Alpha galactosidase A activity in Parkinson's disease.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 µmol/l/h versus 3.12 µmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 µmol/l/h versus 3.10 µmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 µmol/l/h versus 3.10 µmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Canonical and cellular pathways timing gamete release in Acropora digitifera, Okinawa, Japan.

Natural light cycles are important for synchronizing behavioural and physiological rhythms over varying time periods in both plants and animals. An endogenous clock, regulated by positive and negative elements, interacting in feedback loops controls these rhythms. Many corals exhibit diel cycles of polyp expansion and contraction entrained by solar light patterns and monthly cycles of spawning or planulation that correspond to nocturnal lunar light cycles. However, despite considerable interest in studies of coral reproduction, there is currently not enough molecular information about the cellular pathways involved with synchronizing spawning/planulation in broadcast spawners and brooders. To determine whether the endogenous clock is implicated in the regulation of reproductive behaviour in corals, we characterized the transcriptome of Acropora digitifera colonies at twelve time points over a 2-month period of full and new moons, starting with the day of spawning in June 2014. We identified 608 transcripts with differential expression only on the spawning night during the coral setting phase and gamete release. Our data revealed an upregulation of light-sensing molecules and rhodopsin-like receptors that initiate signalling cascades, including the glutamate, SMAD signalling and WNT signalling pathways, neuroactive ligand-receptor interactions and calcium signalling. These are all involved in cell cycling, cell movement, tissue polarity, focal adhesion and cytoskeleton reorganization and together lead to gamete release. These findings can improve the understanding of many time-based cycles and extend our knowledge of the interplay between exogenous signals and the endogenous clock in cnidarians.

Critical peripheral ischemia precipitated by severe episode of Raynaud's phenomenon in a patient with aPL-positive systemic lupus erythematosus, upon high titer anti-RNP seroconversion.

A 35-year-old female with long standing aPL-positive lupus without history of thromboembolic events, who has developed critical peripheral ischemia (CPI) is described. An episode of severe Raynaud's phenomenon rapidly progressed to an extensive digit-threatening ischemia, involving bilateral hands and feet. She was successfully treated with corticosteroids, anticoagulation, iloprost, sildenafil, and nifedipine. Her serological studies were remarkable for the emergence of high titer anti-RNP seroconversion and an increase in aPL titer, suggesting that these autoantibodies played a role in the pathogenesis of CPI. It is important to note that such observation should herald this potentially devastating complication of systemic lupus erythematosus.

A novel long-acting glucose-dependent insulinotropic peptide analogue: enhanced efficacy in normal and diabetic rodents.

AIM: Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. METHODS: AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala(2) ]GIP(1-42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F ß-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu(14) ] exenatide. Human GIP or [d-Ala(2) ]GIP(1-42) were used for comparison. RESULTS: AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala(2) ]GIP(1-42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala(2) ]GIP(1-42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. CONCLUSIONS: These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.

Heterologous ("nonspecific") and sex-differential effects of vaccines: epidemiology, clinical trials, and emerging immunologic mechanisms.

A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated by mechanisms including innate immune memory (also known as "trained immunity") and cross-reacting lymphocytes. Herein we review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen, Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and alter the manner and sequence in which they are given.

Artificial light at night (ALAN) disrupts behavioural patterns of reef corals.

Increasing levels of Artificial Light At Night (ALAN) alter the natural diel cycles of organisms at global scale. ALAN constitutes a potential threat to the light-dependent functioning of symbiotic scleractinian corals, the habit-founders of warm, shallow water reefs. Here, we show that ALAN disrupts the natural diel tentacle expansion and contraction behaviour, a key mechanism for prey capture and nutrient acquisition in corals. We exposed four symbiotic scleractinian coral species to different ALAN treatments (0.4-2.5 µmol quanta m-2 s-1). Exposure to ALAN levels of 1.2 µmol quanta m-2 s-1 and above altered the normal tentacle expansion response in diurnal species (Stylophora pistillata and Duncanopsammia axifuga). The tentacle expansion pattern of nocturnal species (Montastraea cavernosa and Lobophyllia hemprichii) was less affected, which may indicate a greater capacity to tolerate ALAN exposure. The results of this work suggest that ALAN has the potential to affect nutrient acquisition mechanisms of symbiotic corals which may in turn result in changes in the coral community structure in shallow water reefs in ALAN-exposed areas.

Management of glenoid bone loss with impaction and structural bone grafting in reverse shoulder arthroplasty.

