Lactobacillus rhamnosus (LR) ameliorates pulmonary and extrapulmonary acute respiratory distress syndrome (ARDS) via targeting neutrophils.

Pulmonary and extrapulmonary acute respiratory distress syndrome (ARDS) is a life-threatening respiratory failure associated with high mortality. Despite progress in our understanding of the pathological mechanism causing the crippling illness, there are currently no targeted pharmaceutical treatments available for it. Recent discoveries have emphasized the existence of a potential nexus between gut and lung health fueling novel approaches including probiotics for the treatment of ARDS. We thus investigated the prophylactic-potential of Lactobacillus rhamnosus-(LR) in lipopolysaccharide (LPS)-induced pulmonary and cecal ligation puncture (CLP) induced extrapulmonary ARDS mice. Our in-vivo findings revealed that pretreatment with LR significantly ameliorated vascular-permeability (edema) of the lungs via modulating the neutrophils along with significantly reducing the expression of inflammatory-cytokines in the BALF, lungs and serum in both pulmonary and extrapulmonary mice-models. Interestingly, our ex-vivo immunofluorescence and flow cytometric data suggested that mechanistically LR via short chain fatty acids (butyrate being the most potent and efficient in ameliorating the pathophysiology of both pulmonary and extra-pulmonary ARDS) targets the phagocytic and neutrophils extracellular traps (NETs) releasing potential of neutrophils. Moreover, our in-vivo data further corroborated our ex-vivo findings and suggested that butyrate exhibits enhanced potential in ameliorating the pathophysiology of ARDS via reducing the infiltration of neutrophils into the lungs. Altogether, our study establishes the prophylactic role of LR and its associated metabolites in the prevention and management of both pulmonary and extrapulmonary ARDS via targeting neutrophils.

A phase II study of gemcitabine and docetaxel combination in relapsed metastatic or unresectable locally advanced synovial sarcoma.

Synovial sarcoma (SS) is one of the commonest non-rhabdomyosarcoma soft tissue sarcoma with limited treatment options in the relapsed and advanced settings. The combination of gemcitabine and docetaxel has demonstrated its role predominantly in leiomyosarcoma and pleomorphic sarcomas but has not been prospectively studied in SS. This trial assesses the efficacy, tolerability and quality of life (QoL) with this regimen in metastatic/unresectable locally advanced relapsed SS.Patients and methods This was a single-arm, two-stage, phase II, investigator-initiated interventional study among patients with metastatic or unresectable locally advanced SS who had progressed after at least one line of chemotherapy. Gemcitabine 900 mg/m2 on days 1 and 8 and docetaxel 75 mg/m2 on day 8 were administered intravenously every 21 days. The primary endpoint was 3-month progression-free rate (PFR); overall survival (OS), progression-free survival (PFS), overall response rate (ORR), safety and quality of life (QoL) constituted the secondary endpoints.Results Twenty-two patients were enrolled between March 2020 and September 2021 and the study had to be closed early due to slow accrual. The study population comprised of 18 (81.8%) patients with metastatic disease and 4 (18.2%) patients with locally advanced, unresectable disease. The most common primary sites of disease were extremity in 15 (68%) and the median number of lines of prior therapies received was 1 (range 1-4). 3-month PFR was 45.4% (95% CI 24.8-66.1) and ORR was 4.5%. Median progression-free survival (PFS) was 3 months (95% CI 2.3-3.6) and median OS was 14 months (95% CI 8.9-19.0). 7 (31.8%) patients experienced grade 3 or worse toxicities, including anemia (18%), neutropenia (9%) and mucositis (9%). QoL analysis demonstrated significant decline in certain functional and symptom scales, while financial and global health scales remained stable.Conclusion This is the first prospective study on the combination of gemcitabine and docetaxel performed specifically in patients with advanced, relapsed SS. Although the accrual of patients could not be completed as planned, the therapy did produce clinically meaningful outcomes and met its primary endpoint of 3-month PFR. This result, along with the manageable toxicity profile and stable global health status on QoL analysis, should encourage further studies.Trial registration This trial was prospectively registered under the Clinical Trials Registry of India on 26/02/2020 (Registration number: CTRI/2020/02/023612).

Increased Bone Marrow-Specific Adipogenesis by Clofazimine Causes Impaired Fracture Healing, Osteopenia, and Osteonecrosis Without Extraskeletal Effects in Rats.

