Disease-related complications in patients with metastatic hormone-sensitive prostate cancer.

INTRODUCTION: Prostate-specific antigen-based screening for prostate cancer reportedly does not improve cancer-specific survival. However, there remain concerns about the increasing incidence of advanced disease at initial presentation. Here, we investigated the incidences and types of complications that occur during the course of disease in patients with metastatic hormone-sensitive prostate cancer (mHSPC). METHODS: This study included 100 consecutive patients who were diagnosed with mHSPC at five hospitals from January 2016 to August 2017. Analyses were conducted using patient data extracted from a prospectively collected database, along with information about complications and readmission obtained from electronic medical records. RESULTS: The median patient age was 74 years and the median serum prostate-specific antigen level at diagnosis was 202.5 ng/mL. Ninety-nine patients received androgen deprivation therapy; 17 of these patients also received chemotherapy. During a mean follow-up period of 32.9 months, 41 patients reported bone pain; of these patients, 21 developed pathologic fractures and eight had cord compression. Twenty-eight patients developed retention of urine; of these patients, 10 (36%) required surgery and 11 (39%) required long-term urethral catheter use. Among 15 patients who developed ureteral obstruction, four (27%) required ureteral stenting and four (27%) required long-term nephrostomy drainage. Other complications included anaemia (41%) and deep vein thrombosis (4%). Fifty-nine (59%) patients had ≥1 unplanned hospital admission during the course of disease; 16% of such patients had >5 episodes of readmission. CONCLUSION: Among patients with mHSPC, 70% experienced disease-related complications and unplanned hospital admissions, which substantially burdened both patients and the healthcare system.

Effect of remote ischemic conditioning on the immune-inflammatory profile in patients with traumatic hemorrhagic shock in a randomized controlled trial.

Resuscitation induced ischemia/reperfusion predisposes trauma patients to systemic inflammation and organ dysfunction. We investigated the effect of remote ischemic conditioning (RIC), a treatment shown to prevent ischemia/reperfusion injury in experimental models of hemorrhagic shock/resuscitation, on the systemic immune-inflammatory profile in trauma patients in a randomized trial. We conducted a prospective, single-centre, double-blind, randomized, controlled trial involving trauma patients sustaining blunt or penetrating trauma in hemorrhagic shock admitted to a Level 1 trauma centre. Patients were randomized to receive RIC (four cycles of 5-min pressure cuff inflation at 250 mmHg and deflation on the thigh) or a Sham intervention. The primary outcomes were neutrophil oxidative burst activity, cellular adhesion molecule expression, and plasma levels of myeloperoxidase, cytokines and chemokines in peripheral blood samples, drawn at admission (pre-intervention), 1 h, 3 h, and 24 h post-admission. Secondary outcomes included ventilator, ICU and hospital free days, incidence of nosocomial infections, 24 h and 28 day mortality. 50 eligible patients were randomized; of which 21 in the Sham group and 18 in the RIC group were included in the full analysis. No treatment effect was observed between Sham and RIC groups for neutrophil oxidative burst activity, adhesion molecule expression, and plasma levels of myeloperoxidase and cytokines. RIC prevented significant increases in Th2 chemokines TARC/CCL17 (P < 0.01) and MDC/CCL22 (P < 0.05) at 24 h post-intervention in comparison to the Sham group. Secondary clinical outcomes were not different between groups. No adverse events in relation to the RIC intervention were observed. Administration of RIC was safe and did not adversely affect clinical outcomes. While trauma itself modified several immunoregulatory markers, RIC failed to alter expression of the majority of markers. However, RIC may influence Th2 chemokine expression in the post resuscitation period. Further investigation into the immunomodulatory effects of RIC in traumatic injuries and their impact on clinical outcomes is warranted.ClinicalTrials.gov number: NCT02071290.

Outcomes of transperineal and transrectal ultrasound-guided prostate biopsy.

