The clinical and financial impact of remote clinical oncology pharmacist engagement in community-based practices within The US Oncology Network.

INTRODUCTION: The integration of clinical oncology pharmacists into multidisciplinary healthcare teams is not well-described in the community practice setting. This study aims to analyze the clinical and financial impact of a remote-based clinical oncology pharmacist in four community oncology practices within The US Oncology Network. METHODS: Oncology-trained clinical pharmacists electronically reviewed chemotherapy orders for clinical optimization and financial stewardship within four community oncology practices. Each pharmacist was appointed at 0.5 full-time equivalents per practice. Financial, clinical, and workload metrics were tracked to monitor the impact of pharmacist engagement. RESULTS: Over 12 months, 5716 order reviews were completed with an intervention rate of 57%. The most common interventions identified by the pharmacists were interventions with clinical impact on the patient (36%), followed by dose rounding (35%) and therapeutic interchange (30%). Overall, interventions improved the cumulative practice margins by $1,455,033 and reduced total medication costs by $5,962,551. The average program return on investment was 415% (range 100-915%). CONCLUSION: Community oncology practices seek to provide high-value care in a lean, resource-constrained model. An oncology clinical pharmacist is a cost-effective and clinically invaluable care team member in community oncology practice. Pharmacists in this setting identified opportunities to improve medication safety and regimen optimization and demonstrated a significant tremendous financial impact on small-scale budgets in community oncology.

Functional genomics and metabolomics advance the ethnobotany of the Samoan traditional medicine "matalafi".

The leaf homogenate of Psychotria insularum is widely used in Samoan traditional medicine to treat inflammation associated with fever, body aches, swellings, wounds, elephantiasis, incontinence, skin infections, vomiting, respiratory infections, and abdominal distress. However, the bioactive components and underlying mechanisms of action are unknown. We used chemical genomic analyses in the model organism Saccharomyces cerevisiae (baker's yeast) to identify and characterize an iron homeostasis mechanism of action in the traditional medicine as an unfractionated entity to emulate its traditional use. Bioactivity-guided fractionation of the homogenate identified two flavonol glycosides, rutin and nicotiflorin, each binding iron in an ion-dependent molecular networking metabolomics analysis. Translating results to mammalian immune cells and traditional application, the iron chelator activity of the P. insularum homogenate or rutin decreased proinflammatory and enhanced anti-inflammatory cytokine responses in immune cells. Together, the synergistic power of combining traditional knowledge with chemical genomics, metabolomics, and bioassay-guided fractionation provided molecular insight into a relatively understudied Samoan traditional medicine and developed methodology to advance ethnobotany.

Efficacy of supplemental MCT oil on seizure reduction of adult drug-resistant epilepsy - a single-center open-label pilot study.

OBJECTIVE: We set out to determine whether adding medium chain triglyceride (MCT) oil as a dietary supplement to standard diet in adult subjects with intractable epilepsy in a U.S. neurology clinical practice was associated with a reduction in number of seizures. We secondarily aimed to determine whether subjects experienced any side effects and whether there was a presence of urinary ketones while using MCT oil as a dietary supplement. METHODS: Adult patients with intractable epilepsy were recruited at standard of care clinical visits with their epileptologist. Once enrolled, subjects were instructed to supplement their diet with MCT oil as tolerated twice daily for three months (including a 1-2 week titration period, followed by a 1-2 week tapering off window) while keeping a seizure diary to record total number of seizures, presence of urinary ketones, and any side effects. RESULTS: Our data although limited by small sample size, shows that there is an estimated 42% reduction (p < 0.0001) in the rate of seizures. The MCT oil supplementation was well tolerated by most subjects except for minor GI side effects like nausea and loose stools. Most subjects developed ketones in their urine at some point during the trial. CONCLUSIONS: MCT oil supplementation reduced seizure frequency in study participants. The reported side effects included mild nausea, stomachache, loose stools. A placebo-controlled study will be more informative.

Diagnostic performance of S100B as a rule-out test for intracranial pathology in head-injured patients presenting to the emergency department who meet NICE Head Injury Guideline criteria for CT-head scan.

