OPC-67683, a Nitro-Dihydro-Imidazooxazole Derivative with Promising Action against Tuberculosis In Vitro and In Mice

BACKGROUND: Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment. METHODS AND FINDINGS: Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes. CONCLUSIONS: We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment

Normally contracting Lie group actions

We show that there are no normally contracting actions of unimodular Lie groups on closed manifolds.Comment: This paper is withdrawn since it is published in an Elsevier journa

Differences between diffuse and focal autoimmune pancreatitis

AIM: To investigate differences in clinical features between diffuse- and focal-type autoimmune pancreatitis (AIP)

Strategy to differentiate autoimmune pancreatitis from pancreas cancer

Autoimmune pancreatitis (AIP) is a newly described entity of pancreatitis in which the pathogenesis appears to involve autoimmune mechanisms. Based on histological and immunohistochemical examinations of various organs of AIP patients, AIP appears to be a pancreatic lesion reflecting a systemic “IgG4-related sclerosing disease”. Clinically, AIP patients and patients with pancreatic cancer share many features, such as preponderance of elderly males, frequent initial symptom of painless jaundice, development of new-onset diabetes mellitus, and elevated levels of serum tumor markers. It is of uppermost importance not to misdiagnose AIP as pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, and approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological, and histopathological features. Findings suggesting AIP rather than pancreatic cancer include: fluctuating obstructive jaundice; elevated serum IgG4 levels; diffuse enlargement of the pancreas; delayed enhancement of the enlarged pancreas and presence of a capsule-like rim on dynamic computed tomography; low apparent diffusion coefficient values on diffusion-weighted magnetic resonance image; irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography; less upstream dilatation of the main pancreatic duct on magnetic resonance cholangiopancreatography, presence of other organ involvement such as bilateral salivary gland swelling, retroperitoneal fibrosis and hilar or intrahepatic sclerosing cholangitis; negative work-up for malignancy including endoscopic ultrasound-guided fine needle aspiration; and steroid responsiveness. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection

In vivo imaging of spontaneous ultraweak photon emission from a rat's brain correlated with cerebral energy metabolism and oxidative stress, Neuroscience Research 34

Abstract Living cells spontaneously emit ultraweak light during the process of metabolic reactions associated with the physiological state. The first demonstration of two-dimensional in vivo imaging of ultraweak photon emission from a rat's brain, using a highly sensitive photon counting apparatus, is reported in this paper. It was found that the emission intensity correlates with the electroencephalographic activity that was measured on the cortical surface and this intensity is associated with the cerebral blood flow and hyperoxia. To clarify the mechanism of photon emission, intensity changes from whole brain slices were examined under various conditions. The removal of glucose from the incubation medium suppressed the photon emission, and adding 50 mM potassium ions led to temporal enhancement of emission and subsequent depression. Rotenone (20 mM), an inhibitor of the mitochondrial electron transport chain, increased photon emission, indicating electron leakage from the respiratory chain. These results suggest that the photon emission from the brain slices originates from the energy metabolism of the inner mitochondrial respiratory chain through the production of reactive oxygen. Imaging of ultraweak photon emission from a brain constitutes a novel method, with the potential to extract pathophysiological information associated with neural metabolism and oxidative dysfunction of the neural cells

Atypical tumour-like involvement of the colon in secondary systemic amyloidosis which vanished after 1 month of observation

http://dx.doi.org/10.1136/bcr.01.2011.3775 AuthorAmyloidosis occurs as a result of the extracellular deposition of protein fibrils in organs and tissues, thus causing mild to severe pathophysiological changes. The gastrointestinal tract is a common site of amyloid deposition. While intestinal amyloidosis frequently results in polypoid lesions, ulcerations, nodules and petechial mucosal haemorrhage, tumour-like lesions are rarely developed and infrequently diagnosed before the resection because of the difficulty in differentiating them from colon cancer. The authors herein reported a case of intestinal amyloid A amyloidosis with a complication of a tumour-like lesion endoscopically resembling a malignant lesion, which was completely diminished after 1 month of observation with bowel rest. Such conservative treatment is a feasible option to cure intestinal tumour-like lesions in patients with intestinal amyloidosis when no neoplastic change is histologically detected, possibly decreasing the need for surgery of the fragile mucosa