Shifts in predator behaviour following climate induced disturbance on coral reefs.

Coral reefs are increasingly ecologically destabilized across the globe due to climate change. Behavioural plasticity in corallivore behaviour and short-term trophic ecology in response to bleaching events may influence the extent and severity of coral bleaching and subsequent recovery potential, yet our understanding of these interactions in situ remains unclear. Here, we investigated interactions between corallivory and coral bleaching during a severe high thermal event (10.3-degree heating weeks) in Belize. We found that parrotfish changed their grazing behaviour in response to bleaching by selectively avoiding bleached Orbicella spp. colonies regardless of bleaching severity or coral size. For bleached corals, we hypothesize that this short-term respite from corallivory may temporarily buffer coral energy budgets by not redirecting energetic resources to wound healing, and may therefore enable compensatory nutrient acquisition. However, colonies that had previously been heavily grazed were also more susceptible to bleaching, which is likely to increase mortality risk. Thus, short-term respite from corallivory during bleaching may not be sufficient to functionally rescue corals during prolonged bleaching. Such pairwise interactions and behavioural shifts in response to disturbance may appear small scale and short term, but have the potential to fundamentally alter ecological outcomes, especially in already-degraded ecosystems that are vulnerable and sensitive to change.

The funny current If is essential for the fight-or-flight response in cardiac pacemaker cells.

The sympathetic nervous system fight-or-flight response is characterized by a rapid increase in heart rate, which is mediated by an increase in the spontaneous action potential (AP) firing rate of pacemaker cells in the sinoatrial node. Sympathetic neurons stimulate sinoatrial myocytes (SAMs) by activating ß adrenergic receptors (ßARs) and increasing cAMP. The funny current (If) is among the cAMP-sensitive currents in SAMs. If is critical for pacemaker activity, however, its role in the fight-or-flight response remains controversial. In this study, we used AP waveform analysis, machine learning, and dynamic clamp experiments in acutely isolated SAMs from mice to quantitatively define the AP waveform changes and role of If in the fight-or-flight increase in AP firing rate. We found that while ßAR stimulation significantly altered nearly all AP waveform parameters, the increase in firing rate was only correlated with changes in a subset of parameters (diastolic duration, late AP duration, and diastolic depolarization rate). Dynamic clamp injection of the ßAR-sensitive component of If showed that it accounts for ∼41% of the fight-or-flight increase in AP firing rate and 60% of the decrease in the interval between APs. Thus, If is an essential contributor to the fight-or-flight increase in heart rate.

Risk factors and predisposing conditions for urinary tract infection.

Understanding individual and population-specific risk factors associated with recurrent urinary tract infections (UTIs) can help physicians tailor prophylactic strategies. Frequent intercourse, vulvovaginal atrophy, change of the local bacterial flora, history of UTIs during premenopause or in childhood, family history, and a nonsecretor blood type are substantiated risk factors for recurrent uncomplicated UTIs. This is a narrative review based on relevant literature according to the experience and expertise of the authors. Asymptomatic bacteriuria is generally benign; however, during pregnancy it is more common and is associated with an increased likelihood of symptomatic infection, which may harm the mother or fetus. Screening of pregnant women and appropriate treatment with antimicrobials must be balanced with the potential for adverse treatment-related outcomes; appropriate prophylaxis should be considered where possible. High-quality data are currently lacking on risks related to asymptomatic bacteriuria in pregnancy and further data in this hard-to-study population should be a primary concern for researchers. Incomplete voiding represents the primary risk factor for UTIs associated with conditions such as urinary incontinence and prolapse. Correcting the presence of residual urine remains the most effective prophylaxis in these populations. Bladder function alters throughout life; however, changes in function may be particularly profound in clinical populations at high risk of UTIs. Patients with neurogenic bladder will also likely have other evolving medical issues which increase the risk of UTIs, such as repeated catheterization and increasing residual urine volume. More aggressive antimicrobial prophylactic strategies may be appropriate in these patients. Again, the paucity of data on prophylaxis in these high-risk patients requires the attention of the research community.