BACKGROUND: Traumatic brain injury is a common ED presentation. CT-head utilisation is escalating, exacerbating resource pressure in the ED. The biomarker S100B could assist clinicians with CT-head decisions by excluding intracranial pathology. Diagnostic performance of S100B was assessed in patients meeting National Institute of Health and Clinical Excellence Head Injury Guideline (NICE HIG) criteria for CT-head within 6 and 24 hours of injury. METHODS: This multicentre prospective observational study included adult patients presenting to the ED with head injuries between May 2020 and June 2021. Informed consent was obtained from patients meeting NICE HIG CT-head criteria. A venous blood sample was collected and serum was tested for S100B using a Cobas Elecsys-S100 module; >0.1 µg/mL was the threshold used to indicate a positive test. Intracranial pathology reported on CT-head scan by the duty radiologist was used as the reference standard to review diagnostic performance. RESULTS: This study included 265 patients of whom 35 (13.2%) had positive CT-head findings. Within 6 hours of injury, sensitivity of S100B was 93.8% (95% CI 69.8% to 99.8%) and specificity was 30.8% (22.6% to 40.0%). Negative predictive value (NPV) was 97.3% (95% CI 84.2% to 99.6%) and area under the curve (AUC) was 0.73 (95% CI 0.61 to 0.85; p=0.003). Within 24 hours of injury, sensitivity was 82.9% (95% CI 66.4% to 93.44%) and specificity was 43.0% (95% CI 36.6% to 49.7%). NPV was 94.29% (95% CI 88.7% to 97.2%) and AUC was 0.65 (95% CI 0.56 to 0.74; p=0.046). Theoretically, use of S100B as a rule-out test would have reduced CT-head scans by 27.1% (95% CI 18.9% to 36.8%) within 6 hours and 37.4% (95% CI 32.0% to 47.2%) within 24 hours. The risk of missing a significant injury with this approach would have been 0.75% (95% CI 0.0% to 2.2%) within 6 hours and 2.3% (95% CI 0.5% to 4.1%) within 24 hours. CONCLUSION: Within 6 hours of injury, S100B performed well as a diagnostic test to exclude significant intracranial pathology in low-risk patients presenting with head injury. In theory, if used in addition to NICE HIGs, CT-head rates could reduce by one-quarter with a potential miss rate of <1%.

Identification of a Multiplex Biomarker Panel for Hypertrophic Cardiomyopathy Using Quantitative Proteomics and Machine Learning.

Hypertrophic cardiomyopathy (HCM) is defined by pathological left ventricular hypertrophy (LVH). It is the commonest inherited cardiac condition and a significant number of high risk cases still go undetected until a sudden cardiac death (SCD) event. Plasma biomarkers do not currently feature in the assessment of HCM disease progression, which is tracked by serial imaging, or in SCD risk stratification, which is based on imaging parameters and patient/family history. There is a need for new HCM plasma biomarkers to refine disease monitoring and improve patient risk stratification. To identify new plasma biomarkers for patients with HCM, we performed exploratory myocardial and plasma proteomics screens and subsequently developed a multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay to validate the 26 peptide biomarkers that were identified. The association of discovered biomarkers with clinical phenotypes was prospectively tested in plasma from 110 HCM patients with LVH (LVH+ HCM), 97 controls, and 16 HCM sarcomere gene mutation carriers before the development of LVH (subclinical HCM). Six peptides (aldolase fructose-bisphosphate A, complement C3, glutathione S-transferase omega 1, Ras suppressor protein 1, talin 1, and thrombospondin 1) were increased significantly in the plasma of LVH+ HCM compared with controls and correlated with imaging markers of phenotype severity: LV wall thickness, mass, and percentage myocardial scar on cardiovascular magnetic resonance imaging. Using supervised machine learning (ML), this six-biomarker panel differentiated between LVH+ HCM and controls, with an area under the curve of ≥ 0.87. Five of these peptides were also significantly increased in subclinical HCM compared with controls. In LVH+ HCM, the six-marker panel correlated with the presence of nonsustained ventricular tachycardia and the estimated five-year risk of sudden cardiac death. Using quantitative proteomic approaches, we have discovered six potentially useful circulating plasma biomarkers related to myocardial substrate changes in HCM, which correlate with the estimated sudden cardiac death risk.

