Too Much of a Good Thing: Extended Duration of Gut Microbiota Depletion Reverses Protection From Experimental Autoimmune Uveitis.

Purpose: Using the model of experimental autoimmune uveitis (EAU) induced by immunization with a retinal antigen, two studies have reported contradictory results on disease development following oral antibiotic treatment (ABX). We showed that long-term ABX did not affect EAU, but another study showed that short-term ABX was protective. We therefore studied the effects of ABX on EAU, gut microbiota, and host immune responses as a function of treatment duration. Methods: EAU-susceptible mice were treated orally with broad-spectrum antibiotics starting at least 10 weeks (long-term) or 1 week (short-term) before immunization until termination of the experiment. Gut microbiota were characterized by 16S amplicon sequencing, and host gut immune elements were studied phenotypically and functionally. Results: Long-term ABX had no effect, whereas short-term ABX delayed EAU, as previously reported by us and others, respectively. Microbial sequencing revealed progressive reduction of gut microbiota that showed some differences in the two ABX groups. Interestingly, duration of ABX was associated with a gradual disappearance of the CD4+ and CD4+CD8+ subset of gut intraepithelial lymphocytes (IELs). This IEL subset is microbiota dependent and is absent in germ-free mice. Relative abundance of Lactobacillus reuteri correlated with the frequencies of CD4+CD8+ IELs. IELs suppressed antigen-specific activation of autoreactive T cells in culture. Conclusions: Gut microbiota may play dual roles in uveitis development: They promote EAU development but also help maintain IEL populations that have regulatory function against autoreactive T cells. We propose that the progressive loss of this population during long-term ABX reverses the EAU-ameliorating effects of microbiota depletion.

Antibacterial and Antioxidant Activities of Prinsepia utilis Royle Leaf and Seed Extracts.

Our study was designed to screen the antibacterial potency of Princepia utilis leaf and seed extract and to measure their antioxidant effects, total phenol content, total flavonoid content, and total carbohydrate content. Collected samples were extracted by cold maceration. Hexane, ethyl acetate, methanol, and distilled water were used as extraction solvents. In the disc diffusion method, P. utilis ethyl acetate leaf extract was most prominent against Staphylococcus epidermis with a zone of inhibition (ZOI) of 13.83 mm. Similarly, methanolic leaf extract was most prominent against Staphylococcus aureus (ZOI-12.33 mm). Furthermore, the methanolic seed extract was most sensitive against Klebsiella pneumoniaee (ZOI-11.66 mm) Escherichia coli (ZOI-9.0 mm). The lowest minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values of 0.5 mg/mL and 0.6 mg/mL, respectively, were shown by ethyl acetate leaf extract against S. epidermis. Similarly, the highest values of MIC and MBC, i.e., 20.8 mg/mL and 33.3 mg/mL, respectively, were shown by hexane leaf extract against S. epidermidis. On the other hand, evaluation of antioxidant capacity revealed that ethyl acetate leaf extract showed the maximum antioxidant effect (IC50: 66.69 µg/mL). The total flavonoid contents of different extracts were measured in the range of 37 ± 0.74 µg QE/mg dry extract weight (methanolic seed extract) to 321.84 ± 4.82 µg QE/mg dry extract weight (hexane seed extract). Likewise, the total polyphenol content ranged from the hexane leaf extract (17.33 ± 0.642 µg GAE/mg dry extract weight) to ethyl acetate leaf extract (62.56 ± 1.284 µg GAE/mg dry extract weight). We found a variation in total carbohydrate content in the range of 23.55 ± 1.125 µg glucose/mg dry extract weight (hexane leaf extract) to 96.63 ± 2.253 µg glucose/mg dry extract weight (aqueous leaf extract). Overall, this study revealed that leaf and seed extract of P. utilis exhibited noteworthy antibacterial effects against diverse pathogenic microorganisms.

Tuberculosis-Associated Septic Shock: A Case Series.

