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Objective: To evaluate the impact of enhanced healthcare provider counseling and practical demonstrations of correct breastfeeding techniques on improving exclusive breastfeeding practices. Study Design: Prospective follow-up study. Place and Duration of Study: This study was conducted at Alkhidmat-Raazi Hospital, Rawalpindi, Pakistan, from 17 September 2022 to 7 April 2023. Materials and Methods: A total of 309 mothers were enrolled in the study based on specific inclusion and exclusion criteria. A structured counseling intervention was implemented for postnatal care, incorporating bedside guidance during hospital stays and follow-up sessions conducted monthly over six months. Breastfeeding compliance was assessed through in-person and telephonic interviews documented in standardized data sheets. Data were analyzed using SPSS version 24. Descriptive statistics summarized the demographic characteristics and breastfeeding practices of participants. Chi-square tests were applied for categorical variables to assess the impact of the intervention. A p value ≤ 0.05 was considered statistically significant. Results: The response rate for follow-up visits was 76%. Early breastfeeding initiation (within one hour of birth) was observed in 52.8% of mothers, and exclusive breastfeeding at six months increased to 65.4%. Conclusion: Systematic postnatal counseling and hands-on guidance significantly improved breastfeeding practices. Continued support over six months facilitated better adherence to the exclusive breastfeeding code, emphasizing the importance of healthcare provider engagement in promoting optimal breastfeeding practices.

Background: Stroke ranked third in terms related to mortality and impairment worldwide and second common reason of death (11.6%). It greatly affects people quality of life and mobility. For faster recovery different rehabilitation approaches used like Transcranial Direct Current Stimulation (tDCS) device, a small intensity of electrical current is produced that can stimulate specific areas of the brain which are affected due to stroke. The tDCS device can be effective in improving motor skills and aiding in the recovery process after a stroke. Physical exercise is also crucial for stroke rehabilitation. But when we used these approaches together in rehabilitation of stroke patients it enhance recovery effectively. Objective: The objective of this systematic review is to evaluate the effects of non-invasive transcranial direct current stimulation (tDCS) and physical exercises on the rehabilitation outcomes of stroke patients. Methodology: This systematic review followed the guidelines of PRISMA. Used several online search engine known as PubMed, Cochrane Library, Google scholar to search eligible data availability. PICO framework used as screening criteria tool. Data relevant to study was extracted using self-developed data table based on previous literature. The Studies on stroke patients from subacute to chronic conditions with age limit 20 to 80 years, using tDCS device as an intervention and physical exercises were included in this review. Studies before 2019, Grey or unreported, not using tDCS device and non-English studies were excluded. Studies on stroke used tDCS and physical exercises were included in this review. Studies which conducted before the year 2019 and Non-English studies were excluded. Results: In this systematic review 35 studies were included with 1242 subjects after fulfill the requirements. In which 30 studies revealed significant improvement in stroke patients used noninvasive electrical stimulation tDCS and physical exercises with p value

This article discusses religious coping behaviors in relation to Islamic spiritual care practices. Islamic spiritual care is an established practice, integrated in many European countries’ health and welfare services, and an emerging field of research. I have 17 years of experience as a Muslim chaplain in Danish hospitals and a prison, working with counseling, educating staff, and policymaking in the field of Muslim chaplaincy. In this article, I use psychological theory to analyze positive and negative religious coping, first demonstrating that spiritual care is a practice in Islam that is embedded in its theological and psychological (re)sources. Then, based on two case examples, I analyze negative religious coping among Muslims, which is a topic that has received little scholarly attention. The article contributes to the emerging field of Islamic practical theology and the interdisciplinary relationship between practical theology and psychology of religion.

At present, there is limited theoretical clarity on the nature of Islamic spiritual care, which is a developing discipline around the world. How it is defined will be instrumental for spiritual care institutions, professionals and recipients of spiritual care in the years to come. This article wishes to understand and explore the idea and vision behind Islamic spiritual care and why this line of investigation may be of importance to care providers with different faith backgrounds.

