Hyperglycemia modulates M1/M2 macrophage polarization in chronic diabetic patients with pulmonary tuberculosis infection.

Increased susceptibility to bacterial infections like tuberculosis (TB) is one of the complications of type 2 diabetes, however the underlying mechanisms remains poorly characterized. To explore how chronic hyperglycemia in diabetes affects progression of active TB, we examined mRNA expression of M1 (proinflammatory) and M2 (anti-inflammatory) cytokines/markers, in monocyte-derived macrophages obtained from patients with PTB + DM (pulmonary TB + diabetes mellitus type 2), patients with DM alone, patients with PTB alone, and healthy individuals (controls). Our findings indicate a dysregulated cytokine response in patients with both PTB and DM, characterized by decreased expression levels of interferon-gamma (IFN-γ) and inducible nitric oxide synthase (iNOS), along with increased expression levels of interleukin-1 beta (IL-1ß) and CD206. Furthermore, we observed a positive correlation of IL-1ß and CD206 expression with levels of glycosylated hemoglobin (HbA1c) in both PTB + DM and DM groups, while IFN-γ showed a positive correlation with HbA1c levels, specifically in the PTB + DM group. Additionally, M1 cytokines/markers, IL-1ß and iNOS were found to be significantly associated with the extent of sputum positivity in both PTB and PTB + DM groups, suggesting it to be a function of increased bacterial load and hence severity of infection. Our data demonstrates that tuberculosis in individuals with PTB + DM is characterized by altered M1/M2 cytokine responses, indicating that chronic inflammation associated with type 2 diabetes may contribute to increased immune pathology and inadequate control of tuberculosis infection.

Exploring the role of neutrophils in infectious and noninfectious pulmonary disorders.

With the change in global environment, respiratory disorders are becoming more threatening to the health of people all over the world. These diseases are closely linked to performance of immune system. Within the innate arm of immune system, Neutrophils are an important moiety to serve as an immune defense barrier. They are one of the first cells recruited to the site of infection and plays a critical role in pathogenesis of various pulmonary diseases. It is established that the migration and activation of neutrophils can lead to inflammation either directly or indirectly and this inflammation caused is very crucial for the clearance of pathogens and resolution of infection. However, the immunopathological mechanisms involved to carry out the same is very complex and not well understood. Despite there being studies concentrating on the role of neutrophils in multiple respiratory diseases, there is still a long way to go in order to completely understand the complexity of the participation of neutrophils and mechanisms involved in the development of these respiratory diseases. In the present article, we have reviewed the literature to comprehensively provide an insight in the current development and advancements about the role of neutrophils in infectious respiratory disorders including viral respiratory disorders such as Coronavirus disease (COVID-19) and bacterial pulmonary disorders with a focused review on pulmonary tuberculosis as well as in noninfectious disorders like Chronic obstructive pulmonary disease (COPD) and asthma. Also, future directions into research and therapeutic targets have been discussed for further exploration.

Respiratory illnesses are becoming more prevalent and a substantial source of sickness and mortality worldwide as a result of the changes in the global environment. Although diagnostic and therapeutic approaches for respiratory disorders have improved over the years, a thorough and in-depth approach is still required to understand the underlying immuno-pathophysiological mechanisms. Neutrophils are a crucial part of innate immune system which functions as a first line defense against various pulmonary infections. They are known to be involved in resistance against invading pulmonary pathogens and also play an important role in repairing of damaged lung tissue by removing debris. However, emerging evidences suggest that neutrophils may also be involved in promoting and aggravating the unabating inflammation in several pulmonary disorders by release of various proteases, forming neutrophil extracellular traps or by attracting and activating other immune cells at the site of inflammation. In this article, we have discussed diverse roles and responses of neutrophils and their use in potential future research and therapeutic approaches in infectious pulmonary disorders like Tuberculosis and COVID-19 and noninfectious pulmonary disorders like Chronic obstructive pulmonary disease (COPD) and asthma.

Mental health during COVID-19 lockdown in India: Role of psychological capital and internal locus of control.

The Government of India implemented a nationwide lockdown from March 24, 2020 in response to the Coronavirus disease (COVID-19) outbreak. This study examines the effects of two positive psychological resources on the mental health of Indian citizens during the early days of the lockdown. The effects of psychological capital (PsyCap) and internal locus of control on psychological distress of people via affect balance were tested. Data were collected through an online survey from 667 participants. Psychological distress was assessed using the GHQ-12, and affect balance was assessed as the preponderance of positive over negative affect. Results reveal that psychological capital and internal locus of control were negatively associated with psychological distress. In addition, affect balance mediated the relationship between psychological capital and psychological distress and the relationship between internal locus of control and psychological distress. Thus, both the psychological resources through affect balance acted as buffers protecting people from mental health deterioration during COVID-19 lockdown. However, the direct and indirect effects of psychological capital on psychological distress is stronger than that of internal locus of control. Implications and directions for future research are discussed.

Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis.

Diabetes mellitus (DM) alters immune responses and given the rising prevalence of DM in tuberculosis (TB) endemic countries; hyperglycemia can be a potential risk factor for active TB development. However, the impact of hyperglycemia on TB-specific innate immune response in terms of macrophage functions remains poorly addressed. We assessed macrophage effector functions in uncontrolled DM patients with or without TB infection (PTB+DM and DM), non-diabetic TB patients (PTB), and non-diabetic-uninfected controls. Phagocytic capacity against BCG and surface expression of different pattern recognition receptors (PRRs) (CD11b, CD14, CD206, MARCO, and TLR-2) were measured via flow cytometry. Effector molecules (ROS and NO) required for bacterial killing were assessed via DCFDA and Griess reaction respectively. A systematic dysregulation in phagocytic capacity with concurrent alterations in the expression pattern of key PRRs (CD11b, MARCO, and CD206) was observed in PTB+DM. These altered PRR expressions were associated with decreased phagocytic capacity of macrophages. Similarly, ROS was aberrantly higher while NO was lower in PTB+DM. These altered macrophage functions were positively correlated with increasing disease severity. Our results highlight several key patterns of immune dysregulation against TB infection under hyperglycemic conditions and highlight a negative impact of hyperglycemia with etiology and progression of TB.

Understanding coronaphobia.

COVID-19 pandemic, in addition to being a global health emergency, has multiple socioeconomic and psychological ramifications. COVID-19 research and media reports have revealed a rise in fears related to contracting the virus. Though fear is a common psychological outcome during pandemics, the COVID-19 pandemic is a continuously evolving disease outbreak and has unique risk factors. Therefore, fear related to COVID-19 might manifest in not only fear and anxiety related to disease contraction and dying, but also associated sociooccupational stress. We attempt to understand the psychosocial process of the development of coronaphobia and postulate what constitutes coronaphobia, a new emerging phobia specific to COVID-19. We present a conceptual model delineating the risk factors causing coronaphobia and the underlying mechanisms, for a better understanding of its developmental process. From review of relevant research, the factors identified are, an unforeseen reality, unending uncertainties, need of acquiring new practices and avoidance behavior, loss of faith in health infrastructure, contraction of COVID-19 by head of states, cautionary statements from international bodies, and infodemia. These factors are assumed to cause interference with routine life, catastrophizing interpretation of benign symptoms, and social amplification of risk which lead to coronaphobia. The conceptualization of coronaphobia and the model will aid future research in developing psychometric measure of coronaphobia for use in clinical and research settings and design of policies and interventions for mitigating risk factors.

Common skin cancers and their precursors.

This review of precancerous and cancerous skin lesions serves as an overview for the general surgeon in clinical practice. Because these lesions are common in the general population, it is likely that they will be encountered frequently, perhaps even during consultation for an unrelated issue. General surgeons have a unique role in caring for these common skin cancers both primarily and by understanding the basis for referral to a specialist. With these goals in mind, we discuss the pathophysiology of cutaneous malignancy as well as the diagnosis and treatment of the three most common cutaneous malignancies in the United States: basal cell, squamous cell, and melanoma skin cancers.

Generation of a tumor-specific systemic response after intratumoral injection of IL-12 and IL-18-loaded polylactic acid microspheres.

We evaluated the impact and mechanism of interleukin (IL)-18 alone or in combination with IL-12 or tumor necrosis factor-alpha when delivered intratumorally via polylactic acid microspheres (PLAMs). C57BL6 mice with established B16 melanomas underwent a single intratumoral injection of IL-12, tumor necrosis factor-alpha, or IL-18 PLAM, alone or in combination. Tumor draining lymph nodes and splenocytes were assessed for specific antitumor response by FACS analysis and IFN-gamma release assay and enzyme-linked immunosorbent spot. Mice with established pulmonary metastases were killed for enumeration of pulmonary metastatic nodules after treatment of the primary tumor. Intratumoral treatment with IL-12 in combination with IL-18 led to significant tumor suppression compared with either cytokine alone. FACS analysis revealed the combination of IL-12 and IL-18 resulted in an increase in the percentage of CD3+ cells within the tumor draining lymph node, attributable to increases in both CD4+ and CD8+ T cells. Both IFN-gamma release assay and enzyme-linked immunosorbent spot demonstrated a significant and substantial increase in tumor-specific response with the combination. Treatment of the primary tumor with IL-12 and IL-18 PLAM led to a significant decrease in pulmonary metastases and improvement in survival compared with either cytokine alone. The systemic effects were abrogated after depletion of CD8+ or natural killer cells, but not CD4+ cells. IL-12 and IL-18, when released intratumorally in a sustained fashion as can be accomplished through the use of PLAM, demonstrate both local effects on tumor growth and the generation of a tumor-specific response capable of eradicating distant disease.

