Damage sensing through TLR9 Promotes Viral Clearance and Recovery During Influenza Infection.

Host response aimed at eliminating the infecting pathogen, as well as the pathogen itself, can cause tissue injury. Tissue injury leads to the release of a myriad of cellular components including mitochondrial DNA, which the host senses through pattern recognition receptors. How the sensing of tissue injury by the host shapes the anti-pathogen response remains poorly understood. In this study, we utilized mice that are deficient in toll-like receptor-9 (TLR9), which binds to unmethylated CpG DNA sequences such as those present in bacterial and mitochondrial DNA. To avoid direct pathogen sensing by TLR9, we utilized the influenza virus, which lacks ligands for TLR9, to determine how damage sensing by TLR9 contributes to anti-influenza immunity. Our data show that TLR9-mediated sensing of tissue damage promotes an inflammatory response during early infection, driven by the myeloid cells and associated cytokine responses. Along with the diminished inflammatory response, the absence of damage sensing through TLR9 led to impaired viral clearance manifested as a higher and prolonged influenza burden in the lung. The absence of TLR9 led to extensive infection of myeloid cells including monocytes and macrophages rendering them highly inflammatory, despite having a low initial inflammatory response. The persistent inflammation driven by infected myeloid cells led to persistent lung injury and impaired recovery in influenza-infected TLR9-/- mice. Further, we show elevated circulating TLR9 ligands in the plasma samples of patients with influenza, demonstrating its clinical relevance. Overall, over data show an essential role of damage sensing through TLR9 in promoting anti-influenza immunity.

The Impact of Coronavirus Disease 2019 on Viral, Bacterial, and Fungal Respiratory Infections.

Although coronavirus disease 2019 (COVID-19) remains an ongoing threat, concerns regarding other respiratory infections remain. Throughout the COVID-19 pandemic various epidemiologic trends have been observed in other respiratory viruses including a reduction in influenza and respiratory syncytial virus infections following onset of the COVID-19 pandemic. Observations suggest that infections with other respiratory viruses were reduced with social distancing, mask wearing, eye protection, and hand hygiene practices. Coinfections with COVID-19 exist not only with other respiratory viruses but also with bacterial pneumonias and other nosocomial and opportunistic infections. Coinfections have been associated with increased severity of illness and other adverse outcomes.

Helicopter parenting, from good intentions to poor outcomes. What parents needs to know?

Background: A single child is precious for every parent. There is an increasing demand for children to perform and to excel in all aspects of their lives. Due to increased unemployment and less job opportunities, tough competition to get admission in good school and college and to get respectable job put every parent under constant stress. These circumstances lead to parents starting micromanagement of their children. This micromanagement can be harmful to the mental and emotional wellbeing of the child, and is especially seen in single-child parents. Objective: This study aimed to ascertain if parents of single child show behavior of helicopter parenting as compared to patents having more than one child. Methods: This is an open-ended observational study, wherein 100 families with single child and 50 families with more than one child were interviewed based on self-explanatory questionnaire methods. Results: We noted that 83% parents showed behavior of helicopter parenting, especially those who have single child as compared to those having more than one child. Conclusion: Based on our survey, we can conclude that parents of single child showed behavior of helicopter parenting as compared to patents having more than one child because only child is precious and center of attraction in the families especially in Indian culture. However, large studies are required to reach a definitive conclusion.

Hypoplastic femur with pathologic femoral shaft fracture associated with extensive arteriovenous malformations. A series of five cases.

Introduction: Extremities arteriovenous malformations are uncommon vascular lesions that usually go unnoticed until a fracture occurs or imaged for other medical problems. The lesion is invariably quiescent, infiltrative in nature, and leads to the destruction of soft tissue and bone. Worldwide 20-30 % incidence of arteriovenous malformations has been noted in bones. This arteriovenous malformation greatly affects bone growth as compared to the normal side and leads to pathological fracture. However, few reports on the management of such pathologic fractures associated with AVM have been published in the literature.The main problem is to decide the types of implants and whether open or closed reduction. Here, we present a case series of pathologic femoral shaft fracture associated with multiple hemangiomas in the thigh that was treated successfully by minimally invasive distal femoral locking plate fixation and teriparatide. Case Presentation: We are describing our one index case. A 39-year-old woman, otherwise healthy, sustained a fall and developed a left femoral shaft fracture. At the time of admission, she had swelling and venous varicosities and non-itchy, blanchable violet patches over the left thigh. Plain radiography of the left thigh revealed Hypoplastic femoral shaft with a markedly obliterated medullary canal with distal 1/3 rd fracture with calcification of soft tissue. We planned open reduction and distal locking femoral plating because medullary canal was very small to accommodate intramedullary nail following embolization of the feeding artery. While performing open reduction, a considerable amount of bleeding (1300 ml) after incision of subcutaneous tissue occurred. After successful fracture fixation, union was achieved with administration of teriparatide 12 months postoperatively. At present patient is able to walk using elbow support. Conclusion: We present the five cases of pathologic fracture associated with large AVMs that achieved fracture union using minimally invasive distal femoral locking plate fixation and teriparatide.

