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DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolone class of antibacterials. However, owing to increasing drug resistance as well as a concomitant reduction in the availability of newer classes of antibiotics, fluoroquinolones are increasingly being over-utilized in order to treat serious infections, including multi-drug resistant tuberculosis. This, in turn, increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in gyrA, leading to class-wide resistance. In this review, we provide an overview of the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and development status.

Aims β casein fragment peptide (54–59) downregulates Basic Transcription factor 3a (BTF3a) in macrophages and exhibits enhanced clearance of M. bovis BCG and several other intracellular pathogens. However, the direct effect of BTF3a downregulation on Mycobacterium tuberculosis (Mtb) survival and the probable pathways involved have not yet been studied. Therefore, the present study was undertaken to deduce the antimycobacterial significance of BTF3a in human macrophages. Main methods CRISPR/Cas 9 gRNA was designed to downregulate BTF3a in THP1 derived macrophages. Fold change in BTF3a, p62 and Lamp 1 expression was evaluated through immune blot analysis. CFU assay was done to enumerate the intracellular burden of Mtb H37Rv. LC3B-II turnover and Lamp 1 expression was checked through immunoblotting and also visualized through confocal microscopy. Colocalization of Mtb H37Rv with LC3B, Lysotracker and Rab 7 was visualized through confocal microscopy. Key findings The current study identifies BTF3a as a critical host factor assisting intracellular survival of Mtb. In THP1 derived macrophages, infection with Mtb H37Rv resulted in upregulation of BTF3a and targeted depletion of BTF3a resulted in augmented Mtb clearance. Furthermore, BTF3a knockdown demonstrated increased autophagy flux and ameliorated the lysosomal targeting of Mtb containing autophagosomes for lysosomal degradation. Significance Deep understanding of macrophage-Mtb interactions and their roles in the pathogenesis can offer exciting new therapeutic targets for alternative host-specific adjunct therapies in tuberculosis treatment. The present study highlights a novel and significant role of BTF3a in curbing the intracellular survival of Mtb through modulation of autophagy and lysosome biogenesis.

Relapse of anti-NMDA receptor (NMDAR) encephalitis should be considered in all patients with history of anti-NMDAR encephalitis presenting with new acute-onset encephalopathy or psychosis.

We report a case of a 60-year-old right-handed woman with hypertension, hyperlipidemia, and hypothyroidism who presented with a three-week history of recurrent thunderclap headaches accompanied by photophobia, phonophobia, nausea, and vomiting. She reported one brief episode of slurred speech, expressive aphasia, right facial droop, and right hemiparesis suggestive of a TIA. Family history was remarkable for primary angiitis of the CNS (PACNS) in the mother. Neurologic examination was unremarkable. CT of the head was negative; CT angiography (CTA) of the head and neck suggested fibromuscular dysplasia in bilateral cervical internal carotid arteries and distal right vertebral artery. MRI of the brain showed no correlating abnormalities. A digital subtraction angiography (DSA) revealed multivessel intracranial medium and large vessel narrowing and fusiform dilatations, suggestive of reversible cerebral vasoconstriction syndrome (RCVS) vs vasculitis. Subsequent MR intracranial vessel wall imaging (IVWI) showed multifocal concentric vessel wall thickening and enhancement consistent with vasculitis (figure). Transcranial Doppler showed no evidence of elevated intracranial velocities. CSF studies were unremarkable with an opening pressure of 10 cm H2O, 2 white blood cells (normal 0–5/mm3), 2 red blood cells (normal 0–1/mm3), 58 mg/dL glucose (normal 40–70, serum glucose 87), 41 mg/dL protein (normal 15–45), normal Q-albumin ratio, normal IgG synthetic rate, and IgG index. Serum inflammatory and infectious studies had been negative thus far. Empiric high-dose IV steroids lead to complete symptom resolution. Final infectious workup revealed strongly positive serum Bartonella IgM titer of 1:256 and negative IgG, consistent with her reported cat exposure. She was started on an outpatient two-week course of doxycycline, rifampin, and oral steroids. Four weeks later, repeat vessel wall MRI and Bartonella serologies (IgM titer 1:80) showed improvement. The authors thank Dr. Gadhia for his mentorship.

A 50-year-old woman with a recent diagnosis of poorly differentiated nonteratomatous cervicouterine cancer presented to our hospital for breath-holding episodes resulting in perioral cyanosis. Her medical history was significant for chickenpox at age 8 and shingles at age 15. Before her admission and 10 days after her cancer diagnosis, she was admitted to an outside hospital for confusion and intermittent catatonia. Workup at the outside hospital was unremarkable, and she was diagnosed with adjustment disorder. At home, she continued to decompensate and ultimately became incomprehensible, anorexic, and bedbound, prompting admission to our hospital. The authors thank Dr. Jennifer Chu for her invaluable help in interpreting the patient's EEG studies.

Objective Yttrium-90 (Y-90) radioembolization is an emerging treatment option for unresectable neuroendocrine liver metastases (NELM). However, the data regarding this treatment are currently limited. This study evaluates the efficacy and tolerability of Y-90 radioembolization and identifies prognostic factors for radiographic response and survival. Methods and materials Thirty-eight patients underwent Y-90 radioembolization for NELM at our institution between April 2004 and February 2012. Patients were assessed radiographically (RECIST criteria, enhancement), serologically, and clinically at 1 month, and then at every 3 months after treatment for tumor response, toxicity, and survival outcomes. Results Median length of follow-up was 17.0 months (IQR, 9.0–37.0). Median survival was 29.2 months. Three patients (9%) had a radiographic complete response to treatment, 6 (17%) had a partial response, 21 (60%) had stable disease, and 5 (14%) developed progressive disease. Two factors were significantly associated with a good radiographic response (complete/partial response): islet cell histological subtype (p = 0.043) and hepatic tumor burden ≥ 33% (p = 0.031). Multivariate analysis revealed that patients requiring multiple Y-90 treatments (HR 2.9, p = 0.035) and patients who had previously failed systemic therapy with octreotide/chemotherapy (HR 4.4, p = 0.012) had worse survival. Grade 3 serologic toxicity was observed in 2 patients (5%; hyperbilirubinemia, elevated alkaline phosphatase) after treatment. Grade 3 non-serologic toxicities included abdominal pain (11%), fatigue (11%), nausea/vomiting (5%), ascites (5%), dyspnea (3%), diarrhea (3%), and peripheral edema (3%). No grade 4 or 5 toxicity was reported. Conclusions Y-90 radioembolization is a promising treatment option for inoperable NELM and is associated with low rates of grade ≥ 3 toxicity.

Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes.A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival.A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P0.00001), and 46% had TLC500 cells/mm. Patients with TLC500 cells/mm 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3 mo, P=0.03) and PFS (4.9 vs. 9.0 mo, P=0.15). Multivariate analysis revealed TLC500 cells/mm to be an independent predictor of inferior survival (HR=2.879, P=0.001) along with baseline serum albumin (HR=3.584, P=0.0002), BUN (HR=1.060, P=0.02), platelet count (HR=1.004, P=0.005), and radiation planning target volume (HR=1.003, P=0.0006).Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.