Prevention of recurrent urinary tract infections: bridging the gap between clinical practice and guidelines in Latin America.

The branches of the immune system work in concert to defend against pathogens and prevent tissue damage due to excessive inflammation. Uropathogens in general, and uropathogenic Escherichia coli (UPEC) in particular, have evolved a diverse range of virulence mechanisms to avoid detection and destruction by the mucosal immune system of the urinary tract. Research towards a vaccine active against UPEC continues but has yet to be successful. Orally administered immunomodulatory bacterial lysates both stimulate and modulate the immune response in the urinary tract via the integrated mucosal immune system. The 2018 European Association of Urology (EAU) guidelines on treating acute uncomplicated cystitis recommend aiming for rapid resolution of symptoms, reduction of morbidity, and prophylaxis against reinfection. Recommended short-term antibiotic therapy has the advantage of good compliance, low cost, few adverse events, and low impact on bacterial flora. Antibiotic treatment of asymptomatic bacteriuria is only indicated during pregnancy and before invasive interventions. For recurrent infection, prophylaxis using behavioral modification and counseling should be employed first, then nonantibiotic prophylaxis, and, finally, low-dose continuous or postcoital antibiotic prophylaxis. The 2018 EAU guidelines give a strong recommendation for the oral bacterial lysate immunomodulator OM-89. All other nonantibiotic prophylactic strategies require more data, except for topical estrogen for postmenopausal women. For last-resort antibiotic prophylaxis, nitrofurantoin or fosfomycin trometamol are recommended. Guidelines for Latin America are currently being drafted, taking into account the unique ethnicity, availability of medicines, prevalence of antibiotic resistance, and healthcare practices found throughout the region.

Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1.

In skeletal muscle, residues 720-764/5 within the CaV1.1 II-III loop form a critical domain that plays an essential role in transmitting the excitation-contraction (EC) coupling Ca2+ release signal to the type 1 ryanodine receptor (RyR1) in the sarcoplasmic reticulum. However, the identities of proteins that interact with the loop and its critical domain and the mechanism by which the II-III loop regulates RyR1 gating remain unknown. Recent work has shown that EC coupling in skeletal muscle of fish and mice depends on the presence of Stac3, an adaptor protein that is highly expressed only in skeletal muscle. Here, by using colocalization as an indicator of molecular interactions, we show that Stac3, as well as Stac1 and Stac2 (predominantly neuronal Stac isoforms), interact with the II-III loop of CaV1.1. Further, we find that these Stac proteins promote the functional expression of CaV1.1 in tsA201 cells and support EC coupling in Stac3-null myotubes and that Stac3 is the most effective. Coexpression in tsA201 cells reveals that Stac3 interacts only with II-III loop constructs containing the majority of the CaV1.1 critical domain residues. By coexpressing Stac3 in dysgenic (CaV1.1-null) myotubes together with CaV1 constructs whose chimeric II-III loops had previously been tested for functionality, we reveal that the ability of Stac3 to interact with them parallels the ability of these constructs to mediate skeletal type EC coupling. Based on coexpression in tsA201 cells, the interaction of Stac3 with the II-III loop critical domain does not require the presence of the PKC C1 domain in Stac3, but it does require the first of the two SH3 domains. Collectively, our results indicate that activation of RyR1 Ca2+ release by CaV1.1 depends on Stac3 being bound to critical domain residues in the II-III loop.

Junctional trafficking and restoration of retrograde signaling by the cytoplasmic RyR1 domain.

