Nevirapine derivatives with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.

A series of nevirapine derivatives has been synthesized in an effort to enhance the spectrum of chemotherapeutic properties for the effective treatment of AIDS and AIDS-related opportunistic infections. The nevirapine derivative bearing isoniazid moiety (3a) was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index of>15,723 which also exhibited 90% inhibition against Mycobacterium tuberculosis at 6.25 microg/ml. Compound 3c showed 100% inhibition against M. tuberculosis and also exhibited potent antibacterial activity against 24 pathogenic bacteria with MIC less than 1 microg/ml.     

Three-dimensional directional nerve guide conduits fabricated by dopamine-functionalized conductive carbon nanofibre-based nanocomposite ink printing

A potential issue in current nerve guides is that they do not transmit electrical nerve impulses between the distal and proximal end of an injured nerve, i.e. a synapse. Conductivity is a desirable property of an ideal nerve guide that is being considered for peripheral nerve regeneration. Most conductive polymers reported for the fabrication of tissue engineering scaffolds, such as polypyrrole and polyaniline, are non-biodegradable and possess weak mechanical properties, and thus cannot be fabricated into 3D structures. Herein, we have designed a new nanocomposite material composed of dopamine, carbon nanofibers (CNF) and polycaprolactone (PCL) for the fabrication of nerve conduits, which facilitates the growth and migration of neurons toward the targeted end of an injured nerve. This support and navigation of the scaffold leads to better sensory and motor function. The results showed that the mechanical properties of the printed PCL increased by 30% in comparison with the pure PCL film, which is comparable with human nerves. The in vitro cell study of human glioma cells showed that the printed lines provided support for neural cell attachment, migration and differentiation toward the targeted end. In contrast, in the absence of printed lines in the scaffold, the cells attach and grow in random directions, forming a flower shape (cell cluster) on the surface of PCL. Thus, the proposed scaffold is a promising candidate for nerve guide application based on its signal transmission and navigating neurons in a correct pathway towards the targeted end.

Directional growth induced by dopamine-functionalized CNF-based nanocomposite ink printing.     

Bio-cleaning improves the mechanical properties of lignin-based carbon fibers

Production of carbon fibers (CF) using renewable precursors has gained importance particularly in the last decade to reduce the dependency on conventional petroleum-based precursors. However, pre-treatment of these renewable precursors is still similar to that of conventional ones. Little work is put into greener pre-treatments and their effects on the end products. This work focuses on the use of bio-cleaned lignin as a green precursor to produce CF by electrospinning. Bio-cleaned kraft lignin A (Bio-KLA) and uncleaned kraft lignin A (KLA) were used to explore the effect of bio-cleaning on the diameter and mechanical properties of lignin fibers and CF. The effect of electric field, lignin-to-poly(ethylene oxide) (PEO) ratio and PEO molecular weight (MW) were evaluated by 3³ factorial design using Design of Experiment (DOE). The electrospinning process parameters were optimized to obtain a balance between high elastic modulus and small fiber diameter. The model predicted optimized conditions were 50 kV m⁻¹ electric field, 95/5 lignin-to-PEO ratio and 1000 kDa MW of PEO. When compared to KLA, Bio-KLA CFs showed a 2.7-fold increase in elastic modulus, 2-fold increase in tensile strength and 30% decrease in fiber diameter under the same optimum conditions. The results clearly show that bio-cleaning improved the mechanical properties of lignin derived CF.

Waste lignin (KLA) and bio-cleaned lignin (Bio-KLA) precursors, used to produce parameter-optimized-electrospun carbon fibers showed improved mechanical properties for Bio-KLA.     

Clinical profile and follow-up of 51 pediatric neurocysticercosis cases: A study from Eastern India

Introduction:

Our present observational study attempted to evaluate the clinical profiles, diagnosis, treatment and follow-up results of 51 pediatric neurocysticercosis patients over a mean duration of five years (from January 2006 to December 2010).