Synergistic effect of intratumoral IL-12 and TNF-alpha microspheres: systemic anti-tumor immunity is mediated by both CD8+ CTL and NK cells.

Neoadjuvant immunotherapy with the combination of intratumoral IL-12 and TNF-alpha encapsulated in poly-lactic acid microspheres (PLAM) generate a greater systemic immune response than either cytokine alone. We sought to examine the effector cells responsible for this synergy using the poorly immunogenic B16 melanoma and MCA205 sarcoma cell lines. Splenocytes from MCA205 bearing mice treated with IL-12 and TNF-alpha PLAM contained significantly more tumor-specific IFN-gamma secreting cells than IL-12 alone. Adoptive transfer of lymphocytes from mice treated by the combination mediated significant tumor regression in mice bearing established pulmonary metastases. In mice bearing bilateral tumors, treatment of the primary with IL-12 and TNF-alpha PLAM, resulted in suppression of contralateral tumor growth. Both the local and distant effects were absent in mice depleted of CD8+ T-cells. In B16 bearing mice with established pulmonary disease, only the combination of intratumoral IL-12 and TNF-alpha resulted in a significant reduction of lung nodules. Both the local and distant effects were eradicated in mice depleted of either CD8+ T-cells or NK cells. The local and sustained release of IL-12 and TNF-alpha using PLAM synergistically activate both a cytotoxic T-cell and NK cell response, although their impact varies with MHC class I expression.

Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy.

BACKGROUND: With the introduction of sentinel lymph node (SLN) biopsy for melanoma, inguinal lymph node dissections (ILND) are more commonly performed for microscopic disease than for clinically palpable disease. We sought to examine the effect this change has on the morbidity of the operation. METHODS: A retrospective review was performed of all patients who underwent an ILND for melanoma between October 1997 and April, 2006. Clinical and pathologic data were collected and correlated by multivariate analysis with the incidence of a major wound complication. RESULTS: We identified 212 patients, 132 who underwent an ILND for a positive SLN and 80 for clinically palpable disease. Age, sex, and body mass index (BMI) were similar in both groups. Patients with clinically palpable disease had a significantly greater number of involved nodes (3.0 vs 1.96, P = .0013), more often had >or=4 involved nodes (29% vs 9%, P < .001), and a greater incidence of extranodal extension (47% vs 5%, P < .001). Of the 212 patients, 41 (19%) had a significant wound complication. This complication was significantly higher among patients with clinical disease compared to patients with a positive SLN (28% vs 14%, P = .02). Only BMI (odds ratio of 1.1) and the indication for the procedure (odds ratio of 2.2) were independent predictors of a major wound complication. Lymphedema occurred in 30% of the patients and was only significantly associated with clinical disease (41% vs 24%, P = .025). With a median follow-up of 2 years, regional recurrence was not significantly greater in patients with clinically palpable disease (13% vs 9%, P = not significant [ns]), although this result was possibly due to the significantly greater rate of distant recurrence (49% vs 18%, P < .001) and death (48% vs 21%) in these patients. CONCLUSIONS: Patients undergoing an ILND for a positive SLN have a significantly lower risk of postoperative complication or lymphedema than do patients undergoing ILND for clinically palpable disease. There is a benefit in regard to the morbidity of treatment in surgically staging melanoma patients by SLN biopsy and preventing ILND for palpable disease.

Adoptive immunotherapy of breast cancer with lymph node cells primed by cryoablation of the primary tumor.