OBJECTIVE: To compare the clinical outcomes and pathological findings of transperineal ultrasound-guided prostate biopsy (TPUSPB) and transrectal ultrasound-guided prostate biopsy (TRUSPB) in a secondary referral hospital. METHODS: This was a retrospective study of 100 TPUSPBs and 100 TRUSPBs performed in our centre. Pre-biopsy patient parameters (eg, patient age, clinical staging, serum prostate-specific antigen [PSA] level, prostate size, and PSA density), as well as pathological results and 30-day complication and readmission rates, were retrieved from the patients' medical records and compared between the two groups. RESULTS: One hundred TPUSPBs performed from January 2018 to May 2018 and 100 TRUSPBs performed from January 2016 to April 2016 were included for analysis. Mean age did not significantly differ between the groups. The TPUSPB group had a higher mean PSA level, smaller prostate size, and higher PSA density, compared with the TRUSPB group. The overall prostate cancer detection rate was similar between the TPUSPB and TRUSPB groups (35% vs 25%, P=0.123). There were no significant differences between the groups in prostate cancer detection rates after stratification according to PSA density and clinical staging. With respect to complications, no patients developed fever in the TPUSPB group, while 4% of patients in the TRUSPB group had fever and required at least 1-week admission for intravenous antibiotic administration. CONCLUSION: For prostate biopsy, TPUSPB is safer, with no infection complications, and has similar prostate cancer detection rate compared with TRUSPB.

Validation of the Hong Kong Cantonese Version of World Health Organization Five Well-Being Index for People with Severe Mental Illness.

OBJECTIVE: The World Health Organization Five Well-Being Index (WHO-5) has been developed to measure psychological wellbeing. Translation and linguistic validation of the WHO-5 into a Cantonese version has been accomplished for local use but it is not yet validated in people with severe mental illness in Hong Kong. This study aimed to examine the applicability of WHO-5 in measuring the psychological wellbeing dimension of people with severe mental illness. A brief and easily administrated tool to measure psychological wellbeing of people with severe mental illness can be used to provide an outcome measure in research studies and clinical trials. METHODS: Subjects were randomly recruited from the Extended-Care Patient Intensive Treatment, Early Diversion and Rehabilitation Stepping-Stone Project (EXITERS) and the Rehabilitation Activity Centre (RAC) of Kwai Chung Hospital in Hong Kong. They were invited to complete the abbreviated version of Hong Kong Chinese World Health Organization Quality of Life (WHOQOL-BREF [HK]) and WHO-5 (Cantonese version) separately and concurrent validity was examined. RESULTS: A total of 84 subjects were recruited, 42 each from EXITERS and RAC. In all, 49 (58%) were male and 35 (42%) were female. The mean ± standard deviation age was 43.2 ± 9.7 years. Their mean duration of mental illness was 16.4 ± 10.5 years and the mean years of education was 10.17 ± 2.5 years, i.e. about junior secondary school level in Hong Kong. The internal consistency of the WHO-5 was satisfactory (0.86) and was comparable with previous reports. Regarding validity, 1-factor structure with an eigenvalue of 3.24 explained 64.8% of total variance of WHO-5 for people with severe mental illness. Concurrent validity was established with moderate correlation (0.41-0.51) between WHO-5 and 4 domains of the WHOQOL-BREF (HK). CONCLUSION: The WHO-5 (Cantonese version) is a reliable and valid tool to assess the psychological wellbeing of people with severe mental illness in Hong Kong. It can be used to monitor the effectiveness of psychological intervention aimed at improving the wellbeing of such patients.

Intracerebroventricular delivery of self-complementary adeno-associated virus serotype 9 to the adult rat brain.

Gene therapy for the central nervous system is poised to become a powerful treatment for numerous neurological disorders. Adeno-associated viral vectors based on serotype 9 (AAV9) have proven themselves to be strong candidates for delivering gene-based therapies throughout the brain and spinal cord when administered intravenously, intrathecally, intracisternally, and intracerebroventricularly (i.c.v.). Previous studies of i.c.v.-delivered self-complimentary AAV9 have been performed in neonatal mice with delivery of a single dose. However, before clinical trials can be considered, more information is required about the dose-response relationship for transduction efficiency in adult animals. In the current study, three doses of self-complementary AAV9 were administered to adult rats. High levels of transduction were observed in the hippocampus, cerebellum and cerebral cortex, and transduction increased with increasing dosage. Both neurons and astrocytes were transduced. There was no evidence of astrocytosis at the doses tested. Preliminary results from pigs receiving i.c.v. self-complementary AAV9 are also presented. The results of this study will serve to inform dosing studies in large animal models before clinical testing.

Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening.

STAT3 regulates a variety of genes involved with cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity. The purpose of this study was to apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90000 natural product and natural product-like compounds. The virtual screening campaign furnished 14 hit compounds, from which compound 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and with comparable potency to the well-known STAT3 inhibitor S3I-201. Furthermore, compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation. Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro. Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain. This study also validates the use of in silico techniques to identify inhibitors of protein-protein interactions, which are typically considered difficult to target with small molecules.

A cyclometallated iridium(III) complex as a c-myc G-quadruplex stabilizer and down-regulator of c-myc oncogene expression.

