The Intracellular Environment of Human Macrophages That Produce Nitric Oxide Promotes Growth of Mycobacteria

Nitric oxide (NO) is a diffusible radical gas produced from the activity of nitric oxide synthase (NOS). NOS activity in murine macrophages has a protective role against mycobacteria through generation of reactive nitrogen intermediates (RNIs). However, the production of NO by human macrophages has remained unclear due to the lack of sensitive reagents to detect NO directly. The purpose of this study was to investigate NO production and the consequence to mycobacteria in primary human macrophages. We found that Mycobacterium bovis BCG or Mycobacterium tuberculosis infection of human macrophages induced expression of NOS2 and NOS3 that resulted in detectable production of NO. Treatment with gamma interferon (IFN-γ), l-arginine, and tetrahydrobiopterin enhanced expression of NOS2 and NOS3 isoforms, as well as NO production. Both of these enzymes were shown to contribute to NO production. The maximal level of NO produced by human macrophages was not bactericidal or bacteriostatic to M. tuberculosis or BCG. The number of viable mycobacteria was increased in macrophages that produced NO, and this requires expression of nitrate reductase. An narG mutant of M. tuberculosis persisted but was unable to grow in human macrophages. Taken together, these data (i) enhance our understanding of primary human macrophage potential to produce NO, (ii) demonstrate that the level of RNIs produced in response to IFN-γ in vitro is not sufficient to limit intracellular mycobacterial growth, and (iii) suggest that mycobacteria may use RNIs to enhance their survival in human macrophages.     

Rosiglitazone: safety and efficacy in combination with insulin in poorly controlled type 2 diabetes mellitus patients treated with insulin alone

AIMS: To assess the safety and efficacy of rosiglitazone and insulin treatment in combination in poorly controlled insulin-treated type 2 diabetes mellitus (T2DM) patient. METHOD: In this prospective, open-labelled, nonrandomised study, rosiglitazone was added to the insulin therapy in T2DM patients with baseline HbA1c>or=7.5%. Patients were followed for 12 months. Insulin dosage was adjusted as necessary. RESULTS: Insulin and rosiglitazone combination was used in 53 patients (29 male, 24 female) for 12 months. Baseline vs. 12-month results shown as mean+/-S.D.: HbA1c reduction 1.53% (9.82+/-1.12 vs. 8.29+/-1.45, P=.0001), insulin dosage reduction 10 U (74+/-34 vs. 64+/-34 U), percentage insulin dose reduction 13.53%, and weight gain 1.0 kg only (84+/-19.93 vs. 85+/-25.73 kg, P=.1). Systolic blood pressure 144+/-22.9 vs. 134+/-15.8 mm Hg (P=.03), total cholesterol 6.18+/-4.15 vs. 4.75+/-2.71 micromol/L, triglyceride 2.62+/-1.49 vs. 2.07+/-1.44 micromol/L, and HDL cholesterol 1.43+/-0.71 vs. 1.63+/-0.36 micromol/L (P=.02). Alanine transaminase actually reduced significantly from 26+/-22 to 19+/-9 IU/L (P=.001). Improved glycaemic control was associated with favourable reduction in cardiovascular risk factors. Rosiglitazone was discontinued only in nine patients (weight gain-4, no improvement noticed-4, ankle swelling-1). No hepatotoxicity was observed. CONCLUSION: Rosiglitazone+insulin combination is safe and effective in inadequately controlled insulin-treated T2DM patients.     

Bacterial biopolymers: From production to applications in biomedicine

Bacterial polymers obtained tremendous attention over the decades owing to its widespread use in biomedical applications. A better understanding on metabolic pathways and development of improved production strategies through metabolic engineering tools to synthesize tailor made polymer materials to meet their applicability in biomedicine. This review focuses on wide range of these biocompatible polymeric materials include polysaccharides, polyesters, polyamides and polyphosphates with wound healing, antioxidant, antitumor, antimicrobial activities. This review focuses on the advantages of various biomaterials to obtain controlled/sustained drug release and tissue engineering applications in biomedical field and the applications of microbial polysaccharides as drugs in pharmaceutical industry. This review describes the most prominent biomedical applications of bacterial biopolymer material as wound healing bandages, drug delivery, tissue engineering, ortho-dental applications and hydrogels. Reviews the future aspects based on economic feasibility and challenges in mass production and downstream processing of biopolymers and its tailor made synthesis to accomplish diverse applications.     

Activation of Opioid Receptors in the Mediobasal Hypothalamus Stimulates Prolactin Secretion in the Conscious Rat

In an attempt to localize the opioid receptor(s) (mu, delta and kappa) involved in opioid-stimulated prolactin release in the conscious male rat, opioid agonists were microinjected into the mediobasal hypothalamus and prolactin levels measured before and after injection. The specific mu agonist, DAGO ((D-Ala², NMe-Phe⁴, Gly-ol⁵)-enkephalin) was the most effective in eliciting prolactin release, the smallest effective dose being 0.01 nmoles. The specific delta agonist, DPDPE ((D-Pen², D-Pen⁵)-enkephalin) had no significant effect even at the highest dose of 10 nmoles. The specific kappa agonist, U50,488H ((trans-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzene acetamide) was effective at the doses 1.0 and 10 nmoles. We conclude that mu and kappa opioid receptors in the mediobasal hypothalamus are involved in opioid-stimulated prolactin release and that delta receptors are not.     