INTRODUCTION: Glenoid bone loss is a commonly encountered problem in complex primary and revision shoulder arthroplasty. Addressing glenoid bone loss is critical to avoid complications like early loosening, impingement, notching and instability. A large number of techniques like bone grafting using autograft or allograft, eccentric reaming, augmented base plates, patient-specific instrumentations and custom-made implants are available to tackle bone loss. MATERIALS AND METHODS: We prospectively collected the data of all patients with glenoid defects undergoing primary or revision reverse shoulder replacement between 2004 and 2017. This included demographic data, ranges of motion, Constant-Murley score and Subjective Shoulder Value (SSV). A pre-operative CT scan was done as well to plan the surgery and calculate the glenoid version. At each follow-up, the clinical function and shoulder scores were assessed. Additionally, the radiographs were assessed for graft incorporation, evidence of lysis and calculation of glenoid version. RESULTS: Between 2004 and 2017, 37 patients underwent glenoid bone grafting during reverse shoulder arthroplasty. Average age was 72 years (range 46-88). Indications for surgery were cuff tear arthropathy (6 patients); revision of failed other prosthesis (23); primary osteoarthritis (4); rheumatoid arthritis (3); and second-stage revision for infection (1). The glenoid defect was contained in 24 patients, and therefore, impaction graft with a combination of bone graft substitute and/or humeral head autograft was performed. In 13 patients the glenoid defect was severe and uncontainable and therefore a graft-implant composite glenoid was implanted using humeral head autograft or allograft. Average follow-up was 3.6 years (range 1-10). Mean Constant score improved from 34 before surgery to 63 after surgery. Mean SSV score improved from 0.9/10 to 8.3/10. Active movements improved significantly with forward elevation increasing from 54° to 123°; abduction from 48° to 123°; external rotation from 24° to 38°; internal rotation from 57° to 70°. Radiographs at final follow-up showed no radiolucencies around the glenoid component and no evidence of loosening of the implant. In 2 cases there was a grade I notching. There was 100% survivorship at the last follow-up. CONCLUSION: Impaction bone grafting along with structural grafting when required is an effective and reproducible way of managing severe glenoid bone loss. This technique gives consistent and good clinical and radiological results.

Prediction and hydrogen acceleration of ordering in iron-vanadium alloys.

Ab initio calculations of binary metallic systems often predict ordered compounds in contrast to empirical reports of solid solutions or disordered phases. These discrepancies are usually attributed to slow kinetics that retains metastable structures at low temperatures. The Fe-V system is an example of this phenomenon, in which we predict two ordered stable ground states, Fe3V and FeV3, whereas a disordered σ phase is reported. We propose to overcome this difficulty by hydrogen absorption, which facilitates metal atom mobility through vacancy formation and separation between the two elements due to their opposite affinities towards it, thus accelerating transformation kinetics. Hydrogen also increases the relative stability of the ordered structures compared with that of the σ phase without affecting the shape of the phase diagram. The hydrogen-induced formation of the ordered structures is expressed by a reversible decrease of the electrical resistivity with increasing hydrogen pressure. Such behavior has not been reported before in thin H absorbing films. Formation of the ordered structures is further substantiated by the kinetics of the resistivity changes upon variation of the hydrogen pressure, where two stages are distinguished: a fast initial stage and a much slower subsequent process in which the resistivity changes direction, associated with hydrogen dissolution and phase transformation, respectively.

Reverse shoulder replacement versus hemiarthroplasty for proximal humeral fracture in elderly patients: a systematic review.

This systematic review of the literature aims to analyse current knowledge to inform choice between hemiarthroplasty (HA) and reverse total shoulder arthroplasty (rTSA) for managing proximal humerus fractures (PHF) in elderly patients; the aim is to understand if rTSA can be considered the gold standard for treating PHF in the elderly when surgical fixation or conservative treatment is not viable options. Studies reporting outcomes and complications of PHF treated with shoulder arthroplasty in the elderly were included. Studies were in English and published after 2008. Evidence levels I, II, III and IV were included. According to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a comprehensive literature search was conducted using Medline, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and PubMed search engines, as well as the Cochrane Central Register of Controlled Trials. General data collected were study design, number of patients treated with HA and rTSA, age of patients (mean, mean and SD, mean and range), length of follow-up, type of implant, and clinical outcomes. rTSA can be regarded as the gold standard for surgical management of displaced 3 and 4-part fractures in the elderly. However, the literature offers mostly low-quality studies, thereby requiring further work to achieve a full understanding of this important topic.

Outcome of a metaphyseal reverse total shoulder replacement in rheumatoid arthritis.

