A comparative study of the proliferation and osteogenic differentiation of human periodontal ligament cells cultured on β-TCP ceramics and demineralized bone matrix with or without osteogenic inducers in vitro

The repair of bone defects that result from periodontal diseases remains a clinical challenge for periodontal therapy. β-tricalcium phosphate (β-TCP) ceramics are biodegradable inorganic bone substitutes with inorganic components that are similar to those of bone. Demineralized bone matrix (DBM) is an acid-extracted organic matrix derived from bone sources that consists of the collagen and matrix proteins of bone. A few studies have documented the effects of DBM on the proliferation and osteogenic differentiation of human periodontal ligament cells (hPDLCs). The aim of the present study was to investigate the effects of inorganic and organic elements of bone on the proliferation and osteogenic differentiation of hPDLCs using three-dimensional porous β-TCP ceramics and DBM with or without osteogenic inducers. Primary hPDLCs were isolated from human periodontal ligaments. The proliferation of the hPDLCs on the scaffolds in the growth culture medium was examined using a Cell‑Counting kit‑8 (CCK-8) and scanning electron microscopy (SEM). Alkaline phosphatase (ALP) activity and the osteogenic differentiation of the hPDLCs cultured on the β-TCP ceramics and DBM were examined in both the growth culture medium and osteogenic culture medium. Specific osteogenic differentiation markers were examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). SEM images revealed that the cells on the β-TCP were spindle-shaped and much more spread out compared with the cells on the DBM surfaces. There were no significant differences observed in cell proliferation between the β-TCP ceramics and the DBM scaffolds. Compared with the cells that were cultured on β-TCP ceramics, the ALP activity, as well as the Runx2 and osteocalcin (OCN) mRNA levels in the hPDLCs cultured on DBM were significantly enhanced both in the growth culture medium and the osteogenic culture medium. The organic elements of bone may exhibit greater osteogenic differentiation effects on hPDLCs than the inorganic elements.

Evolution to a chronic disease niche correlates with increased sensitivity to tryptophan availability for the obligate intracellular bacterium Chlamydia pneumoniae

The chlamydiae are obligate intracellular parasites that have evolved specific interactions with their various hosts and host cell types to ensure their successful survival and consequential pathogenesis. The species Chlamydia pneumoniae is ubiquitous, with serological studies showing that most humans are infected at some stage in their lifetime. While most human infections are asymptomatic, C. pneumoniae can cause more-severe respiratory disease and pneumonia and has been linked to chronic diseases such as asthma, atherosclerosis, and even Alzheimer's disease. The widely dispersed animal-adapted C. pneumoniae strains cause an equally wide range of diseases in their hosts. It is emerging that the ability of C. pneumoniae to survive inside its target cells, including evasion of the host's immune attack mechanisms, is linked to the acquisition of key metabolites. Tryptophan and arginine are key checkpoint compounds in this host-parasite battle. Interestingly, the animal strains of C. pneumoniae have a slightly larger genome, enabling them to cope better with metabolite restrictions. It therefore appears that as the evolutionarily more ancient animal strains have evolved to infect humans, they have selectively become more "susceptible" to the levels of key metabolites, such as tryptophan. While this might initially appear to be a weakness, it allows these human C. pneumoniae strains to exquisitely sense host immune attack and respond by rapidly reverting to a persistent phase. During persistence, they reduce their metabolic levels, halting progression of their developmental cycle, waiting until the hostile external conditions have passed before they reemerge.