The type 1 ryanodine receptor (RyR1) in skeletal muscle is a homotetrameric protein that releases Ca2+ from the sarcoplasmic reticulum (SR) in response to an "orthograde" signal from the dihydropyridine receptor (DHPR) in the plasma membrane (PM). Additionally, a "retrograde" signal from RyR1 increases the amplitude of the Ca2+ current produced by CaV1.1, the principle subunit of the DHPR. This bidirectional signaling is thought to depend on physical links, of unknown identity, between the DHPR and RyR1. Here, we investigate whether the isolated cytoplasmic domain of RyR1 can interact structurally or functionally with CaV1.1 by producing an N-terminal construct (RyR11:4300) that lacks the C-terminal membrane domain. In CaV1.1-null (dysgenic) myotubes, RyR11:4300 is diffusely distributed, but in RyR1-null (dyspedic) myotubes it localizes in puncta at SR-PM junctions containing endogenous CaV1.1. Fluorescence recovery after photobleaching indicates that diffuse RyR11:4300 is mobile, whereas resistance to being washed out with a large-bore micropipette indicates that the punctate RyR11:4300 stably associates with PM-SR junctions. Strikingly, expression of RyR11:4300 in dyspedic myotubes causes an increased amplitude, and slowed activation, of Ca2+ current through CaV1.1, which is almost identical to the effects of full-length RyR1. Fast protein liquid chromatography indicates that ∼25% of RyR11:4300 in diluted cytosolic lysate of transfected tsA201 cells is present in complexes larger in size than the monomer, and intermolecular fluorescence resonance energy transfer implies that RyR11:4300 is significantly oligomerized within intact tsA201 cells and dyspedic myotubes. A large fraction of these oligomers may be homotetramers because freeze-fracture electron micrographs reveal that the frequency of particles arranged like DHPR tetrads is substantially increased by transfecting RyR-null myotubes with RyR11:4300 In summary, the RyR1 cytoplasmic domain, separated from its SR membrane anchor, retains a tendency toward oligomerization/tetramerization, binds to SR-PM junctions in myotubes only if CaV1.1 is also present and is fully functional in retrograde signaling to CaV1.1.

Outcomes from patients with multi-vessel disease following primary PCI: staged PCI imparts very low mortality.

BACKGROUND: CABG and PCI are effective means for revascularization of patients with multi-vessel coronary artery disease, but previous studies have not focused on treatment of patients that first undergo primary PCI. METHODS: Among patients enrolled in the global registry of acute coronary events (GRACE), clinical outcomes for patients presenting with STEMI treated with primary PCI were compared according to whether residual stenoses were treated medically, surgically, or with staged PCI. Clinical characteristics and data pertaining to major adverse cardiac events during hospitalization and 6 months after discharge were collected. RESULTS: Of the 1,705 patients included, 1,345 (79%) patients were treated medically, 303 (18%) underwent staged PCI, and 57 (3.3%) underwent CABG following primary PCI. Hospital mortality was lowest among patients treated with staged PCI (Medical = 5.7%; PCI = 0.7%; CABG = 3.5%; P < 0.001 [PCI vs. Medical]), a finding that persisted after risk adjustment (Odds Ratio PCI vs. Medical 5 0.16, [0.04-0.68]; P 5 0.01). Six month postdischarge mortality likewise was lowest in the staged PCI group (Medical = 3.1%; PCI = 0.8%; CABG = 4.0%; P = 0.04 [PCI vs. Medical]). Patients revascularized surgically were rehospitalized less frequently (Medical = 20%; PCI = 19%; CABG = 6.3%; P < 0.05) and underwent fewer unscheduled procedures (Medical 5 9.8%; PCI = 10.0%; CABG = 0.0%; P < 0.02). CONCLUSIONS: The results of this multinational registry demonstrate that hospital mortality in patients who undergo staged percutaneous revascularization of multivessel coronary disease following primary PCI is very low. Patients undergoing CABG following primary PCI are hospitalized less frequently and undergo fewer unplanned catheter-based procedures.

The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections.

