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.

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.

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.

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.

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.

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.

Relationship between visual outcomes and retinal fluid resorption in patients with diabetic macular edema treated with ranibizumab.

PURPOSE: We assessed the relationship between visual acuity (VA) recovery and a qualitative criterion - complete retinal fluid resorption (CRFR) - among patients treated with ranibizumab for diabetic macular edema (DME) METHODS: All consecutive diabetic patients with central DME received a loading dose of 3 monthly injections of ranibizumab 0.5mg, followed by retreatments on an as-needed basis as determined by monthly follow-up. Patients were divided into 3 groups: CRFR (defined as a CRT <300µm and restoration of the foveolar pit) with BCVA≤70 letters (group 1: G1), CRFR with BCVA>70 letters (20/40) (G2), and persistent retinal fluid throughout the follow-up (G3). RESULTS: Forty eyes were included. Mean baseline VA was 48.7 letters and no patient had VA>70 letters. Twenty-four (60%) eyes achieved CRFR: 12 (30%) in G1 and 12 (30%) in G2. In 16 patients (40%), the efficacy of the treatment was partial without CRFR (G3). At the time of the initial CRFR, VA was 57.4 letters in G1 (min-max: 30-65) and 77.5 letters in G2 (71-85). In G3, maximal VA during follow-up was 55 letters (25-70) and no patient achieved a VA >70 letters. CONCLUSIONS: In this study, CRFR was required but not sufficient to achieve a VA>70 letters.

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.

Artroplastia de revisión de prótesis de superficie de hombro hacia prótesis invertida no cementada con vástago corto / Revision shoulder arthroplasty from resurfacing to non-cemented short-stem reverse prosthesis

Objetivo. Valorar los parámetros perioperatorios y los resultados clínicos y radiológicos de la cirugía de revisión de las prótesis de superficie de hombro recambiadas hacia prótesis invertida no cementada con vástago corto. Material y métodos. Entre 2005 y 2012, se realizaron 23 revisiones de prótesis de superficie de hombro a prótesis invertidas. La edad media fue 70,3 años ± 11,95. Un 82,6% (19/23) de los recambios se realizaron por rotura secundaria del manguito rotador; 13,04% (3/23) por aflojamiento aséptico del componente glenoideo más insuficiencia del manguito y 4,35% (1/23) por fractura periprotésica. Se documentaron: necesidad de ventanas humerales y aloinjerto estructural, duración del procedimiento, pérdidas hemáticas, transfusiones y fracturas intraoperatorias. Seguimiento mínimo de 25 meses. Resultados. En ninguno de los casos se necesitó realizar una ventana humeral para la extracción del implante de superficie, así como tampoco aloinjerto estructural. En 8,69% (2/23) de los casos se requirió aloinjerto para reconstrucción glenoidea. La duración del procedimiento fue 113,35 ± 21,30 min. Las pérdidas hemáticas intraoperatorias fueron 374 ± 245,09 mls. Se requirió hemotransfusión en un caso. Se produjo una fractura intraoperatoria. El Constant mejoró de 17,32 a 59,78 (ajustado por sexo y edad, 84). La satisfacción general aumentó de 1,37 a 8,04. El recorrido articular aumentó 79,57° en elevación anterior; 72,88° en abducción; 38,06° en rotación interna; y 13,57° en rotación externa. No hubo evidencia de radiolucencias, hundimientos, ni resorción ósea. Conclusión. La artroplastia de revisión de las prótesis de superficie de hombro recambiadas hacia prótesis invertida no cementada con vástago corto ofrece buenos resultados clínicos y radiológicos, representando una técnica con complejidades intraoperatorias mínimas. Nivel de evidencia IV, serie de casos (AU)

