St. John’s wort and Kava in treating major depressive disorder with comorbid anxiety : a randomised double-blind placebo-controlled pilot trial

Objective - We report the first randomised controlled trial (RCT) using a combination of St. John’s wort (SJW) and Kava for the treatment of major depressive disorder (MDD) with comorbid anxiety. Methods - Twenty-eight adults with MDD and co-occurring anxiety were recruited for a double-blind RCT. After a placebo run-in of 2 weeks, the trial had a crossover design testing SJW and Kava against placebo over two controlled phases, each of 4 weeks. The primary analyses used intention-to-treat and completer analyses. Results - On both intention-to-treat ( p¼0.047) and completer analyses ( p¼0.003), SJW and Kava gave a significantly greater reduction in self-reported depression on the Beck Depression Inventory (BDI-II) over placebo in the first controlled phase. However, in the crossover phase, a replication of those effects in the delayed medication group did not occur. Nor were there significant effects on anxiety or quality of life. Conclusion - There was some evidence of antidepressant effects using SJW and Kava in a small sample with comorbid anxiety. Possible explanations for the absence of anxiolysis may include a potential interaction with SJW, the presence of depression, or an inadequate dose of Kava.

Biotribological assessment for artificial synovial joints : the role of boundary lubrication

Biotribology, the study of lubrication, wear and friction within the body, has become a topic of high importance in recent times as we continue to encounter debilitating diseases and trauma that destroy function of the joints. A highly successful surgical procedure to replace the joint with an artificial equivalent alleviates dysfunction and pain. However, the wear of the bearing surfaces in prosthetic joints is a significant clinical problem and more patients are surviving longer than the life expectancy of the joint replacement. Revision surgery is associated with increased morbidity and mortality and has a far less successful outcome than primary joint replacement. As such, it is essential to ensure that everything possible is done to limit the rate of revision surgery. Past experience indicates that the survival rate of the implant will be influenced by many parameters, of primary importance, the material properties of the implant, the composition of the synovial fluid and the method of lubrication. In prosthetic joints, effective boundary lubrication is known to take place. The interaction of the boundary lubricant and the bearing material is of utmost importance. The identity of the vital active ingredient within synovial fluid (SF) to which we owe the near frictionless performance of our articulating joints has been the quest of researchers for many years. Once identified, tribo tests can determine what materials and more importantly what surfaces this fraction of SF can function most optimally with. Surface-Active Phospholipids (SAPL) have been implicated as the body’s natural load bearing lubricant. Studies in this thesis are the first to fully characterise the adsorbed SAPL detected on the surface of retrieved prostheses and the first to verify the presence of SAPL on knee prostheses. Rinsings from the bearing surfaces of both hip and knee prostheses removed from revision operations were analysed using High Performance Liquid Chromatography (HPLC) to determine the presence and profile of SAPL. Several common prosthetic materials along with a novel biomaterial were investigated to determine their tribological interaction with various SAPLs. A pin-on-flat tribometer was used to make comparative friction measurements between the various tribo-pairs. A novel material, Pyrolytic Carbon (PyC) was screened as a potential candidate as a load bearing prosthetic material. Friction measurements were also performed on explanted prostheses. SAPL was detected on all retrieved implant bearing surfaces. As a result of the study eight different species of phosphatidylcholines were identified. The relative concentrations of each species were also determined indicating that the unsaturated species are dominant. Initial tribo tests employed a saturated phosphatidylcholine (SPC) and the subsequent tests adopted the addition of the newly identified major constituents of SAPL, unsaturated phosphatidylcholine (USPC), as the test lubricant. All tribo tests showed a dramatic reduction in friction when synthetic SAPL was used as the lubricant under boundary lubrication conditions. Some tribopairs showed more of an affinity to SAPL than others. PyC performed superior to the other prosthetic materials. Friction measurements with explanted prostheses verified the presence and performance of SAPL. SAPL, in particular phosphatidylcholine, plays an essential role in the lubrication of prosthetic joints. Of particular interest was the ability of SAPLs to reduce friction and ultimately wear of the bearing materials. The identification and knowledge of the lubricating constituents of SF is invaluable for not only the future development of artificial joints but also in developing effective cures for several disease processes where lubrication may play a role. The tribological interaction of the various tribo-pairs and SAPL is extremely favourable in the context of reducing friction at the bearing interface. PyC is highly recommended as a future candidate material for use in load bearing prosthetic joints considering its impressive tribological performance.