The ARESC (Antimicrobial Resistance Epidemiological Survey on Cystitis) study is an international survey to investigate the prevalence and susceptibility of pathogens causing cystitis. Female patients (n=4264) aged 18-65 years with symptoms of uncomplicated cystitis were consecutively enrolled in nine European countries as well as Brazil during 2003-2006. Pathogens were identified and their susceptibility to nine antimicrobials was determined. Escherichia coli accounted for 76.7% of isolates. Among E. coli, 10.3% of the isolates were resistant to at last three different classes of antimicrobial agents. Resistance was most common to ampicillin (48.3%), trimethoprim/sulfamethoxazole (29.4%) and nalidixic acid (18.6%). Fosfomycin, mecillinam and nitrofurantoin were the most active drugs (98.1%, 95.8% and 95.2% susceptible strains, respectively) followed by ciprofloxacin, amoxicillin/clavulanic acid and cefuroxime (91.7%, 82.5% and 82.4%, respectively). Resistance to ciprofloxacin was >10% in Brazil, Spain, Italy and Russia. Overall, Proteus mirabilis were more susceptible to beta-lactams and less susceptible to non-beta-lactams than E. coli, whereas Klebsiella pneumoniae strains, which are intrinsically resistant to ampicillin, were less susceptible to mecillinam (88.8%), fosfomycin (87.9%), cefuroxime (78.6%) and nitrofurantoin (17.7%). Resistance was rare in Staphylococcus saprophyticus, with the exception of ampicillin (36.4%) and trimethoprim/sulfamethoxazole (10.2%). In Italy, Spain, Brazil and Russia, the countries most affected by antimicrobial resistance, extended-spectrum beta-lactamase (ESBL) enzymes (mainly CTX-M type) were detected in 48 strains (39 E. coli, 6 K. pneumoniae and 3 P. mirabilis). Despite wide intercountry variability in bacterial susceptibility rates to the other antimicrobials tested, fosfomycin and mecillinam have preserved their in vitro activity in all countries investigated against the most common uropathogens.

Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy.

BACKGROUND: Uncomplicated cystitis in females is among the most frequent infections in community. OBJECTIVE: To determine clinical aspects, epidemiology, and antimicrobial susceptibility of uropathogens. INTERVENTION: Patients were investigated clinically and with urinalysis and urine culture. MEASUREMENTS: This survey started in 2003 and ended in 2006 including 68 centres in nine European countries and in Brazil. Female patients between 18 and 65 yr with symptoms of uncomplicated cystitis were consecutively enrolled and clinically evaluated. Uropathogens were identified and their susceptibility tested for nine antimicrobials. RESULTS AND LIMITATIONS: Clinical data of 4264 eligible patients were analysed. A positive urine culture was found in 74.6%. Within the 3018 pathogens, Escherichia coli (E. coli) was most frequent (76.7%), followed by Enterococcus faecalis (4.0%), Staphylococcus saprophyticus (3.6%), Klebsiella pneumoniae (3.5%), and Proteus mirabilis (3.5%). E. coli showed the highest rate of susceptibility to fosfomycin (98.1%) followed by mecillinam (95.8%), nitrofurantoin (95.2%), and ciprofloxacin (91.8%). The lowest rate was found for ampicillin (45.1%). For the total spectrum the order was fosfomycin (96.4%), mecillinam (95.9%), ciprofloxacin (90.3%), and nitrofurantoin (87.0%). In all countries a susceptibility rate to E. coli above 90% was found only for fosfomycin, mecillinam, and nitrofurantoin. The susceptibility rates varied significantly from country to country (p<0.0001), except for fosfomycin, mecillinam, and nitrofurantoin. CONCLUSIONS: Despite wide cross-country variability of bacterial susceptibility/resistance rates to the other antimicrobials tested, fosfomycin, mecillinam, and nitrofurantoin have preserved their in vitro activity in all countries investigated. They may represent good options for the empiric therapy of female patients with uncomplicated cystitis.