Coronavirus Lung Infection Impairs Host Immunity against Secondary Bacterial Infection by Promoting Lysosomal Dysfunction.

Postviral bacterial infections are a major health care challenge in coronavirus infections, including COVID-19; however, the coronavirus-specific mechanisms of increased host susceptibility to secondary infections remain unknown. In humans, coronaviruses, including SARS-CoV-2, infect lung immune cells, including alveolar macrophages, a phenotype poorly replicated in mouse models of SARS-CoV-2. To overcome this, we used a mouse model of native murine ß-coronavirus that infects both immune and structural cells to investigate coronavirus-enhanced susceptibility to bacterial infections. Our data show that coronavirus infection impairs the host ability to clear invading bacterial pathogens and potentiates lung tissue damage in mice. Mechanistically, coronavirus limits the bacterial killing ability of macrophages by impairing lysosomal acidification and fusion with engulfed bacteria. In addition, coronavirus-induced lysosomal dysfunction promotes pyroptotic cell death and the release of IL-1ß. Inhibition of cathepsin B decreased cell death and IL-1ß release and promoted bacterial clearance in mice with postcoronavirus bacterial infection.

Awareness regarding foot self-care practices among diabetic patients in Northeast part of India. Can primary care physician make a difference? A hospital based cross-sectional study.

Background: About 10% of patients with type 2 diabetes mellitus at the time of diagnosis have more than one risk factor for developing foot ulceration, and it increases to 15% in a lifetime. The risk of development of Diabetic foot ulcers/gangrene can be prevented by the patient's self-foot care practice at home. The present study aimed to determine the prevalence of awareness of self-foot care practice among diabetic patients in a rural setting. The study also aimed to identify the factors preventing dry or wet diabetic gangrene development and subsequent amputation. Methods: A hospital-based cross-sectional study was carried out among 1687 people with diabetes mellitus (DM) who attended orthopedic and diabetic OPD in a tertiary care hospital in Kamrup, Assam, India. An appropriate self-explanatory questionnaire about knowledge of self-foot care practice was given to all study participants. Foot examination was performed by authors participated in the study on all patients. The observations and results were categorized according to the International Diabetes Federation foot risk categories. Results: Of 1687 patients included in this study, 298 (17.7%) had foot ulcers of various grades, 164 (9.76%) had peripheral vascular disease, and 484 (28.7%), had peripheral neuropathy of different grades. After multivariate analysis, patients on insulin and combination therapy and peripheral neuropathy were significantly associated with the presence of foot ulcers. The mean knowledge score was as low as 9.7 ± 4.8 out of a total score of 23. Low awareness and knowledge were associated with low mean scores due to a lack of formal education (8.3 ± 6.1). Among the 1687 patients, only 381 (22.5%) are aware and have some knowledge about self-foot care, and 686 (40.6%) had their feet examined by a doctor only once since their initial diagnosis. The incidence of development of diabetic-related complications was significantly low in those who know about foot self-care as well as those whose feet had been inspected by a physician at least once. Conclusion: The incidence of development of diabetic-related complications was significantly low in those who know about foot self-care as well as those whose feet had been examined by a physician of family doctors at least once. There is a need to educate all patients of diabetes about self-foot care. It is prudent to establish an integrated foot care services within primary care centers and in the diabetic clinic to identify feet at risk, institute early preventive measures, and provide continuous foot care education through images videos on WhatsApp to patients and primary health care givers.

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is recognized as a disease of accelerated lung aging. Over the past two decades, mounting evidence suggests an accumulation of senescent cells within the lungs of patients with COPD that contributes to dysregulated tissue repair and the secretion of multiple inflammatory proteins, termed the senescence-associated secretory phenotype (SASP). Cellular senescence in COPD is linked to telomere dysfunction, DNA damage, and oxidative stress. This review gives an overview of the mechanistic contributions and pathologic consequences of cellular senescence in COPD and discusses potential therapeutic approaches targeting senescence-associated signaling in COPD.

Distinct Roles of Type I and Type III Interferons during a Native Murine ß Coronavirus Lung Infection.