The current and future aspects of glioblastoma: Immunotherapy a new hope?

Glioblastoma (GBM) is the most perilous and highly malignant in all the types of brain tumor. Regardless of the treatment, the diagnosis of the patients in GBM is very poor. The average survival rate is only 21 months after multimodal combinational therapies, which include chemotherapy, radiation, and surgery. Due to the intrusive and infiltrative nature of GBM, it requires elective therapy for specific targeting of tumor cells. Tumor vaccine in a form of immunotherapy has potential to address this need. Nanomedicine-based immunotherapies have clutch the trigger of systemic and specific immune response against tumor cells, which might be the approach to eliminating the unrelieved cancer. In this mechanism, combination of immunomodulators with specific target and appropriate strategic vaccines can stifle tumor anti-immune defense system and/or increase the capabilities of the body to move up immunity against the tumor. Here, we explore the different types of immunotherapies and vaccines for brain tumor treatment and their clinical trials, which bring the feasibility of the future of personalized vaccine of nanomedicine-based immunotherapies for the brain tumor. We believe that immunotherapy could result in a significantly more stable reaction in GBM patients.

Enhanced Solubility and Bioavailability of Dolutegravir by Solid Dispersion Method: In Vitro and In Vivo Evaluation-a Potential Approach for HIV Therapy.

Being a candidate of BCS class II, dolutegravir (DTG), a recently approved antiretroviral drug, possesses solubility issues. The current research was aimed to improve the solubility of the DTG and thereby enhance its efficacy using the solid dispersion technique. In due course, the miscibility study of the drug was performed with different polymers, where Poloxamer 407 (P407) was found suitable to move forward. The solid dispersion of DTG and P407 was formulated using solvent evaporation technique with a 1:1 proportion of drug and polymer, where the solid-state characterization was performed using differential scanning calorimetry, Fourier transform infrared spectroscopy and X-ray diffraction. No physicochemical interaction was found between the DTG and P407 in the fabricated solid dispersion; however, crystalline state of the drug was changed to amorphous as evident from the X-ray diffractogram. A rapid release of DTG was observed from the solid dispersion (>95%), which is highly significant (p<0.05) as compared to pure drug (11.40%), physical mixture (20.07%) and marketed preparation of DTG (35.30%). The drug release from the formulated solid dispersion followed Weibull model kinetics. Finally, the rapid drug release from the solid dispersion formulation revealed increased Cmax (14.56 µg/mL) when compared to the physical mixture (4.12 µg/mL) and pure drug (3.45 µg/mL). This was further reflected by improved bioavailability of DTG (AUC: 105.99±10.07 µg/h/mL) in the experimental Wistar rats when compared to the AUC of animals administered with physical mixture (54.45±6.58 µg/h/mL) and pure drug (49.27±6.16 µg/h/mL). Therefore, it could be concluded that the dissolution profile and simultaneously the bioavailability of DTG could be enhanced by means of the solid dispersion platform using the hydrophilic polymer, P407, which could be projected towards improved efficacy of the drug in HIV/AIDS.

Case 273: Pancreatic Duct-to-Portal Vein Fistula with Secondary Portal Vein Pyophlebitis-A Rare Complication of Chronic Pancreatitis.

HistoryA 55-year-old man with a history of chronic pancreatitis secondary to chronic alcohol abuse presented to the hospital with acute abdominal pain, generalized weakness, weight loss, and pyrexia. A clinical examination revealed he was tender to touch in the upper abdomen. Laboratory tests revealed a serum alkaline phosphatase level of 370 U/L (6.1 µkat/L) (normal range, 30-130 U/L [0.5-2.2 µkat/L]), a lipase level of 172 U/L (2.9 µkat/L) (normal range, 0-60 U/L [0-1.0 µkat/L]), a C-reactive protein level of 159 mg/L (1514 nmol/L) (normal value, <8.0 mg/L [76.2 nmol/L]), and a white cell count of 7 × 109/L (normal range, [4-11] × 109/L). During the present admission, the patient underwent urgent CT for his acute symptoms. His relevant medical history included a hospital admission 2 months earlier for abdominal discomfort. Given his history of chronic pancreatitis, baseline abdominal MRI was performed to determine the cause of his symptoms and to assess the pancreas.