Silylation of layered double hydroxides via a calcination−rehydration route

Silylated layered double hydroxides (LDHs) were synthesized through a surfactant-free method involving an in situ condensation of silane with the surface hydroxyl group of LDHs during its reconstruction in carbonate solution. X-ray diffraction (XRD) patterns showed the silylation reaction occurred on the external surfaces of LDHs layers. The successful silylation was evidenced by 29Si cross-polarization magic-angle spinning nuclear magnetic resonance (29Si CP/MAS NMR) spectroscopy, attenuated total reflection Fourier transform infrared (ATR FTIR) spectroscopy, and infrared emission spectroscopy (IES). The ribbon shaped crystallites with a “rodlike” aggregation were observed through transmission electron microscopy (TEM) images. The aggregation was explained by the T2 and T3 types of linkage between adjacent silane molecules as indicated in the 29Si NMR spectrum. In addition, the silylated products show high thermal stability by maintained Si related bands even when the temperature was increased to 1000 °C as observed in IES spectra.

Modeling multivariate autoregressive conditional heteroskedasticity with the double smooth transition conditional correlation GARCH Model

In this paper, we propose a multivariate GARCH model with a time-varying conditional correlation structure. The new double smooth transition conditional correlation (DSTCC) GARCH model extends the smooth transition conditional correlation (STCC) GARCH model of Silvennoinen and Teräsvirta (2005) by including another variable according to which the correlations change smoothly between states of constant correlations. A Lagrange multiplier test is derived to test the constancy of correlations against the DSTCC-GARCH model, and another one to test for another transition in the STCC-GARCH framework. In addition, other specification tests, with the aim of aiding the model building procedure, are considered. Analytical expressions for the test statistics and the required derivatives are provided. Applying the model to the stock and bond futures data, we discover that the correlation pattern between them has dramatically changed around the turn of the century. The model is also applied to a selection of world stock indices, and we find evidence for an increasing degree of integration in the capital markets.

The doctrine of double effect

• The doctrine of double effect is an exception to the general rule that taking active steps that end life is unlawful. • The essence of the doctrine at common law is intention. • Hastening a patient’s death through palliative care will be lawful provided the primary intention is to relieve pain, and not cause death, even if that death is foreseen. • Some States have enacted legislative excuses that deal with the provision of palliative care. • These statutory excuses tend to be stricter than the common law as they impose other requirements in addition to having an appropriate intent, such as adherence to some level of recognised medical practice.

Repair and regeneration of osteochondral defects in the articular joints

People suffering from pain due to osteoarthritic or rheumatoidal changes in the joints are still waiting for a better treatment. Although some studies have achieved success in repairing small cartilage defects, there is no widely accepted method for complete repair of osteochondral defects. Also joint replacements have not yet succeeded in replacing of natural cartilage without complications. Therefore, there is room for a new medical approach, which outperforms currently used methods. The aim of this study is to show potential of using a tissue engineering approach for regeneration of osteochondral defects. The critical review of currently used methods for treatment of osteochondral defects is also provided. In this study, two kinds of hybrid scaffolds developed in Hutmacher's group have been analysed. The first biphasic scaffold consists of fibrin and PCL. The fibrin serves as a cartilage phase while the porous PCL scaffold acts as the subchondral phase. The second system comprises of PCL and PCL-TCP. The scaffolds were fabricated via fused deposition modeling which is a rapid prototyping system. Bone marrow-derived mesenchymal cells were isolated from New Zealand White rabbits, cultured in vitro and seeded into the scaffolds. Bone regenerations of the subchondral phases were quantified via micro CT analysis and the results demonstrated the potential of the porous PCL and PCL-TCP scaffolds in promoting bone healing. Fibrin was found to be lacking in this aspect as it degrades rapidly. On the other hand, the porous PCL scaffold degrades slowly hence it provides an effective mechanical support. This study shows that in the field of cartilage repair or replacement, tissue engineering may have big impact in the future. In vivo bone and cartilage engineering via combining a novel composite, biphasic scaffold technology with a MSC has been shown a high potential in the knee defect regeneration in the animal models. However, the clinical application of tissue engineering requires the future research work due to several problems, such as scaffold design, cellular delivery and implantation strategies.