Mycobacterium leprae infection causes bone lesions and osteoporosis, however, the effect of antileprosy drugs on the bone is unknown. We, therefore, set out to address it by investigating osteogenic differentiation from bone marrow (BM)-derived mesenchymal stem cells (MSCs). Out of 7 antileprosy drugs, only clofazimine (CFZ) reduced MSCs viability (IC50 ∼ 1 µM) and their osteogenic differentiation but increased adipogenic differentiation on a par with rosiglitazone, and this effect was blocked by a peroxisome proliferator-activated receptor gamma antagonist, GW9662. CFZ also decreased osteoblast viability and resulted in impaired bone regeneration in a rat femur osteotomy model at one-third human drug dose owing to increased callus adipogenesis as GW9662 prevented this effect. CFZ treatment decreased BM MSC population and homing of MSC to osteotomy site despite drug levels in BM being much less than its in vitro IC50 value. In adult rats, CFZ caused osteopenia in long bones marked by suppressed osteoblast function due to enhanced adipogenesis and increased osteoclast functions. A robust increase in marrow adipose tissue (MAT) by CFZ did not alter the hematologic parameters but likely reduced BM vascular bed leading to osteonecrosis (ON) characterized by empty osteocyte lacunae. However, CFZ had no effect on visceral fat content and was not associated with any metabolic and hematologic changes. Levels of unsaturated fatty acids in MAT were higher than saturated fatty acids and CFZ further increased the former. From these data, we conclude that CFZ has adverse skeletal effects and could be used for creating a rodent ON model devoid of extraskeletal effects.

Cytological diagnosis of Langerhans cell histiocytosis: A series of 47 cases.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare disease affecting predominantly children and young adults but can be found in any age group. Diagnosis of LCH is often difficult and can be delayed because of its rarity. The present study highlights the cytomorphological features in a large cohort of cases. An accurate cytological diagnosis may avoid unnecessary biopsy and guide appropriate management. METHOD: Fourty seven (47) cases of LCH diagnosed on cytological material & fine-needle aspiration (FNA) over a period of 14 years (2003-2016) were retrieved from the archives. The cytological smears were evaluated and microscopic findings collected by semi-quantitative assessment done by two different pathologists RESULT: The age at the diagnosis of the patients ranged from 9 months to 28 years. The majority of cases were in the age group of 0-5 years. The most common site was head and neck region, which included cervical lymphadenopathy and scalp swelling. Two cases were diagnosed each from inguinal lymph node and bronchio-alveolar lavage (BAL). Cytological smears in the majority of the cases were moderate to highly cellular (58%) and showing abundant Langerhans cell in (72%) of cases. Areas of necrosis were seen in 38%, while 78% of cases showed giant cells. The majority of cases showed mild eosinophilia (61%), sparse lymphocytosis (83%) and mild neutrophilic infiltration (64%). There were 1-2 mitoses per 10 high power field in 12 cases (25.5%). No abnormal mitoses were identified. CONCLUSION: The presence of cells with features of Langerhans cells associated with the expression of selected immunohistochemical markers allow the diagnosis of LCH on cytological samples, sparing more invasive procedure as a biopsy.

Exosome proteomic analyses identify inflammatory phenotype and novel biomarkers in African American prostate cancer patients.

African American men face a stark prostate cancer (PCa)-related health disparity, with the highest incidence and mortality rates compared to other races. Additional and innovative measures are warranted to reduce this health disparity. Here, we focused on the identification of a novel serum exosome-based "protein signature" for potential use in the early detection and better prognosis of PCa in African American men. Nanoparticle tracking analyses showed that compared to healthy individuals, exosome concentration (number/ml) was increased by ~3.2-fold (P Ë‚ 0.05) in the sera of African American men with PCa. Mass spectrometry-based proteomic analysis of serum exosomes identified seven unique and fifty-five overlapping proteins (up- or downregulated) in African Americans with PCa compared to healthy African Americans. Furthermore, ingenuity pathway analyses identified the inflammatory acute-phase response signaling as the top pathway associated with proteins loaded in exosomes from African American PCa patients. Interestingly, African American PCa E006AA-hT cells secreted exosomes strongly induced a proinflammatory M2-phenotype in macrophages and showed calcium response on sensory neurons, suggesting a neuroinflammatory response. Additionally, proteomic analyses showed that the protein Isoform 2 of Filamin A has higher loading (2.6-fold) in exosomes from African Americans with PCa, but a lesser loading (0.6-fold) was observed in exosomes from Caucasian men with PCa compared to race-matched healthy individuals. Interestingly, TCGA and Taylor's dataset as well as IHC analyses of PCa tissue showed a lower Filamin A expression in tissues of PCa patients compared with normal subjects. Overall, these results support the usefulness of serum exosomes to noninvasively detect inflammatory phenotype and to discover novel biomarkers associated with PCa in African American men.