Case 275: Multiple Hepatic Hydatid Cysts.

HistoryA 61-year-old woman presented to the cardiology service with sinus tachycardia. As part of her work-up, she underwent routine echocardiography that showed a normal heart but incidentally revealed multiple lesions in the liver. An outpatient CT scan was performed to characterize the liver lesions. The patient had emigrated to Canada from the Middle East several years earlier and had no medical history of note; in particular, there was no history of cancer or predisposing factors for chronic liver disease. The patient's clinical examination findings; laboratory test results, including complete blood count; and liver function test results were normal.

Clozapine reduces infiltration into the CNS by targeting migration in experimental autoimmune encephalomyelitis.

BACKGROUND: Atypical antipsychotic agents, such as clozapine, are used to treat schizophrenia and other psychiatric disorders by a mechanism that is believed to involve modulating the immune system. Multiple sclerosis is an immune-mediated neurological disease, and recently, clozapine was shown to reduce disease severity in an animal model of MS, experimental autoimmune encephalomyelitis (EAE). However, the mode of action by which clozapine reduces disease in this model is poorly understood. METHODS: Because the mode of action by which clozapine reduces neuroinflammation is poorly understood, we used the EAE model to elucidate the in vivo and in vitro effects of clozapine. RESULTS: In this study, we report that clozapine treatment reduced the infiltration of peripheral immune cells into the central nervous system (CNS) and that this correlated with reduced expression of the chemokines CCL2 and CCL5 transcripts in the brain and spinal cord. We assessed to what extent immune cell populations were affected by clozapine treatment and we found that clozapine targets the expression of chemokines by macrophages and primary microglia. Furthermore, in addition to decreasing CNS infiltration by reducing chemokine expression, we found that clozapine directly inhibits chemokine-induced migration of immune cells. This direct target on the immune cells was not mediated by a change in receptor expression on the immune cell surface but by decreasing downstream signaling via these receptors leading to a reduced migration. CONCLUSIONS: Taken together, our study indicates that clozapine protects against EAE by two different mechanisms; first, by reducing the chemoattractant proteins in the CNS; and second, by direct targeting the migration potential of peripheral immune cells.

Caution in using 3D-EAUS as the first-line diagnostic tool in the preoperative work up for perianal fistulas.

MRI is considered the de facto imaging modality for evaluating perianal fistulas, primarily due to its excellent soft tissue contrast, operator independence, multiplanar capabilities and excellent field of view. Tridimensional endoanal ultrasound (3D-EAUS) is inferior to MRI in identifying and/or evaluating ischiorectal/supralevator tracks/extensions and therefore could end up providing incomplete and even inaccurate information (e.g. misclassification of tracks) to the surgeon, with a missed track potentially leading to recurrence of the disease.

Hepatic hemangiomas: the various imaging avatars and its mimickers.

Hemangiomas are the most common benign tumors of the liver. These lesions are typically asymptomatic, solitary and almost always discovered incidentally, and in recent years with advances in imaging technology these lesions are being detected more frequently. Although, in majority of the cases, the imaging diagnosis of a liver hemangioma is clearly and confidently established, not all hemangiomas present with their characteristic or typical appearance on imaging. Occasionally, these lesions do present with an atypical pattern, and can be confused with other malignant lesions such as hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular-cholangiocarcinoma and angiosarcoma. In this article, we review with illustrations the diverse imaging appearances of hemangiomas on the commonly used imaging modalities, as well as provide a gamut of common and uncommonly encountered hemangioma mimickers. Knowledge of the various atypical avatars of this benign lesion is important and can help one circumvent diagnostic errors, thereby potentially avoiding unnecessary surgeries.

3D Printing Technologies: Recent Development and Emerging Applications in Various Drug Delivery Systems.