Falls in Parkinson's disease : kinematic evidence for impaired head and trunk control

Changes in stride characteristics and gait rhythmicity characterize gait in Parkinson's disease and are widely believed to contribute to falls in this population. However, few studies have examined gait in PD patients who fall. This study reports on the complexities of walking in PD patients who reported falling during a 12-month follow-up. Forty-nine patients clinically diagnosed with idiopathic PD and 34 controls had their gait assessed using three-dimensional motion analysis. Of the PD patients, 32 (65%) reported at least one fall during the follow-up compared with 17 (50%) controls. The results showed that PD patients had increased stride timing variability, reduced arm swing and walked with a more stooped posture than controls. Additionally, PD fallers took shorter strides, walked slower, spent more time in double-support, had poorer gait stability ratios and did not project their center of mass as far forward of their base of support when compared with controls. These stride changes were accompanied by a reduced range of angular motion for the hip and knee joints. Relative to walking velocity, PD fallers had increased mediolateral head motion compared with PD nonfallers and controls. Therefore, head motion could exceed “normal” limits, if patients increased their walking speed to match healthy individuals. This could be a limiting factor for improving gait in PD and emphasizes the importance of clinically assessing gait to facilitate the early identification of PD patients with a higher risk of falling.

Double jeopardy : comorbid anxiety and depression in later life

Comorbid depression and anxiety in late life present challenges for geriatric mental health care providers. These challenges include identifying the often complex diagnostic presentations both clinically and in a research context. This potent comorbidity can be conceived as double jeopardy in older adults, further diminishing their quality of life. Geriatric health care providers need to understand psychiatric comorbidity of this type for accurate diagnosis and early referral to specialists, and to coordinate interdisciplinary care. Researchers in the field also need to recognize potential multiple impacts of comorbidities with respect to assessment and treatment domains. This article describes the prevalence of late-life depression and anxiety disorders and reviews studies on this comorbidity in older adults. Risk factors and protective factors for anxiety and depression in later life are reviewed, and information is provided about comparative symptoms, the selection of assessment tools, and challenges to the provision of interdisciplinary, evidence-based care.

Manipulating double-decker molecules at the liquid-solid interface

We have used a scanning tunneling microscope to manipulate heteroleptic phthalocyaninato, naphthalocyaninato, porphyrinato double-decker molecules at the liquid/solid interface between 1-phenyloctane solvent and graphite. We employed nano-grafting of phthalocyanines with eight octyl chains to place these molecules into a matrix of heteroleptic double-decker molecules; the overlayer structure is epitaxial on graphite. We have also used nano-grafting to place double-decker molecules in matrices of single-layer phthalocyanines with octyl chains. Rectangular scans with a scanning tunneling microscope at low bias voltage resulted in the removal of the adsorbed doubledecker molecular layer and substituted the double-decker molecules with bilayer-stacked phthalocyanines from phenyloctane solution. Single heteroleptic double-decker molecules with lutetium sandwiched between naphthalocyanine and octaethylporphyrin were decomposed with voltage pulses from the probe tip; the top octaethylporphyrin ligand was removed and the bottom naphthalocyanine ligand remained on the surface. A domain of decomposed molecules was formed within the double-decker molecular domain, and the boundary of the decomposed molecular domain self-cured to become rectangular. We demonstrated a molecular “sliding block puzzle” with cascades of double-decker molecules on the graphite surface.

Long term immunity to live attenuated Japanese encephalitis chimeric virus vaccine : randomized, double-blind, 5-year phase II study in healthy adults.