Leg massage by mother resulting in fatal pulmonary thromboembolism.

We report the sudden death of a 23-year-old male with hairline ankle fracture after massage of the leg by his mother. Autopsy confirmed the cause of death as pulmonary thromboembolism due to deep vein thrombosis of the leg veins which was dislodged and travelled to his lungs consequent to the leg massage. The treating doctors did not warn the patient of the risk of developing pulmonary thromboembolism.

Fine needle aspiration cytology diagnosis of metastatic malignant diffuse type tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TGCTs) arise from the synovium of joint, bursa, and tendon sheath, and are classified into localized and diffuse types. Diffused type often affects the large joint, and has more recurrence, metastasis, and malignant transformation potential compared to the localized type. Malignant diffused TGCT (D-TGCT) usually occurs as a large tumor (>5 cm), in older patients, and its histopathologic features include necrosis, cellular anaplasia, prominent nucleoli, high nuclear cytoplasmic ratio, brisk mitosis, discohesion of tumor cells, paucity of giant cells, and a diffuse growth pattern. At least five of these criteria are required for the histopathologic diagnosis of malignant TGCT because the benign TGCT also shares many of these morphological features. We describe the cytomorphologic features of a malignant D-TGCT from an unusual case of pulmonary metastasis in an adult patient. Fine needle aspiration cytologic features of malignant D-TGCT have not been described earlier in the English literature.

Rotary ultrasonic drilling on bone: A novel technique to put an end to thermal injury to bone.

Bone drilling is common in orthopedic procedures and the heat produced during conventional experimental drilling often exceeds critical temperature of 47 °C and induces thermal osteonecrosis. The osteonecrosis may be the reason for impaired healing, early loosening and implant failure. This study was undertaken to control the temperature rise by interrupted cutting and reduced friction effects at the interface of drill tool and the bone surface. In this work, rotary ultrasonic drilling technique with diamond abrasive particles coated on the hollow drill tool without any internal or external cooling assistance was used. Experiments were performed at room temperature on the mid-diaphysis sections of fresh pig bones, which were harvested immediately after sacrifice of the animal. Both rotary ultrasonic drilling on bone and conventional surgical drilling on bone were performed in a five set of experiments on each process using identical constant process parameters. The maximum temperature of each trial was recorded by K-type thermocouple device. Ethylenediaminetetraacetic acid decalcification was done for microscopic examination of bone. In this comparative procedure, rotary ultrasonic drilling on bone produced much lower temperature, that is, 40.2 °C ± 0.4 °C and 40.3 °C ± 0.2 °C as compared to that of conventional surgical drilling on bone, that is, 74.9 °C ± 0.8 °C and 74.9 °C ± 0.6 °C with respect to thermocouples fixed at first and second position, respectively. The conventional surgical drilling on bone specimens revealed gross tissue burn, microscopic evidence of thermal osteonecrosis and tissue injury in the form of cracks due to the generated force during drilling. But our novel technique showed no such features. Rotary ultrasonic drilling on bone technique is robust and superior to other methods for drilling as it induces no thermal osteonecrosis and does not damage the bone by generating undue forces during drilling.

Sudden death of a child due to pyogenic bacterial myocarditis.

Bacterial myocarditis is an uncommon condition and only a few fatal cases in adults are reported in the scientific literature. Death from acute bacterial myocarditis in children is extremely rare. We report an unusual case of fatal bacterial myocarditis in a seven-year-old girl, who had a history of cough for a month and fever for two days. She was given symptomatic treatment by a local physician without suspecting her clinical condition. Her condition rapidly deteriorated and she was brought in dead to the hospital. Autopsy revealed pyogenic bacterial myocarditis associated with bilateral lobar pneumonia caused by Gram-positive cocci. Death from bacterial myocarditis can be prevented by early diagnosis and appropriate antibiotics.

Primary ovarian non-Hodgkin lymphoma: Diagnosis of two cases on fine needle aspiration cytology.

