Detection and Management of Deep Vein Thrombosis

The accuracy of diagnosis of deep venous thrombosis is significantly improved by combining clinical evaluation with other adjunctive methods, especially fibrinogen uptake tests, technetium scans, Doppler techniques and phlebography. Using these studies, early treatment with intravenous administration of heparin can be begun and in selected cases with long-term risks, warfarin is often useful. These same drugs, in different dosage schedules, may also be helpful as prophylaxis. With these methods of treatment, thrombectomy and caval interruption are required less often. If interruption of inferior vena cava flow becomes necessary, several new methods utilizing intracaval filters are proving to be very useful.     

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis,fibrosis and inflammation

The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines.     

γ-H2AX and other histone post-translational modifications in the clinic

Chromatin is a dynamic complex of DNA and proteins that regulates the flow of information from genome to end product. The efficient recognition and faithful repair of DNA damage, particularly double-strand damage, is essential for genomic stability and cellular homeostasis. Imperfect repair of DNA double-strand breaks (DSBs) can lead to oncogenesis. The efficient repair of DSBs relies in part on the rapid formation of foci of phosphorylated histone H2AX (γ-H2AX) at each break site, and the subsequent recruitment of repair factors. These foci can be visualized with appropriate antibodies, enabling low levels of DSB damage to be measured in samples obtained from patients. Such measurements are proving useful to optimize treatments involving ionizing radiation, to assay in vivo the efficiency of various drugs to induce DNA damage, and to help diagnose patients with a variety of syndromes involving elevated levels of γ-H2AX. We will survey the state of the art of utilizing γ-H2AX in clinical settings. We will also discuss possibilities with other histone post-translational modifications. The ability to measure in vivo the responses of individual patients to particular drugs and/or radiation may help optimize treatments and improve patient care. This article is part of a Special Issue entitled: Chromatin in time and space.     

Artemisinin-Ginkgo biloba extract combination therapy for Plasmodium yoelii

Malaria remains a widespread life-threatening infectious disease, leading to an estimated 219 million cases and around 435,000 deaths. After an unprecedented success, the antimalarial progress is at a standstill. Therefore, new methods are urgently needed to decrease drug resistant and enhance antimalarial efficacy. According to the alteration of erythrocyte biomechanical properties and the immune evasion mechanism of parasites, drugs, which can improve blood circulation, can be chosen to combine with antimalarial drugs for malaria treatment. Ginkgo biloba extract (GBE), one of drug for vascular disease, was used to combine with artemisinin for Plasmodium yoelii therapy. Artemisinin-GBE combination therapy (AGCT) demonstrated remarkable antimalarial efficacy by decreasing infection rate, improving blood microcirculation and modulating immune system. Besides, the expression of invasion related genes, such as AMA1, MSP1 and Py01365, can be suppressed by AGCT, hindering invasion process of merozoites. This new antimalarial strategy, combining antimalarial drugs with drugs that improve blood circulation, may enhance the antimalarial efficacy and ameliorate restoration ability, proving a potential method for finding ideal compatible drugs to improve malaria therapy     

Naringin attenuates cisplatin- and aminoglycoside-induced hair cell injury in the zebrafish lateral line via multiple pathways

Exposure to ototoxic drugs is a significant cause of hearing loss that affects about 30 thousand children with potentially serious physical, social and psychological dysfunctions every year. Cisplatin (CP) and aminoglycosides are effective antineoplastic or bactericidal drugs, and their application has a high probability of ototoxicity which results from the death of hair cells (HCs). Here, we describe the therapeutic effect of the flavonoid compound naringin (Nar) against ototoxic effects of cisplatin and aminoglycosides include gentamicin (GM) and neomycin (Neo) in zebrafish HCs. Animals incubated with Nar (100-400 μmol/L) were protected against the pernicious effects of CP (150-250 μmol/L), GM (50-150 μmol/L) and Neo (50-150 μmol/L). We also provide evidence for the potential mechanism of Nar against ototoxicity, including antioxidation, anti-apoptosis, promoting proliferation and hair cell regeneration. We found that mRNA levels of the apoptotic- and pyroptosis-related genes are regulated by Nar both in vivo and in vitro. Finally, by proving that Nar does not affect the anti-tumour efficacy of CP and antibacterial activity of aminoglycosides in vitro, we highlight its value in clinical application. In conclusion, these results unravel a novel therapeutic role for Nar as an otoprotective drug against the adverse effects of CP and aminoglycosides.     