Abstract Background Many interventions to motivate community health workers to perform better rely on financial incentives, even though it is not clear that monetary gain is the main motivational driver. In Pakistan, Lady Health Workers (LHW) are responsible for delivering community level primary healthcare, focusing on rural and urban slum populations. There is interest in introducing large-scale interventions to motivate LHW to be more actively involved in improving tuberculosis case-finding, which is low in Pakistan. Methods Our study investigated how to most effectively motivate LHW to engage more actively in tuberculosis case-finding. The study was embedded within a pilot intervention that provided financial and other incentives to LHW who refer the highest number of tuberculosis cases in three districts in Sindh province. We conducted semi-structured interviews with 20 LHW and 12 health programme managers and analysed these using a framework categorising internal and external sources of motivation. Results Internal drivers of motivation, such as religious rewards and social recognition, were salient in our study setting. While monetary gain was identified as a motivator by all interviewees, programme managers expressed concerns about financial sustainability, and LHW indicated that financial incentives were less important than other sources of motivation. LHW emphasised that they typically used financial incentives provided to cover patient transport costs to health facilities, and therefore financial incentives were usually not perceived as rewards for their performance. Conclusions This study indicated that interventions in addition to, or instead of, financial incentives could be used to increase LHW engagement in tuberculosis case-finding. Our finding about the strong role of internal motivation (intrinsic, religious) in Pakistan suggests that developing context-specific strategies that tap into internal motivation could allow infectious disease control programmes to improve engagement of community health workers without being dependent on funding for financial incentives.

Rationale: Cross-sectional studies demonstrate an association between metabolic syndrome and impaired lung function.Objectives: To define if metabolic syndrome biomarkers are risk factors for loss of lung function after irritant exposure.Methods: A nested case-control study of Fire Department of New York personnel with normal pre-September 11th FEV(1) and who presented for subspecialty pulmonary evaluation before March 10, 2008. We correlated metabolic syndrome biomarkers obtained within 6 months of World Trade Center dust exposure with subsequent FEV(1). FEV(1) at subspecialty pulmonary evaluation within 6.5 years defined disease status; cases had FEV(1) less than lower limit of normal, whereas control subjects had FEV(1) greater than or equal to lower limit of normal.Measurements and Main Results: Clinical data and serum sampled at the first monitoring examination within 6 months of September 11, 2001, assessed body mass index, heart rate, serum glucose, triglycerides and high-density lipoprotein (HDL), leptin, pancreatic polypeptide, and amylin. Cases and control subjects had significant differences in HDL less than 40 mg/dl with triglycerides greater than or equal to 150 mg/dl, heart rate greater than or equal to 66 bpm, and leptin greater than or equal to 10,300 pg/ml. Each increased the odds of abnormal FEV(1) at pulmonary evaluation by more than twofold, whereas amylin greater than or equal to 116 pg/ml decreased the odds by 84%, in a multibiomarker model adjusting for age, race, body mass index, and World Trade Center arrival time. This model had a sensitivity of 41%, a specificity of 86%, and a receiver operating characteristic area under the curve of 0.77.Conclusions: Abnormal triglycerides and HDL and elevated heart rate and leptin are independent risk factors of greater susceptibility to lung function impairment after September 11, 2001, whereas elevated amylin is protective. Metabolic biomarkers are predictors of lung disease, and may be useful for assessing risk of impaired lung function in response to particulate inhalation. [ABSTRACT FROM AUTHOR]

Osteoarthritis is one of the most common degenerative conditions affecting knee joint. As our understanding in the disease pathogenesis is evolving, so do the treatment modalities. One of the postulated mechanisms suggests the production of inflammatory cytokines secondary to repeated micro trauma than in turn lead to cartilage damage overtime. Cartilage being avascular structure has limited potential for repair. Based on this, recent studies have been focusing on stimulating cartilage-healing process by growth factors. This is where platelet-rich plasma comes in to light. Literature is showing promising results of platelet-rich plasma in treating knee osteoarthritis. In this review we have discussed the preparation, composition, classification, uses of platelet-rich plasma as well as evidence for its efficacy and complications.