Tuberculosis septic shock (TBSS) is a rare diagnosis due to inherent diagnostic difficulty or attribution to alternate causes. We report six cases of TBSS, along with comorbidities, clinical characteristics, hospital course, and in-hospital outcomes. All patients were middle-aged, with a median age of 54.5 years (interquartile range (IQR): 47-62). Four patients were males, whereas two were females. Majority (n = 4, 66.7%) of patients had comorbidities. Diabetes mellitus (n = 3, 50%), systemic hypertension (n = 2, 33.3%), and chronic obstructive pulmonary disease (n = 1, 16.7%) were the reported comorbidities in included patients. Median Acute Physiology and Chronic Health Evaluation (APACHE) II score at admission was 12 (IQR: 12-16). All patients had a microbiologic diagnosis of tuberculosis (TB). Four patients (66.7%) had respiratory secretions positive for Mycobacterium tuberculosis (MTB) by acid-fast bacilli (AFB) smear or cartridge-based nucleic acid amplification test (CBNAAT), two had sputum positivity, one had induced sputum positivity, whereas another had bronchoalveolar lavage specimen positive for MTB. One patient had lymph node aspirate positivity, and another had chest wall abscess positive for MTB. All had drug-sensitive TB. Five patients could be prescribed all four primary antitubercular drugs; one patient had deranged liver enzymes, requiring initiation of modified antitubercular therapy (ATT). Five patients were discharged successfully, whereas one patient died during the hospital stay. In-hospital mortality was 16.7%.

Chronic Laryngotracheal Granulomatous Disease Secondary to Sporothrix schenckii in an Immunocompromised Patient.

OBJECTIVE: To describe a rare presentation of laryngotracheal granulomatous disease secondary to sporotrichosis. METHODS: The authors report a case of laryngeal sporotrichosis in an immunocompromised patient, with accompanying endoscopic images and pathology. RESULTS/CASE: A 72-year-old immunocompromised female with a history of rose-handling presented with a year of hoarseness and breathy voice. Flexible nasolaryngoscopy showed diffuse nodularity; biopsy of the lesions demonstrated granulomatous inflammatory changes, and fungal culture grew Sporothrix schenkii. Long-term itraconazole treatment was initiated, with improvement in dysphonia and few residual granulomas on follow-up examination. CONCLUSION: When evaluating granulomatous disease of the airway, a broad differential including infectious or inflammatory etiologies should be considered, especially in immunocompromised patients. Adequate tissue samples should be collected to facilitate special staining. The current recommendations for laryngeal sporotrichosis include treatment with a prolonged course of itraconazole.

Normal reference value of orthodromic and antidromic sensory nerve conduction velocity of median nerve with intact palmaris longus tendon in apparently healthy individuals.

OBJECTIVES: The aim of this study was to determine normative electrophysiological reference values of median sensory nerve conduction studies among security guards with the palmaris longus tendon (PLT). METHODS: Sensory nerve conduction studies of the median nerve using antidromic and orthodromic methods were conducted in the upper limbs of 101 healthy male security guards between the ages of 21 and 42 years. The presence of the PLT was recorded in both hands using a standard test. A scatter plot was used to determine the correlation between different parameters using the ortho and antidromic methods. RESULTS: The mean age (years), weight (kg), height (cm), and BMI (kg/m2) were 28.77 ± 5.14, 70.53 ± 11.28, 171.71 ± 7.12, and 23.91 ± 3.45, respectively. In the median nerve (sensory) by antidromic method, the mean distal latency (DL) was 2.65 ± 0.33 ms and 2.64 ± 0.37, SNCV (sensory nerve conduction velocity) was 53.45 ± 5.28 m/s and 53.84 ± 5.68 and the amplitude was 27.33 ± 12.38 µV and 29.41 ± 12.97 in the left- and right-hand wrist, respectively. By orthodromic method the DL was 2.54 ± 0.53 ms and 2.51 ± 0.44, SNCV was 55.93 ± 6.09 m/s and 55.93 ± 5.24 and the sensory nerve action potential amplitude was 12.00 ± 8.82 µV and 11.72 ± 6.24 in the left and right hand, respectively. Spearman correlations were used to determine the variables influenced by hand sidedness. CONCLUSIONS: The normative reference parameters of sensory nerve conduction velocity of the median nerve were established by both methods using a standardized technique.

Perivascular epithelioid cell tumor (PEComa) of the pterygopalatine fossa.

Perivascular epithelioid cell tumors (PEComas) are a rare group of mesenchymal tumors associated with tuberous sclerosis. These tumors are typically treated with resection and rarely recur or exhibit malignant behavior. A 78-year-old woman presented with an incidentally discovered pterygopalatine fossa/retroantral mass. Excisional biopsy was performed and revealed pathology consistent with PEComa. Upon review of the literature, there have been 43 reported cases of PEComa of the head and neck. There is only one previously reported case of PEComa in the skull base, and none reported in the pterygopalatine fossa. Of note, the previously reported case of skull base PEComa involved an aggressive tumor with widespread metastasis. Here, we report the first case of a PEComa of the pterygopalatine fossa/retroantral region, which was treated conservatively. This rare pathology should be considered in the differential diagnosis for atypical skull base tumors.

Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case.