Objective. To assess the surgical parameters and the clinical and radiological outcomes of revisions of resurfacing shoulder arthroplasty to non-cemented short-stem reverse total shoulder arthroplasty. Material and methods. A total of 23 revisions from resurfacing shoulder arthroplasty to reverse total shoulder arthroplasty were performed. The mean age was 70.3 ± 11.95 years. The patients included 82.6% (19/23) revised for cuff failure; 13.04% (3/23) cuff failure and aseptic loosening, and 4.35% (1/23) peri-prosthetic fracture. The need for humeral osteotomy or structural allograft, operation length, blood loss, blood transfusions and intraoperative fractures were recorded. Minimum follow-up 25 months. Results. No humeral osteotomy or humeral structural allograft was required, and 2/23 (8.69%) required allograft for glenoid reconstruction. The mean operation time was 113.35 ± 21.30 minutes. Intra-operative blood loss was 374 ± 245.09 mls. Blood transfusion was required in one case. Intra-operative fracture occurred in 1 case. The Constant score improved from 17.32 to 59.78 (age/sex adjusted, 84). Overall satisfaction improved from 1.37 to 8.04. The range of motion increased 79.57° in forward elevation; 72.88° in abduction; 38.06° in internal rotation; and 13.57° in external rotation. There was no evidence of radiolucency, subsidence, or bone resorption. Conclusion. Revisions of resurfacing implants to non-cemented short-stem reverse prosthesis show good clinical and radiological outcomes, with minimal intra-operative complexities. Level of evidence IV, case series (AU)

[Topical cyclosporine in ophthalmology: Pharmacology and clinical indications]. / La ciclosporine topique en ophtalmologie : pharmacologie et indications thérapeutiques.

Cyclosporine A (CsA) is a cyclic undecapeptide, which is an immunosuppressive drug in the calcineurin inhibitor class. CsA was initially used as a systemic immunosuppressant to minimize rejection of solid organ transplants. In ophthalmology, topically applied CsA was first used to inhibit corneal allograft rejection in the 1980s and later in various inflammatory ocular surface disorders (OSD). Currently, topical ophthalmic CsA is available as a licensed commercial emulsion or is prepared by hospital pharmacies with concentration ranging from 0.05 to 2%. Many of its pharmacological effects on the ocular surface are direct consequences of its ability to inhibit T ciclosporine activation and apoptosis. Topical CsA differs from topical steroids in its favourable local and systemic tolerability at the concentrations used. Most clinical studies have evaluated topical CsA in moderate to severe dry eye disease (DED) and demonstrated its efficacy for improvement of signs and symptoms, thus providing the sole indication for market approval and treatment protocols. For the other indications - corneal graft rejection, blepharitis, allergic or viral keratitis, and ocular surface disease due to graft versus host disease or post-operative DED - evidence-based medicine remains unclear due to the lack of major randomized controlled trials. Despite the lack of standardized protocols or market approval for these conditions, numerous studies suggest clinical efficacy.

Revision shoulder arthroplasty from resurfacing to non-cemented short-stem reverse prosthesis. / Artroplastia de revisión de prótesis de superficie de hombro hacia prótesis invertida no cementada con vástago corto.

OBJECTIVE: To assess the surgical parameters and the clinical and radiological outcomes of revisions of resurfacing shoulder arthroplasty to non-cemented short-stem reverse total shoulder arthroplasty. MATERIAL AND METHODS: A total of 23 revisions from resurfacing shoulder arthroplasty to reverse total shoulder arthroplasty were performed. The mean age was 70.3±11.95 years. The patients included 82.6% (19/23) revised for cuff failure; 13.04% (3/23) cuff failure and aseptic loosening, and 4.35% (1/23) peri-prosthetic fracture. The need for humeral osteotomy or structural allograft, operation length, blood loss, blood transfusions and intraoperative fractures were recorded. Minimum follow-up 25 months. RESULTS: No humeral osteotomy or humeral structural allograft was required, and 2/23 (8.69%) required allograft for glenoid reconstruction. The mean operation time was 113.35±21.30minutes. Intra-operative blood loss was 374±245.09 mls. Blood transfusion was required in one case. Intra-operative fracture occurred in 1 case. The Constant score improved from 17.32 to 59.78 (age/sex adjusted, 84). Overall satisfaction improved from 1.37 to 8.04. The range of motion increased 79.57° in forward elevation; 72.88° in abduction; 38.06° in internal rotation; and 13.57° in external rotation. There was no evidence of radiolucency, subsidence, or bone resorption. CONCLUSION: Revisions of resurfacing implants to non-cemented short-stem reverse prosthesis show good clinical and radiological outcomes, with minimal intra-operative complexities. LEVEL OF EVIDENCE: IV, case series.

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.

Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease.

Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.

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.