Summary: Despite the efforts of the international community diarrheal diseases still pose a major threat to children in children less than five years of age. Bacterial diarrhea has also emerged as a public health concern due to the proliferation of drug resistant species in many parts of the world. There is a paucity of population-based data about the incidence of shigellosis and Campylobacter infections in Pakistan. We report country specific results for Shigella diarrhea that were derived from a multicenter study conducted in six Asian countries. Disease surveillance was conducted over a 24 month period in urban slums of Karachi, Pakistan, a city with a population of 59,584. Cases were detected through passive detection in study treatment centers. Stool specimens or rectal swabs were collected from all consenting patients. Between January 2002 and December 2003 10,540 enteric infection cases were detected. The incidence rate of treated diarrhea in children under 5 was 488/1000/year. In children, 5 years and older, the diarrhea rate was 22/1000/year. 576 (7%) Campylobacter isolates were detected. The pre-dominant Campylobacter species was C. jenuni with an increase of 29/1000 year in children under 5 years. Shigella species were isolated from 394 of 8032 children under 5 years of age. Shigella flexneri was the dominant species (10/1000/year in children under 5 years) followed by Shigella sonnei (3.9/1000/year), Shigella boydii (2.0/1000/year) and Shigella dysenteriae (1.3/1000/year). Shigellosis and Campylobacter infection rates peaked during the second year of life. The incidence rate of shigellosis increased in old age but such a trend was not observed in Campylobacter infections. Of 394 shigellosis patients 123 (31%) presented with dysentery in contrast to only 54 (9%) of 576 patients with Campylobacter infections (p

Introduction. Nutritional deficiencies are rarely reported in developed countries. We report a child of Pakistani origin brought up in Dubai who developed skeletal manifestations of scurvy due to peculiar dietary habits. Case Presentation. A 4.5 year old boy presented with pain and swelling of multiple joints for three months and inability to walk for two months. Dietary history was significant for exclusive meat intake for the preceding two years. On examination the child’s height and weight were below the 5th percentile for his age. He was pale and tachycardic. There was significant swelling and tenderness over the wrist, knee and ankle joints, along with painful restriction of motion. Basic blood workup was unremarkable except for anemia. However, X-rays showed delayed bone age, severe osteopenia of the long bones, epiphyseal separation, cortical thinning and dense zone of provisional calcification, suggesting a radiological diagnosis of scurvy. The child was started on vitamin C replacement therapy. Over the following two months, the pain and swelling substantially reduced and the child became able to walk. Repeat X-rays showed improvement in the bony abnormalities. Conclusion. Although scurvy is not a very commonly encountered entity in the modern era, inappropriate dietary intake can lead to skeletal abnormalities which may be confused with rickets. A high index of suspicion is thus required for prompt diagnosis of scurvy in patients with bone and joint symptoms.

: PurposeTo determine the duration of action of ketotifen 0.025% eye drops vs placebo taken as single or multiple doses in an allergen challenge model.: DesignTwo randomized, multicenter, double-masked, contralateral placebo-controlled studies, one a single-dose and one a multiple-dose study.: MethodsTwo conjunctival provocation tests (CPTs) were initially conducted to confirm reproducibility of subject responses in both studies. Subjects in study 1 (n = 87) received single doses of ketotifen in one eye and placebo in the other 15 minutes, 6 hours, and 8 hours before CPT. Subjects in study 2 (n = 85) received ketotifen or placebo once 8 hours before CPT. Single-dose efficacy results were used to further qualify a subject as a responder. Responders were re-randomized to a 4-week twice daily dosing regimen with a CPT 8 hours after the final dose. In both studies, ocular symptoms were assessed at three time points 3 to 15 minutes after challenge. There were no significant differences in adverse events between groups.: ResultsFor both studies, ocular itching and vascular injection were significantly reduced (P < .003) at all time points after instillation of ketotifen, with a maximum reduction at 7 minutes postchallenge. In study 2, chemosis, tearing, and lid swelling were also assessed and were significantly reduced (P < .008) after instillation of ketotifen.: ConclusionsKetotifen 0.025% eye drops were safe and statistically effective in preventing ocular itching, injection, and other signs and symptoms of allergic conjunctivitis at 15 minutes, 6 hours, and 8 hours after a single dose and at 8 hours after the final dose of a 4-week twice daily regimen. [Copyright &y& Elsevier]

