A fatal case of meningitis caused by Cryptococcus neoformans var. grubii in an immunocompetent male

The incidence of cryptococcal infection is high in developing countries such as India. Cryptococcal meningitis is considered rare in immunocompetent patients and is mainly a disease of immunocompromised patients. Prognosis in immunocompetent patients is generally considered good. We report a fatal case of cryptococcal meningitis in an immunocompetent male caused by Cryptococcus neoformans var. grubii. Whether the patient is immunocompromised or immunocompetent, the outcome of the disease can be severe unless the disease is diagnosed early in the course of illness.     

In vivo cardioprotection by pitavastatin from ischemic-reperfusion injury through suppression of IKK/NF-κB and upregulation of pAkt-e-NOS

Recent studies have uncovered the beneficial effects of statin in cardiovascular diseases; however, the role of pitavastatin in ischemia-reperfusion (IR)-induced apoptosis and myocardial damage is not established. Therefore, in this study, we aim to investigate whether pitavastatin treatment attenuates myocardial IR injury via regulating oxidative stress, inflammation, apoptosis, and phosphorylated protein kinase B (pAkt) endothelial nitric oxide synthase (e-NOS) pathways. After the 14-day treatment with pitavastatin (0.16-0.64 mg·kg·d, po) or saline, rats were subjected to 45 minutes of ischemia by occluding the left anterior descending coronary artery and to 60 minutes of reperfusion to induce myocardial damage. Pitavastatin at a dose of 0.32 and 0.64 mg/kg significantly improved cardiac function as evidenced by the normalization of the mean arterial pressure, heart rate, ±LVdP/dtmax, and left ventricular end-diastolic pressure as compared with the IR control. Additionally, pitavastatin dose-dependently normalized myocardial antioxidants, lactate dehydrogenase, and thiobarbituric acid reactive substances along with decreased serum tumor necrosis factor-α level and creatine kinase isoenzyme-MB activity. Furthermore, pitavastatin enhanced pAkt, (p) e-NOS, Bcl-2, and suppressed IκB kinase/nuclear factor-kappa B, nitrotyrosine (NO inactivation product), Bax, and capases-3 protein expression in the heart. Morphological assessments of the IR-challenged myocardium showed that 0.32 and 0.64 mg/kg of pitavastatin decrease myocardial necrosis and inflammatory changes. Thus, pitavastatin reduced IR-induced infarction and dysfunction via the augmentation of endogenous antioxidant, suppression of IκB kinase/nuclear factor-kappa B, activation of pAkt-e-NOS, and/or decreased NO inactivation and apoptosis.     

Making sense of therapeutics using antisense technology

Introduction: Antisense oligonucleotides (ASOs) are short synthetic single-stranded DNA sequences that bind to and induce the cleavage of homologous stretches of mRNA sequences. These result in targeted destruction of mRNA and correction of genetic aberrations. ASOs thus can act as drug molecules and potentially rectify many disease conditions. The broad range of applications reported in the literature highlights the advances in the field. Areas covered: This review covers different areas in which use of ASOs has been shown to have therapeutic effects. Some drugs in different stages of preclinical and clinical trials are discussed in detail. The problems faced and the strategies to surmount them are also described. The readers will gain an understanding of the recent developments in the field of ASOs with emphasis on their therapeutic applications. They will also become aware of the different strategies used for targeted delivery of ASOs and their stabilization, which may be useful for their work in this field, or in the area of nucleic acid therapeutics in general. Expert opinion: The design and application of ASOs for recognition of target mRNA sequences have become a fairly straightforward protocol. The main problem lies in designing ASOs which are stable in in vivo milieu. The delivery and bioavailability of the oligonucleotide to the site of action continue to be hurdles in the development of ASOs and therapeutic molecules.     

Temporal lobe pleomorphic xanthoastrocytoma and acquired <Emphasis Type="Italic">BRAF</Emphasis> mutation in an adolescent with the constitutional 22q11.2 deletion syndrome

DiGeorge syndrome, or velocardiofacial syndrome (DGS/VCFS), is a rare and usually sporadic congenital genetic disorder resulting from a constitutional microdeletion at chromosome 22q11.2. While rare cases of malignancy have been described, likely due to underlying immunodeficiency, central nervous system tumors have not yet been reported. We describe an adolescent boy with DGS/VCFS who developed a temporal lobe pleomorphic xanthoastrocytoma. High-resolution single nucleotide polymorphism array studies of the tumor confirmed a constitutional 22q11.21 deletion, and revealed acquired gains, losses and copy number neutral loss of heterozygosity of several chromosomal regions, including a homozygous deletion of the CDKN2A/B locus. The tumor also demonstrated a common V600E mutation in the BRAF oncogene. This is the first reported case of a patient with DiGeorge syndrome developing a CNS tumor of any histology and expands our knowledge about low-grade CNS tumor molecular genetics.     

Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer

Introduction

Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies.

Methods

Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60 Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models.

Results

We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59 Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p = 0.0452), mediastinal sterilization (90% vs 67%, p = 0.0769), and pCR (60% vs 35%, p = 0.0728).

Conclusions

In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates.     

