Reducing length of stay with the direct oral anti-coagulants in low and intermediate risk pulmonary embolism: a single center experience

Journal of Thrombosis and Thrombolysis - Direct oral anti-coagulants (DOACs) reduce hospital length-of-stay (LOS) in patients with acute pulmonary embolism (PE) in clinical trials. There is a...     

In vitro induction of cytotoxicity and DNA strand breaks in CHO cells exposed to cypermethrin, pendimethalin and dichlorvos

The indiscriminate use of pesticides and herbicides to increase crop productivity has aroused a great concern among the environmental and health scientists due to their adverse effects in both target as well as non-target species. Although substantial information is available regarding their environmental and ecological impact, not much is known in regard to its toxicity in the mammalian system. Therefore a study was conducted for the assessment of cytotoxic and genotoxic effects of cypermethrin (Type II pyrethroid) dichlorvos (organophosphate) and pendimethalin (dinitroaniline herbicide) in Chinese hamster ovary (CHO) cells. CHO cells were exposed to 1 μM, 10 μM, 100 μM, 1000 μM, and 10,000 μM, cypermethrin, pendimethalin and dichlorvos for 3 h and cytotoxicity was assessed by MTT assay. Their genotoxic potential was also evaluated by Comet assay. The results demonstrate that dichlorvos and pendimethalin exhibited higher extent of cytotoxicity as compared to cypermethrin. A significant (p < 0.05) concentration dependent increase in DNA damage was observed with dichlorvos (0.01 μM and above) and pendimethalin (0.1 μM and above) as evident by Comet assay parameters viz., Olive tail moment (arbitrary units), tail DNA (%) and tail length (μM). Cypermethrin induced a significant (p < 0.05) DNA damage only at higher concentrations (1000 and 5000 μM). Our data indicates that these chemicals produce cytotoxicity and DNA damage in mammalian cells and should be used with caution.     

Prostatitis: prevalence, health impact and quality improvement strategies

Since its identification as a discrete entity, prostatitis has been a crippling and dreadful disease for the males and from then till date it is well recognized that it has continuously eluded the urologists and the practitioners and the patients were generally avoided. But the newer advent in research has changed the concept of the medical management of prostatitis that had been in stagnation for the past many years. The traditional myths related to the disease were continued to be unlighted with improved understanding of the distribution, cause and measures for the management of this disease. From herbal treatment used by the ethnic communities historically to today's modern treatment modules of antimicrobial and anti-inflammatory agents, though not very successful, but has embarked a light of hope in both practitioners and patients for the effective management of this condition, which has negatively affected the normal as well as intimate life of the sufferers. With newer and more widely accepted classification of the disease the practitioners and patients diagnosed with prostatitis now can hope for a better improvement and management of the disease. The present study tries to encompass the important and useful work reported by several workers and progress in the effective management of this awful condition.     

Multipronged evaluation of genotoxicity in Indian petrol-pump workers

Petrol (gasoline) contains a number of toxicants. This study used human biomonitoring to evaluate the genotoxic effects of exposure to benzene in petrol fumes in 100 Indian petrol-pump workers (PPWs) and an equal number of controls. The study was corroborated with in silico assessments of the Comet assay results from the human biomonitoring study. An in vitro study in human lymphocytes was also conducted to understand the genotoxicity of benzene and its metabolites. In a subset of the population studied, higher blood benzene levels were detected in the PPWs (n = 39; P < 0.01) than the controls (n = 18), and 100-250 ppb benzene was also detected in air samples from the petrol pumps. PPWs had higher levels of DNA damage than the controls (P < 0.01). In addition, the micronucleus assay was performed on lymphocytes from a subset of the subjects, and the micronucleus frequency for PPWs was significantly higher (n = 39; 14.79 +/- 3.92 per thousand) than the controls (n = 18; 7.54 +/- 3.00 per thousand). Human lymphocytes were treated in vitro with benzene and several of its metabolites and assayed for DNA damage with the Comet assay. Benzene and its metabolites produced significant (P < 0.05) levels of DNA damage at and above concentrations of 10 microM. The metabolite, p-benzoquinone, produced the greatest amount of DNA damage, followed by hydroquinone > benzene > catechol > 1,2,4,-benzenetriol > muconic acid. This study demonstrates that, using sensitive techniques, it is possible to detect human health risks at an early stage when intervention is possible. possible.     

Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins

Insulin secretion by pancreatic β cells is a complex and highly regulated process. Disruption of this process can lead to diabetes mellitus. One of the various pathways involved in the regulation of insulin secretion is the activation of heterotrimeric G proteins. Bordetella pertussis toxin (PTX) promotes insulin secretion, suggesting the involvement of one or more of three G(i) and/or two G(o) proteins as suppressors of insulin secretion from β cells. However, neither the mechanism of this inhibitory modulation of insulin secretion nor the identity of the G(i/o) proteins involved has been elucidated. Here we show that one of the two splice variants of G(o), G(o2), is a key player in the control of glucose-induced insulin secretion by β cells. Mice lacking G(o2)α, but not those lacking α subunits of either G(o1) or any G(i) proteins, handle glucose loads more efficiently than wild-type (WT) mice, and do so by increased glucose-induced insulin secretion. We thus provide unique genetic evidence that the G(o2) protein is a transducer in an inhibitory pathway that prevents damaging oversecretion of insulin.     

Significance of plasma copper and caeruloplasmin concentrations in rheumatoid arthritis.

