A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

Medium-term outcomes in single anaesthetic bilateral total knee replacement surgery: a single surgeon series.

BACKGROUND: The lifetime risk of developing symptomatic knee osteoarthritis (OA) is estimated to be 45%, with up to two thirds of patients presenting with bilateral knee symptoms. Patients presenting with end stage bilateral knee OA may benefit from single anaesthetic bilateral total knee replacement (SABTKR). Our study aim was to compare the outcomes of SABTKR with unilateral total knee arthroplasty (TKA) in a single surgeon series over a 20 year period. METHODS: We performed a retrospective review of a single surgeon's data from the New Zealand Joint Registry (NZJR) over a 20-year period from January 1999 to December 2018. This review reports on patient demographics, functional outcomes, revision rates and mortality rates. RESULTS: 1225 total knee replacements were performed by the senior author (995 TKAs and 115 patients underwent SABTKRs) over the 20 year period reviewed. The mean ages of the TKA and SABTKR groups were 67.7 and 66.7 years, respectively. There was 16.9% mortality rate for the TKA group versus 7.8% in SABTKR group. There were no revisions in the SABTKR group versus 17 revisions in the TKA group representing a revision rate of 0.23/100 component years which can be viewed against a 20 year revision rate of 0.48/100 component years (p < 0.05) for all comers in the NZJR. CONCLUSION: This NZJR study demonstrates excellent medium term survival outcomes for selected patients having simultaneous bilateral total knee replacements.

Sex-related differences in response to zinc pyrithione shampoo vs. non-anti-dandruff shampoo.

OBJECTIVE: Sex-related differences in skin properties may be expected to impact dandruff formation and treatment. A meta-analysis approach was undertaken to investigate potential differences between males and females in response to zinc pyrithione (ZnPT) treatment vs. non-anti-dandruff (AD) shampoo. A separate pooled statistical analysis of ceramide and total protein loss endpoints was also undertaken to assess potential sex-related differences in stratum corneum properties that might influence response to ZnPT vs. non-AD shampoo in subjects with dandruff. METHODS: The meta-analysis approach included data from 17 half-head, double-blind, randomized studies (N = 2088) undertaken in Asia to assess the effectiveness of 1% ZnPT shampoo and/or non-AD shampoo in reducing dandruff severity, as assessed by Total Weighted Head Score Adherent Flake (TWHS-AF) methodology. Treatment duration was 4 weeks, with TWHS-AF measured at weekly intervals. Data from an additional three studies (N = 143) conducted in Asia were included in the pooled analysis of ceramide levels and protein loss from scalp skin of subjects with dandruff. RESULTS: Response to 1% ZnPT vs. non-AD shampoo was greater in males than in females at all time points; after 4 weeks, the between-treatment difference in TWHS-AF was -17.5 (95% confidence interval [CI] -19.5, -15.5) in males and -11.1 (-13.2, -8.9) in females. Sex-related differences were observed between males and females in response to both 1% ZnPT and non-AD shampoos. Males had a stronger response than females to treatment with 1% ZnPT shampoo, while dandruff decreased to a greater extent in females than in males when using non-AD shampoo. Statistically significant sex-related differences in ceramide levels and total protein loss were observed (both P < 0.01). Ceramide levels were 0.76 times lower (95% CI 0.60, 0.97) in males than in females, while total protein loss was 1.4 times greater (95% CI 1.1, 1.9) in males than in females. CONCLUSION: Males show a greater response than females to 1% ZnPT shampoo, while females show a greater response than males to non-AD shampoo. These findings may in part be explained by the sex-related differences observed in stratum corneum properties, which may make males more prone to dandruff than females.

Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018.

The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to midportion Achilles tendinopathy. J Orthop Sports Phys Ther 2018;48(5):A1-A38. doi:10.2519/jospt.2018.0302.

Understanding the dandruff scalp before and after treatment: an in vivo Raman spectroscopic study.

OBJECTIVES: To study and characterize the stratum corneum (SC) of dandruff scalp using in vivo Raman spectroscopy, to study how it compares with the non-dandruff scalp and to see the effect of treatment with a zinc pyrithione (ZnPTO)-based anti-dandruff shampoo. METHODS: The scalp skin was measured using a recently developed in vivo Raman probe. This method allows the inherent molecular components of the SC to be measured in vivo and confocally with depth, in particular the levels of natural moisturizing factors (NMF), lipids, lactic acid, urea and water. RESULTS: Depth-profile data for the skin components in dandruff SC in vivo are shown for the first time. The dandruff SC has lower NMF than the non-dandruff SC (0.16 compared with 0.39 a.u.), lower hydration, elevated levels of urea and lower levels of lactic acid. Treatment with an anti-dandruff shampoo containing 1% ZnPTO substantially restores the levels of each of these components close to the non-dandruff levels. Further to this, it is shown that sebum penetrates deeper into dandruff SC and at higher levels compared with non-dandruff SC. The levels of sebum localized within the SC are also brought closer to those of the non-dandruff condition after ZnPTO treatment. CONCLUSION: The in vivo Raman probe has allowed the direct measurement of dandruff-affected skin in situ for the first time. It has been shown that the dandruff SC is different from that of the non-dandruff scalp and that it is changed by treatment with shampoo containing ZnPTO and brought towards the characteristics of non-dandruff scalp. It offers novel insights into how the nature of a healthy scalp should be defined.

