Back to basics: how natural products can provide the basis for new therapeutics

Phytochemicals have potent antitumor properties and have provided multiple active compounds in the past. Although there is an increasing focus on 'designer' targeted therapeutic anticancer agents, the broad spectrum of activity of natural products across multiple signaling pathways remains inadequately explored. The chemical diversity, structural complexity, affordability, lack of substantial toxic effects and inherent biologic activity of natural products makes them ideal candidates for new therapeutics. Natural products not only disrupt aberrant signaling pathways leading to cancer (i.e., proliferation, deregulation of apoptosis, angiogenesis, invasion and metastasis) but also synergize with chemotherapy and radiotherapy. This review focuses on the mechanism of action of key natural products and promising preclinical data on their efficacy as anticancer agents, as single agents and in combination with standard therapies.     

Extrapleural intrathoracic implantation of permanent pacemaker in the pediatric age group

Permanent pacemaker implantation in pediatric patients poses challenges in finding a suitable pocket for generator implantation. We present our experience with 6 patients in whom the pacemaker was placed in an extrapleural intrathoracic location. We find that an extrapleural intrathoracic pocket is a useful site for generator placement in the neonatal and pediatric age group. It is safe, reproducible, and both the lead and generator can be placed through a single incision. We briefly discuss the advantages and disadvantages of other techniques that require a single incision for both lead and generator placement.     

DNA constructs expressing long-hairpin RNA (lhRNA) protect Penaeus monodon against White Spot Syndrome Virus

The use of stable and cost-effective DNA vaccines for silencing genes of White Spot Syndrome Virus (WSSV) in Penaeus monodon through RNA interference has been tested. DNA constructs that express long-hairpin RNA (lhRNA) constitutively in vivo against two WSSV envelop genes vp19 and vp28 (pCMV-VP19-LH and pCMV-VP28-LH) were used to confer protection against the pathogen. A construct expressing lhRNA directed against gfp gene (pCMV-GFP-LH) was used to estimate the non-specific protection and to show that on intramuscular administration the plasmid spreads all across the shrimp body and persists for at least 30 days. Shrimp injected with 10 μg lhRNA expressing constructs were challenged with purified WSSV after 24 h and pCMV-VP28-LH provided best protection as evidenced by higher survival, lower viral load and silencing of the target viral gene. At an increased dose (35 μg), this construct showed better protection with 75% survival and 81% silencing of the target vp28 mRNA. The construct could actually reduce the viral copy number from the initial 10³ to 10⁵ copies to 10–100 copies. The non-specific pCMV-GFP-LH also showed improved survival and silencing of viral genes, although its effect was less than one third of pCMV-VP28-LH. Silencing constructs can be a good prophylactic approach in commercial shrimp hatcheries to protect high value brooders and to check the vertical transmission of virus, which is a major route of viral entry. Silencing by lhRNA expressed in vivo, confirms the presence of a functional microRNA pathway in shrimp.     

Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers

The objective of this study is to determine the safety, tolerability and abuse liability of single intravenous (i.v.) doses of lisdexamfetamine dimesylate (LDX) and immediate-release d-amphetamine sulphate in adult stimulant abusers compared with placebo. Adult substance abusers were enrolled in this phase I, randomized, single-centre, double-blind study. An initial cohort of three subjects was enrolled to assess safety followed by a primary cohort that consisted of nine subjects. Single i.v. doses of LDX (25 or 50 mg), immediate-release d-amphetamine sulphate (10 or 20 mg) or placebo were administered at a minimum of 48-h intervals in a single-dose, three-way crossover design. 20 mg of d-amphetamine showed significantly increased abuse-related liking scores compared with placebo (P < 0.05), whereas the liking effects of 50 mg LDX did not significantly differ from placebo. The mean C(max) of d-amphetamine was 38.9 +/- 8.1 and 105 +/- 91.4 ng/ml after the administration of 50 mg LDX and 20 mg d-amphetamine respectively. The mean T(max) of d-amphetamine was 2.51 h after the administration of 50 mg LDX and 0.82 h after the administration of 20 mg d-amphetamine. LDX was well tolerated in this population. In contrast to d-amphetamine, LDX administered intravenously did not produce significant subjective abuse-related liking scores at assessed doses.     

