Repeated Treatment with 90Y-Microspheres in Intrahepatic Cholangiocarcinoma Relapsed After the First Radioembolization

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Evidence of Significant Ceftriaxone and Quinolone Resistance in Cirrhotics with Spontaneous Bacterial Peritonitis

Abstract

Objectives

There are few studies addressing the impact of cephalosporin and quinolone resistance on hospital length of stay and mortality in spontaneous bacterial peritonitis (SBP). We aim to describe the shifting epidemiology of SBP at our institution and its impact on clinical outcomes.

Methods

We performed a single-center retrospective cohort study of all cases of SBP from 2005 to 2015 at a transplant center. Cases were identified using hospital billing data. Patient data were confirmed using the electronic medical record. Univariate and multivariate logistic regression and Cox proportional hazards models were used to identify factors that were associated with prolonged hospital length of stay and reduced survival. Culture-positive cases (N = 56) were compared to culture-negative cases (N = 104). Subpopulation analysis of the culture-positive cases compared ceftriaxone-resistant (N = 25) to ceftriaxone-susceptible (N = 31) cases.

Results

We identified 160 cases of SBP (56 culture positive and 104 culture negative; 21 nosocomial, 79 hospital associated, and 60 community acquired). Forty-five percent (N = 25 total, 13 hospital associated and 6 nosocomial) of bacterial isolates were resistant to ceftriaxone, with 37.5% (N = 21) being gram positive, including 8 methicillin-resistant staphylococcus and 6 vancomycin-resistant enterococcus. Multivariate analysis identified hospital-associated SBP, age, alcoholic cirrhosis, and MELD-Na score as variables associated with worse survival (P < 0.05), with a trend toward worse survival in culture-positive cases (P = 0.123). Only MELD-Na was associated with prolonged length of stay.

Conclusions

The burden of resistant pathogens causing SBP is significant, notably in hospital-associated SBP. Culture-positive SBP may represent a higher risk group compared to culture-negative SBP.

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Effects of Tec Tyrosine Kinase Inhibition on the Inflammatory Response of Severe Acute Pancreatitis-Associated Acute Lung Injury in Mice

Abstract

Background

The Tec kinase family is involved in acute and chronic inflammatory diseases, but its relationship with severe acute pancreatitis (SAP) remains unclear.

Aims

To investigate whether Tec tyrosine kinase can be used as a target for severe acute pancreatitis-associated acute lung injury (PALI).

Methods

A total of 90 mice were randomly assigned into four groups: SAP (n = 15), control (n = 15), SAP + α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13) (pretreated with Tec kinase inhibitor LFM-A13, n = 15), and SAP + Tec siRNA (pretreated with PBS/negative control siRNA/Tec siRNA, n = 45). SAP was induced by caerulein and lipopolysaccharide. Animals were sacrificed at 0, 3, 24, 48, and 72 h, respectively. Pathological changes and scores of the lung and pancreas were determined using hematoxylin–eosin staining. Expression of Tec and phosphorylated Tec (p-Tec) were examined by real-time polymerase chain reaction, Western blot, and immunoprecipitation. Serum levels of amylase, myeloperoxidase, and pro-inflammatory cytokines were measured by ELISA.

Results

The expression of Tec in lung tissue was significantly higher in the SAP group than in the control group (p < 0.05), and p-Tec expression gradually increased with time. Furthermore, p-Tec expression was significantly lower in the SAP + LFM-A13 group than in the SAP group (p < 0.05); however, Tec expression did not vary. Tec inhibitors, LFM-A13 and Tec siRNA, alleviated pathological damage and release of inflammatory cytokines (p < 0.05).

Conclusions

Tec tyrosine kinase plays a key role in PALI, and is therefore a potential target for clinical treatment.

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Risk Behaviors Associated with Alcohol Consumption Predict Future Severe Liver Disease

Abstract

Background

Excess consumption of alcohol can lead to cirrhosis, but it is unclear whether the type of alcohol and pattern of consumption affects this risk.

Aims

We aimed to investigate whether type and pattern of alcohol consumption early in life could predict development of severe liver disease.

Methods

We examined 43,242 adolescent men conscribed to military service in Sweden in 1970. Self-reported data on total amount and type of alcohol (wine, beer, and spirits) and risk behaviors associated with heavy drinking were registered. Population-based registers were used to ascertain incident cases of severe liver disease (defined as cirrhosis, decompensated liver disease, liver failure, hepatocellular carcinoma, or liver-related mortality). Cox regression models were used to estimate hazard ratios for development of severe liver disease.

Results

During follow-up, 392 men developed severe liver disease. In multivariable analysis, after adjustment for BMI, smoking, use of narcotics, cardiovascular fitness, cognitive ability, and total amount of alcohol, an increased risk for severe liver disease was found in men who reported drinking alcohol to alleviate a hangover ("eye-opener"; aHR 1.47, 95% CI 1.02–2.11) and men who reported having been apprehended for being drunk (aHR 2.17, 95% CI 1.63–2.90), but not for any other risk behaviors. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits.