Vitamin E analogues as a novel group of mitocans: anti-cancer agents that act by targeting mitochondria

Mitochondria have recently emerged as new and promising targets for cancer prevention and therapy. One of the reasons for this is that mitochondria are instrumental to many types of cell death and often lie downstream from the initial actions of anti-cancer drugs. Unlike the tumour suppressor gene encoding p53 that is notoriously prone to inactivating mutations but whose function is essential for induction of apoptosis by DNA-targeting agents (such as doxorubicin or 5-fluorouracil), mitochondria present targets that are not so compromised by genetic mutation and whose targeting overcomes problems with mutations of upstream targets such as p53. We have recently proposed a novel class of anti-cancer agents, mitocans that exert their anti-cancer activity by destabilising mitochondria, promoting the selective induction of apoptotic death in tumour cells. In this communication, we review recent findings on mitocans and propose a common basis for their mode of action in inducing apoptosis of cancer cells. We use as an example the analogues of vitamin E that are proving to be cancer cell-specific and may soon be developed into efficient anti-cancer drugs.     

Autophagy,an accomplice or antagonist of drug resistance in HCC?

Hepatocellular carcinoma (HCC) is a highly lethal malignancy characterized by poor prognosis and a low 5-year survival rate. Drug treatment is proving to be effective in anti-HCC. However, only a small number of HCC patients exhibit sensitive responses, and drug resistance occurs frequently in advanced patients. Autophagy, an evolutionary process responsible for the degradation of cellular substances, is closely associated with the acquisition and maintenance of drug resistance for HCC. This review focuses on autophagic proteins and explores the intricate relationship between autophagy and cancer stem cells, tumor-derived exosomes, and noncoding RNA. Clinical trials involved in autophagy inhibition combined with anticancer drugs are also concerned.Subject terms: Cancer metabolism, Cancer therapeutic resistance     

B cells as under-appreciated mediators of non-auto-immune inflammatory disease

B lymphocytes play roles in many auto-immune diseases characterized by unresolved inflammation, and B cell ablation is proving to be a relatively safe, effective treatment for such diseases. B cells function, in part, as important sources of regulatory cytokines in auto-immune disease, but B cell cytokines also play roles in other non-auto-immune inflammatory diseases. B cell ablation may therefore benefit inflammatory disease patients in addition to its demonstrated efficacy in auto-immune disease. Current ablation drugs clear both pro- and anti-inflammatory B cell subsets, which may unexpectedly exacerbate some pathologies. This possibility argues that a more thorough understanding of B cell function in human inflammatory disease is required to safely harness the clinical promise of B cell ablation. Type 2 diabetes (T2D) and periodontal disease (PD) are two inflammatory diseases characterized by little autoimmunity. These diseases are linked by coincident presentation and alterations in toll-like receptor (TLR)-dependent B cell cytokine production, which may identify B cell ablation as a new therapy for co-affected individuals. Further analysis of the role B cells and B cell cytokines play in T2D, PD and other inflammatory diseases is required to justify testing B cell depletion therapies on a broader range of patients.     

Channelopathies - Emerging Trends in The Management of Inherited Arrhythmias

In spite of their relative rarity, inheritable arrhythmias have come to the forefront as a group of potentially fatal but preventable cause of sudden cardiac death in children and (young) adults. Comprehensive management of inherited arrhythmias includes diagnosing and treating the proband and identifying and protecting affected family members. This has been made possible by the vast advances in the field of molecular biology enabling better understanding of the genetic underpinnings of some of these disease groups, namely congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia and Brugada syndrome. The ensuing knowledge of the genotype-phenotype correlations enables us to risk-stratify, prognosticate and treat based on the genetic test results. The various diagnostic modalities currently available to us, including clinical tools and genetic technologies, have to be applied judiciously in order to promptly identify those affected and to spare the emotional burden of a potentially lethal disease in the unaffected individuals. The therapeutic armamentarium of inherited arrhythmias includes pharmacological agents, device therapies and surgical interventions. A treatment strategy keeping in mind the risk profile of the patients, the local availability of drugs and the expertise of the treating personnel is proving effective. While opportunities for research are numerous in this expanding field of medicine, there is also tremendous scope for incorporating the emerging trends in managing patients and families with inherited arrhythmias in the Indian subcontinent.     

Hereditary sensory motor neuropathy: degenerative disease or a disease with an immune-mediated pathogenesis?