Coronaviruses are a major health care threat to humankind. Currently, the host factors that contribute to limit disease severity in healthy young patients are not well defined. Interferons are key antiviral molecules, especially type I and type III interferons. The role of these interferons during coronavirus disease is a subject of debate. Here, using mice that are deficient in type I (IFNAR1-/-), type III (IFNLR1-/-), or both (IFNAR1/LR1-/-) interferon signaling pathways and murine-adapted coronavirus (MHV-A59) administered through the intranasal route, we define the role of interferons in coronavirus infection. We show that type I interferons play a major role in host survival in this model, while a minimal role of type III interferons was manifested only in the absence of type I interferons or during a lethal dose of coronavirus. IFNAR1-/- and IFNAR1/LR1-/- mice had an uncontrolled viral burden in the airways and lung and increased viral dissemination to other organs. The absence of only type III interferon signaling had no measurable difference in the viral load. The increased viral load in IFNAR1-/- and IFNAR1/LR1-/- mice was associated with increased tissue injury, especially evident in the lung and liver. Type I but not type III interferon treatment was able to promote survival if treated during early disease. Further, we show that type I interferon signaling in macrophages contributes to the beneficial effects during coronavirus infection in mice. IMPORTANCE The antiviral and pathological potential of type I and type III interferons during coronavirus infection remains poorly defined, and opposite findings have been reported. We report that both type I and type III interferons have anticoronaviral activities, but their potency and organ specificity differ. Type I interferon deficiency rendered the mice susceptible to even a sublethal murine coronavirus infection, while the type III interferon deficiency impaired survival only during a lethal infection or during a sublethal infection in the absence of type I interferon signaling. While treatment with both type I and III interferons promoted viral clearance in the airways and lung, only type I interferons promoted the viral clearance in the liver and improved host survival upon early treatment (12 h postinfection). This study demonstrates distinct roles and potency of type I and type III interferons and their therapeutic potential during coronavirus lung infection.

Comparative study of role of physiotherapy alone versus physiotherapy combined with yoga in rehabilitation after a sports injury. What can a primary physician offer?

Background: Posttraumatic rehabilitation of sports injuries involves physiotherapy. Additionally, nonsurgical treatment of sports injuries involves regular physiotherapy as a major treatment therapy. This study aimed to evaluate the effects of yoga in addition to regular physiotherapy on these patients. Materials and Methods: In the present comparative study, we evaluated the effects of regular physiotherapy alone versus physiotherapy combined with yoga on 212 patients following various knee injuries treated nonsurgically. The study was conducted after obtaining hospital ethical, committee clearance, and written informed consent from patients. The patients were assigned into two groups: group C (Conventional) and group Y (Yoga group). The patients in the regular group received physiotherapy rehabilitation program, whereas the yoga group received additional yoga once every day by a yoga expert during their hospital stay. We provided written guidelines and photographs of the yoga asanas and instructed to perform them 3 days/week once they were home. The data on WOMAC score were collected at 6 weeks, 3 months, and at 6 months from the day of discharge from the hospital. Results: We noted that the yoga group patients showed a significant improvement (P < 0.05) in all modalities like pain, stiffness, and function subscales of the WOMAC scale. They experienced significant reduction in pain and stiffness compared with the regular or conventional group on the seventh postinjury day, 6 weeks, 3 months, and 6 months after the initial injury. Conclusion: In this study, a combination of regular physiotherapy and yoga provided better functional outcomes than physiotherapy alone.

Airway Resistance Caused by Sphingomyelin Synthase 2 Insufficiency in Response to Cigarette Smoke.

Sphingomyelin synthase is responsible for the production of sphingomyelin (SGM), the second most abundant phospholipid in mammalian plasma, from ceramide, a major sphingolipid. Knowledge of the effects of cigarette smoke on SGM production is limited. In the present study, we examined the effect of chronic cigarette smoke on sphingomyelin synthase (SGMS) activity and evaluated how the deficiency of Sgms2, one of the two isoforms of mammalian SGMS, impacts pulmonary function. Sgms2-knockout and wild-type control mice were exposed to cigarette smoke for 6 months, and pulmonary function testing was performed. SGMS2-dependent signaling was investigated in these mice and in human monocyte-derived macrophages of nonsmokers and human bronchial epithelial (HBE) cells isolated from healthy nonsmokers and subjects with chronic obstructive pulmonary disease (COPD). Chronic cigarette smoke reduces SGMS activity and Sgms2 gene expression in mouse lungs. Sgms2-deficient mice exhibited enhanced airway and tissue resistance after chronic cigarette smoke exposure, but had similar degrees of emphysema, compared with smoke-exposed wild-type mice. Sgms2-/- mice had greater AKT phosphorylation, peribronchial collagen deposition, and protease activity in their lungs after smoke inhalation. Similarly, we identified reduced SGMS2 expression and enhanced phosphorylation of AKT and protease production in HBE cells isolated from subjects with COPD. Selective inhibition of AKT activity or overexpression of SGMS2 reduced the production of several matrix metalloproteinases in HBE cells and monocyte-derived macrophages. Our study demonstrates that smoke-regulated Sgms2 gene expression influences key COPD features in mice, including airway resistance, AKT signaling, and protease production.