Restricted hip mobility: clinical suggestions for self-mobilization and muscle re-education.

UNLABELLED: Restricted hip mobility has shown strong correlation with various pathologies of the hip, lumbar spine and lower extremity. Restricted mobility can consequently have deleterious effects not only at the involved joint but throughout the entire kinetic chain. Promising findings are suggesting benefit with skilled joint mobilization intervention for clients with various hip pathologies. Supervised home program intervention, while lacking specifically for the hip joint, are demonstrating promising results in other regions of the body. Application of an accompanying home program for the purpose of complementing skilled, in clinic intervention is advisable for those clients that respond favorably to such methodology. LEVEL OF EVIDENCE: 5.

Core stabilization exercise prescription, part I: current concepts in assessment and intervention.

CONTEXT: Injury to the low back can cause significant pain and dysfunction, which can affect an athlete's performance and result in time lost from sport. A common conservative treatment is therapeutic core stabilization exercises, which can address pain and musculoskeletal dysfunction in patients with low back pathology. EVIDENCE ACQUISITION: MEDLINE and CINAHL were searched (from 1966 to March 2013) to identify relevant research. Keywords and keyword combinations searched included motor control exercise, segmental stabilization, core stabilization, transversus abdominis, multifidi, and low back pain. RESULTS: There are 2 popular rehabilitation strategies to assess core function and promote core stabilization. Each has been developed based on biomechanical models of lumbar segmental stability and observed motor control dysfunction in patients with low back pain. CONCLUSION: Controversy exists among clinical and research groups as to the optimal strategy for an athlete with low back pain.

Core stabilization exercise prescription, part 2: a systematic review of motor control and general (global) exercise rehabilitation approaches for patients with low back pain.

CONTEXT: Therapeutic exercises are frequently prescribed to patients with low back pain. Numerous exercise programs for patients with low back pain have been described. Many of these treatment programs are based on 1 of 2 popular rehabilitation strategies: a motor control exercise approach or a general exercise approach. DATA SOURCES: PubMed clinical queries from 1966 to March 2013 for keyword combinations including motor control exercise, core stability exercise, therapeutic exercise, general exercise, global exercise, local exercise, transversus abdominis, segmental stabilization, and low back pain. STUDY SELECTION: Randomized controlled trials that assessed the effects of a motor control exercise approach, a general exercise approach, or both for patients with low back pain that were published in scientific peer-reviewed journals. DATA EXTRACTION: Included studies underwent appraisal for exercise intervention and outcomes. RESULTS: Fifteen studies were identified (8, motor control exercise approach without general exercise comparison; 7, general exercise approach with or without motor control exercise approach comparison). Current evidence suggests that exercise interventions may be effective at reducing pain or disability in patients with low back pain. CONCLUSION: Stabilization exercises for patients with low back pain may help to decrease pain and disability. It may not be necessary to prescribe exercises purported to restore motor control of specific muscles.

Enhanced efficacy and sensory properties of an anti-dandruff shampoo containing zinc pyrithione and climbazole.

Dandruff is a common complaint and is suffered by as much as half of the population at some time post puberty. The condition is characterized by the presence of flakes on the scalp and in the hair, and is often accompanied by itch. The most common treatment for dandruff is the use of shampoo formulations that contain fungistatic agents such as zinc pyrithione (ZPT) and octopirox. Whilst most antidandruff shampoos are effective in resolving the symptoms of dandruff these shampoos can often result in hair condition that is less than acceptable to consumers which can lead to a tendency for them to revert to use of a non-antidandruff shampoo. This can result in a rapid return of dandruff symptoms. The aim of this investigation was to study the impact of using a combination of antidandruff actives and silicones on the resolution of dandruff and to deliver superior sensory properties to the hair. We have demonstrated that shampoo containing the dual active system of ZPT/Climbazole deposits both active agents onto a model skin surface (VitroSkin) and reduces Malassezia furfur regrowth in vitro. Clinical evaluation of the dual active shampoo demonstrated superior efficacy and retained superiority during a regression phase where all subjects reverted to using a non-antidandruff shampoo. We have also demonstrated that it is possible to deposit silicone materials from antidandruff shampoo uniformly over both virgin and damaged hair fibres that results in smoother hair fibres (as evidenced by reduced dry friction). This combination of antidandruff agents and conditioning silicones delivered from a shampoo provides subjects with superior antidandruff efficacy and desired end sensory benefits ensuring compliance and longer term dandruff removal.