To understand the role of copper in initiating protein alterations in rheumatoid arthritis (RA) as reported previously, concentrations of copper anc caeruloplasmin were determined in RA patients. The mean copper concentration of the RA population examined was 24.8 mumol/l (157.5 mug/100 ml), and the mean caeruloplasmin concentration in this RA population was 45.52 mg/100 ml. These values are not different from those reported by previous workers. However, when the RA population was divided into three groups according to sex and oestrogen therapy it was found that caeruloplasmin and copper concentrations in the group of female RA patients on oestrogens was significantly different from other groups (P less than 0.001). A highly significant (P less than 0.01) positive correlation was obtained between copper and caeruloplasmin concentrations (r = 0.91). Concentrations of copper and caeruloplasmin failed to explain the low sulphydryl content of plasma which was observed to be independent of these two parameters. Increased alpha2-globulin concentration, which was refractory to chrysotherapy but 'finger-printed' with a pure preparation of caeruloplasmin in electrophoresis, along with the absence of Kayser-Fleischer rings, supports the contention that copper is not present in a free ionic state in RA patients. This study shows that only a concurrent oestrogen therapy raises copper and caeruloplasmin concentration significantly in a female RA population. Past investigators appear to have overlooked this fact, and it could be that a disproportionate sex distribution (more female rheumatoid arthritics) could cause misleading results in RA studies. The role of oestrogens, copper, and caeruloplasmin in causing exacerbation of RA symptoms is discussed.     

DNA and oxidative damage induced in somatic organs and tissues of mouse by municipal sludge leachate

Pollution by waste landfill leachate has prompted a number of studies on the toxic and potential health effects. This study assessed the genotoxicity of a municipal sludge leachate (MSL) in the somatic tissues (blood and bone marrow) and organs (liver, kidney, and spleen) of mice using the alkaline Comet assay. The possible cause of DNA damage via the study of antioxidant system (lipid peroxidation [LPO]; catalase [CAT]; reduced glutathione [GSH]; and superoxide dismutase [SOD]) responses in mouse liver was also investigated. Different concentrations (2.5%, 5%, 10%, and 15%) of the leachate were administered intraperitoneally for 5 consecutive days to male Swiss albino mice (4 mice/group). A significant (p < 0.05) increase in DNA damage in organs and tissues of treated mice compared to the negative control was observed as evident from the Comet assay parameters: olive tail moment (OTM, arbitrary units) and tail DNA (%). Bone marrow showed maximum DNA damage followed by liver > spleen > kidney > blood as evident by the OTM. A significant increase (p < 0.05) in the level of antioxidant enzymes (CAT and SOD) and LPO with a concurrent decrease in GSH in the liver of treated mice was also observed. Our finding demonstrates that the MSL induces DNA damage in the somatic tissues and organs of mouse as well as induces oxidative stress in the liver. These tissues and organs may be the potential targets in animal and human populations exposed to MSL. This is of relevance to public health; as such exposure could lead to adverse health effects via systemic genotoxicity.     

Avidin as a model for charge driven transport into cartilage and drug delivery for treating early stage post-traumatic osteoarthritis

Local drug delivery into cartilage remains a challenge due to its dense extracellular matrix of negatively charged proteoglycans enmeshed within a collagen fibril network. The high negative fixed charge density of cartilage offers the unique opportunity to utilize electrostatic interactions to augment transport, binding and retention of drug carriers. With the goal of developing particle-based drug delivery mechanisms for treating post-traumatic osteoarthritis, our objectives were, first, to determine the size range of a variety of solutes that could penetrate and diffuse through normal cartilage and enzymatically treated cartilage to mimic early stages of OA, and second, to investigate the effects of electrostatic interactions on particle partitioning, uptake and binding within cartilage using the highly positively charged protein, Avidin, as a model. Results showed that solutes having a hydrodynamic diameter ≤10 nm can penetrate into the full thickness of cartilage explants while larger sized solutes were trapped in the tissue's superficial zone. Avidin had a 400-fold higher uptake than its neutral same-sized counterpart, NeutrAvidin, and >90% of the absorbed Avidin remained within cartilage explants for at least 15 days. We report reversible, weak binding (K_D ∼ 150 μm) of Avidin to intratissue sites in cartilage. The large effective binding site density (N_T ∼ 2920 μm) within cartilage matrix facilitates Avidin's retention, making its structure suitable for particle based drug delivery into cartilage.     

DNA damage and mutagenicity induced by endosulfan and its metabolites

Endosulfan is a widely used broad-spectrum organochlorine pesticide, which acts as a contact and stomach poison. Nontarget species, such as cattle, fish, birds, and even humans, are also affected. Studies on the genotoxicity and mutagenicity of endosulfan have been inconsistent and nothing is known about the genotoxicity of its metabolites. In the present study, endosulfan (as a commercial isomeric mixture and as the alpha- and beta-isomers), and metabolites of endosulfan (the sulfate, lactone, ether, hydroxyether, and diol derivatives) were assayed for their ability to induce DNA damage in Chinese hamster ovary (CHO) cells and human lymphocytes using the Comet assay and were assayed for their mutagenicity using the Salmonella reversion assay (Ames test with TA98, TA97a, TA102, TA104, and TA100, with and without S9 activation). The compounds produced statistically significant (P < 0.01), concentration-dependent (0.25-10 microM) increases in DNA damage in both CHO cells and human lymphocytes. Endosulfan lactone caused the most DNA damage in CHO cells, while the isomeric mixture of endosulfan produced the greatest response in lymphocytes. The test compounds also were mutagenic in Salmonella strains at concentrations of 1-20 mug/plate (P < 0.05), with TA98 being the most sensitive strain and the diol and hydroxyether metabolites producing the highest responses. The results indicate that exposure to sublethal doses of endosulfan and its metabolites induces DNA damage and mutation. The contribution of the metabolites to the genotoxicity of the parent compound in Salmonella and mammalian cells, however, is unclear, and the pathways leading to bacterial mutation and mammalian cell DNA damage appear to differ.