Lymphoma of the female genital tract is a rare condition. Involvement of the ovary by non- Hodgkin lymphoma (NHL) is usually secondary to systemic disease and primary ovarian lymphomas are unusual. In most cases, the diagnosis is not suspected initially and is confirmed only after detailed histopathological evaluation. We describe two cases of primary ovarian NHL which were diagnosed on fine needle aspiration cytology (FNAC). One of the patients was a 40 years old female who presented with abdominal distension and lump. She was found to have bilateral adnexal masses on ultrasound and computed tomography (CT) scan. A USG guided fine needle aspiration of the ovarian masses was performed, following which a diagnosis of primary ovarian diffuse large B-cell lymphoma was established. The second patient was a 14 years old female who presented with pelvic lump, which was lobulated and mildly enhancing on contrast enhanced CT. A diagnosis of high grade NHL of ovaries was made on cytology. Subsequently, the lymphoma was characterized as Burkitt's on histopathological examination. Both the patients were started on R-CHOP chemotherapy regimen. FNAC serves as an extremely useful minimally invasive procedure for the diagnosis of ovarian lymphomas and early institution of appropriate chemotherapeutic regimens.

A prospective randomized study to compare systemic emboli using the computer-assisted and conventional techniques of total knee arthroplasty.

BACKGROUND: Conventional total knee arthroplasty is performed with use of an intramedullary alignment guide, which produces elevated intramedullary pressure that can create fat emboli. Total knee arthroplasty performed via computer-assisted surgery does not require an intramedullary femoral rod, raising the question of whether computer-assisted surgery generates less embolic material than conventional total knee arthroplasty. The purpose of this study was to compare the emboli produced in the two techniques. METHODS: Fifty-seven patients were randomized into two groups: the computer-assisted surgery group (n = 29) and the conventional total knee arthroplasty group (n = 28). An intramedullary femoral alignment jig was used in the conventional total knee arthroplasty group but not in the computer-assisted surgery group. Intraoperative invasive monitoring was performed with use of transesophageal echocardiography and a pulmonary artery catheter. RESULTS: The mean embolic score was 6.21 points for the conventional technique group and 5.48 points for the computer-assisted surgery group (p = 0.0161). After tourniquet deflation, fat emboli were observed in the blood of five patients in the conventional surgery group and one patient in the computer-assisted surgery group. CONCLUSIONS: The patients in the computer-assisted surgery group had lower embolic loads compared with the patients in the conventional total knee arthroplasty group. In patients with an uncompromised cardiopulmonary system, the embolic load difference between the techniques was not clinically relevant. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

"Normal" liver stiffness measure (LSM) values are higher in both lean and obese individuals: a population-based study from a developing country.

UNLABELLED: The liver stiffness measure (LSM) needs to be explored in ethnically and anthropometrically diverse healthy subjects (to derive an acceptable normal range) and also in patients with liver disease. In view of this objective, LSM was performed by transient elastography (TE) using FibroScan in 437 healthy subjects with normal alanine aminotransferase (ALT) levels, recruited from a free-living population of the Birbhum Population Project (BIRPOP; www.shds.in), a Health and Demographic Surveillance System (HDSS), and from 274 patients with liver disease attending the Hepatology Clinic of the School of Digestive and Liver Diseases (SDLD; Institute of Post Graduate Medical Education & Research [IPGME&R], Kolkata, India) including 188 with nonalcoholic fatty liver disease (NAFLD) and 86 with chronic hepatitis of viral and other etiologies. Liver biopsy was performed in 125 patients. The range of normal values for LSM, defined by 5th and 95th percentile values in healthy subjects, was 3.2 and 8.5 kPa, respectively. Healthy subjects with a lower body mass index (BMI; < <18.5 kg/m(2)) had a higher LSM compared with subjects who had a normal BMI; this LSM value was comparable to that of obese subjects (6.05 ± 1.78 versus 5.51 ± 1.59 and 6.60 ± 1.21, P = 0.016 and 0.349, respectively). Liver disease patients without histologic fibrosis had significantly higher LSM values compared with healthy subjects (7.52 ± 5.49 versus 5.63 ± 1.64, P < 0.001). Among the histologic variables, stage of fibrosis was the only predictor for LSM. LSM did not correlate with inflammatory activity and ALT in both NAFLD and chronic hepatitis groups. CONCLUSION: LSM varies between 3.2 and 8.5 kPa in healthy subjects of South Asian origin. Both lean and obese healthy subjects have higher LSM values compared with subjects with normal BMI. Liver stiffness begins to increase even before fibrosis appears in patients with liver disease.

