Nanocarrier-based interventions for the management of MDR/XDR-TB

Emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB over the past decade presents an unprecedented public health challenge to which countries of concern are responding far too slowly. Global Tuberculosis Report 2014 marks the 20th anniversary of the Global Project on Anti-Tuberculosis Drug Resistance Surveillance, indicating the highest global level of drug-resistance ever recorded detection of 97?000 patients with MDR-TB resulting in 170?000 deaths in 2013. Treatment of MDR-TB is expensive, complex, prolonged (18–24 months) and associated with a higher incidence of adverse events. In this context, nanocarrier delivery systems (NDSs) efficiently encapsulating considerable amounts of second-line anti tubercular drugs (^sATDs), eliciting controlled, sustained and more profound effect to trounce the need to administer ^sATDs at high and frequent doses, would assist in improving patient compliance and avoid hepatotoxicity and/or nephrotoxicity/ocular toxicity/ototoxicity associated with the prevalent ^sATDs. Besides, NDSs are also known to inhibit the P-glycoprotein efflux, reduce metabolism by gut cytochrome P-450 enzymes and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review first provides a holistic account on MDR-TB and discusses the molecular basis of Mycobacterium tuberculosis resistance to anti-tubercular drugs. It also provides an updated bird’s eye view on current treatment strategies and laboratory diagnostic test for MDR-TB. Furthermore, a relatively pithy view on patent studies on second-line chemotherapy using NDSs will be discussed.     

Mathematical Models for Estimating the Risks of Bovine Spongiform Encephalopathy (BSE)

When the bovine spongiform encephalopathy (BSE) epidemic first emerged in the United Kingdom in the mid 1980s, the etiology of animal prion diseases was largely unknown. Risk management efforts to control the disease were also subject to uncertainties regarding the extent of BSE infections and future course of the epidemic. As understanding of BSE increased, mathematical models were developed to estimate risk of BSE infection and to predict reductions in risk in response to BSE control measures. Risk models of BSE-transmission dynamics determined disease persistence in cattle herds and relative infectivity of cattle prior to onset of clinical disease. These BSE models helped in understanding key epidemiological features of BSE transmission and dynamics, such as incubation period distribution and age-dependent infection susceptibility to infection with the BSE agent. This review summarizes different mathematical models and methods that have been used to estimate risk of BSE, and discusses how such risk projection models have informed risk assessment and management of BSE. This review also provides some general insights on how mathematical models of the type discussed here may be used to estimate risks of emerging zoonotic diseases when biological data on transmission of the etiological agent are limited.     

A multicenter retrospective study defining the clinical and hematological manifestations of brucellosis and pancytopenia in a large series: Hematological malignancies, the unusual cause of pancytopenia in patients with brucellosis

The aim of the study is to review the clinical manifestations and the hematological findings of brucellosis and pancytopenia, with or without hematological malignancies. The records of 202 patients with brucellosis were evaluated retrospectively. Among these cases of brucellosis seen in a 6 year period between April 1999 and June 2005, 30 patients with pancytopenia were identified. The most common manifestation was fever, followed by weight loss, anorexia, malaise, arthralgia, and hepatosplenomegaly. Bone marrow biopsies revealed hypercellularity or normocellularity. The most common findings in the bone marrow evaluation were histiocytic hemophagocytosis and granulomas. Among all cases, we diagnosed 5 hematological malignancies (1 acute myelogenous leukemia, 2 acute lymphoblastic leukemia, and 2 multiple myeloma) concurrently with brucellosis. The clinical symptoms and findings were similar in patients with and without malignancies. In cases with malignancies, the bone marrow biopsy revealed predominant primary disease involvement. Significant increases in ESR and CRP, severe anemia and thrombocytopenia were observed in patients with malignancies. Peripheral blood counts in patients without malignancies returned to normal after antibiotic treatment for brucellosis. However, pancytopenia in two patients with malignancies did not recover because of primary resistant disease. We conclude that while histiocytic hemophagocytosis may be considered as a major cause of pancytopenia, leukemic infiltration can also be an extreme and unusual cause of pancytopenia in patients in whom brucellosis was concurrently diagnosed with hematological malignancies.     

