Simultaneous progression of oxidative stress,angiogenesis, and cell proliferation in prostate carcinoma

ObjectivesTo understand the association between markers of oxidative stress, levels of vascular endothelial growth factor (VEGF), and cell proliferation index in relation to disease progression, clinical stage, and cytologic grade in pathophysiology of prostate carcinoma.Patients and methodsCase control study comprised of 40 prostate carcinoma patients along with 40 age- and sex-matched healthy subjects as controls. Levels of 8-hydroxy-2-deoxy guanosine, protein carbonyl, and malondialdehyde along with total antioxidant status were measured to study the oxidative stress status in the study subjects. Angiogenesis was evaluated by studying the VEGF level and cell proliferation index.ResultsThe levels of markers of oxidative stress along with VEGF and cell proliferation index were found to be significantly higher with significantly decreased levels of antioxidant activity in the study subjects in comparison with healthy controls. The results indicate oxidative stress, angiogenesis, and cell proliferation activity increase progressively with the increase in staging and progression of disease.ConclusionsOxidative stress parameters, angiogenesis, and cell proliferation activity point clearly that with the progression of oxidative stress there is a simultaneous progression of angiogenesis, regulation and control of endothelial cell proliferation in relation to disease progression, clinical stage, and cytologic grade in the pathophysiology of prostate carcinoma.     

Tumor necrosis factor-alpha (TNF-α)-induced optic neuropathy in rabbits

Abstract

Both in vitro and in vivo studies have implicated a role for tumor necrosis factor-alpha (TNFoc) in various demyelinating diseases/ including HIV-related encephalopathy. To investigate whether intravitreal TNFoc can induce optic nerve axonal damage in a rabbit eye model, fifteen rabbit eyes were initially injected with TNFoc (final concentrations: 2U, 20U, and 200U respectively) and studied at varying time intervals for up to 24 weeks post-injection, using light and electron microscopy. Control optic nerves (no injection or diluent injection only) had normal myelinated axons and glia; the myelinated regions, neural retina, retinal glia and vasculature of control retinas were normal. In TNFa-exposed optic nerves, intact, degenerating and demyelinated axons were interspersed. Astrogliosis was present, particularly from 8 weeks p.i. and was noted up to 24 weeks. Oligodendrocytes were not severely affected in TNFoc-exposed optic nerves> and activated macrophages or microglia were not obvious. Axonal degeneration was visible among the more superficial myelinated fibers in TNFoc-exposed retinas however the neural retina glia were unaffected. These observations suggest that the axonal degeneration induced in TNFoc- exposed rabbit optic nerves over a 24 week period was most likely related to direct effects of TNFoc on optic nerve axons, and not primarily due to anterograde degeneration from retinal lesions. In-so-far as neurological pathology in generaland optic nerve degeneration in particular; has been described in AIDS, and TNFoc levels may be elevated in this disease, it is of great clinical significance that TNFoc has the capacity to mediate neuronal or axonal injury. If so, strategies to block or inhibit TNFoc can be pursued for treatment for the neurological symptoms of AIDS. [Neurol Res 1996; 18: 176–184]     

Anterior cervical discectomy plus intervertebral polyetheretherketone cage fusion over three and four levels without plating is safe and effective long-term

Anterior cervical discectomy and fusion (ACDF) is an established treatment for single-level cervical spondylotic myelopathy and radiculopathy, yet its stand-alone use for multi-level disease of the subaxial cervical spine remains controversial. We report a prospectively studied case series of 30 patients receiving polyetheretherketone (PEEK) cage fusion over three and four cervical levels without anterior plating. Seven (23.3%) four-level procedures (all C3 to C7) were performed, the other 23 (76.7%) being three-level, with 19 (64.4%) at C4 to C7 and four (12.3%) at C3 to C6. Long-term follow-up of more than 2 years was available in 67% of patients. This cohort showed statistically significant improvements in visual analogue score for neck pain (p = 0.0006), arm pain (p = 0.0003) and Japanese Orthopaedic Association myelopathy score (p = 0.002). Fused segment heights increased by 0.6–1.1%. Adjacent segment disease requiring ACDF at C3–4 was seen in 6.7% of patients (one after trauma) at a mean follow-up of 62 months. Same segment recurrence requiring posterior decompression with instrumented fusion was found in 10% of patients at a mean follow-up of 49 months, only one of whom had radiological evidence of cage subsidence. The results suggest the procedure is safe and effective with potentially less morbidity than anterior plating, shorter inpatient stays than posterior approaches, acceptable same segment recurrence and lower than predicted adjacent segment disease rates.     

Phenotype of dent disease in a cohort of Indian children

Objective

To describe the clinical and genotypic features of Dent disease in children diagnosed at our center over a period of 10 years.

Design

Case series.

Setting

Pediatric Nephrology Clinic at a referral center in Northern India.

Methods

The medical records of patients with Dent disease diagnosed and followed up at this hospital from June 2005 to April 2015 were reviewed. The diagnosis of Dent disease was based on presence of all three of the following: (i) low molecular weight proteinuria, (ii) hypercalciuria and (iii) one of the following: nephrolithiasis, hematuria, hypophosphatemia or renal insufficiency, with or without mutation in CLCN5 or OCRL1 genes.