Cigarette smoke exposure reduces leukemia inhibitory factor levels during respiratory syncytial viral infection.

Background: Viral infections are considered a major driving factor of chronic obstructive pulmonary disease (COPD) exacerbations and thus contribute to disease morbidity and mortality. Respiratory syncytial virus (RSV) is a frequently detected pathogen in the respiratory tract of COPD patients during an exacerbation. We previously demonstrated in a murine model that leukemia inhibitory factor (LIF) expression was increased in the lungs during RSV infection. Subduing LIF signaling in this model enhanced lung injury and airway hypersensitivity. In this study, we investigated lung LIF levels in COPD patient samples to determine the impact of disease status and cigarette smoke exposure on LIF expression. Materials and methods: Bronchoalveolar lavage fluid (BALF) was obtained from healthy never smokers, smokers, and COPD patients, by written informed consent. Human bronchial epithelial (HBE) cells were isolated from healthy never smokers and COPD patients, grown at the air-liquid interface and infected with RSV or stimulated with polyinosinic:polycytidylic acid (poly (i:c)). Mice were exposed to cigarette smoke daily for 6 months and were subsequently infected with RSV. LIF expression was profiled in all samples. Results: In human BALF, LIF protein was significantly reduced in both smokers and COPD patients compared to healthy never smokers. HBE cells isolated from COPD patients produced less LIF compared to never smokers during RSV infection or poly (i:c) stimulation. Animals exposed to cigarette smoke had reduced lung levels of LIF and its corresponding receptor, LIFR. Smoke-exposed animals had reduced LIF expression during RSV infection. Two possible factors for reduced LIF levels were increased LIF mRNA instability in COPD epithelia and proteolytic degradation of LIF protein by serine proteases. Conclusions: Cigarette smoke is an important modulator for LIF expression in the lungs. Loss of LIF expression in COPD could contribute to a higher degree of lung injury during virus-associated exacerbations.

Knowledge about Informed Consent among Doctors of Various Specialities: A Pilot Survey.

BACKGROUND: Informed consent is an integral part of clinical practice. Improper informed consent can lead to mistrust between doctors and patients as well as medico-legal issues. Awareness and knowledge of various aspects of consent is essential in present day medical practice. METHODS: A paper and web-based survey was undertaken to evaluate knowledge about informed consent among doctors. A law and a medical student generated a list of questions based upon available case laws and legislations which were further validated by experts. 500 doctors undertook the survey and of these 457 completed the survey of 18 questions. Both univariate and multivariate models were used to analyze responses. RESULTS: 413 complete questionnaires were included in the analysis. The proportion of respondents furnishing correct responses varied between 49.6% and 93.7%. There were 9 questions for which, over 25% respondents provided inappropriate responses. The questions included those enquiring whether initial consent for diagnostic or therapeutic procedures could apply to extended procedures or surgery and who was capable of giving consent for different procedures. There were significant differences of knowledge between residents and consultants for few questions. The physicians fared worse than surgeons and anesthetists although the difference was not statistically significant. CONCLUSION: Significant knowledge gaps were identified. There were deficiencies in providing correct response particularly in practical scenarios. There is a need to include knowledge about different aspects of informed consent in the medical curriculum.

Treatment of postmenopausal osteoporosis.

Osteoporosis is a skeletal disease characterized by low bone mass and microarchitectural deterioration with a resulting increase in bone fragility and hence susceptibility to fracture. Calcium and vitamin D are the most commonly used therapies for osteoporosis, although their efficacy in osteoporotic fracture prevention remains uncertain. Biphosphonates are the most frequently prescribed medication for treatment of osteoporosis and are often considered as first-line therapy for the treatment of osteoporosis. Currently, hormone replacement therapy is only approved by the Food and Drug Administration (FDA) for short-term treatment of severe postmenopausal symptoms with the lowest dose used for the shortest time. In view of its lack of effect on the prevention of nonvertebral fractures, the use of raloxifene should be limited to women with spinal osteoporosis. Most experts agree that it is preferable to treat osteoporosis with a more potent agent than calcitonin and manage the pain separately. Currently, the FDA recommends the use of parathyroid hormone for treatment of osteoporosis for a maximum of 2 years because of the concern of development of osteosarcoma.

