Malleostapedotomy for otosclerosis,our experience of nitinol piston on twelve patients

ObjectiveMalleostapedotomy allows to completely by-pass the incus in otosclerosis surgery. Recently its use has been rivaled by hydroxyapatite cement for cases of mild and moderate necrosis of the incus. However, it remains gold standard for cases of extensive necrosis, incus dislocation, or epitympanic fixation. Modern heat-crimping pistons make surgery easier and safer. This study focuses on our experience with this technique.MethodsRetrospective analysis of patient’s files and pre- and post-operative audiograms, for cases of surgically treated otosclerosis with malleostapedotomy.ResultsTwelve patients underwent malleostapedotomy for otosclerosis between 2011 and 2019. Amongst them there were 10 revision surgeries and 2 primary cases. 75% had incus long-process necrosis, 17% had epitympanic fixation and one had a history of incus transposition. Nine patients (75%) had closure of air-bone gap (ABG) of <10 dB (p < 0.001) and 11 (92%) had a threshold of 20 dB (p < 0.001). Mean pre-operative ABG was 31 dB (15 dB–55 dB), and mean post-operative ABG was 7 dB (0 dB–21 dB; p < 0.001). There was no sensorineural hearing loss nor any other post-operative complication.ConclusionsMalleostapedotomy is a safe and reliable technique, allowing an ABG closure comparable to conventional incus to vestibule prosthesis. It remains the preferred technique whenever the incus cannot be used.     

Qualitative evidence for Resilience,Stress, and Ethnicity (RiSE): A program to address race-based stress among Black women at risk for cardiovascular disease

ObjectiveGrowing evidence demonstrates that perceived discrimination and racism are significant contributing factors to psychological distress, low-grade chronic inflammation, and cardiovascular health disparities among minorities, particularly among Black women. Despite this evidence, there are no evidence-based complementary therapy interventions available to ameliorate chronic stress associated with racism and discrimination. The purpose of this study was to examine the feasibility and effectiveness of a novel, 8-week, group-based stress reduction program, Resilience, Stress and Ethnicity (RiSE), designed to help Black women at risk for cardiovascular disease (CVD) develop effective coping skills for dealing with chronic stress uniquely associated with being a minority.MethodsWe conducted two semi-structured focus groups with Black women (N = 22) following their participation in the 8-week RiSE program. We analyzed the data using constant comparative qualitative methods.ResultsAttrition rate was low (13%) with all participants attending at least 6 of the 8 classes. Participants reported high levels of satisfaction with the program and the majority (81%) reported practicing the skills that they learned in real-life stressful situations. In describing the participants’ response to the program, four key categories emerged from the data: (1) Increasing awareness of stressors associated with perceived discrimination and racism; (2) Coping with race-based stressors; (3) Coping with other sources of stress; and (4) Increasing sense of empowerment and emotion regulation.ConclusionsFindings suggest that RiSE is feasible and effective in helping Black women at risk for CVD cope with chronic stress associated with being a minority. Given evidence that perceived discrimination and racism are underlying factors in many inflammatory-based chronic diseases, this research may have broader implications for reducing health disparities across a wide-spectrum of chronic illnesses in which women minorities are disproportionately affected.     

Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

The Second Victim Phenomenon: How Are Midwives Affected?

Perinatal care providers are likely to encounter adverse events such as intrapartum emergencies, traumatic births, or maternal or fetal deaths. As a result of being directly or indirectly involved in an adverse event, health care providers can be considered second victims. The experience of the second victim phenomenon can lead to significant physical, psychological, and psychosocial sequelae that can negatively impact the provider's personal and professional life for either a short or long duration of time. When health care providers experience an adverse event, they may manifest symptoms of guilt, shame, blame, flashbacks, nightmares, insomnia, isolation, helplessness, and hopelessness, thereby becoming the second victim. Following an adverse event, health care providers who experience second victim phenomenon experience stages of recovery that influence subsequent professional and personal well‐being. Persons who experience the second victim phenomenon can incorporate self‐care behaviors to assist with recovery. Health care organizations have a responsibility to implement efficacious support programs that promote the provider's recovery and a return to safe and full function in the workplace.     

Biomarker directed chronic wound therapy – A new treatment paradigm

AimTo develop a treatment paradigm for chronic leg ulcers that incorporates new biomarkers of wound healing with currently available therapies.MethodsRecently published data on GM-CSF and MMP-13 as biomarkers of venous leg ulcer (VLU) healing status with accuracies of 92% and 78% respectively, was reviewed along with the wound bed preparation (WBP) theoretical framework for treatment of chronic wounds. The broad categories of wound treatments that align with the WBP concepts were identified. These were then considered in a hierarchical order that initially improves the wound bed and subsequently incorporates more complex advanced wound therapies. Identification of the non-healing status of the wound is the driver to advance through the different treatments.ResultsA point of care test of wound healing status is the key to the systematic use of currently available therapies for chronic leg ulcers in a timely fashion. The different therapies address – debridement, moisture control, bacterial contamination, protease inhibition, formation of granulation tissue, application of growth factors, application of matrix constructs, and application of cellular components. Progression through this hierarchical order of therapies is directed by the leg ulcer remaining in a non-healing state with the previous therapies having been implemented.ConclusionCombining a validated point of care test of wound healing with a systematic approach to wound therapies, has the potential to create a new paradigm of chronic leg ulcer treatment - biomarker directed wound therapy.     

Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Metastatic melanoma is the most deadly skin neoplasm in the United States. Outcomes for this lethal disease have improved dramatically due to the use of both targeted and immunostimulatory drugs. Immunogenic cell death (ICD) has emerged as another approach for initiating antitumor immunity. ICD is triggered by tumor cells that display damage-associated molecular patterns (DAMPs). These DAMP molecules recruit and activate dendritic cells (DCs) that present tumor-specific antigens to T cells which eliminate neoplastic cells. Interestingly, the expression of DAMP molecules occurs in an endoplasmic reticulum (ER) stress-dependent manner. We have previously shown that ER stress was required for the cytotoxic activity of the endocannabinoid metabolite, 15-deoxy, Δ^12,14 prostamide J₂ (15dPMJ₂). As such, the current study investigates whether 15dPMJ₂ induces DAMP signaling in melanoma. In B16F10 cells, 15dPMJ₂ caused a significant increase in the cell surface expression of calreticulin (CRT), the release of ATP and the secretion of high-mobility group box 1 (HMGB1), three molecules that serve as surrogate markers of ICD. 15dPMJ₂ also stimulated the cell surface expression of the DAMP molecules, heat shock protein 70 (Hsp70) and Hsp90. In addition, the display of CRT and ATP was increased by 15dPMJ₂ to a greater extent in tumorigenic compared to non-tumorigenic melanocytes. Consistent with this finding, the activation of bone marrow-derived DCs was upregulated in co-cultures with 15dPMJ₂-treated tumor compared to non-tumor melanocytes. Moreover, 15dPMJ₂-mediated DAMP exposure and DC activation required the electrophilic cyclopentenone double bond within the structure of 15dPMJ₂ and the ER stress pathway. These results demonstrate that 15dPMJ₂ is a tumor-selective inducer of DAMP signaling in melanoma.     

Review/overview of pain in sickle cell disease

Sickle cell disease (SCD) is a highly complex inherited disorder of hemoglobin structure. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Its manifestations could be acute, chronic, nociceptive, neuropathic that could occur singly or in various combinations. Pain continues to be the major factor of SCD phenotypic complications and the most common cause of admissions to the Emergency Department and/or the hospital. Although progress has been made in understanding the pathophysiology of SCD as well as in developing curative therapies such as hematopoietic stem cell transplantation and gene therapy, effective pain management continues to lag behind. Palliative therapies continue to be the major approach to the management of SCD and its complications. The advent of hydroxyurea made partial success in preventing the frequency of vaso-occlusive crises and l-glutamine awaits post-trial confirmation of benefits. The search for additional pharmacotherapeutic agents that could be used singly or in combination with hydroxyurea and/or l-glutamine awaits their dawn hopefully in the near future. The purpose of this review is to describe the various manifestations of SCD, their pathophysiology and their current management. Recent impressive advances in understanding the pathophysiology of pain promise the determination of agents that could replace or minimize the use of opioids.     

Anti-inflammatory and anti-oxidant effects of aloe vera in rats with non-alcoholic steatohepatitis

BACKGROUND Aloe vera exerts several biological activities, such as, anti-inflammatory, antioxidant, and antimicrobial effects. It was recently shown to reduce insulin resistance and triglyceride level. We hypothesized that aloe vera would have beneficial effects in alleviating non-alcoholic steatohepatitis(NASH) in rats.AIM To examine the therapeutic effects of aloe vera in NASH rats.METHODS All rats were randomly divided into 3 groups(n = 6 in each group). Rats in the control group were fed ad libitum with a standard diet for 8 wk. Rats in the NASH group were fed ad libitum with a high-fat high-fructose diet(HFHFD) for 8 wk. Rats in the aloe vera group were fed ad libitum with a HFHFD and aloe vera in dimethylsulfoxide(50 mg/kg) by gavage daily for 8 wk. Liver samples were collected at the end of the treatment period.RESULTS Hepatic malondialdehyde(MDA) levels increased significantly in the NASH group as compared with the control group(377 ± 77 nmol/mg vs 129 ± 51 nmol/mg protein, respectively, P 0.001). Glutathione(GSH) levels were significantly lower in the NASH group than the control group(9 ± 2 nmol/mg vs 24 ± 8 nmol/mg protein, respectively, P = 0.001). The expression of interleukin-18(IL-18), nuclear factor-kappa β, and caspase-3 increased, while peroxisome proliferator-activated receptor gamma decreased in the NASH group compared with the controls. Following aloe vera administration, MDA levels decreased(199 ± 35 nmol/mg protein) and GSH increased(18 ± 4 nmol/mg protein) markedly. Steatosis, hepatocyte ballooning, lobular inflammation and increased hepatocyte apoptosis were observed in the NASH group. Aloe vera treatment attenuated these changes in liver histology.CONCLUSION Aloe vera attenuated oxidative stress, hepatic inflammation and hepatocyte apoptosis, thus improving liver pathology in rats with NASH.     

NADPH oxidase inhibition rescues keratinocytes from elevated oxidative stress in a 2D atopic dermatitis and psoriasis model

Emerging evidence suggests oxidative stress plays a role in the pathophysiology of both atopic dermatitis (AD) and psoriasis (PSO). We established in vitro models of AD and PSO skin, and characterized these models in regard to their oxidative stress state. Both AD and PSO model keratinocytes exhibited elevated reactive oxygen species (ROS) levels and accumulated more DNA damage than control cells after oxidative stress induced by 250 µmol/L H₂O₂. Elevated ROS levels and DNA damage accumulation could be inhibited by the NADPH oxidase (NOX) inhibitor diphenyleneiodonium (DPI). Further, immunofluorescence analysis revealed the presence of both NOX1 and NOX4 in keratinocytes. By inhibiting NOX1, stress-related signalling cascades and elevated ROS levels could be abrogated, and survival of AD and PSO cells improved. Taken together, this study reveals that inhibition of NOX inhibition could abrogate elevated oxidative stress in a 2D model of AD and PSO.