As the largest secondary metabolite to be discovered as of yet, the polyether marine neurotoxin maitotoxin constitutes a major structural and synthetic challenge. After its originally proposed ...structure ( 1) had been questioned on the basis of biosynthetic considerations, we provided computational and experimental support for structure 1. In an effort to provide stronger experimental evidence of the molecular architecture of maitotoxin, its GHIJKLMNO ring system 3 was synthesized. The (13)C NMR chemical shifts of synthetic 3 matched closely those corresponding to the same domain of the natural product providing strong evidence for the correctness of the originally proposed structure of maitotoxin ( 1).
Despite the high rate of resolution, ejaculatory dysfunction still is the most common side effect related to surgical treatment of bladder outlet obstruction (BOO). The aim of the present systematic ...review was to compare several technological treatment modalities for the management of lower urinary tract symptoms/BOO in terms of functional and sexual outcomes.
All English language randomized controlled trials assessing the impact of different endoscopic treatments for BOO were evaluated. We followed the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement to evaluate PubMed®, Scopus®, and Web of Science™ databases (up to June 2019).
Our electronic search identified a total of 2221 papers in PubMed, Scopus, and Web of Science. Of these, 142 publications were identified for detailed review, which yielded 21 included in the present systematic review. All groups appeared similar with regards to preoperative IPSS/AUA Score, Qmax, and prostate volume (cc). Patients undergoing endoscopic treatments using ThuLEP, Greenlight or Prostate Artery Embolization techniques had lower-but not statistically significant- relative risk (RR) of retrograde ejaculation compared with conventional transurethral resection of the prostate (TURP) (RR: 0.90; P=0.35; RR: 0.71; P=0.1; RR0.73; P=0.11). Efficacy of those techniques was equal to TURP.
Data reporting anterograde ejaculation preservation after endoscopic treatment in patients with benign prostatic enlargement are sparse and heterogeneous. Pooled analyses suggest that new technological alternatives to conventional TURP might improve sexual outcomes, especially for non-ablative treatments.
Sea level rise has accelerated during recent decades, exceeding rates recorded during the previous two millennia, and as a result many coastal habitats and species around the globe are being ...impacted. This situation is expected to worsen due to anthropogenically induced climate change. However, the magnitude and relevance of expected increase in sea level rise (SLR) is uncertain for marine and terrestrial species that are reliant on coastal habitat for foraging, resting or breeding. To address this, we showcase the use of a low-cost approach to assess the impacts of SLR on sea turtles under various Intergovernmental Panel on Climate Change (IPCC) SLR scenarios on different sea turtle nesting rookeries worldwide. The study considers seven sea turtle rookeries with five nesting species, categorized from vulnerable to critically endangered including leatherback turtles (Dermochelys coriacea), loggerhead turtles (Caretta caretta), hawksbill turtles (Eretmochelys imbricata), olive ridley turtles (Lepidochelys olivacea) and green turtles (Chelonia mydas). Our approach combines freely available digital elevation models for continental and remote island beaches across different ocean basins with projections of field data and SLR. Our case study focuses on five of the seven living sea turtle species. Under moderate climate change scenarios, by 2050 it is predicted that at some sea turtle nesting habitats 100% will be flooded, and under an extreme scenario many sea turtle rookeries could vanish. Overall, nesting beaches with low slope and those species nesting at open beaches such as leatherback and loggerheads sea turtles might be the most vulnerable by future SLR scenarios.
Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease ...2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 76%). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
Different mosquito species show a full range of activity patterns, including diurnal, crepuscular, and nocturnal behaviors. Although activity and blood-feeding rhythms are controlled by the circadian ...clock, it is not yet known whether such species-specific differences in behavior are controlled directly by core clock genes or instead reflect differences in how the information of the central clock is translated into output signals. The authors have analyzed the circadian expression of clock genes in two important mosquito vectors of tropical diseases, Aedes aegypti and Culex quinquefasciatus . Although these two species show very different locomotor activity patterns and are estimated to have diverged more than 22 million years ago, they show conserved circadian expression patterns for all major cycling clock genes except mammalian-like cryptochrome2 (cry2). The results indicate that different mechanisms for cry2 regulation may exist for the two species. The authors speculate that the correlation between the differences in behavior between Ae. aegypti and Cx. quinquefasciatus and their corresponding cry2 mRNA profiles suggests a potential role for this clock gene in controlling species-specific rhythmic behavior. However, further work is needed to establish that this is the case as the different cry2 expression patterns might reflect differences between the Aedes and Culex lineages that are not directly related to changes in behavior.
Although numerous existing studies have analyzed the prognostic factors of patients who have had surgical intervention for lung metastases of colorectal carcinoma (CRC), many of the results obtained ...until now have been contradictory. As a consequence, there is no established consensus about which group of prognostic factors could have a greater value when considered together.
This was a multicenter prospective cohort study that included all patients who underwent a first pulmonary metastasectomy of CRC, with radical intent, during a 2-year period (March 2008 to February 2010). The follow-up continued until March 2013, and an analysis of disease-specific survival (DSS), determined from the first pulmonary metastasectomy, was implemented. The selection of the best submodel was taken based on their coefficient of determination (R(2)) and how parsimonious they were depending on the number of variables included.