In a randomized, double-blind study, 202 healthy adults were randomized to receive a live, attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and placebo 28 days apart in a cross-over design. A subgroup of 98 volunteers received a JE-CV booster at month 6. Safety, immunogenicity, and persistence of antibodies to month 60 were evaluated. There were no unexpected adverse events (AEs) and the incidence of AEs between JE-CV and placebo were similar. There were three serious adverse events (SAE) and no deaths. A moderately severe case of acute viral illness commencing 39 days after placebo administration was the only SAE considered possibly related to immunization. 99% of vaccine recipients achieved a seroprotective antibody titer ≥ 10 to JE-CV 28 days following the single dose of JE-CV, and 97% were seroprotected at month 6. Kaplan Meier analysis showed that after a single dose of JE-CV, 87% of the participants who were seroprotected at month 6 were still protected at month 60. This rate was 96% among those who received a booster immunization at month 6. 95% of subjects developed a neutralizing titer ≥ 10 against at least three of the four strains of a panel of wild-type Japanese encephalitis virus (JEV) strains on day 28 after immunization. At month 60, that proportion was 65% for participants who received a single dose of JE-CV and 75% for the booster group. These results suggest that JE-CV is safe, well tolerated and that a single dose provides long-lasting immunity to wild-type strains

Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine : randomized double-blind phase II evaluation of safety and immunogenicity

A randomized, double-blind, study was conducted to evaluate the safety, tolerability and immunogenicity of a live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) co-administered with live attenuated yellow fever (YF) vaccine (YF-17D strain; Stamaril(®), Sanofi Pasteur) or administered successively. Participants (n = 108) were randomized to receive: YF followed by JE-CV 30 days later, JE followed by YF 30 days later, or the co-administration of JE and YF followed or preceded by placebo 30 days later or earlier. Placebo was used in a double-dummy fashion to ensure masking. Neutralizing antibody titers against JE-CV, YF-17D and selected wild-type JE virus strains was determined using a 50% serum-dilution plaque reduction neutralization test. Seroconversion was defined as the appearance of a neutralizing antibody titer above the assay cut-off post-immunization when not present pre-injection at day 0, or a least a four-fold rise in neutralizing antibody titer measured before the pre-injection day 0 and later post vaccination samples. There were no serious adverse events. Most adverse events (AEs) after JE vaccination were mild to moderate in intensity, and similar to those reported following YF vaccination. Seroconversion to JE-CV was 100% and 91% in the JE/YF and YF/JE sequential vaccination groups, respectively, compared with 96% in the co-administration group. All participants seroconverted to YF vaccine and retained neutralizing titers above the assay cut-off at month six. Neutralizing antibodies against JE vaccine were detected in 82-100% of participants at month six. These results suggest that both vaccines may be successfully co-administered simultaneously or 30 days apart.

Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair

Damage to genetic material represents a persistent and ubiquitous threat to genomic stability. Once DNA damage is detected, a multifaceted signaling network is activated that halts the cell cycle, initiates repair, and in some instances induces apoptotic cell death. In this article, we will review DNA damage surveillance networks, which maintain the stability of our genome, and discuss the efforts underway to identify chemotherapeutic compounds targeting the core components of DNA double-strand breaks (DSB) response pathway. The majority of tumor cells have defects in maintaining genomic stability owing to the loss of an appropriate response to DNA damage. New anticancer agents are exploiting this vulnerability of cancer cells to enhance therapeutic indexes, with limited normal tissue toxicity. Recently inhibitors of the checkpoint kinases Chk1 and Chk2 have been shown to sensitize tumor cells to DNA damaging agents. In addition, the treatment of BRCA1- or BRCA2-deficient tumor cells with poly(ADP-ribose) polymerase (PARP) inhibitors also leads to specific tumor killing. Due to the numerous roles of p53 in genomic stability and its defects in many human cancers, therapeutic agents that restore p53 activity in tumors are the subject of multiple clinical trials. In this article we highlight the proteins mentioned above and catalog several additional players in the DNA damage response pathway, including ATM, DNA-PK, and the MRN complex, which might be amenable to pharmacological interventions and lead to new approaches to sensitize cancer cells to radio- and chemotherapy. The challenge is how to identify those patients most receptive to these treatments.