Angioedema is a rare but known side effect of angiotensin-converting enzyme (ACE) inhibitor therapy. The most common presentations of ACE inhibitor-induced angioedema describe swellings in the oropharyngeal and periorbital regions. We describe a rare case of a 58-year-old female with a history of type 2 diabetes and hypertension taking lisinopril for the past three years and presented with recurrent episodes of abdominal pain, nausea, and vomiting around the same time she started taking the drug. Multiple computed tomography (CT) scans were performed, which showed findings consistent with edema in the proximal small bowel. Due to the recurrent nature of these episodes over the last three years, along with consistent findings of small bowel edema on imaging, lisinopril-induced angioedema was suspected. As a result, the patient was switched from lisinopril to amlodipine. During our follow-up with the patient, she reported that her symptoms had resolved following the withdrawal of lisinopril., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Pirzada et al.)

The twenty-first century has revolutionized the management of congestive heart failure with the widespread use of left ventricular assist devices and other treatment modalities that improve morbidity and mortality after the failure of medical management. These novel devices come with significant side effects. One of the most common side effects of left ventricular assist devices is the increased frequency of lower gastrointestinal bleeding compared to heart failure patients without left ventricular assist devices. Multiple etiologies of recurrent gastrointestinal bleeding in such patients have been studied. The decreased amount of von Willebrand factor polymers is now recognized as one of the most common causes of increased incidence of gastrointestinal bleeding in patients with left ventricular assist devices alongside increased arteriovenous malformations. Multiple treatment modalities have been identified to prevent and treat gastrointestinal bleeding in these patients. Since the use of left ventricular assist devices is becoming more prevalent in patients with advanced heart failure, we decided to conduct this systematic review. The article summarizes the incidence, pathophysiology, and management of lower gastrointestinal bleeding in patients with left ventricular assist devices., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The evolving epidemic of type 2 diabetes mellitus has challenged health-care professionals. It stands among the leading causes of mortality in the present world. It warrants new and versatile approaches to improve mortality and the associated huge quality-adjusted life years lost to it once diagnosed. A possible venue to lower the incidence is to assess the safety and efficacy of various diabetes prevention strategies. Diet and exercise have a well-developed role in the prevention of weight gain and, ultimately, diabetes mellitus type II in high-risk individuals. However, high-risk individuals can also benefit from adjunct pharmacotherapy. In light of this information, we decided to conduct a systematic review of randomized controlled trials. This article summarizes the evidence in the literature on the pharmacological prevention of diabetes in high-risk individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Naveed et al.)

Rationale: Metabolic syndrome, inflammatory and vascular injury markers measured in serum after World Trade Center (WTC) exposures predict abnormal FEV1. We hypothesized that elevated LPA levels predict FEV₁ < LLN., Methods: Nested case-control study of WTC-exposed firefighters. Cases had FEV₁ < LLN. Controls derived from the baseline cohort. Demographics, pulmonary function, serum lipids, LPA and ApoA1 were measured., Results: LPA and ApoA1 levels were higher in cases than controls and predictive of case status. LPA increased the odds by 13% while ApoA1 increased the odds by 29% of an FEV₁ < LLN in a multivariable model., Conclusions: Elevated LPA and ApoA1 are predictive of a significantly increased risk of developing an FEV₁ < LLN.