Results

The phenotype in 18 patients diagnosed with Dent disease during this period was characterized by early age at onset (median 1.8 y), and polyuria, polydipsia, salt craving, hypophosphatemic rickets and night blindness. Rickets was associated with severe deformities, fractures or loss of ambulation in six patients. Nephrocalcinosis was present in three patients, while none had nephrolithiasis. Generalized aminoaciduria was seen in 13 patients, two had glucosuria alone, and one had features of Fanconi syndrome. Over a median follow up of 2.7 years, one patient developed renal failure. Genetic testing (n=15) revealed 5 missense mutations and 3 nonsense mutations in CLCN5 in 13 patients. Five of these variations (p.Met504Lys, p.Trp58Cys, p.Leu729X, p.Glu527Gln and p.Gly57Arg) have not been reported outside the Indian subcontinent.

Conclusion

Our findings suggest a severe phenotype in a cohort of Indian patients with Dent disease.

     

Facilitators and barriers in implementing the Minimum Initial Services Package (MISP) for reproductive health in Nepal post-earthquake

Background

Following the Nepal earthquake in April 2015, UNFPA estimated that 1.4 million women of reproductive age were affected, with approximately 93,000 pregnant and 28,000 at risk of sexual violence. A set of priority reproductive health (RH) actions, the Minimum Initial Services Package (MISP), was initiated by government, international and local actors. The purpose of this study was to identify the facilitators and barriers affecting the implementation of priority RH services in two districts.

Methods

In September 2015, a mixed methods study design was used in Kathmandu and Sindhupalchowk districts to assess the implementation of the priority RH services five months post-earthquake. Data collection activities included 32 focus group discussions with male and female participants aged 18–49; 26 key informant interviews with RH, gender-based violence (GBV), and human immunodeficiency virus (HIV) experts; and 17 health facility assessments.

Results

The implementation of priority RH services was achieved in both districts. In Kathmandu implementation of emergency RH services started within days of the earthquake. Facilitating factors for successful implementation included disaster preparedness; leadership and commitment among national, international, and district level actors; resource mobilization; strong national level coordination; existing reproductive and child health services and community outreach programs; and supply chain management. Barriers included inadequate MISP training for RH coordinators and managers; weak communication between national and district level stakeholders; inadequate staffing; under-resourced and fewer facilities in rural areas; limited attention given to local GBV and HIV organizations; low availability of clinical management of rape services; and low awareness of GBV services and benefits of timely care.

Conclusion

Ensuring RH is included in emergency preparedness and immediate response efforts and is continued through the transition to comprehensive care is critical for national governments and humanitarian response agencies. The MISP for RH remains a critical component of response efforts, and the humanitarian community should consider these learnings in future emergency response.

     

Phenolic amides from <Emphasis Type="Italic">Tribulus terrestris</Emphasis> and their inhibitory effects on nitric oxide production in RAW 264.7 cells

A new phenolic amide, named cis-terrestriamide (7), together with ten known compounds (1–6, 8–11), were isolated from the methanolic extract of the fruits of Tribulus terrestris. The structure of 7 was elucidated on the basis of extensive analyses of 1D and 2D nuclear magnetic resonance spectroscopic and high resolution mass spectrometry data. Compounds 1, 2, 5, 6, 8, 9, and 11 exhibited inhibitory effects on the lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 cells, with IC₅₀ values of 18.7–49.4 μM.     

State insurance mandates and off‐label use of chemotherapy

Access to cancer drugs used off‐label is important to cancer patients but may drive up healthcare costs with little evidence of clinical benefit. We hypothesized that state health insurance mandates for private insurers to provide coverage for off‐label use of cancer drugs cause higher rates of off‐label use. We used Truven MarketScan data from 1999 to 2007 on utilization of 35 infused chemotherapy drugs in private health plans in the United States, covering the period when eight states implemented off‐label coverage laws. We studied trends in off‐label use of drugs, distinguishing between appropriate and inappropriate off‐label use according to drug compendia, and estimated difference‐in‐difference regressions of the effect of state laws on off‐label use. We estimate 41% of utilization was off‐label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in off‐label use over time. We also find no discernable effect of state laws mandating coverage of off‐label use of cancer drugs on utilization patterns under multiple empirical specifications. Our conclusion is that policymakers should consider shifting away from mandating coverage as a way to ensure access to drugs off‐label and towards incentivizing adherence to clinical practice guidelines to improve the quality and value of off‐label use.     

<Emphasis Type="Italic">αvβ</Emphasis>3 Integrin Receptor Targeting and Near-Infrared Imaging of Solid Tumors Using Surface-Modified Nanoliposomes

Purpose

Abundance of receptors on tumor vasculature presents a prominent target for theranostic applications. The alphavbeta3 integrin receptors expressed on vascular endothelial cells during angiogenesis were therefore considered targets for imaging. Non-invasive visualization of tumor growth and/or delivery systems can appreciate tumor localization and disposition kinetics of carriers, respectively. Herein, we report near-infrared fluorescence imaging (NIRFI) of solid tumors using targeted fluorescence nanoliposomes in vivo.

Methods

Fluorescence nanoliposomes surface modified with cRGD-peptide were injected into CD1 athymic (nu/nu) mice bearing C6 glioblastoma xenografts (300 mm³). At different time points, mice were subjected to NIRFI for visualization of tumor xenografts and nanocarrier tracing in vivo.

Results

NIRFI showed tumor localization of 1,1′-dioctadecyl-3,3,3′,3′-tetramethyl indotricarbocyanine iodide (DiR₁₈)-incorporated-targeted liposomes with maximum tumor-to-tissue occurring at 24-h post-liposome administration. Interaction of integrin receptors with targeted liposomes had contributed to an intense NIRF signal. Molecular studies showed an elevated expression of alphavbeta3 integrin receptors in tumor xenografts.

Conclusion

From the studies, it can be concluded that non-invasive localization of tumors and tracing of liposome carriers had been achieved using receptor targeting and NIRFI approaches.