Intraabdominal myositis ossificans: a report of 9 new cases

Intraabdominal myositis ossificans (IMO) is a rare benign disorder characterized by reactive bone formation in intraabdominal soft tissue that should be distinguished from a malignant condition. We retrospectively searched our patient records and report 9 new cases of IMO. The lesions occurred in 7 men and 2 women with a mean age of 50 years (range, 24--76 years), 5 of whom had previous abdominal surgery. Histologically, all the cases were similar, consisting of a reactive mesenchymal process in adipose tissue. Mitosis was observed, but with no atypical forms, and the lesions lacked malignant cytologic features. IMO is an uncommon benign lesion that develops relatively rapidly. The pathogenesis is related to intraabdominal surgical procedures, but the exact mechanism remains to be determined.     

Buerger's disease: clinical and histomorphological study

There is an extremely high prevalence of Thromboangiitis Obliterans (TAO) or Buerger's disease (BD) in India among people of low socioeconomic class who smoke beedies (homemade cigarettes with raw tobacco). The aim of this study was to study the clinical and histo-morphological aspects of Buerger's disease with relevance to age at presentation in the local population. The study comprised of 25 cases (all were men and were smokers) of clinically diagnosed BD based on Shionoya's criteria. The mean age was 47 years. The specimens consisted of 21 biopsies, 2 end-arterectomies and 2 amputations. Formalin fixed, routinely processed, paraffin embedded tissue sections were stained with Haematoxylin and Eosin (H and E) and Verhoeff's elastic stain. They had claudication pain either in the ankle (5) or in the calf (2) or both (13). 24 had infrapopliteal disease and 9 showed upper limb involvement. 21 showed migratory thrombophlebitis also. Histomorphological presentation included the following features: Luminal thrombosis (14), fresh thrombosis (4), chronic inflammation in the vessel wall (10), within the thrombus (1) and around perivascular channels and nerve bundles (4). Internal elastic lamina showed reduplication in 13, undulation in 9 and fragmentation in 9 cases. Media of the vessel showed the following features: fibrosis (9), hypertrophy (9) and calcification (5) Adventitial haemorrhage, cholesterol clefts and atherosclerotic plaque formation were the other changes seen. In our study the following histopathological features were consistently seen. Thrombus (with or without recanalisation), inflammatory cell infiltrate (within the thrombus wall or periadventitial tissue), subintimal and medial fibrosis and changes in internal elastic lamina. These features were also highlighted in other studies. However in our study, medial hypertrophy and calcification were observed as additional features.     

The effect of drugs on orthodontic tooth movement

OBJECTIVE: Molecules produced in various diseased tissues, or drugs and nutrients consumed regularly by patients, can reach the mechanically stressed paradental tissues through the circulation, and interact with local target cells. The combined effect of mechanical forces and one or more of these agents may be inhibitory, additive or synergistic. The objective of this review is to outline the mechanisms of action and effects of some commonly used drugs on tissue remodeling and orthodontic tooth movement. DESIGN: All the existing published literature on the effects of various drugs that are prescribed by orthodontists, which are consumed by patients for systemic diseases and those that are known to promote and retard the tooth movement process was obtained and subjected to thorough review process. RESULTS: All the drugs reviewed have therapeutic effects, as well as side effects, that may influence the cells targeted by orthodontic forces. Therefore, it is imperative that the orthodontist pays close attention to the drug consumption history of each and every patient, before and during the course of orthodontic treatment. When the use of drugs is revealed, their effects and side effects on tissue systems should be explored, to determine their potential influence on the outcome of mechanotherapy. CONCLUSION: Drug-consumption history must be an integral part of every orthodontic diagnosis and treatment plan.     

Molecular characterization of the VP1, VP2, VP4, VP6, NSP1 and NSP2 genes of bovine group B rotaviruses: identification of a novel VP4 genotype

Studies on bovine group B rotaviruses (GBRs) are limited. To date, only the VP6 gene of a single bovine GBR strain and the VP7 and NSP5 genes of a few bovine GBR strains have been sequenced and analyzed. In the present study, using a single-primer amplification method, we have determined the full-length nucleotide sequences of the VP1, VP2, VP4, VP6, NSP1 and NSP2 genes of three bovine GBR strains from eastern India. In all six of these genes, the bovine GBR strains shared high genetic relatedness among themselves but exhibited high genetic diversity with cognate genes of human, murine and ovine GBRs. Interestingly, as with group A rotaviruses, the bovine GBR VP1, VP2, VP6 and NSP2 genes appeared to be more conserved than the VP4 and NSP1 genes among strains of different species. The present study provides important insights into the genetic makeup and diversity of bovine GBRs, and also identifies a novel GBR VP4 genotype.