Rationale: After 9/11/2001, most FDNY workers had persistent lung function decline but some exposed workers recovered. We hypothesized that the protease/anti-protease balance in serum soon after exposure predicts subsequent recovery., Methods: We performed a nested case-control study measuring biomarkers in serum drawn before 3/2002 and subsequent forced expiratory volume at one second (FEV1) on repeat spirometry before 3/2008. Serum was assayed for matrix metalloproteinases (MMP-1,2,3,7,8,9,12 and 13) and tissue inhibitors of metalloproteinases (TIMP-1,2,3,4). The representative sub-cohort defined analyte distribution and a concentration above 75th percentile defined elevated biomarker expression. An FEV1 one standard deviation above the mean defined resistance to airway injury. Logistic regression was adjusted for pre-9/11 FEV1, BMI, age and exposure intensity modeled the association between elevated biomarker expression and above average FEV1., Results: FEV1 in cases and controls declined 10% of after 9/11/2001. Cases subsequently returned to 99% of their pre-exposure FEV1 while decline persisted in controls. Elevated TIMP-1 and MMP-2 increased the odds of resistance by 5.4 and 4.2 fold while elevated MMP-1 decreased it by 0.27 fold., Conclusions: Resistant cases displayed healing, returning to 99% of pre-exposure values. High TIMP-1 and MMP-2 predict healing. MMP/TIMP balance reflects independent pathways to airway injury and repair after WTC exposure.

Background: Firefighters exposed to World Trade Center (WTC) dust have developed chronic rhinosinusitis (CRS) and abnormal forced expiratory volume in 1 s (FEV1). Overlapping but distinct immune responses may be responsible for the clinical manifestations of upper and lower airway injury. We investigated whether a panel of inflammatory cytokines, either associated or not associated with WTC-LI, can predict future chronic rhinosinusitis disease and its severity., Methods: Serum obtained within six months of 9/11/2001 from 179 WTC exposed firefighters presenting for subspecialty evaluation prior to 3/2008 was assayed for 39 cytokines. The main outcomes were medically managed CRS (N = 62) and more severe CRS cases requiring sinus surgery (N = 14). We tested biomarker-CRS severity association using ordinal logistic regression analysis., Results: Increasing serum IL-6, IL-8, GRO and neutrophil concentration reduced the risk of CRS progression. Conversely, increasing TNF-α increased the risk of progression. In a multivariable model adjusted for exposure intensity, increasing IL-6, TNF-α and neutrophil concentration remained significant predictors of progression. Elevated IL-6 levels and neutrophil counts also reduced the risk of abnormal FEV1 but in contrast to CRS, increased TNF-α did not increase the risk of abnormal FEV1., Conclusions: Our study demonstrates both independent and overlapping biomarker associations with upper and lower respiratory injury, and suggests that the innate immune response may play a protective role against CRS and abnormal lung function in those with WTC exposure., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: After 9/11/2001, some Fire Department of New York (FDNY) workers had excessive lung function decline. We hypothesized that early serum matrix metalloproteinases (MMP) expression predicts World Trade Center-Lung Injury (WTC-LI) years later., Methods: This is a nested case-control analysis of never-smoking male firefighters with normal pre-exposure Forced Expiratory Volume in one second (FEV1) who had serum drawn up to 155 days post 9/11/2001. Serum MMP-1, 2,3,7,8, 9, 12 and 13 were measured. Cases of WTC-LI (N = 70) were defined as having an FEV1 one standard deviation below the mean (FEV1 ≤ 77%) at subspecialty pulmonary evaluation (SPE) which was performed 32 months (IQR 21-53) post-9/11. Controls (N = 123) were randomly selected. We modeled MMP's ability as a predictor of cases status with logistic regression adjusted for time to blood draw, exposure intensity, weight gain and pre-9/11 FEV1., Results: Each log-increase in MMP-3 and MMP-12 showed reduced odds of developing WTC-LI by 73% and 54% respectively. MMP-3 and MMP-12 consistently clustered together in cases, controls, and the cohort. Increasing time to blood draw significantly and independently increased the risk of WTC-LI., Conclusions: Elevated serum levels of MMP-3 and MMP-12 reduce the risk of developing WTC-LI. At any level of MMP-3 or 12, increased time to blood draw is associated with a diminished protective effect.

Purpose: World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction., Methods: With a nested case-control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after 1 second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N = 125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N = 126). In a secondary analysis, resistant cases (N = 66) had FEV1 (≥107%) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function., Results: Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1 ≥ 107%. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort., Conclusions: Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline.

