to July 2011 were reviewed for postoperative complications. In 134 patients, at least one kind of MBP was performed before the surgery (PREP group). MBP was omitted in 30 patients (NO-PREP group). There was no statistical difference between the groups in the rates of evisceration, colocolic, or cologastric anastomotic dehiscence and death. However, in the NO-PREP group, the incidence of cervical leakage (6.6%) was significantly decreased in comparison with the classical PREP group (25.3%) (P= 0.03). The results of this study suggest that the omission of MBP has a positive impact on the incidence of postoperative complications in esophagocoloplasty.

Fear and/or anxiety of children and parents associated with the dental environment.

AIM: To assess levels of anxiety in children concerning different dental instruments and equipment and to relate them with parents' anxiety levels moments before the appointment. MATERIALS AND METHODS: Fifty children from 4 to 12 years of age (average of 10±3.07) and their respective parents were evaluated. A facial scale was used to assess children's anxiety levels, while the Dental Anxiety Scale (DAS) was used to assess parents. Friedman test was applied to check any differences in children's anxiety levels relative to the equipment/instruments, and this was complemented by the use of the Wilcoxon test for two-by-two comparison. In order to assess correlation between parents' and their children's anxiety levels, the study used Spearman correlation coefficient. RESULTS: With regard to parents' anxiety levels, 4% resulted as null, 18% were low, 56% were moderate, and 22% were exacerbated; children's anxiety level results were: 52% light, 44% intermediate, and 4% intense. Anxiety levels related to instruments/equipment were, in descending order: carpule syringe > paediatric forceps > dental explorer > x-ray machine > rubber dam punch > high speed handpiece > rubber dam forceps > mouth mirror > clinical tweezers > dental chair. No correlation was found between parents' anxiety levels and those of their children (p=0.546). CONCLUSION: The instruments/equipment used in the assessment generated different anxiety levels in the children. No correlation was found between parents' anxiety levels and those of their children.

NMR Relaxation by Redfield equation in a spin system I=7/2.

The Redfield master equation was solved analytically for a nuclear system with spin I=7/2. Using the irreducible tensor operator basis, the solutions of each density matrix element were computed. The experimental setup consisted of the 133Cs nuclei of the cesium-pentadecafluorooctanoate molecule in a lyotropic liquid crystal sample in the nematic phase at room temperature. Experimental longitudinal and transverse magnetization dynamics of the 133Cs nuclei were monitored, and the theoretical approach was used to generate valuable mathematical expressions with the highest accuracy through numerical procedures. This methodology can be extended to other nuclei with minimal difficulties.

Use of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase in wound healing in diabetic rats.

Diabetes mellitus is associated with neural and micro- and macrovascular complications. Therapeutic options for these complications are limited and the delivery of mesenchymal stem cells into lesions have been reported to improve the healing process. In this work, the effects of the administration of a lineage of human bone marrow mesenchymal stem cells immortalized by the expression of telomerase (hBMSC-TERT) as a potential therapeutic tool for wound healing in diabetic rats were investigated. This is the first description of the use of these cells in diabetic wounds. Dorsal cutaneous lesions were made in streptozotocin-induced diabetic rats and hBMSC-TERT were subcutaneously administered around the lesions. The healing process was evaluated macroscopically, histologically, and by birefringence analysis. Diabetic wounded rats infused with hBMSC-TERT (DM-TERT group) and the non-diabetic wounded rats not infused with hBMSC-TERT (CW group) had very similar patterns of fibroblastic response and collagen proliferation indicating improvement of wound healing. The result obtained by birefringence analysis was in accordance with that obtained by the histological analysis. The results indicated that local administration of hBMSC-TERT in diabetic wounds improved the wound healing process and may become a therapeutic option for wounds in individuals with diabetes.

Alcohol-free hand sanitizer and other quaternary ammonium disinfectants quickly and effectively inactivate SARS-CoV-2.

