Detection of pancreatic metastases by EUS-guided fine-needle aspiration

BACKGROUND: Metastases to the pancreas are usually found incidentally. Tissue diagnosis is imperative because imaging alone is incapable of differentiating them from primary pancreatic tumors. This study tested whether it is possible to differentiate metastases from other focal pancreatic lesions by using EUS-guided fine-needle aspiration (EUS-FNA) for cytodiagnosis. METHODS: One hundred fourteen consecutive patients (mean age 61 years) with focal pancreatic masses, detected on CT, underwent EUS-FNA by using a linear-array echoendoscope and 22-gauge needles. RESULTS: Adequate specimens were obtained from 112 lesions. Carcinomas were identified in 68 cases (60.7%), 56 (50%) of pancreatic origin and 12 (10.7%) from distant primary tumors. The metastases were all located in the head and body of the pancreas and measured 1.8 to 4.0 cm. The echo-texture was heterogeneous or hypoechoic in all cases and resembled that of primary tumors. Six of the 12 patients with metastatic disease had a prior diagnosis of cancer (breast, 3; renal cell, 2; salivary gland, 1), 4 of them with a recurrence and 2 with a second carcinoma metastasizing to the pancreas. Six patients without a prior diagnosis of cancer had metastases from renal cell, colonic, ovarian, and esophageal carcinomas; one metastasis was from an unknown primary and another was from a malignant lymphoma. These findings influenced the therapeutic strategy in 8 patients who underwent nonsurgical palliation. There were no complications. CONCLUSIONS: Pancreatic metastasis is an important cause of focal pancreatic lesions, but the EUS features are not diagnostic. Simultaneous EUS-FNA allows cytodiagnosis and can have a decisive influence on the selection of appropriate therapeutic strategies.     

Cranial Electrotherapy Stimulation for the Management of Depression,Anxiety, Sleep Disturbance,and Pain in Patients With Advanced Cancer: A Preliminary Study

Context

Cranial electrotherapy stimulation (CES) is a safe modulation of brain activity for treating depression, anxiety, insomnia, and pain. However, there are no published studies in patients with advanced cancer (ACPs).

Divergent outcomes of gut microbiota alteration upon use of spectrum antibiotics in high sugar diet-induced diabetes in rats

Background: A sugar rich diet induces inflammation and insulin resistance (IR) mainly through gut microbiota alteration. Gut dysbiosis increases lipopolysaccharide (LPS) and reduces propionate and butyrate levels to impair the insulin signalling cascades by different molecular pathways, which progresses into IR. The present study was designed to investigate the effect of spectrum specific antibiotics on the modulation of gut microbiota and its signalling pathways to prevent diet-induced diabetes. Methods: Healthy male Wistar rats were divided into a non-diabetic group with a control diet (CD), a diabetic group with a high sucrose diet (HSD) and two antibiotic fed groups (linezolid and cefdinir; administered by oral gavage) along HSD. Physiological, biochemical, inflammatory and microbiome parameters were examined. Results: Cefdinir administration in HSD rats reduced fasting glucose, serum triglyceride, and cholesterol levels compared to HSD alone. In addition, cefdinir reduced serum LPS by decreasing the population of Gram-negative phyla, that is, Bacteroidetes and Proteobacteria in the fecal content. Furthermore, cefdinir treatment decreased hepatic/ileal/colonic Tlr4, Nlr1, and Nf-κB at the mRNA level. Moreover, cefdinir-treated rats had shown increased fecal butyrate and propionate and reduced acetate levels compared to HSD alone. Cefdinir treatment also induced ileal/colonic Gpr43 and Glut4 at the mRNA level after 12 weeks of administration. Conclusions: Taken together, these data suggest that administration of a Gram-negative spectrum antibiotic, that is, cefdinir, has modulated the gut microbiota, and reduced serum LPS and triglycerides, which prevented the progression of IR and inflammation in HSD rats.

A sugar rich diet induces inflammation and insulin resistance (IR) mainly through gut microbiota alteration.     

Interleukin-1 is both morphogenic and cytotoxic to cultured rat ovarian cells: obligatory role for heterologous, contact-independent cell-cell interaction.