The clinical data proving that some hereditary motor-sensory neuropathies (HMSN type 1) are steroid sensitive may indicate inflammatory or immunomediated mechanisms as cofactors contributing to the clinical course of these disorders. The finding of HLA-DR positivity of Schwann cells in HMSN type I along with the presence in some cases of inflammatory infiltrates in nerve sections provides further evidence for this hypothesis.     

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.     

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease

A large MERRF pedigree permitted the direct testing of the predictions for a mitochondrial DNA (mtDNA) mutation. A mtDNA mutation was demonstrated by proving maternal inheritance and by identifying specific deficiencies in muscle energetics and mitochondrial respiratory complexes I and IV. mtDNA heteroplasmy (a mixture of mutant and wild-type mtDNAs) was demonstrated by showing variation in the mitochondrial energetic capacity between family members. The phenotypic consequences of differential tissue-specific reliance on mitochondrial ATP was shown by correlating individual respiratory deficiency with the nature and severity of patients' clinical manifestations. The observed spectrum of clinical manifestations resulting from this heteroplasmic mtDNA mutation implies that mtDNA disease may be much more prevalent than previously anticipated.     

Fibrosing alveolitis

Fibrosing alveolitis is a disease of unknown cause mainly involving the gas-exchanging portions of the lungs. It may occur in isolation and be called cryptogenic or idiopathic, in which case the clinical manifestations are mainly respiratory, or it may be associated with other disorders, such as rheumatoid arthritis. The histopathologic abnormalities of the pulmonary tissue are identical in either instance. Other names used for the disease have included usual interstitial pneumonia, desquamative interstitial pneumonia and the Hamman-Rich syndrome; these terms may describe different stages of the same pathologic process. Many authors in North America and those in the United Kingdom favour the term fibrosing alveolitis when describing chronic interstitial pneumonias. There may be accompanying nonspecific Immunologic abnormalities, which may denote that fibrosing alveolitis is part of the wide spectrum of diseases known as connective tissue disorders. Recently immune complexes have been found in the lung parenchyma; they probably result in the granulocyte destruction and reticuloendothelial proliferation seen in the acute phase of the disease.There are no specific diagnostic tests for the disease apart from lung biopsy, which can be performed at the time of thoracotomy or transbronchially, with the use of a flexible fibreoptic bronchoscope. Lavaged cells from the alveoli have also been obtained via the bronchoscope; in persons with fibrosing alveolitis a high proportion of these cells are neutrophils, and after corticosteroid treatment the proportion decreases. The progress of the disease can be followed by examination of these washings as well as by lung scanning with gallium-67 citrate. Newer methods of treatment using combinations of corticosteroids and immunosuppressant drugs are being evaluated and are initially proving to be successful.     

Current status and perspectives of biopharmaceutical drugs

Since the first approval of recombinant human insulin three decades ago, more than 150 biopharmaceutical drugs have been marketed, and some of them became blockbuster drugs in market size. The patent expiration of the oldest biopharmaceutical drugs resulted in the development of biosimilar drugs. However the short serum half-life of biopharmaceutical drugs incurs a frequent injection to maintain a target clinical outcome in patients. The other major critical concern of biopharmaceutical drugs is immunogenicity producing anti-drug antibodies. These antibodies may reduce clinical efficacy by neutralizing biological activity, and may not only cause a severe allergic reaction but also other serious adverse reactions by blocking endogenous proteins. In order to improve pharmaceutical properties and reduce immunogenicity, the next generation biobetter drugs were achieved by glycoengineering technology, pegylation technology and protein engineering technology. Other biobetter drugs having optimized binding sites were also generated by in vitro display technology. Many of those biobetter drugs have been developed and/or are under development, and come into the clinical field in the near future.     