The 3D printing is considered as an emerging digitized technology that could act as a key driving factor for the future advancement and precise manufacturing of personalized dosage forms, regenerative medicine, prosthesis and implantable medical devices. Tailoring the size, shape and drug release profile from various drug delivery systems can be beneficial for special populations such as paediatrics, pregnant women and geriatrics with unique or changing medical needs. This review summarizes various types of 3D printing technologies with advantages and limitations particularly in the area of pharmaceutical research. The applications of 3D printing in tablets, films, liquids, gastroretentive, colon, transdermal and intrauterine drug delivery systems as well as medical devices have been briefed. Due to the novelty and distinct features, 3D printing has the inherent capacity to solve many formulation and drug delivery challenges, which are frequently associated with poorly aqueous soluble drugs. Recent approval of Spritam® and publication of USFDA technical guidance on additive manufacturing related to medical devices has led to an extensive research in various field of drug delivery systems and bioengineering. The 3D printing technology could be successfully implemented from pre-clinical phase to first-in-human trials as well as on-site production of customized formulation at the point of care having excellent dose flexibility. Advent of innovative 3D printing machineries with built-in flexibility and quality with the introduction of new regulatory guidelines would rapidly integrate and revolutionize conventional pharmaceutical manufacturing sector.

Case 275.

HistoryA 61-year-old woman presented to the cardiology service with sinus tachycardia. As part of her work-up, she underwent routine echocardiography that showed a normal heart but incidentally revealed multiple lesions in the liver (Fig 1). An outpatient CT scan was performed to characterize the liver lesions (Figs 2-5). The patient had emigrated to Canada from the Middle East several years earlier and had no medical history of note; in particular, there was no history of cancer or predisposing factors for chronic liver disease. The patient's clinical examination findings; laboratory test results, including complete blood count; and liver function test results were normal.[Figure: see text][Figure: see text][Figure: see text][Figure: see text][Figure: see text].

Case 273.

HistoryA 55-year-old man with a history of chronic pancreatitis secondary to chronic alcohol abuse presented to the hospital with acute abdominal pain, generalized weakness, weight loss, and pyrexia. A clinical examination revealed he was tender to touch in the upper abdomen. Laboratory tests revealed a serum alkaline phosphatase level of 370 U/L (6.1 µkat/L) (normal range, 30-130 U/L [0.5-2.2 µkat/L]), a lipase level of 172 U/L (2.9 µkat/L) (normal range, 0-60 U/L [0-1.0 µkat/L]), a C-reactive protein level of 159 mg/L (1514 nmol/L) (normal value, <8.0 mg/L [76.2 nmol/L]), and a white cell count of 7 × 109/L (normal range, [4-11] × 109/L). During the present admission, the patient underwent urgent CT for his acute symptoms. His relevant medical history included a hospital admission 2 months earlier for abdominal discomfort. Given his history of chronic pancreatitis, baseline abdominal MRI was performed to determine the cause of his symptoms and to assess the pancreas (Figs 1-3).Figure 1a:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1b:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1c:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 1d:(a, b) Images from axial fat-suppressed T2-weighted MRI (repetition time msec/echo time msec, 1000/87; section thickness, 6 mm) of the upper abdomen obtained 2 months prior to admission. (c, d) Images from axial fat-suppressed T1-weighted MRI (3.69/1.62; section thickness, 4 mm) of the upper abdomen acquired 60 seconds after intravenous administration of gadopentetate dimeglumine (0.1 mL per kilogram of body weight; Magnevist; Bayer Healthcare, East Mississauga, Ontario) during the current admission.Figure 2:Coronal T2-weighted MRI (repetition time msec/echo time msec, 1000/89; section thickness, 4 mm) of the upper abdomen obtained 2 months prior to admission.Figure 3:Coronal CT image of the abdomen acquired 60 seconds after administration of intravenous contrast material (100 mL of iohexol, Omnipaque 350; GE Healthcare, Princeton, NJ). This CT examination was performed during the current admission.

Development of Asialoglycoprotein Receptor-Targeted Nanoparticles for Selective Delivery of Gemcitabine to Hepatocellular Carcinoma.