Materials and Methods:

Diagnosis was mainly based on clinical features, computed tomography (CT)/magnetic resonance imaging scan and exclusion of other causes. Patients with active, transitional cysts and seizure were treated with albendazole for 28 days, steroids and anticonvulsants.

Results:

A total of 38 patients completed this study. Mean age of the presentation was 8.47 ± 3.19 years 52.6% of the patients were female. Overall patients presented with generalized seizure in 55.3%, focal in 31.6%, headache ± vomiting in 63.2%, focal neurodeficit in 10.5% and combination of symptoms in 60.5% cases. Contrast CT brain showed a solitary lesion in 27 (71.1%) and multiple in the rest. At presentation lesions were transitional in 58.2%, inactive in 20% and mixed in 14.6%. After a mean of 2 years, seizure persisted in 9 (23.7%) and headache in 8 (21.1%) of whom six had normal electroencephalography (EEG) while one each showed focal slowing, generalized slowing and epileptiform discharges. During the follow-up, CT scan brain 44.7% lesions calcified, 31.6% disappeared, 10.5% regressed and the rest persisted.

Conclusion:

Solitary ring enhancing lesions (transitional stage) involving the parietal lobe was the commonest CT picture at presentation. Generalized tonic-clonic seizure was the most common type of seizure. Number of lesions, persistence of lesion, number of seizures, EEG abnormality at presentation were not found to be prognostically significant (P > 0.05).Key Words: Brain, epilepsy, lesion, neurocysticercosis, parenchyma, solitary     

Primary Prevention of Falls: Effectiveness of a Statewide Program

Objectives. We examined a population-wide program, Pennsylvania’s Healthy Steps for Older Adults (HSOA), designed to reduce the incidence of falls among older adults. Older adults completing HSOA are screened and educated regarding fall risk, and those identified as being at high risk are referred to primary care providers and home safety resources.Methods. From 2010 to 2011, older adults who completed HSOA at various senior center sites (n = 814) and a comparison group of older adults from the same sites who did not complete the program (n = 1019) were recruited and followed monthly. Although participants were not randomly allocated to study conditions, the 2 groups did not differ in fall risk at baseline or attrition. We used a telephone interactive voice response system to ascertain the number of falls that occurred each month.Results. In multivariate models, adjusted fall incidence rate ratios (IRRs) were lower in the HSOA group than in the comparison group for both total (IRR = 0.83; 95% confidence interval [CI] = 0.72, 0.96) and activity-adjusted (IRR = 0.81; 95% CI = 0.70, 0.93) months of follow-up.Conclusions. Use of existing aging services in primary prevention of falls is feasible, resulting in a 17% reduction in our sample in the rate of falls over the follow-up period.The public health significance of falls among older adults is clear. As noted by the National Council on Aging,

falls are the leading cause of injury related deaths of older adults, the primary reason for older adult injury emergency department visits, and the most common cause of hospital admissions for trauma.1