Magnitude and direction of mechanical stress at the osseointegrated interface of the microthread implant

Background: The mechanism by which the microthread implant preserves peri‐implant crestal bone is not known. The objective of this research is to assess the effect of microthreads on the magnitude and direction of the stress at the bone–implant interface using finite element analysis modeling. Methods: Three‐dimensional finite element models representing the microthreaded implant (microthread model) and smooth surface implant (smooth model) installed in the mandibular premolar region were created based on microscopic and computed tomography images. The mesh size was determined based on convergence tests. Average maximum bite force of adults was used with four loading angles on the occlusal surface of the prosthesis. Results: Regardless of the loading angle, principal stresses at the bone–implant interface of the microthread model were always perpendicular to the lower flank of each microthread. In the smooth model, stresses were affected by the loading angle and directed obliquely to the smooth interface, resulting in higher shear stress. The interfacial stresses decreased gradually in the apical direction in both models but with wavy pattern in the microthread model and smooth curve for the smooth model. Although peak principal stress values were higher around the microthread implant, peri‐implant bone volume exhibiting a high strain level >4,000 μ was smaller around the microthread implant compared to the smooth implant. Conclusion: Stress‐transferring mechanism at the bone–implant interface characterized by the direction and profile of interfacial stresses, which leads to more compressive and less shear stress, may clarify the biomechanical aspect of microthread dental implants.     

Embolia cutis medicamentosa (Nicolau syndrome) after endodontic treatment: a case report

Introduction

Embolia cutis medicamentosa (Nicolau syndrome) is a rare iatrogenic event of tissue necrosis after intramuscular or intraarticular application of cristalloid suspensions. Clinically, it presents as a livid discoloration of the skin, local pain, and signs of inflammation.

Methods

This article presents the first case of Nicolau syndrome after the endodontic application of calcium hydroxide paste into the distal root canal of tooth 18. The patient presented to the Department for Maxillofacial Surgery and hospitalized for several days.

Results

The application of calcium hydroxide paste led to a thrombosis of the inferior alveolar artery and various branches of the maxillary artery. A definite necrosis of the left-side infraorbital skin area and concomitant hypaesthesia of the infraorbital nerve and of the mental nerve were observed.

Conclusions

Calcium hydroxide paste is appropriate for the medicamentous treatment of root canals, but is not suitable to stanch bleeding from periapical arteries.     

Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target

Fat cells or adipocytes are distributed ubiquitously throughout the body and are often regarded purely as energy stores. However, recently it has become clear that these adipocytes are engine rooms producing large numbers of metabolically active substances with both endocrine and paracrine actions. White adipocytes surround almost every blood vessel in the human body and are collectively termed perivascular adipose tissue (PVAT). It is now well recognized that PVAT not only provides mechanical support for any blood vessels it invests, but also secretes vasoactive and metabolically essential cytokines known as adipokines, which regulate vascular function. The emergence of obesity as a major challenge to our healthcare systems has contributed to the growing interest in adipocyte dysfunction with a view to discovering new pharmacotherapeutic agents to help rescue compromised PVAT function. Very few PVAT studies have been carried out on human tissue. This review will discuss these and the hypotheses generated from such research, as well as highlight the most significant and clinically relevant animal studies showing the most pharmacological promise. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.     

Nisin and class IIa bacteriocin resistance among Listeria and other foodborne pathogens and spoilage bacteria

Food safety has been an important issue globally due to increasing foodborne diseases and change in food habits. To inactivate foodborne pathogens, various novel technologies such as biopreservation systems have been studied. Bacteriocins are ribosomally synthesized peptides or proteins with antimicrobial activity produced by different groups of bacteria, but the bacteriocins produced by many lactic acid bacteria offer potential applications in food preservation. The use of bacteriocins in the food industry can help reduce the addition of chemical preservatives as well as the intensity of heat treatments, resulting in foods that are more naturally preserved. However, the development of highly tolerant and/or resistant strains may decrease the efficiency of bacteriocins as biopreservatives. Several mechanisms of bacteriocin resistance development have been proposed among various foodborne pathogens. The acquiring of resistance to bacteriocins can significantly affect physiological activity profile of bacteria, alter cell-envelope lipid composition, and also modify the antibiotic susceptibility/resistance profile of bacteria. This article presents a brief review on the scientific research about the various possible mechanisms involved in the development of resistance to nisin and Class IIa bacteriocins among the foodborne pathogens.     

Fiber loop ringdown DNA and bacteria sensors

We report a new type of refractive index-based biosensor using a fiber loop ringdown evanescent field (FLRD-EF) sensing scheme, in which the sensing signal is a time constant and detection sensitivity is enhanced by the multipass nature of the ringdown technique. Bulk index-based detections of three different single strand DNAs and one type of bacteria are demonstrated for the FLRD-EF sensors that utilize a partially-etched single mode fiber as the sensor head. Stepwise coating of the sensor head with poly-L-lysine and a probe DNA has enabled surface index-based label-free target DNA sensing. We expect an array of FLRD-EF biosensors to be created, which are superior to counterparts in terms of simplicity, low cost, and high sensitivity.