Biosynthesis of the galactan component of the mycobacterial cell wall

The structural core of the cell walls of Mycobacterium spp. consists of peptidoglycan bound by a linker unit (-alpha-L-Rhap-(1-->3)-D-GlcNAc-P-) to a galactofuran, which in turn is attached to arabinofuran and mycolic acids. The sequence of reactions leading to the biogenesis of this complex starts with the formation of the linker unit on a polyprenyl-P to produce polyprenyl-P-P-GlcNAc-Rha (Mikusová, K., Mikus, M., Besra, G. S., Hancock, I., and Brennan, P. J. (1996) J. Biol. Chem. 271, 7820-7828). We now establish that formation of the galactofuran takes place on this intermediate with UDP-Galf as the Galf donor presented in the form of UDP-Galp and UDP-Galp mutase (the glf gene product) and is catalyzed by galactofuranosyl transferases, one of which, the Mycobacterium tuberculosis H37Rv3808c gene product, has been identified. Evidence is also presented for the growth of the arabinofuran on this polyprenyl-P-P-linker unit-galactan intermediate catalyzed by unidentified arabinosyl transferases, with decaprenyl-P-Araf or 5-P-ribosyl-PP as the Araf donor. The product of these steps, the lipid-linked-LU-galactan-arabinan has been partially characterized in terms of its heterogeneity, size, and composition. Biosynthesis of the major components of mycobacterial cell walls is proving to be extremely complex. However, partial definition of arabinogalactan synthesis, the site of action of several major anti-tuberculosis drugs, facilitates the present day thrust for new drugs to counteract multiple drug-resistant tuberculosis.     

The natural antiviral and immune stimulant effects of Allium cepa essential oil onion extract against virulent Newcastle disease virus

Fifty broiler chicks were divided into five groups to study the antiviral and immune-stimulant effect of Allium cepa essential oils (ACEO). The effect of Allium cepa essential oils administration single or combined with NVD vaccine in broilers, more than one parameter was studied in this study i.e., the clinical symptoms that appeared on the chicks after the experimental infection with velogenic Newcastle disease virus, postmortem lesions, pathological lesions scoring, mortality rate (MR), and viral shedding, birds immunity was assessed by HI test and protection percent post-challenge with vNDV. Our result showed that mild clinical signs, lesion scoring, decreased viral shedding in ACEO treated groups 3 (G 3) more than control groups post-challenge with vNDV. Delayed onset of mild clinical signs in G3 followed by complete recovery 7th-day post-challenge (DPC). Low MR (40 and 0%) and high protection percent (100 and 60%) in ACEO treated G3 and G5, respectively. spleen, thymus, cecal tonsil, proventriculus, and cerebrum lesions scoring in G3 and G5 were significantly ((p ≤ 0.05).) lower than the control group, proving a decrease in NDV replication and effective antiviral activity of ACEO. HI titer significantly increased (p ≤ 0.05) In G3, G4 and G5 compared with control groups. There is no significant difference in HI titer in ACEO treated groups and vaccinated groups. In conclusion, oral administration of ACEO combined with NDV vaccines significantly reduces or eliminates lethal clinical signs, lesions, viral shedding, and enhances immune response and protection percent after vNDV challenge proving the natural antiviral and immune stimulant effect of ACEO onion extract. Implementing such a regime might aid NDV control in broiler flocks in endemic areas and reduce the epidemiological load of NDV in the environment.     

Treatment of onchocerciasis with ivermectin in Sierra Leone

Ivermectin chemotherapy is proving to be a major advance in the management of onchocerciasis. In this article, James Whitworth reviews the work done on onchocerciasis and ivermectin in Sierra Leone and examines the evidence that mass treatment might control the clinical features of the disease and its transmission in West Africa. Ivermectin is safe and effectively reduces microfilarial (mf) loads, with major improvement in some ocular manifestations o f disease. This alone makes mass distribution to communities at risk of blindness worthwhile, even though the impact on other clinical features is less clear cut. Repeated doses have a cumulative effect on adult worms, which may cause more reduction in transmission than hitherto thought likely.     

Clinical pharmacokinetics: a comprehensive system for therapeutic drug monitoring and prescribing.

Clinical pharmacokinetics is an expanding scientific discipline which can make an impact on treatment in coronary care, intensive care, paediatrics, general medicine and surgery, and general practice. The aim of this study was to establish a rapid system of drug assay, to report the result, to assess the influence of pathological and clinical factors on the pharmacokinetics of certain drugs, and to use a computer to determine the optimum dosage of drugs. The clinical pharmacokinetics laboratory in Stobhill is available to all clinical departments and to general practitioners in the area. Digoxin, theophylline, and phenytoin have been assessed. Initial samples of these drugs showed that only about a third were in the therapeutic range; samples obtained after the issue of the laboratory report showed an improvement. The predictive performance of the computer program improved with feedback of one or two drug concentrations. Dosages of drugs chosen on an empirical basis may not lead to optimum treatment, and by testing samples early the dosage of the drug can be adjusted. It is hoped that the results achieved will encourage other clinical, pharmaceutical, and scientific colleagues to develop laboratories along similar lines.