Pulmonary vascular loss is an early feature of chronic obstructive pulmonary disease. Biomarkers of inflammation and of metabolic syndrome predict loss of lung function in World Trade Center (WTC) lung injury (LI). We investigated if other cardiovascular disease (CVD) biomarkers also predicted WTC-LI. This nested case-cohort study used 801 never-smoker, WTC-exposed firefighters with normal pre-9/11 lung function presenting for subspecialty pulmonary evaluation (SPE) before March 2008. A representative subcohort of 124 out of 801 subjects with serum drawn within 6 months of 9/11 defined CVD biomarker distribution. Post-9/11 forced expiratory volume in 1 s (FEV1) at defined cases were as follows: susceptible WTC-LI cases with FEV1 ≤77% predicted (66 out of 801) and resistant WTC-LI cases with FEV1 ≥107% predicted (68 out of 801). All models were adjusted for WTC exposure intensity, body mass index at SPE, age on 9/11 and pre-9/11 FEV1. Susceptible WTC-LI cases had higher levels of apolipoprotein-AII, C-reactive protein and macrophage inflammatory protein-4 with significant relative risks (RRs) of 3.85, 3.93 and 0.26, respectively, with an area under the curve (AUC) of 0.858. Resistant WTC-LI cases had significantly higher soluble vascular cell adhesion molecule and lower myeloperoxidase, with RRs of 2.24 and 2.89, respectively (AUC 0.830). Biomarkers of CVD in serum 6 months post-9/11 predicted either susceptibility or resistance to WTC-LI. These biomarkers may define pathways either producing or protecting subjects from pulmonary vascular disease and associated loss of lung function after an irritant exposure.

Background: The World Trade Center (WTC) collapse on September 11, 2001, produced airflow obstruction in a majority of firefighters receiving subspecialty pulmonary evaluation (SPE) within 6.5 years post-September 11, 2001., Methods: In a cohort of 801 never smokers with normal pre-September 11, 2001, FEV1, we correlated inflammatory biomarkers and CBC counts at monitoring entry within 6 months of September 11, 2001, with a median FEV(1) at SPE (34 months; interquartile range, 25-57). Cases of airflow obstruction had FEV(1) less than the lower limit of normal (LLN) (100 of 801; 70 of 100 had serum), whereas control subjects had FEV(1) greater than or equal to LLN (153 of 801; 124 of 153 had serum)., Results: From monitoring entry to SPE years later, FEV(1) declined 12% in cases and increased 3% in control subjects. Case subjects had elevated serum macrophage derived chemokine (MDC), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor, and interferon inducible protein-10 levels. Elevated GM-CSF and MDC increased the risk for subsequent FEV(1) less than LLN by 2.5-fold (95% CI, 1.2-5.3) and 3.0-fold (95% CI, 1.4-6.1) in a logistic model adjusted for exposure, BMI, age on September 11, 2001, and polymorphonuclear neutrophils. The model had sensitivity of 38% (95% CI, 27-51) and specificity of 88% (95% CI, 80-93)., Conclusions: Inflammatory biomarkers can be risk factors for airflow obstruction following dust and smoke exposure. Elevated serum GM-CSF and MDC levels soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Biomarkers of inflammation may help identify pathways producing obstruction after irritant exposure.