A comparison of treatment options for management of end stage kidney disease in elderly patients : a systematic review

Background Chronic kidney disease is a global public health problem of increasing prevalence. There are five stages of kidney disease, with Stage 5 indicating end stage kidney disease (ESKD) requiring dialysis or death will eventually occur. Over the last two decades there have been increasing numbers of people commencing dialysis. A majority of this increase has occurred in the population of people who are 65 years and over. With the older population it is difficult to determine at times whether dialysis will provide any benefit over non-dialysis management. The poor prognosis for the population over 65 years raises issues around management of ESKD in this population. It is therefore important to review any research that has been undertaken in this area which compares outcomes of the older ESKD population who have commenced dialysis with those who have received non-dialysis management. Objective The primary objective was to assess the effect of dialysis compared with non-dialysis management for the population of 65 years and over with ESKD. Inclusion criteria Types of participants This review considered studies that included participants who were 65 years and older. These participants needed to have been diagnosed with ESKD for greater than three months and also be either receiving renal replacement therapy (RRT) (hemodialysis [HD] or peritoneal dialysis [PD]) or non-dialysis management. The settings for the studies included the home, self-care centre, satellite centre, hospital, hospice or nursing home. Types of intervention(s)/phenomena of interest This review considered studies where the intervention was RRT (HD or PD) for the participants with ESKD. There was no restriction on frequency of RRT or length of time the participant received RRT. The comparator was participants who were not undergoing RRT. Types of studies This review considered both experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, before and after studies, prospective and retrospective cohort studies, case control studies and analytical cross sectional studies. This review also considered descriptive epidemiological study designs including case series, individual case reports and descriptive cross sectional studies for inclusion. This review included any of the following primary and secondary outcome measures: •Primary outcome – survival measures •Secondary outcomes – functional performance score (e.g. Karnofsky Performance score) •Symptoms and severity of end stage kidney disease •Hospital admissions •Health related quality of life (e.g. KDQOL, SF36 and HRQOL) •Comorbidities (e.g. Charlson Comorbidity index).

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Self-management programs in stage 1-4 chronic kidney disease : a literature review.

Background Chronic kidney disease (CKD) is a complex health problem, which requires individuals to invest considerable time and energy in managing their health and adhering to multifaceted treatment regimens. Objectives To review studies delivering self-management interventions to people with CKD (Stages 1–4) and assess whether these interventions improve patient outcomes. Design: Systematic review. Methods Nine electronic databases (MedLine, CINAHL, EMBASE, ProQuest Health & Medical Complete, ProQuest Nursing & Allied Health, The Cochrane Library, The Joanna Briggs Institute EBP Database, Web of Science and PsycINFO) were searched using relevant terms for papers published between January 2003 and February 2013. Results The search strategy identified 2,051 papers, of which 34 were retrieved in full with only 5 studies involving 274 patients meeting the inclusion criteria. Three studies were randomised controlled trials, a variety of methods were used to measure outcomes, and four studies included a nurse on the self-management intervention team. There was little consistency in the delivery, intensity, duration and format of the self-management programmes. There is some evidence that knowledge- and health-related quality of life improved. Generally, small effects were observed for levels of adherence and progression of CKD according to physiologic measures. Conclusion The effectiveness of self-management programmes in CKD (Stages 1–4) cannot be conclusively ascertained, and further research is required. It is desirable that individuals with CKD are supported to effectively self-manage day-to-day aspects of their health.

Engineered microenvironments provide new insights into ovarian and prostate cancer progression and drug responses

Tissue engineering technologies, which have originally been designed to reconstitute damaged tissue structure and function, can mimic not only tissue regeneration processes but also cancer development and progression. Bioengineered approaches allow cell biologists to develop sophisticated experimentally and physiologically relevant cancer models to recapitulate the complexity of the disease seen in patients. Tissue engineering tools enable three-dimensionality based on the design of biomaterials and scaffolds that re-create the geometry, chemistry, function and signalling milieu of the native tumour microenvironment. Three-dimensional (3D) microenvironments, including cell-derived matrices, biomaterial-based cell culture models and integrated co-cultures with engineered stromal components, are powerful tools to study dynamic processes like proteolytic functions associated with cancer progression, metastasis and resistance to therapeutics. In this review, we discuss how biomimetic strategies can reproduce a humanised niche for human cancer cells, such as peritoneal or bone-like microenvironments, addressing specific aspects of ovarian and prostate cancer progression and therapy response.