Cryoablation of cancer leaves tumor-associated antigens intact in an inflammatory microenvironment that can stimulate a regional anti-tumor immune response. We examined whether cryoablated tumor draining lymph nodes (CTDLN) as adoptive immunotherapy may be an effective immunotherapeutic approach in the adjuvant treatment of breast cancer. BALB/c mice with MT-901 mammary adenocarcinoma tumors underwent cryoablation, resection or no treatment and tumor draining lymph nodes were harvested. Cryoablation resulted in only a mild increase in the absolute number of T-cells but a significant increase in the fraction of tumor-specific T-cells as evidenced on IFN-gamma release assay. FACS analysis demonstrated no significant relative shift in the proportion of CD4(+) or CD8(+) cells. The adoptive transfer of CTDLN resulted in a significant reduction of pulmonary metastases as compared to TDLN from either tumor-bearing mice or mice who underwent surgical excision. Cryoablation prior to surgical resection of breast cancer can be used as a method to generate effector T-cells for adjuvant adoptive cellular immunotherapy.

Neoadjuvant intratumoral cytokine-loaded microspheres are superior to postoperative autologous cellular vaccines in generating systemic anti-tumor immunity.

BACKGROUND: Sustained intratumoral cytokine release using poly-lactic acid microspheres (PLAMs) can induce a systemic immune response, shifting immunotherapy to the neoadjuvant setting. METHODS: C57BL6 mice with established B16 melanomas underwent a single intralesional injection of IL-12, TNF-alpha or GM-CSF PLAM, alone or in combination. Tumor draining lymph nodes (TDLN) and spleens were assessed for a specific anti-tumor response by IFNgamma release assay and ELISPOT. RESULTS: Intralesional injection of TNF-alpha, alone or in combination, resulted in significant tumor ablation. The induction of tumor specific reactive T-cells in the TDLN was greatest with IL-12 and TNF-alpha. Only mice treated with IL-12 and TNF-alpha demonstrated a substantial T-cell response in cultured splenocytes. This combination resulted in a significant reduction in new tumors after re-challenge. Adjuvant therapy, using irradiated B16 cells in combination with equivalent doses of IL-12 and TNF-alpha, failed to generate a similar T-cell response or prevent re-challenge. CONCLUSIONS: Intratumoral IL-12 and TNF-alpha loaded PLAM leads to both local eradication of tumor and the induction of specific anti-tumor T-cells in the lymph nodes and spleens, resulting in memory immune response. Neoadjuvant treatment was significantly superior to postoperative autologous cellular vaccines using IL-12 and TNF-alpha PLAM.

Wide excision without radiation for desmoplastic melanoma.

BACKGROUND: Adjuvant radiation has been proposed for the treatment of patients with desmoplastic melanoma, who reportedly have local recurrence rates as high as 40-60%. The authors investigated local recurrence rates at a tertiary referral center to determine the success of wide excision alone for patients with desmoplastic melanoma. METHODS: A review of a prospectively maintained melanoma clinical data base identified 65 patients between March 1997 and March 2004 with pure cutaneous desmoplastic melanoma. Complete surgical, histopathologic, and staging information was collected along with data on outcome, including local, regional, and distant recurrence and survival. RESULTS: Similar to previous reports, patients with desmoplastic melanoma had a male-to-female ratio of 2 to 1, a mean age of 65.0 years (range, 31-92 yrs), and the majority of their tumors (55%) were located on the head and neck. The mean Breslow depth at diagnosis was 4.21 mm, with 38% of tumors thicker than 4.0 mm. All patients in this series underwent wide excision without radiation therapy. Surgical margins < or = 2 cm were obtained for all trunk and extremity lesions and for 63% of head and neck lesions that measured > 1 mm in depth (63%). Margins of 1-2 cm were obtained for the remaining patients. Among 49 patients who had a minimum of 2 years of follow-up (mean, 3.7 yrs), the local recurrence rate was 4% (2 of 49 patients). Seventy-eight percent of the patients studied remained alive with no evidence of disease. CONCLUSIONS: Local recurrence rates in the current series were considerably lower than the historically reported rates. This finding suggests that, for patients with desmoplastic melanoma, wide local excision with careful attention to appropriate margins produces excellent local control rates without the need for adjuvant radiation.

Influence of key variables on the patients' choice of a physician.

BACKGROUND: Customer orientation is becoming as important in providing health care services as it is in other services. In addition to expecting good health care, patients are also expecting good customer service from their health care providers. Selection of a family physician is a deliberate choice process. OBJECTIVE: This study investigated the variables that influence the choice of a family care physician. METHOD: This study used an experimental design to investigate the influence of physician's communication style, physician's expertise and role of office staff, appointment availability, etc on the selection of a physician. RESULTS: The results show the significance of physician's expertise and the role of office staff in the choice of a physician.