Metastatic carcinomatosis to the liver is a pattern of malignant infiltration that tends to provoke hepatic fibrosis. It is a rare complication of multiple solid tumor types and often seen in the absence of discrete tumor mass in the liver. We report a case of a 69-year-old woman with metastatic ductal carcinoma of the breast who presented with rising serum tumor markers and mildly cirrhotic contour of the liver on a CT scan. An early diagnosis of occult spread to the liver was made by means of a percutaneous liver biopsy showing desmoplastic response to invasive breast cancer cells found diffusely in the liver. This case highlights a rare pattern of metastatic spread of breast cancer as well as predisposing and prognostic features.

Clinical implications of prostatic capsular abutment or bulging on multiparametric magnetic resonance imaging.

BACKGROUND: The presence of capsular abutment or bulging can raise concern when planning surgery. In this study we aimed to test the clinical implications of capsular abutment or bulging on preoperative multiparametric magnetic resonance imaging (mpMRI). METHODS: We analyzed the data of 291 patients who underwent radical prostatectomy (RP) for a cT1-2N0 prostate cancer in a single surgeon series. All patients underwent preoperative staging with mpMRI. PIRADS v2 was used for characterizing lesions. The role of capsular abutment or bulging was tested in a multivariable logistic regression adjusting for prostate-specific antigen and highest ipsilateral biopsy Gleason grade. The presence of focal versus extensive extracapsular extension (ECE) was investigated. RESULTS: Overall, ECE on final pathology was documented in 35 (12%) cases and ECE was focal in 32 (91%) patients. Overall, mpMRI demonstrated capsule bulging or abutment in 12 (24%) cases. After adjusting for confounders, capsule bulging or abutment on mpMRI emerged as predictor for ECE (OR=6.70; 95% CI: 2.97-15.12, P<0.001). The sensitivity and specificity of capsule abutment or bulging in predicting ECE were 43% and 95%, respectively. Sensitivity and specificity were 36% and 48% respectively to predict focal ECE. CONCLUSIONS: The PIRADS v2 scoring system has a grey zone concerning ECE as defined by capsule abutment or bulging. We found an increased risk of ECE and specifically focal ECE when capsule bulging or abutment on mpMRI are documented.

Predictive value of pseudouridine in prostate cancer.

BACKGROUND: Recent studies have shown that certain small nucleolar RNAs (H/ACA snoRNAs) and the protein dyskerin (DKC1) are upregulated in prostate cancer and are thought to contribute to progression of disease. These components convert uridine to pseudouridine (abbreviated ψ), a type of post-transcriptional modification of RNA. Given the increased abundance of H/ACA snoRNAs and expression of DKC1 in prostate carcinomas, and because whole-body turnover of RNA increases in support of rapidly-growing cancer cells, we examined the value of pseudouridine as a biomarker for prostate cancer. METHODS: Using a monoclonal antibody against pseudouridine, we tested its ability to distinguish between two 25-base RNA oligonucleotide sequences that differed by only one ψ-substitution, and subsequently measured ψ in RNA isolated from several prostate cancer cell lines representing different stages of disease using dot blot assays and pseudouridinylated RNA linked immunosorbent assay (PURLISA). We also performed immunohistochemistry on a tissue micro array (12 cases/24 cores) containing prostate adenocarcinomas and normal adjacent tissue (NAT). RESULTS: High levels of pseudouridine were detected in androgen-independent cell lines (PC3 and Du145) compared to androgen-sensitive (LNCaP) and immortalized human prostate (RWPE) cells. Immunohistochemistry of a tissue micro array (TMA) containing normal adjacent and cancerous prostate tissue revealed a significant difference in immunoreactivity between normal and malignant tissue (P ≤ 0.0001). CONCLUSION: Our results provide new information on the relationship between pseudouridine expression and clinical progression of prostate cancer.

HIV-Associated Vacuolar Encephalomyelopathy.

We report a case of human immunodeficiency virus (HIV)-associated vacuolar encephalomyelopathy with progressive central nervous system dysfunction and corresponding vacuolar degeneration of the spinal cord, cranial nerves, and brain, the anatomic extent of which has not previously been described.

Downgrading of Grade Group After Radical Prostatectomy: Comparison of Multiparametric Magnetic Resonance Imaging Guided Fusion Biopsy and Standard 12-Core Biopsy.