Coexistence of narcolepsy and Alzheimer's disease.

A recent publication suggested that hypocretin (Hcrt, orexin) may mediate the neuropathological process leading to Alzheimer's disease (AD) and that antagonism of hypocretin receptors decreases this process. Narcoleptics have an approximately 90% loss of Hcrt neurons and commensurate reductions in the levels of Hcrt in their cerebrospinal fluid beginning at disease onset, usually before the age of 30. If Hcrt mediates the disease process, narcoleptics should be protected against AD. We examined the postmortem neuropathology and clinical records of 12 sequentially encountered cases of human narcolepsy. We found that AD was present in 4 of these narcoleptics, a prevalence that is similar to that of the general population.

Cardiac arrest in pregnancy and perimortem cesarean delivery: case report and discussion.

Cardiac arrest in pregnancy is a rare occurrence, particularly in the emergency department setting. The resuscitation of a pregnant patient in cardiac arrest is unique in a number of ways. Early identification and treatment of possible etiologies, appropriate response to the physiologic changes present in pregnancy, relief of potential vena cava obstruction by the gravid uterus, and expeditious preparation for possible cesarean delivery are important considerations for a successful resuscitation. We report and discuss the case of a pregnant patient with pulmonary edema and cardiac dysfunction who presented with severe hypoxemia and subsequent cardiac arrest and underwent a perimortem cesarean delivery and simultaneous fetal and maternal resuscitation in the emergency department.

CD23/FcεRII: molecular multi-tasking.

CD23 is the low-affinity receptor for immunoglobulin (Ig)E and plays important roles in the regulation of IgE responses. CD23 can be cleaved from cell surfaces to yield a range of soluble CD23 (sCD23) proteins that have pleiotropic cytokine-like activities. The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure-function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets.

The Morscher Press Fit acetabular component: a nine- to 13-year review.

We reviewed the results at nine to 13 years of 125 total hip replacements in 113 patients using the monoblock uncemented Morscher press-fit acetabular component. The mean age at the time of operation was 56.9 years (36 to 74). The mean clinical follow-up was 11 years (9.7 to 13.5) and the mean radiological follow-up was 9.4 years (7.7 to 13.1). Three hips were revised, one immediately for instability, one for excessive wear and one for deep infection. No revisions were required for aseptic loosening. A total of eight hips (7.0%) had osteolytic lesions greater than 1 cm, in four around the acetabular component (3.5%). One required bone grafting behind a well-fixed implant. The mean wear rate was 0.11 mm/year (0.06 to 0.78) and was significantly higher in components with a steeper abduction angle. Kaplan-Meier survival curves at 13 years showed survival of 96.8% (95% confidence interval 90.2 to 99.0) for revision for any cause and of 95.7% (95% confidence interval 88.6 to 98.4) for any acetabular re-operation.

Preliminary images from an adaptive imaging system.

I-ImaS (Intelligent Imaging Sensors) is a European project aiming to produce real-time adaptive X-ray imaging systems using Monolithic Active Pixel Sensors (MAPS) to create images with maximum diagnostic information within given dose constraints. Initial systems concentrate on mammography and cephalography. In our system, the exposure in each image region is optimised and the beam intensity is a function of tissue thickness and attenuation, and also of local physical and statistical parameters in the image. Using a linear array of detectors, the system will perform on-line analysis of the image during the scan, followed by optimisation of the X-ray intensity to obtain the maximum diagnostic information from the region of interest while minimising exposure of diagnostically less important regions. This paper presents preliminary images obtained with a small area CMOS detector developed for this application. Wedge systems were used to modulate the beam intensity during breast and dental imaging using suitable X-ray spectra. The sensitive imaging area of the sensor is 512 x 32 pixels 32 x 32 microm(2) in size. The sensors' X-ray sensitivity was increased by coupling to a structured CsI(Tl) scintillator. In order to develop the I-ImaS prototype, the on-line data analysis and data acquisition control are based on custom-developed electronics using multiple FPGAs. Images of both breast tissues and jaw samples were acquired and different exposure optimisation algorithms applied. Results are very promising since the average dose has been reduced to around 60% of the dose delivered by conventional imaging systems without decrease in the visibility of details.

Membrane traffic in cytokinesis.