Obscure GI bleeding in the tropics: impact of introduction of double-balloon and capsule endoscopies on outcome.

BACKGROUND: Innovative but costly small-bowel enteroscopies, capsule endoscopy (CE), and double-balloon endoscopy (DBE) have revolutionized the management of obscure GI bleeding (OGIB). OBJECTIVE: To measure the impact of these procedures on outcomes of OGIB in a resource-poor setting. DESIGN: Prospective cohort study and comparison with a historical cohort. SETTING: Tertiary-care center in India. PATIENTS: Fifty-three patients with OGIB, diagnosed by American Gastroenterological Association criteria. INTERVENTIONS: DBE and/or CE were performed. Patients were then offered specific treatment and/or hematinics. MAIN OUTCOME MEASUREMENTS: The etiology of OGIB in a tropical country and yield of DBE and/or CE. The number of investigations required, follow-up hemoglobin, rebleeds, and interventions/transfusions needed were compared between the present and historical cohort. RESULTS: Mean age was 46.4 years with hemoglobin (mean +/- standard deviation) of 8.3 +/- 2.3 g/dL at evaluation. OGIB was overt in 33 and occult in 20. They underwent 173 investigations before referral. DBE and/or CE localized the source of bleeding in 43 (yield 81%). Angiodysplasias, tumors, Crohn's disease, intestinal tuberculosis, and hookworm infestation were predominant etiologies. Compared with the historical cohort, DBE and/or CE have reduced the number of investigations per patient, increased the yield of mid intestinal source of OGIB, and reduced the number of surgeries, especially emergency laparotomies. There was no significant alteration in the overall yield, mortality, and rebleeding rates. LIMITATION: Small cohort without economic analysis. CONCLUSIONS: The demographic profile and etiological spectrum of OGIB in the tropics is different. DBE and/or CE have made a favorable impact on management.

Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.

UNLABELLED: There is a paucity of community-based epidemiological data on nonalcoholic fatty liver (NAFL) among nonaffluent populations in developing countries. Available studies are radiological and/or biochemical and lack histological assessment, limiting their strength. We conducted a prospective epidemiological study comprising a 1:3 subsample of all adult (>18 years) inhabitants of a rural administrative unit of West Bengal, India. Subjects positive for hepatitis B virus and/or hepatitis C virus infection and consuming any amount of alcohol were excluded. Diagnosis of NAFL was by dual radiological screening protocol consisting of ultrasonographic and computed tomographic examination of the liver. Transient elastographic examination and liver biopsy were performed in a subset to identify significant liver disease. The risk factors of having NAFL were analyzed. A total of 1,911 individuals were analyzed, 7% of whom were overweight and 11% of whom had abdominal obesity. The prevalence of NAFL, NAFL with elevated alanine aminotransferase, and cryptogenic cirrhosis was 8.7%, 2.3%, and 0.2%, respectively. Seventy-five percent of NAFL subjects had a body mass index (BMI) <25 kg/m(2), and 54% were neither overweight nor had abdominal obesity. The subjects with the highest risk of having NAFL were those with a BMI >25 kg/m(2) (odds ratio 4.3, 95% confidence interval 1.6-11.5). Abdominal obesity, dysglycemia (fasting plasma glucose >100 mg/dL or elevated homeostatic model assessment of insulin resistance), and higher income were the other risk factors. Even having a normal BMI (18.5-24.9 kg/m(2)) was associated with a 2-fold increased risk of NAFL versus those with a BMI <18.5 kg/m(2). CONCLUSION: There is a significant prevalence of NAFL and potentially significant liver disease, including cryptogenic cirrhosis, in this predominantly nonobese, nonaffluent population in a developing country. NAFL will be a major determinant of future liver disease burden in countries of the developing world.

Superficial basal cell carcinoma on face treated with 5% imiquimod cream.

Imiquimod, an immune response modifier, is known to possess both anti-viral and anti-tumor effect. We report our experience of treating a large superficial spreading basal cell carcinoma with 5% imiquimod cream. A 65-year-old male had an asymptomatic, hyperpigmented, slowly progressive, indurated, 3 x 4 cm plaque on the left cheek for two months. Biopsy from the lesion showed features of basal cell carcinoma. The patient was treated with imiquimod 5% cream, topically three times a week for six months with complete resolution of the lesion and without any side-effects. There was no clinical or histological recurrence after three months of stopping the treatment.