Atherosclerotic vascular disease may be associated with osteoporosis or osteopenia in postmenopausal women: a preliminary study.

The objective of this study was to determine if there is an association between osteoporosis or osteopenia and atherosclerotic vascular disease (AVD) (two conditions quite prevalent in nursing homes) in a sample of postmenopausal women. We conducted a retrospective chart review on 101 postmenopausal women in a university-affiliated nursing home to investigate if there is an association between osteoporosis or osteopenia and AVD. Bone mineral density (BMD) was measured by DEXA scan obtained from a computerized radiology database. Low BMD was defined as > or =1.5 standard deviations below the mean of a cohort of young women. AVD was diagnosed if documented coronary artery disease, cerebrovascular disease, or peripheral arterial disease was present. The mean age and prevalence of smoking, hypertension, diabetes mellitus, and hypercholesterolemia were not significantly different between 51 women with osteoporosis or osteopenia and 50 women with normal BMD. AVD was present in 31 of 51 women (51%) with osteoporosis or osteopenia and in 19 of 50 women (38%) with a normal BMD (p<0.025).

Underuse of procedures for diagnosing osteoporosis and of therapies for osteoporosis in older nursing home residents.

OBJECTIVE: To investigate the prevalence of osteoporosis, the prevalence of utilization of bone mineral density (BMD) measurements for diagnosis of osteoporosis, and prevalence of use of calcium and vitamin D supplements and other antiresorptive therapies for treatment of osteoporosis in postmenopausal women in an academic nursing home. METHODS: The charts of all women aged 56 years and older residing in an academic nursing home were analyzed by one of the authors for the prevalence of osteoporosis, the prevalence of use of BMD measurements to diagnose osteoporosis, and the prevalence of use of calcium and vitamin D supplements and other antiresorptive therapies for treatment of osteoporosis. RESULTS: Of 136 postmenopausal women, mean age 79 +/- 10 years, 66 (49%) had measurements of BMD. Of these 66 women, 31 (47%) had osteoporosis, 21 (32%) had osteopenia, and 14 (21%) had normal BMD. Elemental calcium carbonate 1500 mg daily was prescribed to 17 of 31 women (55%) with osteoporosis, to 12 of 21 women (57%) with osteopenia, to 2 of 14 women (14%) with normal BMD, and to 27 of 70 women (39%) with no BMD obtained. Any dose of calcium was prescribed to 78 of 136 elderly women (58%). Vitamin D supplements were prescribed to 13 of 31 women (42%) with osteoporosis, to 9 of 21 women (43%) with osteopenia, to 2 of 14 women (14%) with normal BMD, and to 20 of 70 women (29%) with no BMD obtained. Vitamin D supplements were prescribed to 44 of 136 elderly women (32%). Biphosphonates were prescribed to 19 of 31 women (61%) with osteoporosis. Of 20 women on medications that increased the risk of osteoporosis, 6 (30%) had BMD measured. Nine of these 20 women (45%) were on calcium supplements. CONCLUSIONS: Older postmenopausal women in an academic nursing home have a high prevalence of osteoporosis and osteopenia, a low prevalence of measurement of BMD, and underuse of calcium, vitamin D supplements, and other antiresorptive therapies for treatment of osteoporosis.

Hormone replacement therapy. An analysis of efficacy based on evidence.

Hormone replacement therapy (HRT) has long been a staple of management of the postmenopausal life phase. Over time, and after estrogen therapy was modified to include progestin, an increasing number of observational reports suggested that HRT conferred benefits well beyond those of managing or minimizing not flashes, mood swings, and vaginal dryness. In short, HRT was believed to improve women's health and even extend life. One of the most significant theorized benefits was protection against cardio- and cerebrovascular events. Other benefits--protection against osteoporosis, reduction in incontinence symptoms, and improved cognition--have also been linked with HRT. The validity of these theories depended largely on observational studies and anecdotal reports, and only lightly (or not at all) on randomized clinical trial data. Nevertheless, significant clinical data refuting HRT's proposed benefits has been available for several years. Findings from these investigations, including new results from two very large trials, show that beyond managing traditional menopause symptoms, HRT has little or no role in protection against certain diseases or conditions associated with aging. Indeed, long-term use of HRT may be contraindicated in most older women with intact uteruses.