AIM: To assess the clinical and radiological results of a metaphyseal reverse total shoulder arthroplasty (rTSA) without diaphyseal stem, in rheumatoid arthritis (RA) patients. METHODS: Forty-five shoulders in 36 consecutive RA patients (2005-2015) underwent rTSA with a bone impaction technique. Patients were assessed clinically and radiographically preoperatively, at 3 weeks, 3 months, 6 months, 12 months post-operatively, and yearly thereafter, using constant score (CS), pain score, subjective shoulder value (SSV) and patient satisfaction score. RESULTS: Forty-four shoulders with mean follow-up of 67 months (range 24 m-146 m (12y)) were available for follow-up. Mean age at surgery was 68.7 years (range 39-86). CS improved from 17.5 ± 10.5(SD) (age/sex adjusted 23.9 ± 14.5(SD)) preoperatively to 60.9 ± 17.4 (SD) (age/sex adjusted 86.5 ± 24.5 (SD)) at last follow-up (P < 0.001). Pain score and SSV also significantly improved (p < 0.001). Mean range of movement improved to 140°active forward flexion, 134°active abduction, 47°active external rotation (AER) and 70°active internal rotation (AIR). The results were maintained over time. Combined early and late complication rate was 15.6%, which is lower than described in the literature for RA. No lucencies, loosening, subsidence or stress shielding were evident radiographically. CONCLUSION: Metaphyseal rTSA without a diaphyseal stem is successful and safe in RA patients. Patients achieve good function and have high satisfaction rates. LEVEL OF EVIDENCE: Case series: Level IV.

The mammary gland iodide transporter is expressed during lactation and in breast cancer.

The sodium/iodide symporter mediates active iodide transport in both healthy and cancerous thyroid tissue. By exploiting this activity, radioiodide has been used for decades with considerable success in the detection and treatment of thyroid cancer. Here we show that a specialized form of the sodium/iodide symporter in the mammary gland mediates active iodide transport in healthy lactating (but not in nonlactating) mammary gland and in mammary tumors. In addition to characterizing the hormonal regulation of the mammary gland sodium/iodide symporter, we demonstrate by scintigraphy that mammary adenocarcinomas in transgenic mice bearing Ras or Neu oncogenes actively accumulate iodide by this symporter in vivo. Moreover, more than 80% of the human breast cancer samples we analyzed by immunohistochemistry expressed the symporter, compared with none of the normal (nonlactating) samples from reductive mammoplasties. These results indicate that the mammary gland sodium/iodide symporter may be an essential breast cancer marker and that radioiodide should be studied as a possible option in the diagnosis and treatment of breast cancer.

The spectral quality of light is a key driver of photosynthesis and photoadaptation in Stylophora pistillata colonies from different depths in the Red Sea.

Depth zonation on coral reefs is largely driven by the amount of downwelling, photosynthetically active radiation (PAR) that is absorbed by the symbiotic algae (zooxanthellae) of corals. The minimum light requirements of zooxanthellae are related to both the total intensity of downwelling PAR and the spectral quality of the light. Here we used Stylophora pistillata colonies collected from shallow (3 m) and deep (40 m) water; colonies were placed in a respirometer under both ambient PAR irradiance and a filter that only transmits blue light. We found that the colonies exhibited a clear difference in their photosynthetic rates when illuminated under PAR and filtered blue light, with higher photosynthetic performance when deep colonies were exposed to blue light compared with full-spectrum PAR for the same light intensity and duration. By contrast, colonies from shallow water showed the opposite trend, with higher photosynthetic performances under full-spectrum PAR than under filtered blue light. These findings are supported by the absorption spectra of corals, with deeper colonies absorbing higher energy wavelengths than the shallow colonies, with different spectral signatures. Our results indicate that S. pistillata colonies are chromatically adapted to their surrounding light environment, with photoacclimation probably occurring via an increase in photosynthetic pigments rather than algal density. The spectral properties of the downwelling light are clearly a crucial component of photoacclimation that should be considered in future transplantation and photoacclimation studies.

Skewed pattern of Toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life.