The series, consisting of 522 patients, presented the following survival rates: median, 54.9 months; 3-year DSS, 69.4% (95% confidence interval CI, 65% to 73.8%); and 5-year DSS, 46.1% (95% CI, 38.5% to 53.7%). The resulting survival model consisted of disease-free interval of 12 months or less (hazard ratio HR, 1.76; 95% CI, 1.21 to 2.54; p = 0.003), carcinoembryonic antigen level exceeding 5 ng/mL (HR, 1.50; 95% CI, 1.04 to 2.17; p = 0.028), bilateral lung disease (HR, 1.81; 95% CI, 1.20 to 2.75; p = 0.005), and thoracic lymph node involvement (HR, 2.71; 95% CI, 1.44 to 5.12; p = 0.002).
According to these results from the Spanish Group of Lung Metastases of Colo-Rectal Cancer, the combination of these four variables-disease-free interval, carcinoembryonic antigen level, laterality, and thoracic lymph node involvement-constitutes the first-choice survival causal model based on the clinical and pathologic factors most frequently referenced in literature.
The prevalence of celiac disease (CD) is unknown in Chile. We have recently noted a rise in the number of cases diagnosed among adults.
To describe the clinical characteristics of a group of adult ...celiac patients.
Clinical data of patients older than 15 years with positive antitransglutaminase or antiendomysial autoantibodies and a duodenal biopsy characteristic of CD were retrospectively reviewed. Age at diagnosis, symptoms and signs and laboratory, endoscopic and histological findings, were analyzed.
Thirty seven patients (28 women), were studied. Median age at diagnosis was 41 years (range 15-69). Main symptoms and signs were diarrhea (78%), weight loss (38%) and abdominal pain (38%). Anemia was found in 49%, elevation of ESR in 57%, elevation of alkaline phosphatases in 54%, elevation of aspartate aminotransferase in 38% and a rise in alanine aminotransferase in 27%. Antiendomysial antibodies were positive in 17/22 (77%) and antitransglutaminase in 19/22 (86%) patients. Endoscopic findings were suggestive of CD in 47% of cases and duodenal biopsy showed intestinal villi atrophy in 34 (92%) patients. The three patients with normal histology had positive serology and a good response to gluten free diet.
CD should be considered in the differential diagnosis of patients with unespecific digestive symptons, even when they present late in adult life. Serologic markers are a good diagnostic tool. A normal duodenal pathology does not exclude the diagnosis, if other diagnostic features are present.
Circadian rhythms are oscillations in behavior, metabolism and physiology that have a period close to 24 h. These rhythms are controlled by an internal pacemaker that evolved under strong selective ...pressures imposed by environmental cyclical changes, mainly of light and temperature. The molecular nature of the circadian pacemaker was extensively studied in a number of organisms under controlled laboratory conditions. But although these studies were fundamental to our understanding of the circadian clock, most of the environmental conditions used resembled rather crudely the relatively constant situation at lower latitudes. At higher latitudes light-dark and temperature cycles vary considerably across different seasons, with summers having long and hot days and winters short and cold ones. Considering these differences and other external cues, such as moonlight, recent studies in more natural and semi-natural situations revealed unexpected features at both molecular and behavioral levels, highlighting the dramatic influence of multiple environmental variables in the molecular clockwork. This emphasizes the importance of studying the circadian clock in the wild, where seasonal environmental changes fine-tune the underlying circadian mechanism, affecting population dynamics and impacting the geographical variation in clock genes. Indeed, latitudinal clines in clock gene frequencies suggest that natural selection and demography shape the circadian clock over wide geographical ranges. In this review we will discuss the recent advances in understanding the molecular underpinnings of the circadian clock, how it resonates with the surrounding variables (both in the laboratory and in semi-natural conditions) and its impact on population dynamics and evolution. In addition, we will elaborate on how next-generation sequencing technologies will complement classical reductionist approaches by identifying causal variants in natural populations that will link genetic variation to circadian phenotypes, illuminating how the circadian clock functions in the real world.
We aimed to identify a lipidic profile associated with type 2 diabetes mellitus (T2DM) development in coronary heart disease (CHD) patients, to provide a new, highly sensitive model which could be ...used in clinical practice to identify patients at T2DM risk.
This study considered the 462 patients of the CORDIOPREV study (CHD patients) who were not diabetic at the beginning of the intervention. In total, 107 of them developed T2DM after a median follow-up of 60 months. They were diagnosed using the American Diabetes Association criteria. A novel lipidomic methodology employing liquid chromatography (LC) separation followed by HESI, and detection by mass spectrometry (MS) was used to annotate the lipids at the isomer level. The patients were then classified into a Training and a Validation Set (60-40). Next, a Random Survival Forest (RSF) was carried out to detect the lipidic isomers with the lowest prediction error, these lipids were then used to build a Lipidomic Risk (LR) score which was evaluated through a Cox. Finally, a production model combining the clinical variables of interest, and the lipidic species was carried out.
LC-tandem MS annotated 440 lipid species. From those, the RSF identified 15 lipid species with the lowest prediction error. These lipids were combined in an LR score which showed association with the development of T2DM. The LR hazard ratio per unit standard deviation was 2.87 and 1.43, in the Training and Validation Set respectively. Likewise, patients with higher LR Score values had lower insulin sensitivity (P = 0.006) and higher liver insulin resistance (P = 0.005). The receiver operating characteristic (ROC) curve obtained by combining clinical variables and the selected lipidic isomers using a generalised lineal model had an area under the curve (AUC) of 81.3%.
Our study showed the potential of comprehensive lipidomic analysis in identifying patients at risk of developing T2DM. In addition, the lipid species combined with clinical variables provided a new, highly sensitive model which can be used in clinical practice to identify patients at T2DM risk. Moreover, these results also indicate that we need to look closely at isomers to understand the role of this specific compound in T2DM development. Trials registration NCT00924937.
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