In 2011, the rate of nonfatal fall injuries requiring emergency department care was 2301 per 100 000 among people aged 50 to 54 years but 14 159 per 100 000 among people 85 years or older.2Self-report measures from health surveys confirm that there is a high prevalence of falls (30%–40%) among people 65 years or older and that the prevalence increases with age (40%–50% among those 80 years or older), as does the inability to get up from falls.3,4 Even noninjurious falls are disabling in that they are associated with activity restriction, isolation, deconditioning, and depression.5–8 In 2005, medical care costs associated with falls in the United States among people 50 years or older totaled about $13.5 billion (including deaths, hospital care, and emergency department admissions).2 A challenge for public health is to decrease the risk of falls without encouraging reduced physical activity, which carries other risks.Risk factors for falls include sedative use, cognitive impairment, lower extremity weakness, poor reflexes, balance and gait abnormalities, foot problems, and environmental hazards.9,10 Community-level efforts have adapted clinical interventions in addressing such risk factors. A review of 5 prospective but nonrandomized community trials involving matched control communities suggested that fall-related fractures could potentially be reduced by 6% to 33%,11 and meta-analyses and systematic reviews provide support for the effectiveness of multifactorial assessments and management of fall risk.12 The Centers for Disease Control and Prevention (CDC) has compiled a compendium of successful interventions that can be used by public health practitioners and community-based organizations.13,14Recommendations for optimal means of preventing falls are still evolving.15,16 A Cochrane review reported that exercise and home safety programs reduce the rate of falls and risk of falling but did not reveal any benefits of interventions that increase knowledge regarding fall prevention without additional components.3Pennsylvania’s Department of Aging has opted for a hybrid program in which older adults can take advantage of an intervention that offers, within the current aging service infrastructure, risk screening for falls and education regarding prevention. This voluntary program, Healthy Steps for Older Adults (HSOA), is available to all adults 50 years or older. Those identified as having a high risk for falls are referred to primary care providers and encouraged to complete home safety assessments. Because it relies on referrals to physician care rather than direct clinical interventions, the program may be less effective among people at high risk for falls; however, it is scalable across the state and reaches large numbers of people. In the case of some public health challenges, such a strategy may be more effective than more intensive interventions targeting high-risk individuals.17There is a lack of evidence regarding the effectiveness of this short-term, low-cost, population-wide program in reducing the incidence of falls among its participants, however. Here we report the results of a statewide evaluation of HSOA, which uses the state’s network of providers of aging services in its primary prevention efforts.     

Green-synthesized gold nanoparticles from black tea extract enhance the chemosensitivity of doxorubicin in HCT116 cells via a ROS-dependent pathway

Green gold nanoparticles (GNPs) were prepared from black tea extract (BTE) and used to examine the chemosensitivity of doxorubicin in colon cancer cell line HCT116. BTE-GNPs were prepared by a single-step method and characterized by UV-Vis spectroscopy, FTIR spectroscopy, SEM, DLS and zeta-potential. The MTT assay was performed to determine the cytotoxicity of HCT116 cells and also normal kidney cells HEK293. Apoptosis and ROS generation were investigated by flow cytometry. The inhibition of ROS levels by the inhibitor NAC was determined by both spectrofluorimetry and confocal microscopy. Expression levels of pro- and anti-apoptotic proteins were determined by a western blot technique. BTE-GNPs significantly enhanced the cytotoxic effect of DOX with its co-treatment in HCT116 cells. The cytotoxic effect of BTE-GNP + DOX was involved in apoptosis via a ROS-dependent pathway by enhancing the pro-apoptotic protein expression. Therefore, our results indicated that green gold nanoparticles of black tea extract (BTE-GNP) may be potent chemosensitizers of doxorubicin.

Green gold nanoparticles (GNPs) were prepared from black tea extract (BTE) and used to examine the chemosensitivity of doxorubicin in colon cancer cell line HCT116.     

Changes in the antioxidant defense and hepatic drug metabolizing enzyme and isoenzyme levels, 8-hydroxydeoxyguanosine formation and expressions of c-raf.1 and insulin-like growth factor II genes during the stages of development of hepatocellular carcinoma in rats.