An increasing body of information now suggests that intraovarian interleukin-1 (IL-1) may play an intermediary role in the ovulatory process. Given that follicular rupture inevitably requires marked tissue remodeling and possibly cell death, we set out to examine the morphogenic potential of IL-1 under in vitro circumstances. Treatment of freshly plated whole ovarian dispersates from immature rats with any one of several batches of IL-1 (10 ng/ml) for up to 96 h produced marked time-dependent morphological alterations, including cellular retraction, rounding, clumping, aggregation, blebbing, swelling, and, ultimately, irreversible detachment. Evidence of (asynchronous) cell death consisted of reduced total cell number, diminished cellular protein content, enhanced cellular release of lactic dehydrogenase, failure to exclude trypan blue, and attenuated reduction of the tetrazolium dye 3-[4,5-dimethylthiazol-2-y]2,5-diphenyltetrazolium bromide to spectrophotometrically detectable formazan. Comparable results were obtained when using established day 4 cultures, arguing against a possible critical action of IL-1 at the time of plating. Dose-response curves revealed IL-1 beta (EC50, 0.2-0.4 ng/ml) to be substantially more potent than IL-1 alpha (EC50, 2.7-2.8 ng/ml). Importantly, the concurrent provision of an IL-1 beta-directed polyclonal antibody yielded complete immunoneutralization of the IL-1 beta effect, arguing against the possible involvement of a non-IL-1 contaminant. An unrelated polyclonal antiserum raised against insulin-like growth factor-I was without effect. IL-1 action proved relatively specific, in that tumor necrosis factor-alpha (10 ng/ml), a putative cytotoxic principle, as well as IL-1-inducible ILs (IL-2 and -6; 100 U/ml) were without effect. Although minimally effective at the level of the isolated granulosa or theca-interstitial cell, IL-1 proved highly potent in heterologous (but not homologous), contact-dependent and independent cocultures of these somatic cell types, strongly suggesting obligatory cell-cell cooperation. These observations further indicate that IL-1 action is indirect and may require the induction of an intermediary soluble principle to serve as the final effector. Taken together, these findings indicate that relatively low concentrations of IL-1 (beta > alpha), possible of somatic ovarian cell or resident ovarian macrophage origin, are capable of exerting specific dose- and time-dependent (immunoneutralizable) morphogenic as well as cytotoxic effects at the level of ovarian cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antigen-specific therapy of experimental allergic encephalomyelitis by soluble class II major histocompatibility complex-peptide complexes.

Experimental allergic encephalomyelitis is a T-cell-mediated, major histocompatibility complex (MHC) class II gene-linked autoimmune demyelinating disease of the central nervous system. To develop therapies that will specifically inactivate only the autoantigen-reactive T cells, mice were treated with soluble MHC class II molecules that had been complexed with encephalitogenic peptides. Intravenous injections of 300 micrograms of complexes consisting of encephalitogenic peptide 91-103 of myelin basic protein plus I-As protein on day 0, 4, and 7 were effective in preventing experimental allergic encephalomyelitis. Similarly, administration of 45 micrograms of I-As protein complexed to peptide 139-151 from proteolipoprotein on day 1, 4, and 7 prevented mortality and significantly reduced paralysis induced by immunization with the encephalitogenic proteolipoprotein peptide. Histological examination of sections of animal brains revealed that treatment with I-As protein plus myelin basic protein 91-103 peptide prevents the development of inflammatory lesions characteristic of experimental allergic encephalomyelitis. Thus, treatment with MHC-self-peptide complexes could serve as a highly specific therapeutic modality in treating autoimmune disease when the putative autoantigen and the MHC restricting elements are known.     

Clinical profile of acute kidney injury in a pediatric intensive care unit from Southern India: A prospective observational study

Background:

Although the term acute renal failure was replaced by acute kidney injury (AKI) recently, there is a paucity of data on the incidence and profile of AKI in critically ill children from the developing world.

Objectives:

The objective of this study is to determine the incidence, etiology, short term outcome and predictors of fatality in critically ill children admitted to the pediatric intensive care unit (PICU) with AKI, aged 1 month to 13 years.

Materials and Methods:

In this prospective observational study, from June 2010 to March 2011, 215 children admitted to the PICU were screened for AKI, defined according to the AKI Network criteria. The patients with AKI were followed-up until discharge/death. Their clinical and biochemical data were recorded.

Results:

The incidence of AKI among 215 patients screened was 54 (25.1%). The common etiologies were infections, [34 (62.9%)], acute glomerulonephritis (7.6%), snake envenomation (5.7%), hemolytic uremic syndrome (3.8%) and congestive cardiac failures (3.8%). Among infections, pneumonia and septicemia constituted 26.5% each, meningoencephalitis accounted for 23.5%, and dengue, scrub typhus, tuberculosis and malaria constituted 9.3% of children with AKI. 27.8% of patients required dialysis. Overall mortality was 46.3%. On logistic regression analysis, requirement of mechanical ventilation was an independent predictor of fatality in AKI.

Conclusions:

Besides the high incidence of AKI in critically ill-children admitted to the PICU (25.1%), the condition was associated with adverse outcomes, including high mortality (46.3%) and need for dialysis (27.8%). Infections dominated the etiological profile. Requirement of mechanical ventilation predicted an adverse outcome in our patient population.     