A new cyclometallated iridium(III) complex with the 2,2'-biquinoline N-donor ligand has been synthesized and characterized. The interaction and affinity of the complex towards c-myc G-quadruplex and duplex DNA have been investigated using UV/Vis spectroscopy and gel mobility shift assay. These studies revealed that complex 1 binds to c-myc G-quadruplexes (Pu22 and Pu27) with high affinity but does not interact with duplex DNA either by intercalation or groove binding. The ability of 1 to stabilize c-myc G-quadruplex DNA in vitro has also been examined through a PCR stop assay and a cell-based luciferase reporter assay. Complex 1 displays promising cytotoxic activity against the HeLa cell line with sub-micromolar potency.

PRAP1 is a novel executor of p53-dependent mechanisms in cell survival after DNA damage.

p53 has a crucial role in governing cellular mechanisms in response to a broad range of genotoxic stresses. During DNA damage, p53 can either promote cell survival by activating senescence or cell-cycle arrest and DNA repair to maintain genomic integrity for cell survival or direct cells to undergo apoptosis to eliminate extensively damaged cells. The ability of p53 to execute these two opposing cell fates depends on distinct signaling pathways downstream of p53. In this study, we showed that under DNA damage conditions induced by chemotherapeutic drugs, gamma irradiation and hydrogen peroxide, p53 upregulates a novel protein, proline-rich acidic protein 1 (PRAP1). We identified functional p53-response elements within intron 1 of PRAP1 gene and showed that these regions interact directly with p53 using ChIP assays, indicating that PRAP1 is a novel p53 target gene. The induction of PRAP1 expression by p53 may promote resistance of cancer cells to chemotherapeutic drugs such as 5-fluorouracil (5-FU), as knockdown of PRAP1 increases apoptosis in cancer cells after 5-FU treatment. PRAP1 appears to protect cells from apoptosis by inducing cell-cycle arrest, suggesting that the induction of PRAP1 expression by p53 in response to DNA-damaging agents contributes to cancer cell survival. Our findings provide a greater insight into the mechanisms underlying the pro-survival role of p53 in response to cytotoxic treatments.

Comparative in vitro cytotoxicity study on uncoated magnetic nanoparticles: effects on cell viability, cell morphology, and cellular uptake.

Magnetic iron oxide nanoparticles (MIONPs) must be biocompatible, and a thorough knowledge on their potential cytotoxicity is crucial for their biomedical applications. However, the detailed study about the effects of iron oxide nanoparticles on cell viability, cell morphology, and cellular uptake of different mammalian cells is still insufficient. In this paper, comparative cytotoxicity study of uncoated magnetite nanoparticles at different concentrations was performed on human cervical cancer cell line (HeLa) and immortalized normal human retinal pigment epithelial cell line (RPE). The size, structure, and magnetic behavior of the MIONPs were characterized using transmission electron microscopy (TEM), X-ray diffractometry (XRD), and vibrating sample magnetometry (VSM) respectively. After 24-hour incubation with the MIONPs, the cell viability was determined by live/dead assay, the cell morphology at high magnification was observed under scanning electron microscopy (SEM), and the cellular uptake of MIONPs was measured under TEM and verified by energy-dispersive X-ray spectroscopy (EDX) analysis. Our results indicate that the uncoated MIONPs at a high concentration (0.40 mg/ml) were toxic to both HeLa and RPE cells. However, the cytotoxicity of uncoated MIONPs at low concentrations was cell-type specific, and RPE cells were more susceptible to these MIONPs than HeLa cells. The effects of the MIONPs on cell morphology and the nanoparticles uptake also showed different features between these two cell lines. Hence cell type should be taken into consideration in the in vitro cytotoxicity study of uncoated MIONPs. Additionally, it should be noticed that the cell morphological changes and the uptake of nanoparticles can take place even though no toxic effect of these MIONPs at low concentrations was reflected in the traditional cell viability assay.

Automatic semantic annotation of real-world web images.

As the number of web images is increasing at a rapid rate, searching them semantically presents a significant challenge. Many raw images are constantly uploaded with little meaningful direct annotations of semantic content, limiting their search and discovery. In this paper, we present a semantic annotation technique based on the use of image parametric dimensions and metadata. Using decision trees and rule induction, we develop a rule-based approach to formulate explicit annotations for images fully automatically, so that by the use of our method, semantic query such as " sunset by the sea in autumn in New York" can be answered and indexed purely by machine. Our system is evaluated quantitatively using more than 100,000 web images. Experimental results indicate that this approach is able to deliver highly competent performance, attaining good recall and precision rates of sometimes over 80%. This approach enables a new degree of semantic richness to be automatically associated with images which previously can only be performed manually.