Unresolved, atraumatic breast hematoma: post-irradiation or secondary breast angiosarcoma

Post-irradiation or secondary angiosarcoma of the breast was first described in the 1980s in patients treated with breast conserving therapy for cancer. The primary management of radiation-induced breast angiosarcoma has focused on surgical resection with an emphasis on achieving negative tumor margins. While surgery remains a key component of treatment, novel therapeutic approaches have surfaced. Despite such advances in treatment, prognosis remains poor.     

Drug carriers in pharmaceutical design: promises and progress

Ever since pure molecular entities have been adapted as drug, varied manifestations other than elimination of infections are frequently been acknowledged as side effects. Contemporary drug research focuses on these issues besides developing new molecules for the restoration of unnatural functional deviations in various tissues and organs. The most promising advancement to achieve this concept of ideal drug is the encapsulation of drug in biocompatible nano or microspheres. Encapsulation can insulate the toxic drugs and lease a better half life to molecules undergoing spontaneous degradation under physiological conditions. It is also worthwhile to incorporate along some immunomodulators to strengthen and channelize the innate immune response of the host in right direction. This holistic approach would also prevent the physiological modulations dictated by invading pathogens, which paralyze the important functionaries of the host. Lipoproteins, lipid like molecules and probiotic non-colonizing bacterial membrane mimics might prove to be the best ingredients for encapsulation. Some synthetic non-immunogenic supra molecules like fullarenes and dendrimers also exhibit great potential for the development of new encapsulation technology. Here an attempt is made to review the progress in terms of aims and achievements in the area of drug carriers and encapsulation with its overall impact on therapeutic industry.     

Distribution of d-amino acid oxidase (DAO) activity in the medulla and thoracic spinal cord of the rat: implications for a role for d-serine in autonomic function

The activity and regional distribution of

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-amino acid oxidase (DAO), an enzyme that inactivates

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-serine, were examined in the medulla and spinal cord of the rat by biochemical and histochemical procedures. DAO activity was noticeably low or absent in the nucleus of the solitary tract, ventrolateral medulla and intramediolateral cell column of the spinal cord. This may be indicative of a neuromodulatory role for endogenous

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-serine (at the NMDA-glycine site) in the central control of blood pressure.     

Delayed adjuvant hormonal therapy and its impact on mortality in women with breast cancer

Adjuvant hormonal therapy (HT) is important for the management of hormone‐sensitive breast cancer. However, the timeliness for adjuvant HT and the consequences of delayed initiation of treatment have not been analyzed. The purpose of this study was to characterize delays to HT and assess the impact on clinical outcomes. The study cohort consisted of female patients with invasive ductal and/or lobular, hormone receptor‐positive breast cancer diagnosed between 2010 and 2015. Initiation of HT >6 months (180 days) after surgery was defined as delayed. Patients receiving chemotherapy were excluded from the study cohort. Multivariable logistic regression modeling was performed to establish associations between delayed HT and demographic, facility, and clinical factors. Survival analysis was performed using the Kaplan‐Meier estimation and Cox proportional hazards regression to evaluate overall survival. Of 179 590 women assessed in the National Cancer Database, 3.2% had a delay in the initiation of adjuvant HT. Positive demographic‐related risk factors were younger age, ethnic minority groups, and multiple comorbidities. Clinical factors significantly associated with delayed initiation of adjuvant HT were high‐grade tumor, larger tumor size, greater lymph node involvement, having an unplanned readmission within 30 days of surgery, and positive final surgical margins. Adjusted survival analysis showed a survival disadvantage of delayed initiation of HT. Risk factors for delayed initiation of HT specific to demographic and clinical characteristics were identified. Delayed initiation of HT was associated with a survival detriment.     

Morphology and Morphometry of Cauda Epididymal Spermatozoa in Rattus rattus L.

Sperm morphometry, in combination with other morphological traits and sperm parameters, can be useful for developing a fertility index. In present study various morphological and morphometric characters of cauda epididymal spermatozoa from 30 house rats were measured. About 100 spermatozoa of each rat with normal morphology and abnormalities like abnormal head, midpiece swelling, coiled tail, bent tail, detached heads and cytoplasmic droplets were counted in different fields and percentage of each was calculated. About 50 spermatozoa of each rat were measured for head length (HL), mid piece length (MPL), tail length (TL), head area (HA) and head perimeter (HP) using Magnus pro analytic software. In cauda epididymal spermatozoa of rat primary abnormalities included abnormal heads and mid piece swelling and secondary abnormalities included cytoplasmic droplet, coiled tails, bent tails, free heads. Variation among the sperm abnormalities was considerably high (>50?%). There was little variation in HL, MPL, TL, HA and HP of cauda epididymal spermatozoa of 30 rats (<13?%).