This is an extensive study in a defined initiation-promotion hepatocellular carcinoma model of hepatocarcinogenesis (in rats) in which many important marker enzymes and isoenzymes and 8-hydroxydeoxyguanosine formation have been studied together with two very important cellular proliferating genes, insulin-like growth factor II and c-raf.1, known for their role in hepatocellular cancer development. Experiments were carried out on hepatic tissues of male Sprague-Dawley rats. Variations in different enzyme/isoenzyme activities/contents/expression pattern and 8-hydroxydeoxyguanosine-positive cells were studied. Insulin-like growth factor II and c-raf.1 gene expressions were monitored. A direct shift with increase in size and numbers of lesions was found to occur in different experimental groups. In this study, glutathione peroxidase (1.14 and 1.46-fold) and reduced triphosphopyridine nucleotide (TPNH)-cytochrome-c-reductase (1.94 and 2.94-fold) activities, cytochrome b5 (1.57 and 3.28-fold) and P-450 contents (1.45 and 1.22-fold), glutathione content (1.27 and 1.45-fold) and superoxide dismutase and catalase (1.16 and 1.39-fold) activities in group A animals were found to be lower than those in initiation and promotion studies, respectively. 8-Hydroxydeoxyguanosine-positive nuclei count showed that oxidative damage of nuclear DNA enhanced with the progress of the disease. The insulin-like growth factor II expression was found to be predominant in hepatocellular carcinoma and in early preneoplastic lesions. Unlike insulin-like growth factor II, c-raf.1 expression was located in the late basophilic lesions associated with hepatocellular carcinoma. During the various stages of the development of hepatocellular carcinoma, the enzymes played a significant role in metabolizing carcinogens and thereby scavenging various toxic metabolites or free radicals produced. A sequence of cellular changes starting from the appearance of glycogen storage foci to basophilic foci leading to hepatocellular carcinoma via mixed cell foci varied the activity/content or expression pattern of the enzymes and isoenzymes and in 8-hydroxydeoxyguanosine formation. It has been established that c-raf.1-induced signaling pathways activated by insulin-like growth factor II is implicated in the late stage of development of cancer.     

HRQoL in HIV-infected children using PedsQL™ 4.0 and comparison with uninfected children

Purpose  

To assess the reliability and validity of Pediatric Quality of Life Inventory 4.0 (PedsQL^TM 4.0) in children living with HIV. Also to determine the association of HIV infection, treatment regimens, and type of care received on quality of life (QoL) in pediatric patients.     

Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer

Purpose

Prostate-specific membrane antigen (PSMA) is highly up-regulated in prostate tumor cells, providing an ideal target for imaging applications of prostate cancer. CTT-1297 (IC₅₀?=?27 nM) is an irreversible phosphoramidate inhibitor of PSMA that has been conjugated to the CB-TE1K1P chelator for incorporation of Cu-64. The resulting positron emission tomography (PET) agent, [⁶⁴Cu]ABN-1, was evaluated for selective uptake both in vitro and in vivo in PSMA-positive cells of varying expression levels. The focus of this study was to assess the ability of [⁶⁴Cu]ABN-1 to detect and distinguish varying levels of PSMA in a panel of prostate tumor-bearing mouse models.

Procedures

CTT-1297 was conjugated to the CB-TE1K1P chelator using click chemistry and radiolabeled with Cu-64. Internalization and binding affinity of [⁶⁴Cu]ABN-1 was evaluated in the following cell lines having varying levels of PSMA expression: LNCaP late-passage?>?LNCaP early passage?≈?C4-2B?>?CWR22rv1 and PSMA-negative PC-3 cells. PET/X-ray computed tomography imaging was performed in NCr nude mice with subcutaneous tumors of the variant PSMA-expressing cell lines.

Results

[⁶⁴Cu]ABN-1 demonstrated excellent uptake in PSMA-positive cells in vitro, with ～80 % internalization at 4 h for each PSMA-positive cell line with uptake (fmol/mg) correlating to PSMA expression levels. The imaging data indicated significant tumor uptake in all models. The biodistribution for late-passage LNCaP (highest PSMA expression) demonstrated the highest specific uptake of [⁶⁴Cu]ABN-1 with tumor-to-muscle and tumor-to-blood ratios of 30?±?11 and 21?±?7, respectively, at 24 h post-injection. [⁶⁴Cu]ABN-1 cleared through all tissues except for PSMA-positive kidneys.

Conclusion

[⁶⁴Cu]ABN-1 demonstrated selective uptake in PSMA-positive cells and tumors, which correlated to the level of PSMA expression. The data reported herein suggest that [⁶⁴Cu]ABN-1 will selectively target and image variant PSMA expression and in the future will serve as a non-invasive method to follow the progression of prostate cancer in men.