Background: The WTC collapse exposed over 300,000 people to high concentrations of WTC-PM; particulates up to ∼50 mm were recovered from rescue workers' lungs. Elevated MDC and GM-CSF independently predicted subsequent lung injury in WTC-PM-exposed workers. Our hypotheses are that components of WTC dust strongly induce GM-CSF and MDC in AM; and that these two risk factors are in separate inflammatory pathways., Methodology/principal Findings: Normal adherent AM from 15 subjects without WTC-exposure were incubated in media alone, LPS 40 ng/mL, or suspensions of WTC-PM(10-53) or WTC-PM(2.5) at concentrations of 10, 50 or 100 µg/mL for 24 hours; supernatants assayed for 39 chemokines/cytokines. In addition, sera from WTC-exposed subjects who developed lung injury were assayed for the same cytokines. In the in vitro studies, cytokines formed two clusters with GM-CSF and MDC as a result of PM(10-53) and PM(2.5). GM-CSF clustered with IL-6 and IL-12(p70) at baseline, after exposure to WTC-PM(10-53) and in sera of WTC dust-exposed subjects (n = 70) with WTC lung injury. Similarly, MDC clustered with GRO and MCP-1. WTC-PM(10-53) consistently induced more cytokine release than WTC-PM(2.5) at 100 µg/mL. Individual baseline expression correlated with WTC-PM-induced GM-CSF and MDC., Conclusions: WTC-PM(10-53) induced a stronger inflammatory response by human AM than WTC-PM(2.5). This large particle exposure may have contributed to the high incidence of lung injury in those exposed to particles at the WTC site. GM-CSF and MDC consistently cluster separately, suggesting a role for differential cytokine release in WTC-PM injury. Subject-specific response to WTC-PM may underlie individual susceptibility to lung injury after irritant dust exposure.

Alveolar macrophages (AMs) are exposed to respirable microbial particles. Similar to phagocytes in the gastrointestinal tract, AMs can suppress inflammation after exposure to nonpathogenic organisms. IL-1R-associated kinase-M (IRAK-M) is one inhibitor of innate immunity, normally suppressing pulmonary inflammation. During pneumonia, polymorphonuclear neutrophils (PMNs) are recruited by chemotactic factors released by AMs to produce an intense inflammation. We report that intact IRAK-M is strongly expressed in resting human AMs but is cleaved in patients with pneumonia via PMN-mediated induction of caspase-6 (CASP-6) activity. PMN contact is necessary and PMN membranes are sufficient for CASP-6 induction in macrophages. PMNs fail to induce TNF-α fully in macrophages expressing CASP-6 cleavage-resistant IRAK-M. Without CASP-6 expression, PMN stimulation fails to cleave IRAK-M, degrade IκBα, or induce TNF-α. CASP-6(-/-) mice subjected to cecal ligation and puncture have impaired TNF-α production in the lung and decreased mortality. LPS did not induce or require CASP-6 activity demonstrating that TLR2/4 signaling is independent from the CASP-6 regulated pathway. These data define a central role for CASP-6 in PMN-driven macrophage activation and identify IRAK-M as an important target for CASP-6. PMNs de-repress AMs via CASP-6-mediated IRAK-M cleavage. This regulatory system will blunt lung inflammation unless PMNs infiltrate the alveolar spaces.

Background: Inflammation in the early stages of sepsis is governed by the innate immune response. Costimulatory molecules are a receptor/ligand class of molecules capable of regulation of inflammation in innate immunity via macrophage/neutrophil contact. We recently described that CD80/86 ligation is required for maximal macrophage activation and CD80/86(-/-) mice display reduced mortality and inflammatory cytokine production after cecal ligation and puncture (CLP). However, these data also demonstrate differential regulation of CD80 and CD86 expression in sepsis, suggesting a divergent role for these receptors. Therefore, the goal of this study was to determine the individual contribution of CD80/86 family members in regulating inflammation in sepsis., Methodology/principal Findings: CD80(-/-) mice had improved survival after CLP when compared to WT or CD86(-/-) mice. This was associated with preferential attenuation of inflammatory cytokine production in CD80(-/-) mice. Results were confirmed with pharmacologic blockade, with anti-CD80 mAb rescuing mice when administered before or after CLP. In vitro, activation of macrophages with neutrophil lipid rafts caused selective disassociation of IRAK-M, a negative regulator of NF-kappaB signaling from CD80; providing a mechanism for preferential regulation of cytokine production by CD80. Finally, in humans, upregulation of CD80 and loss of constitutive CD86 expression on monocytes was associated with higher severity of illness and inflammation confirming the findings in our mouse model., Conclusions: In conclusion, our data describe a differential role for CD80 and CD86 in regulation of inflammation in the innate immune response to sepsis. Future therapeutic strategies for blockade of the CD80/86 system in sepsis should focus on direct inhibition of CD80.