BACKGROUND: SARS-CoV-2 is the virus responsible for the current global pandemic, COVID-19. Because this virus is novel, little is known about its sensitivity to disinfection. METHODS: We performed suspension tests against SARS-CoV-2 using three commercially available quaternary ammonium compound (Quat) disinfectants and one laboratory-made 0.2% benzalkonium chloride solution. FINDINGS: Three of the four formulations completely inactivated the virus within 15 s of contact, even in the presence of a soil load or when diluted in hard water. CONCLUSION: Quats rapidly inactivate SARS-CoV-2, making them potentially useful for controlling SARS-CoV-2 spread in hospitals and the community.

Efficiency of RAPD versus SSR markers for determining genetic diversity among popcorn lines.

Using only one type of marker to quantify genetic diversity generates results that have been questioned in terms of reliability, when compared to the combined use of different markers. To compare the efficiency of the use of single versus multiple markers, we quantified genetic diversity among 10 S(7) inbred popcorn lines using both RAPD and SSR markers, and we evaluated how well these two types of markers discriminated the popcorn genotypes. These popcorn genotypes: "Yellow Pearl Popcorn" (P1-1 and P1-5), "Zélia" (P1-2 and P1-4), "Curagua" (P1-3), "IAC 112" (P9-1 and P9-2), "Avati Pichinga" (P9-3 and P9-5), and "Pisankalla" (P9-4) have different soil and climate adaptations. Using RAPD marker analysis, each primer yielded bands of variable intensities that were easily detected, as well as non-specific bands, which were discarded from the analysis. The nine primers used yielded 126 bands, of which 104 were classified as polymorphic, giving an average of 11.6 polymorphisms per primer. Using SSR procedures, the number of alleles per locus ranged from two to five, giving a total of 47 alleles for the 14 SSR loci. When comparing the groups formed using SSR and RAPD markers, there were similarities in the combinations of genotypes from the same genealogy. Correlation between genetic distances obtained through RAPD and SSR markers was relatively high (0.5453), indicating that both techniques are efficient for evaluating genetic diversity in the genotypes of popcorn that we evaluated, though RAPDs yielded more polymorphisms.

Reaching task performance is associated to neuromuscular junction adaptations in rats with induced diabetes mellitus.

Upper limb performance is affected by diabetes mellitus (DM). Neuromuscular junction (NMJ) is a key structure to understand the relationship between performance and morphology in DM. The aim of the study was to analyze NMJ plasticity due to DM in an animal model and its relationship with the function of forelimbs in rats. Twelve Wistar rats were divided into control (C) and DM groups. Animals were trained to perform a grasping task, following procedures of habituation, shaping, and reaching task. DM was induced using streptozotocin. Forelimb neuromuscular performance for dexterity was evaluated one day before DM induction and five weeks following induction. After that, biceps, triceps, and finger flexors and extensors were removed. Connective tissue and muscle fiber cross-sectional area (CSA) were measured. NMJ was assessed by its morphometric characteristics (area, perimeter, and maximum diameter), using ImageJ software. Motor performance analyses were made using single pellet retrieval task performance test. Student's t-test was used for comparisons between groups. A significant decrease in all NMJ morphometric parameters was observed in the DM group compared with the C group. Results showed that DM generated NMJ retraction in muscles involved in a reaching task. These alterations are related to signs of muscular atrophy and to poor reaching task performance. In conclusion, induced DM caused NMJ retraction and muscular atrophy in muscles involved in reaching task performance. Induced DM caused significantly lower motor performance, especially in the final moments of evaluation, when DM compromised the tropism of the muscular tissue.

Cerebral phaeohyphomycosis caused by Alternaria spp.: A case report.

Phaeohyphomycosis is a group of infections caused by pigmented, black, dematiaceous fungi and is responsible for cutaneous, superficial and deep mycoses, disseminated infection and brain abscesses. The primary agents involved include Alternaria spp., Exophiala spp. and Cladophialophora spp. Invasive systemic presentation is rare and in most cases is associated with immunosuppression; for this reason, reported cases of Alternaria spp. infection are scarce. This report describes the case of a 66-year-old man with a history of renal transplantation from a cadaveric donor 1 year ago, which was considered as the primary risk factor. The characteristics of the infection, procedures performed, microbiological findings and treatment provided are described.