Delamanid when other anti-tuberculosis-treatment regimens failed due to resistance or tolerability

Introduction: The limited availability of effective drugs causes difficulties in the management of multidrug-resistant tuberculosis (MDR-TB) and novel therapeutic agents are needed. Delamanid, a new nitro-hydro-imidazooxazole derivative, inhibits mycolic acid synthesis. This review covers the efficacy and safety of delamanid for MDR-TB.

Area covered: This paper reviews the pharmacological profile of delamanid and the results of clinical trials evaluating its efficacy for treating MDR-TB in combination with other anti-TB drugs. The drug’s safety and tolerability profiles are also considered.

Expert opinion: Delamanid showed potent activity against drug-susceptible and -resistant Mycobacterium tuberculosis in both in vitro and in vivo studies. In clinical trials, the drug showed significant early bactericidal activity in pulmonary TB patients, and increased culture conversion after 2 months of treatment in combination with an optimized background regimen in MDR-TB patients. In addition, decreased mortality was observed in MDR-TB patients who received > 6 months of delamanid treatment. The drug was generally tolerable, but QT prolongation should be monitored carefully using electrocardiograms and potassium levels. Therefore, delamanid could be used as part of an appropriate combination regimen for pulmonary MDR-TB in adult patients when an effective treatment regimen cannot otherwise be composed for reasons of resistance or tolerability.     

Mucosal and systemic antibody responses and protection induced by a prime/boost rotavirus-DNA vaccine in a gnotobiotic pig model

A live rotavirus prime/DNA boost vaccine regimen was evaluated in a gnotobiotic pig model for human rotavirus (HRV) diarrhea. Plasmid DNA expressing rotavirus inner capsid VP6 was administered to pigs intramuscularly (IM) twice after oral priming with attenuated (Att) Wa strain HRV (AttHRV/VP6DNA2x). Other groups included: (1) VP6 DNA IM 2x then AttHRV orally (VP6DNA2x/AttHRV); (2) VP6 DNA IM 3x (VP6DNA3x) and controls. Significant protection (70%) against virus shedding, but lower protection against diarrhea (30%) was achieved only in the AttHRV/VP6DNA2x group after challenge (virulent Wa HRV). The other vaccines (VP6DNA2x/AttHRV and VP6DNA3x) were less effective. Higher protection rates were associated with the highest IgA antibody responses induced by the AttHRV/VP6DNA2x regimen. Interestingly, the VP6 DNA vaccine, although not effective when administered alone, boosted neutralizing and VP4 antibody titers in pigs previously primed with AttHRV, possibly mediated by cross-reactive T helper cells.     

Hemorrhagic hemangioma in the liver: A case report

Hemangioma is the most common type of benign tumor that arises in the liver. Although rupture and hemorrhage of hepatic hemangioma are rare complications, they can be the cause of mortality. The authors report a case of hemorrhagic hepatic hemangioma: in a 54-year-old woman who was admitted with epigastric pain. She had taken oral contraceptives several weeks prior. The results of a blood examination were normal. An abdominal computed tomography scan revealed a tumor in hepatic segment 4, and a hemorrhage inside the cystic mass was suspected. The mass was removed laparoscopically to confirm the tumor properties and control the hemorrhage. The pathologic findings of the resected mass were consistent with hepatic hemangioma with intratumoral hemorrhage. The patient was discharged 8 d after the surgery, without further complications or complaints, and the patient’s condition was found to have improved during follow-up.     