OBJECTIVE: To analyze the factors associated with Grade group (GG) downgrading post-radical prostatectomy. PATIENTS AND METHODS: We performed a retrospective analysis of 536 patients who underwent robot-assisted laparoscopic radical prostatectomy from February 2014 to October 2015. We have analyzed the clinical, radiological, and pathologic factors associated with GG downgrading in final pathology. Downgrading was defined as those patients who downgraded from GG 3, 4, or 5 on biopsy to GG 1 or 2 on final pathology as well as patients who downgraded from GG 2 on biopsy to GG 1 on final pathology. Categorical values were compared with chi-square and Fischer's exact tests. Mann-Whitney U and Kruskal-Wallis were used for analysis of independent variables associated with GG downgrading. RESULTS: Ninety-three patients underwent fusion biopsy (FB) and 443 underwent the standard 12 core biopsy. Baseline clinical characteristics were similar between the 2 groups except for race (P = .009). Downgrading was observed in 76 patients (14.1%). Rate of downgrading was higher in the FB group (n = 22, 23.7% vs n = 54, 12.2%, P = .008). In multivariable logistic regression analysis, FB (OR:2.39, P = .004) and maximum percentage of core involvement (OR:1.01, P = .013) were associated with downgrading after robot-assisted laparoscopic radical prostatectomy. After 1:2 propensity score matching, FB was still associated with an increased rate of downgrading (P = .034). Downgrading had no significant effect on pathologic outcome. CONCLUSION: FB and maximum percentage of core involvement are the only factors associated with GG downgrading in final pathology. However, downgrading did not influence surgical outcome.

Defining Prostate Cancer at Favorable Intermediate Risk: The Potential Utility of Magnetic Resonance Imaging and Genomic Tests.

PURPOSE: We determined whether prostate multiparametric magnetic resonance imaging and genomic biomarkers might help further define patients with favorable intermediate risk prostate cancer which could safely be considered suitable for active surveillance. MATERIALS AND METHODS: From our institutional database we identified 509 patients who underwent radical prostatectomy with preoperative magnetic resonance imaging and a postoperative Decipher® prostate cancer test. According to the NCCN® (National Comprehensive Cancer Network®) risk stratification 125 men had favorable intermediate and 171 had unfavorable intermediate risk disease. Univariable and multivariable binary logistic regression analyses were done to test the utility of different variables in predicting adverse pathology, defined as Gleason Grade Group greater than 2, pT3b or pN1. RESULTS: On univariable analysis favorable intermediate risk, multiparametric magnetic resonance imaging and the prostate cancer test significantly predicted adverse pathology. On multivariable analysis favorable intermediate risk and the prostate cancer test maintained independent predictive value while multiparametric magnetic resonance imaging did not meet statistical significance (p = 0.059). The 19 patients at favorable intermediate risk with high genomic risk had an adverse pathology rate slightly higher than patients at unfavorable intermediate risk (42.1% vs 39.8%, p = 0.56). Those at low genomic risk had an adverse pathology rate slightly lower than patients at very low or low risk (7.5% vs 10.2%, p = 0.84). The 31 patients at favorable intermediate risk but at high multiparametric magnetic resonance imaging and genomic risk had an adverse pathology rate slightly lower than patients at unfavorable intermediate risk (25.8% vs 39.8%, p = 0.14). Those at low multiparametric magnetic resonance imaging and genomic risk had an adverse pathology rate slightly lower than patients at very low or low risk (8.5% vs 10.2%, p = 0.89). CONCLUSIONS: Multiparametric magnetic resonance imaging and the Decipher test allowed us to better define the risk of adverse pathology in patients at favorable intermediate risk who were diagnosed with prostate cancer.

Novel nomogram for the prediction of seminal vesicle invasion including multiparametric magnetic resonance imaging.

OBJECTIVES: To create a model that predicts side-specific seminal vesicle invasion using clinical, biopsy and multiparametric magnetic resonance imaging data. METHODS: We analyzed data from 544 patients who underwent robot-assisted radical prostatectomy at a single institution. To develop a side-specific predictive model, we ultimately considered four variables: prostate-specific antigen, highest ipsilateral biopsy Gleason grade, highest ipsilateral percentage core involvement and seminal vesicle invasion on multiparametric magnetic resonance imaging. A binary multivariable logistic regression model was fitted to predict seminal vesicle invasion. A nomogram was then built based on the coefficients of the resulting logit function. The leave-one-out cross validation method was used for internal validation, and the decision curve analysis for the evaluation of the net clinical benefit. RESULTS: We relied on 804 side-specific cases after excluding negative biopsy observations (n = 284). Seminal vesicle invasion was reported on multiparametric magnetic resonance imaging in 41 (5%) cases, and on final pathology in 64 (8%) cases. All variables in the model emerged as predictors of seminal vesicle invasion (all P ≤ 0.001) and were subsequently considered to build a nomogram. The area under the curve of multiparametric magnetic resonance imaging alone in predicting seminal vesicle invasion was 59.1%; whereas one of the clinical variables only was 85.1%. The area under the curve of the nomogram resulting from their combination was 86.5%. After internal validation, this resulted in 84.7%. The model achieved good calibration and the decision curve analysis showed its clinical benefit, especially when compared with relying only on multiparametric magnetic resonance imaging prediction of seminal vesicle invasion. CONCLUSIONS: A nomogram based on clinical and multiparametric magnetic resonance imaging data can predict seminal vesicle invasion and serve as a tool to urologists for surgical planning.