Selective targeting of anticancer drugs to the tumor site is beneficial in the pharmacotherapy of hepatocellular carcinoma (HCC). This study evaluated the prospective of galactosylated chitosan nanoparticles as a liver-specific carrier to improve the therapeutic efficacy of gemcitabine in HCC by targeting asialoglycoprotein receptors expressed on hepatocytes. Nanoparticles were formulated (G1-G5) by an ionic gelation method and evaluated for various physicochemical characteristics. Targeting efficacy of formulation G4 was evaluated in rats. Physicochemical characteristics exhibited by nanoparticles were optimal for administering and targeting gemcitabine effectively to the liver. The biphasic release behavior observed with G4 can provide higher drug concentration and extend the pharmacotherapy in the liver target site. Rapid plasma clearance of gemcitabine (70% in 30 min) from G4 was noticed in rats with HCC as compared to pure drug (p < 0.05). Higher uptake of gemcitabine predominantly by HCC (64% of administered dose; p < 0.0001) demonstrated excellent liver targeting by G4, while mitigating systemic toxicity. Morphological, biochemical, and histopathological examination as well as blood levels of the tumor marker, alpha-fetoprotein, in rats confirmed the curative effect of G4. In conclusion, this study demonstrated site-specific delivery and enhanced in vivo anti-HCC efficacy of gemcitabine by G4, which could function as promising carrier in hepatoma.

Peloruside E (22-Norpeloruside A), a Pelorusane Macrolide from the New Zealand Marine Sponge Mycale hentscheli, Retains Microtubule-Stabilizing Properties.

A new peloruside congener, peloruside E (5), has been isolated in sub-milligram quantities from a specimen of the New Zealand marine sponge Mycale hentscheli. The structure of 5 differs from the parent compound peloruside A (1) by replacement of the C-10 gem-dimethyl moiety with a monomethyl substituent and represents the first structural deviation in the pelorusane scaffold. Peloruside E (5) is potently antiproliferative (HL-60, IC50 90 nM, cf. 1, 19 nM) and polymerizes purified tubulin, albeit at a rate lower than that of 1.

Zampanolides B-E from the Marine Sponge Cacospongia mycofijiensis: Potent Cytotoxic Macrolides with Microtubule-Stabilizing Activity.

Four new compounds (2-5) structurally related to the microtubule-stabilizing agent (-)-zampanolide (1) have been isolated from the Tongan marine sponge Cacospongia mycofijiensis. Three of these new structures, zampanolides B-D (2-4), exhibit nanomolar cytotoxicity toward the HL-60 cell line, are antimitotic, and induce in vitro tubulin polymerization at levels comparable to 1. Zampanolide E (5), saturated at C-8/C-9, was significantly less potent and does not stabilize purified tubulin, even at 10-fold higher concentrations. The structural differences across these compounds reveal a plasticity of the zampanolide pharmacophore. While unsaturation is required at Δ8, the configuration of this alkene and those of Δ4 and Δ4' have little effect on tubulin polymerization. The first natural co-occurrence of 1 and (-)-dactylolide (6) from the same sponge extract is also noted.

Anti-arthritic activity of cell wall content of Lactobacillus plantarum in freund's adjuvant-induced arthritic rats: involvement of cellular inflammatory mediators and other biomarkers.

Alteration of microbiota is related with rheumatoid arthritis (RA) and administration of certain probiotics showed an improvement in RA. The present study was designed to find out the anti-arthritic activity of cell wall content of Lactobacillus plantarum in complete Freund's adjuvant (CFA)-induced arthritis in rats. Freund's adjuvant was injected into the left footpad in female rats on day 0 and dexamethasone (1 mg kg-1, s.c.) & cell wall content of L. plantarum (105, 107, and 109 cfu/animal, s.c.) treatment were given from day 7 to 21. The change in body weight, paw volume and arthritic index, joint stiffness, gait test, mobility test, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP) level, serum rheumatoid factor (RF), and serum TNF-α was measured on day 21. Cell wall content of L. plantarum treated animals showed improvement in all the parameters as compared to that in CFA-treated animals and exert anti-arthritic activity.

Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis.

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.