Photonic crystal light-emitting diodes fabricated by microsphere lithography.

Instead of using conventional electron lithography, a two-dimensional photonic crystal consisting of a hexagonal array of triangular air-holes was created on the surface of a GaN LED substrate using microsphere lithography. The microspheres self-assemble into a single-layered hexagonal-close-packed array acting as an etch mask. A significant enhancement in photoluminescence intensity was recorded from the PhC LED structure. A twofold increase in electroluminescence was observed from the PhC LED compared to an as-grown LED with identical geometry. Besides geometrical factors due to surface roughening, the dispersive nature of PhCs and diffractive properties of the PhC as a grating contribute to the enhancement of light extraction from the LED.

Polychromatic light-emitting diodes with a fluorescent nanosphere opal coating.

A hexagonally close-packed array consisting of fluorescent nanospheres was coated onto short-wavelength GaN light-emitting diodes to demonstrate polychromatic white light emission. The spherical particles self-assemble into ordered three-dimensional opal structures, performing the role of color conversion to generate a polychromatic spectrum with smooth and uniform emission patterns. Different ratios of green and orange-red fluorescent nanospheres were mixed and coated onto high-extraction-efficiency micro-LEDs. Four devices with different shades of white emission were demonstrated. Device A, with a high content of orange-red nanospheres, offers the highest CRI value of 80, whereas device C with a well-balanced ratio of green and orange-red nanospheres exhibits color characteristics closest to ideal white with CIE coordinate at (0.34, 0.34). At 20 mA driving current, the luminous efficacy of the devices A, B, C, and D are 40.5 lm W(-1), 57.7 lm W(-1), 63.1 lm W(-1), and 67.2 lm W(-1) respectively, while the correlated color temperatures (CCTs) of the corresponding devices are 3587, 4778, 5271, and 13 000 K.

Reversal of multidrug resistance in cancer cells by Rhizoma Alismatis extract.

Prolonged chemotherapy may lead to the selective proliferation of multidrug resistant (MDR) cancer cells. In MDR HepG2-DR and K562-DR cells that over-expressed P-glycoprotein (Pgp), the extract of the rhizomes of Alisma orientalis (Sam) Juzep. showed a synergistic growth inhibitory effect with cancer drugs that are Pgp substrates including actinomycin D, puromycin, paclitaxel, vinblastine and doxorubicin. At the same toxicity levels the herbal extract was more effective than verapamil, a standard Pgp inhibitor, in enhancing cellular doxorubicin accumulation and preventing the efflux of rhodamin-123 from the MDR cells. The extract restored the effect of vinblastine on the induction of G(2)/M arrest in MDR cells. Our data suggest that A. orientalis may contain components that are effective inhibitors of Pgp.

Management of spinal injury.

Spinal injury often affects young adults and results in debilitating neurological status, which in turn places a significant burden on society. This review article describes the current practice and controversies surrounding the management of spinal injury. General principles of pre-hospital management, resuscitation, medical treatment, surgical intervention and future advancement are reviewed.

A randomized controlled trial of surgery vs steroid injection for carpal tunnel syndrome.

BACKGROUND: Decompressive surgery and steroid injection are widely used forms of treatment for carpal tunnel syndrome (CTS) but there is no consensus on their effectiveness in comparison to each other. The authors evaluated the efficacy of surgery vs steroid injection in relieving symptoms in patients with CTS. METHODS: The authors conducted a randomized, single blind, controlled trial. Fifty patients with electrophysiologically confirmed idiopathic CTS were randomized and assigned to open carpal tunnel release (25 patients) or to a single injection of steroid (25 patients). Patients were followed up at 6 and 20 weeks. The primary outcome was symptom relief in terms of the Global Symptom Score (GSS), which rates symptoms on a scale of 0 (no symptoms) to 50 (most severe). Nerve conduction studies and grip strength measurements were used as secondary outcome assessments. RESULTS: At 20 weeks after randomization, patients who underwent surgery had greater symptomatic improvement than those who were injected. The mean improvement in GSS after 20 weeks was 24.2 (SD 11.0) in the surgery group vs 8.7 (SD 13.0) in the injection group (p < 0.001); surgical decompression also resulted in greater improvement in median nerve distal motor latencies and sensory nerve conduction velocity. Mean grip strength in the surgical group was reduced by 1.7 kg (SD 5.1) compared with a gain of 2.4 kg (SD 5.5) in the injection group. CONCLUSION: Compared with steroid injection, open carpal tunnel release resulted in better symptomatic and neurophysiologic outcome but not grip strength in patients with idiopathic carpal tunnel syndrome over a 20-week period.