Multiparametric Magnetic Resonance Imaging Features Identify Aggressive Prostate Cancer at the Phenotypic and Transcriptomic Level.

PURPOSE: Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features. MATERIALS AND METHODS: We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model. RESULTS: Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-ß and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases. CONCLUSIONS: The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.

Development and internal validation of a side-specific, multiparametric magnetic resonance imaging-based nomogram for the prediction of extracapsular extension of prostate cancer.

OBJECTIVES: To develop a nomogram for predicting side-specific extracapsular extension (ECE) for planning nerve-sparing radical prostatectomy. MATERIALS AND METHODS: We retrospectively analysed data from 561 patients who underwent robot-assisted radical prostatectomy between February 2014 and October 2015. To develop a side-specific predictive model, we considered the prostatic lobes separately. Four variables were included: prostate-specific antigen; highest ipsilateral biopsy Gleason grade; highest ipsilateral percentage core involvement; and ECE on multiparametric magnetic resonance imaging (mpMRI). A multivariable logistic regression analysis was fitted to predict side-specific ECE. A nomogram was built based on the coefficients of the logit function. Internal validation was performed using 'leave-one-out' cross-validation. Calibration was graphically investigated. The decision curve analysis was used to evaluate the net clinical benefit. RESULTS: The study population consisted of 829 side-specific cases, after excluding negative biopsy observations (n = 293). ECE was reported on mpMRI and final pathology in 115 (14%) and 142 (17.1%) cases, respectively. Among these, mpMRI was able to predict ECE correctly in 57 (40.1%) cases. All variables in the model except highest percentage core involvement were predictors of ECE (all P ≤ 0.006). All variables were considered for inclusion in the nomogram. After internal validation, the area under the curve was 82.11%. The model demonstrated excellent calibration and improved clinical risk prediction, especially when compared with relying on mpMRI prediction of ECE alone. When retrospectively applying the nomogram-derived probability, using a 20% threshold for performing nerve-sparing, nine out of 14 positive surgical margins (PSMs) at the site of ECE resulted above the threshold. CONCLUSION: We developed an easy-to-use model for the prediction of side-specific ECE, and hope it serves as a tool for planning nerve-sparing radical prostatectomy and in the reduction of PSM in future series.

Development and validation of simulated virtual patients to impart early clinical exposure in endocrine physiology.

In the country presently, preclinical medical students are not routinely exposed to real patients. Thus, when they start clinical postings, they are found to have poor clinical reasoning skills. Simulated virtual patients (SVPs) can improve clinical skills without endangering real patients. This pilot study describes the development of two SVPs in endocrine physiology and their validation in terms of acquisition of clinical knowledge and student engagement. Two SVPs, Nandini Sharma (unintentional weight gain) and Sunil Yadav (polyuria), were created and published on the i-Human Patients platform through an iterative, interdisciplinary, and transdisciplinary collaborative process using the conceptual framework of Kim et al. (Kim S, Phillips WR, Pinsky L, Brock D, Phillips K, Keary J. Med Educ 40: 867-876, 2006). After internal and external peer validation, the SVPs were piloted on 40 students (20 students per virtual patient) over 2 wk. A cognitive pretest was conducted before exposure, and a posttest soon after. Faculty and student feedback were collected. Faculty found SVPs authentic, helpful as teaching-learning tools, and useful for giving feedback and for assessment. Students found SVPs more engaging than paper cases and helpful in developing clinical reasoning and in imparting clinical exposure. Pretest and posttest scores indicated knowledge gain ( P < 0.01). Although challenging to create, SVPs created on the i-Human Patients platform improved learning in endocrine physiology and were well accepted by students and faculty as a means to provide early clinical exposure. More SVPs can be developed through collaboration between stakeholder departments and integrated into the curriculum for greater benefit.

A tell tale handshake.

Myotonic dystrophy is a group of inherited disorders called muscular dystrophies. Clinical presentation of this disease is characterised by progressive muscle weakness with myotonia, cataracts, infertility (in males) and cardiac conduction defects. We present a case of a 35 year old male with lung abscess, later diagnosed to be a case of myotonic dystrophy. Lung abscess is an uncommon presentation of this disease and has never been reported before.