Adenosine-mediated bronchoconstriction and lung inflammation in an allergic mouse model

In this study, we studied the role of adenosine on airway responsiveness and airway inflammation using an allergic mouse model. Mice were sensitized by two i.p. injections of ragweed and three consecutive ragweed aerosol challenges. It was found that inhalation of adenosine causes a dose-related bronchoconstriction in this model. Ragweed sensitized and challenged mice showed increased sensitivity to airway challenge to adenosine compared to control animals. Theophylline, a non-selective adenosine receptor antagonist, blocked adenosine-induced bronchoconstriction, but was unable to inhibit bronchoconstrictor response to methacholine. Mice systemically sensitized and airway challenged with allergen showed a marked airway inflammation manifesting increases in eosinophils, lymphocytes and neutrophils, and decrease in macrophages. Twenty-four hours after airway challenge with allergen, aerosolization of adenosine further potentiated the allergen-induced airway inflammation. Cells in bronchoalveolar lavage fluid after adenosine aerosolization increased by 3.07-fold as compared to control mice, and by 1.8-fold compared to ragweed sensitized and challenged mice. The increases in eosinophils, lymphocytes, and neutrophils caused by allergen were potentiated after adenosine challenge. Unexpectedly, macrophages significantly decreased after adenosine challenge. Theophylline attenuated adenosine-enhanced airway inflammation, but could not reverse allergen-induced airway inflammation. These findings suggested that specific adenosine receptors contribute to airway responsiveness and airway inflammation associated with this model of allergic asthma.     

Risk factors for nosocomial imipenem-resistant Acinetobacter baumannii infections.

OBJECTIVES: To identify the risk factors for nosocomial imipenem-resistant Acinetobacter baumannii (IRAB) infections. METHODS: A prospective case-control study, set in an 1100-bed referral and tertiary-care hospital, of all patients who had nosocomial A. baumannii infections between January 1 and December 31, 2004. Only the first isolation of A. baumannii was considered. RESULTS: IRAB was isolated from 66 (53.7%) patients and imipenem-sensitive Acinetobacter baumannii (ISAB) was isolated from 57 (46.3%) patients during the study period. The mean duration of hospital stay until A. baumannii isolation was 20.8+/-13.6 days in IRAB infections, whereas it was 15.4+/-9.4 days in ISAB infections. Of the patients, 65.2% with IRAB infections and 40.4% with ISAB infections were followed at the intensive care unit (ICU). Previous carbapenem use was present in 43.9% of the patients with IRAB and 12.3% of the patients with ISAB infection. In univariate analysis female sex, longer duration of hospital stay until infection, ICU stay, emergent surgical operation, total parenteral nutrition, having a central venous catheter, endotracheal tube, urinary catheter or nasogastric tube, previous antibiotic use, and previous administration of carbapenems were significant risk factors for IRAB infections (p<0.05). In multivariate analysis, longer duration of hospital stay until A. baumannii isolation (odds ratio (OR) 1.043; 95% confidence interval (CI) 1.003-1.084; p=0.032), previous antibiotic use (OR 5.051; 95% CI 1.004-25.396; p=0.049), and ICU stay (OR 3.100; 95% CI 1.398-6.873; p=0.005) were independently associated with imipenem resistance. CONCLUSIONS: Our results suggest that the nosocomial occurrence of IRAB is strongly related to an ICU stay and duration of hospital stay, and that IRAB occurrence may be favored by the selection pressure of previously used antibiotics.     

Oxidative stress causes renal dopamine D1 receptor dysfunction and salt-sensitive hypertension in Sprague-Dawley rats

Renal dopamine plays an important role in maintaining sodium homeostasis and blood pressure (BP) during increased sodium intake. The present study was carried out to determine whether renal dopamine D1 receptor (D1R) dysfunction contributes to increase in salt sensitivity during oxidative stress. Male Sprague-Dawley rats, divided into various groups, received tap water (vehicle); 1% NaCl (high salt [HS]); L-buthionine sulfoximine (BSO), an oxidant; and HS plus BSO with or without Tempol, an antioxidant, for 12 days. Compared with vehicle, HS intake increased urinary dopamine production and decreased basal renal Na/K-ATPase activity but did not affect BP. BSO-treated rats exhibited oxidative stress and a mild increase in BP. In these rats, D1R expression and G protein coupling were reduced, and SKF38393, a D1R agonist, failed to inhibit Na/K-ATPase activity and promote sodium excretion. Concomitant administration of BSO and HS caused oxidative stress, D1R dysfunction, and a marked increase in BP. Although renal dopamine production was increased, it failed to reduce the basal Na/K-ATPase activity in these animals. Treatment of BSO plus HS rats with Tempol decreased oxidative stress and restored endogenous, as well as exogenous, D1R agonist-mediated Na/K-ATPase inhibition and normalized BP. In conclusion, during HS intake, the increased dopamine production via Na/K-ATPase inhibition prevents an increase in BP. During oxidative stress, D1R function is defective, and there is mild hypertension. However, in the presence of oxidative stress, HS intake causes marked elevation in BP, which results from a defective renal D1R function leading to the failure of dopamine to inhibit Na/K-ATPase and promote sodium excretion.     