A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years

The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced. Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. Thus, we can estimate the date since Neanderthal admixture for present-day and ancient samples simultaneously and use the difference as a direct estimate of the ancient specimen’s age. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12,000 and 45,000 y ago and show an excellent correlation of the genetic and ¹⁴C dates. By considering the slope of the correlation between the genetic dates, which are in units of generations, and the ¹⁴C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26–30 y. Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier.Ancient DNA analyses have transformed research into human evolutionary history, making it possible to directly observe genetic variation patterns that existed in the past, instead of having to infer them retrospectively (1). To interpret findings from an ancient specimen, it is important to have an accurate estimate of its age. The current gold standard is radiocarbon dating, which is applicable for estimating dates for samples up to 50,000 y old (2). This method is based on the principle that, when a living organism dies, the existing ¹⁴C starts decaying to ¹⁴N with a half-life of ∼5,730 y (3). By measuring the ratio of ¹⁴C to ¹²C in the sample and assuming that the starting ratio of carbon isotopes is the same everywhere in the biosphere, the age of the sample is inferred. A complication is that carbon isotope ratios vary among carbon reservoirs (e.g., marine, freshwater, atmosphere) and over time. Thus, ¹⁴C dates must be converted to calendar years using calibration curves based on other sources, including annual tree rings (dendrochronology) or uranium-series dating of coral (2). Such calibrations, however, may not fully capture the variation in atmospheric carbon. In addition, contamination of a sample by modern carbon, introduced during burial or by handling afterwards, can make a sample seem younger than it actually is (2). The problem is particularly acute for samples that antedate 30,000 y ago because they retain very little original ¹⁴C.Here, we describe a genetic approach for dating ancient samples, applicable in cases where DNA sequence data are available, as is becoming increasingly common (1). This method relies on the insight that an ancient genome has experienced fewer generations of evolution compared with the genomes of its living (i.e., extant) relatives. Because recombination occurs at an approximately constant rate per generation, the accumulated number of recombination events provides a molecular clock for the time elapsed or, in the case of an ancient sample, the number of missing generations since it ceased to evolve. This idea is referred to as “branch shortening” and estimates of missing evolution can be translated into absolute time in years by using an estimate of the mean age of reproduction (generation interval) or an independent calibration point such as human–ape divergence time.Branch shortening has been used in studies of population history, for inferring mutation rates, and for establishing time scales for phylogenic trees in humans and other species (4, 5). It was first applied for dating ancient samples on a genome-wide scale by Meyer et al. (6), who used the mutation clock (instead of the recombination clock as proposed here) to estimate the age of the Denisova finger bone, which is probably older than 50,000 y, and has not been successfully radiocarbon dated (6). Specifically, the authors compared the divergence between the Denisova and extant humans and calibrated the branch shortening relative to human–chimpanzee (HC) divergence time. The use of ape divergence time for calibration, however, relies on estimates of mutation rate that are uncertain (7). In particular, recent pedigree studies have yielded a yearly mutation rate that is approximately twofold lower than the one obtained from phylogenetic methods (7). In addition, comparison with HC divergence relies on branch-shortening estimates that are small relative to the total divergence of millions of years, so that even very low error rates in allele detection can bias estimates. These issues lead to substantial uncertainty in estimated age of the ancient samples, making this approach impractical for dating specimens that are tens of thousands of years old, a time period that encompasses the vast majority of ancient human samples sequenced to date.Given the challenges associated with the use of the mutation clock, here we explore the possibility of using a molecular clock based on the accumulation of crossover events (the recombination clock), which is measured with high precision in humans (8). In addition, instead of using a distant outgroup, such as chimpanzees, we rely on a more recent shared event that has affected both extant and ancient modern humans and is therefore a more reliable fixed point on which to base the dating. Previous studies have documented that most non-Africans derive 1–4% ancestry from Neanderthals from an admixture event that occurred ∼37,000–86,000 y before present (yBP) (9, 10), with some analyses proposing a second event (around the same time) into the ancestors of East Asians (11, 12). Because the vast majority of ancient samples sequenced to date were discovered in Eurasia (with estimated ages of ∼2,000–45,000 yBP), postdate the Neanderthal admixture, and show evidence of Neanderthal ancestry, we used the Neanderthal gene flow as the shared event.The idea of our method is to estimate the date of Neanderthal gene flow separately for the extant and ancient genomes. Because the ancient sample is closer in time to the shared Neanderthal admixture event, we expect that the inferred dates of Neanderthal admixture will be more recent in ancient genomes (by an amount that is directly determined by the sample’s age) compared with the dates in the extant genomes. The difference in the dates thus provides an estimate of the amount of missing evolution: that is, the age of the ancient sample. An illustration of the idea is shown in SI Appendix, Fig. S1. An assumption in our approach is that the Neanderthal admixture into the ancestors of modern humans occurred approximately at the same time and that the same interbreeding events contributed to the ancestry of all of the non-African samples being compared. Deviations from this model could lead to incorrect age estimates. Our method is not applicable for dating genomes that do not have substantial Neanderthal ancestry, such as sub-Saharan African genomes.To date the Neanderthal admixture event, we used the insight that gene flow between genetically distinct populations, such as Neanderthals and modern humans, introduces blocks of archaic ancestry into the modern human background that break down at an approximately constant rate per generation as crossovers occur (13–15). Thus, by jointly modeling the decay of Neanderthal ancestry and recombination rates across the genome, we can estimate the date of Neanderthal gene flow, measured in units of generations. Similar ideas have been used to estimate the time of admixture events between contemporary human populations (14–16), as well as between Eurasians and Neanderthals (9, 17). An important feature of our method is that it is expected to give more precise results for samples that are older because these samples are closer in time to the Neanderthal introgression event, thus it is easier to accurately estimate the time of the admixture event for them. Thus, unlike ¹⁴C dating, the genetic approach becomes more reliable with age and, in that regard, complements ¹⁴C dating.