A crucial facet of mammalian cell division is the separation of two daughter cells by a process known as cytokinesis. An early event in cytokinesis is the formation of an actomyosis contractile ring, which functions like a purse string in the constriction of the forming furrow between the cells. Far less well characterized are the membrane-trafficking steps which deliver new membrane to the cell surface during the plasma membrane expansion known to accompany furrow formation. It is now clearly established that the plasma membrane at the cleavage furrow of mammalian cells has a distinct lipid and protein composition from the rest of the plasma membrane. This may reflect a requirement for both increased surface area during furrowing and for the co-ordinated delivery of intracellular signalling or membrane re-modelling activities to the correct spatial coordinates during cleavage. In this review, we discuss recent work within the area of membrane traffic and cytokinesis.

Contrast harmonic ultrasound of spontaneous liver nodules in 32 dogs.

Thirty-two dogs with spontaneous hepatic nodules were given intravenous ultrasound contrast medium (Definity or Sonovue) and imaged with contrast harmonic software on a conventional ultrasound machine system. Digital video images were initially reviewed to describe the perfusion pattern of malignant nodules. The images were reviewed again to test this pattern against all individual nodules. Subjectively, there was improved conspicuity of malignant nodules after contrast enhancement compared with conventional imaging and increased numbers of malignant nodules were often noted. There was decreased conspicuity of benign nodules and no additional nodules were seen after contrast enhancement. There was a highly significant (P < 0.0001) association of malignancy with a hypoechoic nodule at surrounding normal liver peak contrast enhancement. Benign nodules were isoechoic to the surrounding normal liver at peak contrast enhancement. Only one benign nodule (hepatoma) had regions of hypoechogenicity compared with the surrounding normal liver at peak liver contrast enhancement. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were highly significant (P < 0.0001) (100%, 94.1%, 93.8%, 100%, and 96.9%, respectively). No complications or morbidity was noted throughout the course of the study. Contrast harmonic ultrasound appears to be accurate at discriminating between naturally occurring benign and malignant nodules in the liver of dogs.

Effect of toothpaste with natural calcium carbonate/perlite on extrinsic tooth stain.

OBJECTIVE: The current study was designed to determine the effect of natural calcium carbonate toothpaste containing Perlite and microgranules (Whitening toothpaste) on extrinsic tooth stain compared to a standard commercial toothpaste formulation with precipitated calcium carbonate (PCC) as abrasive and a commercial toothpaste with dicalcium phosphate dihydrate (DCPD) as abrasive. METHODS: The toothpastes were evaluated in a double blind, three-cell, stratified (tobacco use; baseline tooth stain level), parallel group design study involving 600 subjects with extrinsic tooth stain. Subjects brushed twice daily with their allocated toothpaste for four weeks. Extrinsic tooth stain was measured using the Macpherson modification of the Lobene stain index. RESULTS: ANCOVA showed significant differences between toothpastes (p=0.037). Subsequent multiple comparisons using pairwise t-tests, showed the Whitening toothpaste to be superior to the DCPD toothpaste (p=0.014) and the PCC toothpaste (p=0.067). When a Box-Cox transformation was made to the data (y0.6) to improve normality, these two differences were more accurately estimated at p=0.004 and p=0.03 respectively. CONCLUSION: The Whitening toothpaste has been shown to be significantly more effective in tooth stain removal than the two standard commercial toothpaste formulations.

Second primary oesophageal cancer following radiation for breast cancer.

The management of 12 women who presented with a second primary oesophageal cancer following radiotherapy for breast cancer was reviewed. It was concluded that nine cases fitted the classical description of a radiation-induced malignancy. Most cases were successfully managed with combined modality therapy in spite of their previous radiotherapy.

An abbreviated caries clinical trial design validated over 24 months.

Conventional caries trials last from 24 to 36 months. This study evaluated whether the previously established difference in efficacy between 1000- and 2500-ppm-fluoride dentifrices could be detected after 12 months. Caries was assessed by clinical visual assessment (CVA-simplified version of Dundee Selectable Threshold Method - DSTM), bitewing radiography, and Fiber Optic Transillumination (FOTI). Changes in status for individual surfaces were classified by means of pre-prepared matrices as 0 (unchanged), +1 (initiation or progression), or -1 (regression) and summed for each subject to yield an event score. Mean group event scores were calculated for each product. DSTM at the D(1) [enamel and dentin] threshold showed significant inter-group differences in mean event scores (p < 0.003) and D(1)MFS increment (< 0.007) at 12 months; these were confirmed at 24 months by traditional increment analysis (CVA & FOTI at the D(3) (dentin only) threshold + radiography, p < 0.03). This study confirms the validity of an abbreviated trial protocol.