The use of batch reading to improve the performance of screening mammography

OBJECTIVE: The objective of our study was to prove that batch reading of screening mammograms can reduce recall rates without sacrificing cancer detection. MATERIALS AND METHODS: We analyzed recall rate, cancer detection, minimal cancer detection, detection of low-stage cancer, and tumor size from consecutive screening mammography examinations from October 2001 to July 2003. The initial 7,984 mammograms were interpreted in the midst of a busy breast imaging practice. Although these studies were not read online, the interpretations were often interrupted for telephone calls, procedures, and diagnostic mammograms. The remaining 1,538 studies were interpreted after the institution of dedicated uninterrupted batch reading. RESULTS: Recall rates were 20.1% before and 16.2% after the introduction of batch reading (p < 0.001). Cancer detection rates were not significantly different: 5.6 cancers were detected per 1,000 examinations without and 7.2 were detected per 1,000 with batch reading. Prognostic factors for breast cancers diagnosed between these groups also were not significantly different. Of the screening-detected cancers diagnosed before batch reading, minimal cancers comprised 67% and low-stage cancers accounted for 76%. Of the cancers diagnosed using batch reading, 73% were minimal and 91% were low stage. The mean size of cancers, 11.7 mm without batch reading and 9.1 mm with batch reading, also showed no statistically significant difference. CONCLUSION: Our experience shows that batch reading can significantly reduce screening mammography recall rates without affecting the cancer detection rate or the proportion of cancers diagnosed with favorable prognostic indicators.     

Effects of Urinary Trypsin Inhibitor on Lipopolysaccharide-Induced Acute Lung Injury in Rabbits

This study was undertaken to clarify the effects of urinary trypsin inhibitor (UTI) on lipopolysaccharide (LPS)-induced acute lung injury. Rabbits were randomly assigned to one of seven groups: saline only, UTI, LPS, pre- or post-UTI-high (infusion of UTI of 25,000 U/kg followed by 25,000 U/kg over 2 h), pre- or post-UTI-low (infusion of UTI of 2,500 U/kg followed by 2,500 U/kg over 2 h). UTI was administered 30 min before (pre-groups) or 15 min after (post-groups) LPS administration. Rabbits were mechanically ventilated with 40% oxygen for 6 h. LPS decreased peripheral blood leukocyte counts and increased wet/dry weight ratio of lung, lung injury score, neutrophil infiltration in lung, and IL-8 production in systemic blood and bronchoalveolar lavage fluid (BALF). Rabbits treated by UTI were protected from LPS-induced lung injury, as determined by wet/dry weight ratio, neutrophil infiltration in lung, lung injury score, and IL-8 in BALF levels. UTI attenuated LPS-induced acute lung injury in rabbits mainly by inhibiting neutrophil and IL-8 responses, which may play a central role in sepsis-related lung injury.     

4D radial contrast-enhanced MR angiography with sliding subtraction.

A method is presented for high spatial and temporal resolution 3D contrast-enhanced magnetic resonance angiography. The overall technique involves a set of interrelated components suited to high-frame-rate angiography, including 3D cylindrical k-space sampling, angular undersampling, asymmetric sampling, sliding window reconstruction, pseudorandom view ordering, and a sliding subtraction mask. Computer simulations and volunteer studies demonstrated the utility of each component of the technique. Angiograms of one hemisphere of the intracranial vasculature were acquired with a pixel size of 1.1 x 1.1 x 2.8 mm and a frame rate of 0.35 sec based on a temporal resolution of 3.5 sec. Such a 3D time-resolved, or "4D," technique has the potential to noninvasively acquire diagnostic quality images of certain anatomic regions with a frame rate fast enough to not only ensure the capture of an uncontaminated arterial phase, but even demonstrate contrast bolus flow dynamics. Clinical applications include noninvasive imaging of arteriovenous shunting, which is demonstrated with a patient study.     

Protection from apoptotic cell death by cilostazol, phosphodiesterase type III inhibitor, via cAMP-dependent protein kinase activation.

This study aimed to elucidate whether the effect of cilostazol to suppress apoptotic cell death is directly coupled to cAMP-dependent protein kinase activation in human umbilical vein endothelial cells (HUVECs). After exposure of HUVECs to LPS (1 microgml(-1)) for 18 h, the endothelial cells irregularly aggregated with loss of cobblestone appearance, which was reversed by cilostazol (1-100 microM), as well as by cilostamide (cilostazol analog), and cilostazol metabolites (OPC-13015 and OPC-31213), respectively. LPS-stimulated production of reactive oxygen species (ROS) was significantly reduced by cilostazol (0.1-10 microM). In line with these, LPS (1 microgml(-1))- and TNF-alpha (200 ngml(-1))-induced DNA fragmentation, assessed by agarose gel electrophoresis, was significantly reduced by treatment with cilostazol (10 microM) as well as by dibutyryl cAMP (100 microM). This effect was reversed by cAMP-dependent protein kinase inhibitor, Rp-cAMPs (200 microM). Further, LPS (1 microgml(-1))-induced decrease in Bcl-2 and increase in Bax protein expression were fully reversed by cilostazol (10 microM) and dibutyryl cAMP (100 microM), all of which were antagonized by Rp-cAMPs (200 microM). Taken together, cilostazol effectively protected HUVECs from LPS- and TNF-alpha-induced cell death associated with oligonucleosomal DNA fragmentation via activation of cAMP-dependent protein kinase.     