Newborns are highly susceptible to infectious diseases, which may be due to impaired immune responses. This study aims to characterize the ontogeny of neonatal TLR-based innate immunity during the first month of life. Cellularity and Toll-like receptor (TLR) agonist-induced cytokine production were compared between cord blood obtained from healthy neonates born after uncomplicated gestation and delivery (n=18), neonatal venous blood obtained at the age of one month (n=96), and adult venous blood (n=17). Cord blood TLR agonist-induced production of the Th1-polarizing cytokines IL-12p70 and IFN-alpha was generally impaired, but for TLR3, 7 and 9 agonists, rapidly increased to adult levels during the first month of life. In contrast, TLR4 demonstrated a slower maturation, with low LPS-induced IL-12p70 production and high IL-10 production up until the age of one month. Polarization in neonatal cytokine responses to LPS could contribute to neonatal susceptibility to severe bacterial infection.

Topical treatment for human papillomavirus-associated genital warts in humans with the novel tellurium immunomodulator AS101: assessment of its safety and efficacy.

BACKGROUND: Various methods are currently used for the treatment of anogenital warts. However, a complete cure is unlikely, and the rate of recurrence is high. OBJECTIVES: The purpose of this open-label, multicentre trial was to evaluate the safety and clinical efficacy of a new treatment using the immunomodulator ammonium trichloro (dioxoethylene-O,O') tellurate (AS101; Biomas Ltd, Kefar Saba, Israel) 15% w/w cream to clear vulval/perianal condylomata acuminata. METHODS: Study participants comprised 48 women and 26 men, age range 18-62 years. Of the 48 woman, 44 were diagnosed with vulval condylomata and four with perianal condylomata. All 26 men were diagnosed with perianal condylomata. All the patients in the study received AS101 15% w/w cream twice a day. Maximal treatment duration was 16 weeks. To evaluate the safety and clinical efficacy, patients were examined and lesional areas photographed on a biweekly basis. RESULTS: By the end of the treatment, 56 of 74 (76%) patients were considered completely cleared. Complete cure was achieved in 35 of 44 (80%) patients with vulval condylomata and in 21 of 30 (70%) patients with perianal condylomata. No scarring of treated areas was observed. Complete cure was achieved within a time range of 10-109 days. The most frequent side-effects observed were mild-to-moderate itching, soreness, burning and erythema. In post-treatment follow up of up to 6 months, disease recurrence was observed in two patients (4%), at 105 and 144 days following completion of treatment. CONCLUSIONS: AS101 15% w/w cream is an effective and safe, self-administered therapy used for the treatment of external vulval and perianal warts. The cream is applied topically twice daily for up to 16 weeks. A very low recurrence rate was reported.

[Adverse drug events in hospitalized elderly patients in a geriatric medicine unit: study of prevalence and risk factors]. / Accidents iatrogènes médicamenteux chez le sujet âgé hospitalisé en court séjour gériatrique : étude de prévalence et des facteurs de risques.

INTRODUCTION: In the elderly, both the presence of a multiple pathology and multiple medication have been shown to be frequent risk factors for adverse drug events. However, a few studies only have included parameters of standardized geriatric assessment for the purpose of identifying other risk factors. Our study compared the parameters of standard geriatric assessment, in the presence or absence of adverse drug events and evaluated the prevalence of adverse drug events in elderly inpatients, the symptoms, and the drugs involved. METHODS: A total of 823 patients were studied during a two-year period. Two groups of patients were identified, according to the presence or absence of an adverse drug event. Eight fields of geriatric assessment were compared: comorbidities, number of drugs, functional status, nutritional status, mobility, mood, neurosensory disorders, and cognition. For patients who experienced an adverse drug event, we also analyzed the drugs involved and the symptoms of the adverse drug events. RESULTS: One hundred and twelve patients (13.6%) aged 82 years+/-7.5 experienced 144 adverse drug events. Significant differences between the two groups were observed in the following: symptoms of depression, problems of mobility, risk of malnutrition (respectively p=0.001, p=0.002, p=0.007), the female sex, number of drugs, number of comorbidities, and the administration of diuretics. Cardiovascular (23.2%), psychotropic (17.9%) and anti-infectious (17%) medicines were the most frequently involved. The symptoms that occurred most frequently were orthostatic hypotension (14.6%), gastrointestinal disorders (12.5%), and neuropsychological (10.4%) disorders. CONCLUSION: Elderly patients with multiple pathology and multiple medication are at high risk for adverse drug events. Other lesser known factors, such as depression, problems of mobility, and malnutrition must be researched, as they are evidence of the underlying the frailty of the elderly population.

Publisher Correction: Tidal and diel orchestration of behaviour and gene expression in an intertidal mollusc.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Determination of the solubility and size distribution of radioactive aerosols in the uranium processing plant at NRCN.