Adenosine deaminase, 5′-nucleotidase,xanthine oxidase,superoxide dismutase,and catalase activities in gastric juices from patients with gastric cancer,ulcer, and atrophic gastritis

Adenosine deaminase (ADA), 5-Nucleotidase (5NT), Xanthine oxidase (XO), Cu-Zn Superoxide dismutase (SOD) and Catalase (CAT) activities were determined in gastric juices from patients with gastric cancer, ulcer, gastritis and from healthy subjects. Enzyme activities were given as units per ml gastric juice and units per mg protein in gastric juice. ADA, 5NT and XO activities were found lower and protein concentrations were found higher in the cancer group than controls. There was however no significant difference between Cu-Zn SOD activities of the cancer and control groups. In all groups including control one, we could not find catalase activities in most of the samples. On the other hand, ADA, 5NT activities and protein concentrations in the gastric juice were lower in the gastritis group than control group. In the ulcer group, we found higher Cu-Zn SOD and XO activities and lower 5NT activity and protein concentrations compared with control values. In an attempt to establish statistical correlations between mean enzyme activities, pH and protein concentrations in the gastric juices of the groups, we found noticeable intra and inter-correlations, which indicated possible relations between DNA and free radical metabolizing enzymes.     

Safety and Efficacy of Intravenous Colistin in Neonates With Culture Proven Sepsis

Background:

Although it is well described among adults, intravenous colistin use and its associated toxicities in newborns are poorly understood.

Objectives:

We present our experience of efficacy and safety of intravenous colistin in the treatment of sepsis in term and preterm neonates.

Patients and Methods:

The records of neonates who received colistin between January 2013 and February 2014 were retrospectively reviewed. All neonates with culture proven nosocomial infections due to multidrug resistant organisms and treated continuously with colistin for more than 72 hours were included in the study.

Results:

Patients were evaluated for clinical and microbiological response to the drug and its and side effects. Twelve newborn infants with mean 31.8 ± 3.5 weeks gestational age and median 1482 (810 - 3200) gram birth weight were included. 11/12 (91.7%) patients showed microbiological clearance with intravenous colistin. One patient who had recurrent cerebrospinal fluid positive culture was treated with intraventricular colistin. The major side effects observed was hyponatremia and hypokalemia in 2 (16.6%) patients, all infants required magnesium supplementation.

Conclusions:

Intravenous colistin administration appears to be safe and efficacious for multidrug-resistant gram-negative infections in neonates, including preterm infants. However, we believe that large prospective controlled studies are needed to confirm its efficacy and safety in neonates.     

Quantitative assessment of muscle stiffness with acoustic radiation force impulse elastography after botulinum toxin A injection in children with cerebral palsy

Purpose

Our objective in this study was to assess the changes in medial gastrocnemius muscle (GCM) stiffness after botulinum toxin A (BTA) injection in children with cerebral palsy (CP) by using acoustic radiation force impulse (ARFI) elastography and to research the usability of this technique in clinical practice.

Materials and methods

Twenty-four spastic lower extremities of 12 children with CP were assessed. BTA injection treatment was applied to the medial GCM. Muscle stiffness was measured with the ARFI technique before the procedure and a month after the procedure. The patients were assessed with the modified Ashworth scale (MAS) in the physiotherapy department at about the same time. Shear wave velocity (SWV) values and MAS scores before and after the treatment were compared.

Results

Mean SWV values were measured as 3.20 ± 0.14 m/s before BTA and as 2.45 ± 0.21 m/s after BTA, and the difference between them was found to be statistically significant (p < 0.001). Mean MAS score (2.33 ± 0.70) after BTA decreased significantly when compared to the score before BTA (2.96 ± 0.62) (p = 0.001). SWV values positively correlated with MAS scores (ρ = 0.578, p = 0.003). The interobserver agreement expressed as interclass correlation coefficient (ICC) was 0.65 (95% CI 0.33–0.84, p < 0.001).

Conclusion

ARFI elastography for identifying structural changes that occur in the spastic muscle after BTA injection in children with CP can yield more valuable information with combined use of MAS.