Effects of different concentrations of formalin on paw edema and pain behaviors in rats

The aim of this study was to determine whether formalin reliably provokes a paw edema and pain behavior. The paw of male Sprague-Dawley rats were injected with 100 microliter of formalin with 2.5% (F2.5), 5% (F5), and 10% (F10) concentrations. Following the formalin (n=8) or saline (control, n=6) injection, the flinching or licking of the paw was recorded for the phase 1 response (0-5 min after injection) and phase 2 response (20-60 min). The formalin-induced paw edema was assessed by measuring the diameters of the injected paws at 4 hr after injection. As for flinching, phase 1 and 2 of all three groups showed higher frequency than those of the control group (p<0.05). As for licking, phase 1 cumulative time of the F2.5 and F10 groups, and phase 2 cumulative time of the F2.5 and F5 groups showed a longer duration than those in the control group (p<0.05). The diameters of the paw in the F10 group were significantly larger than those in the control group (p<0.05). Flinching behavior was more reliably expressed the biphasic response than licking response at all formalin concentrations. Peak of the licking was reached at 2.5% and that of flinching was reached at 5%, whereas the paw edema peaked at 10% concentration. This suggests that there may be some dissociation of nociception from the edema formation.     

Effect of retinoic acid on renal development in newborn mice treated with an angiogenesis inhibitor

Background: A mouse model of impaired renal development was developed and the effect of retinoic acid (RA) was investigated in this animal model. Methods: An angiogenesis inhibitor (SU1498) was injected s.c. into day 3 C57BL/6 newborn mice to create a model of arrested renal development. RA (2 mg/kg) was injected i.p. for 10 days. Morphometry and immunohistochemistry were done. Results: Mice injected with SU1498 demonstrated deranged renal development in tubular structure and glomerular tuft area. Cortical thickness and area of glomerular tuft were significantly decreased after vascular endothelial growth factor (VEGF) inhibitor, and were significantly restored by RA. The length of capillary loops/glomerulus, the number of podocytes/glomerulus, and density of peritubular capillaries on CD31 immunostaining were significantly decreased by VEGF blocking and recovered by RA. Conclusions: VEGF plays a major role in renal development, and RA reverses the inhibited development caused by an angiogenesis inhibitor.     

The Epidemiology and National Trends of Bearing Surface Usage in Primary Total Hip Arthroplasty in Korea

Background

We analyzed the data for primary total hip arthroplasty (THA) in the Korean nationwide database to assess (1) the epidemiology and national trends of bearing surface usage in THAs and (2) the prevalence of each type of bearing surface according to age, gender, hospital type, primary payer, and hospital procedure volume.

Methods

A total of 30,881 THAs were analyzed using the Korean Health Insurance Review and Assessment Service database for 2007 through 2011. Bearing surfaces were sub-grouped according to device code for national health insurance claims and consisted of ceramic-on-ceramic (CoC), metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), and metal-on-metal (MoM). The prevalence of each type of bearing surface was calculated and stratified by age, gender, hospital type, primary payer, and procedure volume of each hospital.

Results

CoC was the most frequently used bearing surface (76.7%), followed by MoP (11.9%), CoP (7.3%), and MoM (4.1%). The proportion of THAs using a CoC bearing surface increased steadily from 71.6% in 2007 to 81.4% in 2011, whereas the proportions using CoP, MoP, and MoM bearing surfaces decreased. The order of prevalence was identical to that in the general population regardless of age, gender, hospital type, primary payer, and hospital procedure volume.

Conclusions

The trends and epidemiology of bearing surface usage in THAs in Korea are different from those in other countries, and the CoC bearing surface is the most prevalent articulation. In future, the results of a large-scale study using nationwide data of THAs involving a CoC bearing surface will be reported in Korea.