Inhalation is the main route of internal exposure to radioactive aerosols in the nuclear industry. To assess the radiation dose from the intake of these aerosols, it is necessary to know their physical (aerodynamic diameter distribution) and chemical (dissolution rate in extracellular lung fluid) characteristics. Air samples were taken from the uranium processing plant at the Nuclear Research Center, Negev. Measurements of aerodynamic diameter distribution using a cascade impactor indicated an average activity median aerodynamic diameter value close to 5 microm, in accordance with the recent recommended values of International Commission on Radiological Protection (ICRP) model. Solubility profiles of these aerosols were determined by performing in vitro solubility tests over 100 d in a simultant solution of the extracellular fluid. The tests indicated that the uranium aerosols should be assigned to an absorption between Types M and S (as defined by the ICRP Publication 66 model).

Simultaneous penetrating keratoplasty and amniotic membrane transplantation in eyes with a history of limbal stem cell deficiency.

PURPOSE: To describe the outcomes of simultaneous penetrating keratoplasty (PK) and amniotic membrane transplantation (AMT) performed both as a ring-shaped graft and as a temporary patch in eyes with a history of limbal stem cell deficiency (LSCD). METHODS: Prospective observational case series including 48 simultaneous PK/AMT procedures (48 patients) in eyes with a history of partial or total LSCD. Patients with total LSCD were first treated with limbal stem cell transplantation. The preoperative indication was graft failure in 58.3% of cases. Most recipients (89.6%) were at high-risk for rejection. RESULTS: The mean graft reepithelialization time was 29.2±30.8 days. Graft reepithelialization was achieved in 30 days in 70.8% of cases. No AMT-related adverse events were observed. The mean time from keratoplasty-to-last visit was 84.5±54.5 months. The 3-year graft survival rate was 62.5%. Recurrence of corneal epithelial defects after graft reepithelialization (47.9%) was associated with lower graft survival (P=0.004). In eyes with successful grafts at the last visit, the mean LogMAR visual acuity was 1.90 (20/1575)±5 lines before keratoplasty and 0.89 (20/155)±10 lines at 5 years. A ring of amniotic membrane was visible between the graft stroma and the corneal epithelium on slit-lamp examination and optical coherence tomography in all successful cases. CONCLUSIONS: In this series of eyes with a history of LSCD and at high-risk of rejection, simultaneous PK and AMT were associated with satisfactory graft survival and no additional adverse events.

Tidal and diel orchestration of behaviour and gene expression in an intertidal mollusc.

Intertidal inhabitants are exposed to the 24-hour solar day, and the 12.4 hour rising and falling of the tides. One or both of these cycles govern intertidal organisms' behaviour and physiology, yet little is known about the molecular clockworks of tidal rhythmicity. Here, we show that the limpet Cellana rota exhibits robust tidally rhythmic behaviour and gene expression. We assembled a de-novo transcriptome, identifying novel tidal, along with known circadian clock genes. Surprisingly, most of the putative circadian clock genes, lack a typical rhythmicity. We identified numerous tidally rhythmic genes and pathways commonly associated with the circadian clock. We show that not only is the behaviour of an intertidal organism in tune with the tides, but so too are many of its genes and pathways. These findings highlight the plasticity of biological timekeeping in nature, strengthening the growing notion that the role of 'canonical' circadian clock genes may be more fluid than previously thought, as exhibited in an organism which has evolved in an environment where tidal oscillations are the dominant driving force.

Update on clinical trials of kidney stone repositioning and preclinical results of stone breaking with one system.

Our goal is an office-based, handheld ultrasound system to target, detach, break, and/or expel stones and stone fragments from the urinary collecting system to facilitate natural clearance. Repositioning of stones in humans (maximum 2.5 MPa, and 3-second bursts) and breaking of stones in a porcine model (maximum 50 cycles, 20 Hz repetition, 30 minutes, and 7 MPa peak negative pressure) have been demonstrated using the same 350-kHz probe. Repositioning in humans was conducted during surgery with a ureteroscope in the kidney to film stone movement. Independent video review confirmed stone movements (≥ 3 mm) in 15 of 16 kidneys (94%). No serious or unanticipated adverse events were reported. Experiments of burst wave lithotripsy (BWL) effectiveness on breaking human stones implanted in the porcine bladder and kidney demonstrated fragmentation of 8 of 8 stones on post mortem dissection. A 1-week survival study with the BWL exposures and 10 specific-pathogen-free pigs, showed all findings were within normal limits on clinical pathology, hematology, and urinalysis. These results demonstrate that repositioning of stones with ultrasonic propulsion and breaking of stones with BWL are safe and effective.