Challenges in improving chronic disease survivorship outcomes using tele-health and self-managed online solutions

The advances in modern information and communication (ICT) technology continue to address the challenges and improve` health outcomes for the survivors of chronic disease such as prostate cancer. The management of survivorship is increasingly becoming an important need for the survivors to manage their chronic conditions. The technology interventions such as tele-health as well as self-managed technology applications have shown a potential to improve survivorship outcomes. However, the application of these tools should be supported by strong health economics evidence. This work discusses the challenges of technology led survivorship care models and presents an integrated approach to address these challenges.

Are bone-anchored prostheses about to revolutionise the world of prosthetics?

Individuals with limb amputation fitted with conventional socket-suspended prostheses often experience socket related discomfort leading to a significant decrease in quality of life. Most of these concerns can be overcome by surgical techniques enabling bone-anchored prostheses. In this case, the prosthesis is attached directly to the residual skeleton through a percutaneous implant. The primary aim of this study is to present the current advances in these surgical techniques worldwide with a strong focus on the developments in Australia. The secondary aim is to provide an overview of the possible critical changes that may occurred in the world of prosthetic following these developments in bone-anchored prostheses.

Epigenetics and migraine; complex mitochondrial interactions contributing to disease susceptibility

Migraine is a common neurological disorder classified by the World Health Organisation (WHO) as one of the top twenty most debilitating diseases in the developed world. Current therapies are only effective for a proportion of sufferers and new therapeutic targets are desperately needed to alleviate this burden. Recently the role of epigenetics in the development of many complex diseases including migraine has become an emerging topic. By understanding the importance of acetylation, methylation and other epigenetic modifications, it then follows that this modification process is a potential target to manipulate epigenetic status with the goal of treating disease. Bisulphite sequencing and methylated DNA immunoprecipitation have been used to demonstrate the presence of methylated cytosines in the human D-loop of mitochondrial DNA (mtDNA), proving that the mitochondrial genome is methylated. For the first time, it has been shown that there is a difference in mtDNA epigenetic status between healthy controls and those with disease, especially for neurodegenerative and age related conditions. Given co-morbidities with migraine and the suggestive link between mitochondrial dysfunction and the lowered threshold for triggering a migraine attack, mitochondrial methylation may be a new avenue to pursue. Creative thinking and new approaches are needed to solve complex problems and a systems biology approach, where multiple layers of information are integrated is becoming more important in complex disease modelling.

Obesity and hypertension have differing oxidant handling molecular pathways in age-related chronic kidney disease

Chronic kidney disease (CKD) in ageing is a burden on health systems worldwide. Rat models of age-related CKD linked with obesity and hypertension were used to investigate alterations in oxidant handling and energy metabolism to identify gene targets or markers for age-related CKD. Young adult (3 months) and old (21–24 months) spontaneously-hypertensive (SHR), normotensive Wistar-Kyoto (WKY) and Wistar rats (normotensive, obese in ageing) were compared for renal functional and physiological parameters, renal fibrosis and inflammation, oxidative stress (hemeoxygenase-1/HO-1), apoptosis and cell injury (including Bax:Bcl-2), phosphorylated and non-phosphorylated forms of oxidant and energy sensing proteins (p66Shc, AMPK), signal transduction proteins (ERK1/2, PKB), and transcription factors (NF-κB, FoxO1). All old rats were normoglycemic. Renal fibrosis, tubular epithelial apoptosis, interstitial macrophages and myofibroblasts (all p < 0.05), p66Shc/phospho-p66 (p < 0.05), Bax/Bcl-2 ratio (p < 0.05) and NF-κB expression (p < 0.01) were highest in old obese Wistars. Expression of phospho-FoxO/FoxO was elevated in old Wistars (p < 0.001) and WKYs (p < 0.01). SHRs had high levels in young and old rats. Expression of PKB, phospho-PKB, ERK1/2 and phospho-ERK1/2 were significantly elevated in all aged animals. These results suggest that obesity and hypertension have differing oxidant handling and signalling pathways that act in the pathogenesis of age-related CKD