Inhibition of histone deacetylase 2 increases apoptosis and p21Cip1/WAF1 expression, independent of histone deacetylase 1.

Histone deacetylases (HDACs) 1 and 2 share a high degree of homology and coexist within the same protein complexes. Despite their close association, each possesses unique functions. We show that the upregulation of HDAC2 in colorectal cancer occurred early at the polyp stage, was more robust and occurred more frequently than HDAC1. Similarly, while the expression of HDACs1 and 2 were increased in cervical dysplasia and invasive carcinoma, HDAC2 expression showed a clear demarcation of high-intensity staining at the transition region of dysplasia compared to HDAC1. Upon HDAC2 knockdown, cells displayed an increased number of cellular extensions reminiscent of cell differentiation. There was also an increase in apoptosis, associated with increased p21Cip1/WAF1 expression that was independent of p53. These results suggest that HDACs, especially HDAC2, are important enzymes involved in the early events of carcinogenesis, making them candidate markers for tumor progression and targets for cancer therapy.

Involvement of NF-kappaB and c-myc signaling pathways in the apoptosis of HL-60 cells induced by alkaloids of Tripterygium hypoglaucum (levl.) Hutch.

Tripterygium hypoglaucum (levl.) Hutch (Celastraceae) (THH) root is a Chinese medicinal herb commonly used for treating autoimmune diseases. In the present study, alkaloids of THH were prepared and their cytotoxicity against the HL-60 cell was investigated. THH-induced apoptosis was observed using flow cytometry, confocal fluorescence microscope, and DNA laddering and caspase assays. The molecular mechanism involved in the induction of HL-60 cell apoptosis by THH alkaloids was examined using cDNA microarrays containing 3000 human genes derived from a leukocyte cDNA library. Sixteen genes were identified to be differentially expressed in HL-60 cells upon THH treatment. Several genes related to the NF-kappaB signaling pathway and cell apoptosis (such as NFKBIB, PRG1 and B2M) were up-regulated. In addition, c-myc binding protein and apoptosis-related cysteine proteases caspase-3 and caspase-8 were also regulated. The changes in c-Myc RNA expression and c-myc protein level were further confirmed by RT-PCR and Western blot analysis. The results demonstrated that THH alkaloids induced apoptosis of HL-60 cells though c-myc and NF-kappaB signaling pathways.

LINAC radiosurgery in recurrent Cushing's disease after transsphenoidal surgery: a series of 5 cases.

INTRODUCTION: Oversecretion of ACTH from pituitary adenomas is associated with morbidity and reduced life expectancies. We hypothesized that radiosurgical treatment may provide effective tumour and hormonal control associated with minimal pituitary insufficiency. METHOD: Data of five patients who underwent LINAC radiosurgery for recurrent or residual Cushing's disease between 1999 and 2002 were prospectively collected. RESULT: Follow-up period ranged from 27 to 49 months (mean 38 months). All patients attained remission in 6-18 months (mean 8.4 months). One patient (20 %) developed biochemical recurrence 12 months after remission. One patient (20 %) developed hydrocortisone deficiency 24 months after radiosurgery. None of the patients had new visual field defect detected on follow-up. CONCLUSION: In this small case series, LINAC radiosurgery was shown to be an effective and safe treatment of persistent or recurrent Cushing's disease following transsphenoidal surgery. Long-term follow-up and larger patient series is recommended for further clarification.

Neurochemical changes in ventilated head-injured patients with cerebral perfusion pressure treatment failure.

The goal of intensive care management of patients with head injury is to provide them with a favourable physiological and metabolic environment for recovery of injury-compromised cells, and to prevent secondary brain insults. Clinical intracerebral microdialysis has enabled documentation of the metabolic derangement after head injury. Treatment targeted at this derangement has emphasized maintenance of optimal cerebral perfusion pressure (CPP). To determine the relationships between CPP and five clinically relevant intracerebral extracellular metabolites (glucose, lactate, glycerol, glutamate and pyruvate) in relation to different therapy intensities, 23 moderate to severe head-injury patients with hourly microdialysis samples were studied. These five metabolites were correlated with CPP and showed a biphasic relation at CPP of 65 to 67 mmHg, which was believed to be the critical CPP indicating irreversible brain damage. Relationship between intracerebral metabolites and CPP in relation to different therapy intensities was studied and suggests the critical CPP threshold in head-injured patients with high ICP and maximum therapy is elevated and should be maintained above 70 mmHg to prevent irreversible brain damage.