Conclusions

Certain risk behaviors can identify young men with a high risk of developing severe liver disease. Wine consumption was not associated with a reduced risk for severe liver disease compared to beer and spirits.

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Understanding the Loss of Maternal Care in Avian Brood Parasites Using Preoptic Area Transcriptome Comparisons in Brood Parasitic and Non-parasitic Blackbirds

Parental care is critical for offspring survival in many species. However, parental behaviors have been lost in roughly 1% of avian species known as the obligate brood parasites. To shed light on molecular and neurobiological mechanisms mediating brood parasitic behavior, we compared brain gene expression patterns between two brood parasitic species and one closely related non-parasitic Icterid (blackbird) species. Our analyses focused on gene expression changes specifically in the preoptic area (POA), a brain region known to play a critical role in parental behavior across vertebrates. Using comparative transcriptomic approaches, we identified gene expression patterns associated with brood parasitism. We evaluated three non-mutually exclusive alternatives for the evolution of brood parasitism: (1) retention of juvenile-like (neotenic) gene expression, (2) reduced expression of maternal care-related genes in the POA, and/or (3) increased expression of genes inhibiting maternal care. We find evidence for neotenic expression patterns in both species of parasitic cowbirds as compared to maternal, non-parasites. In addition, we observed differential expression in a number of genes with previously established roles in mediating maternal care. Together, these results provide the first insight into transcriptomic and genetics mechanisms underlying the loss of maternal behavior in avian brood parasites

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Lost in Translation: On the Problem of Data Coding in Penalized Whole Genome Regression with Interactions

Mixed models can be considered as a type of penalized regression and are everyday tools in statistical genetics. The standard mixed model for whole genome regression (WGR) is ridge regression best linear unbiased prediction (RRBLUP) which is based on an additive marker effect model. Many publications have extended the additive WGR approach by incorporating interactions between loci or between genes and environment. In this context of penalized regressions with interactions, it has been reported that translating the coding of single nucleotide polymorphisms -for instance from -1,0,1 to 0,1,2- has an impact on the prediction of genetic values and interaction effects. In this work, we identify the reason for the relevance of variable coding in the general context of penalized polynomial regression. We show that in many cases, predictions of the genetic values are not invariant to translations of the variable coding, with an exception when only the sizes of the coefficients of monomials of highest total degree are penalized. The invariance of RRBLUP can be considered as a special case of this setting, with a polynomial of total degree 1, penalizing additive effects (total degree 1) but not the fixed effect (total degree 0). The extended RRBLUP (eRRBLUP), which includes interactions, is not invariant to translations because it does not only penalize interactions (total degree 2), but also additive effects (total degree 1). This observation implies that translation-invariance can be maintained in a pair-wise epistatic WGR if only interaction effects are penalized, but not the additive effects. In this regard, approaches of pre-selecting loci may not only reduce computation time, but can also help to avoid the variable coding issue. To illustrate the practical relevance, we compare different regressions on a publicly available wheat data set. We show that for an eRRBLUP, the relevance of the marker coding for interaction effect estimates increases with the number of variables included in the model. A biological interpretation of estimated interaction effects may therefore become more difficult. Consequently, comparing reproducing kernel Hilbert space (RKHS) approaches to WGR approaches modeling effects explicitly, the supposed advantage of an increased interpretability of the latter may not be real. Our theoretical results are generally valid for penalized regressions, for instance also for the least absolute shrinkage and selection operator (LASSO). Moreover, they apply to any type of interaction modeled by products of predictor variables in a penalized regression approach or by Hadamard products of covariance matrices in a mixed model.

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ERF‐related craniosynostosis: The phenotypic and developmental profile of a new craniosynostosis syndrome

Mutations in the ERF gene, coding for ETS2 repressor factor, a member of the ETS family of transcription factors cause a recently recognized syndromic form of craniosynostosis (CRS4) with facial dysmorphism, Chiari‐1 malformation, speech and language delay, and learning difficulties and/or behavioral problems. The overall prevalence of ERF mutations in patients with syndromic craniosynostosis is around 2%, and 0.7% in clinically nonsyndromic craniosynostosis. Here, we present findings from 16 unrelated probands with ERF‐related craniosynostosis, with additional data from 20 family members sharing the mutations. Most of the probands exhibited multisutural (including pan‐) synostosis but a pattern involving the sagittal and lambdoid sutures (Mercedes‐Benz pattern) predominated. Importantly the craniosynostosis was often postnatal in onset, insidious and progressive with subtle effects on head morphology resulting in a median age at presentation of 42 months among the probands and, in some instances, permanent visual impairment due to unsuspected raised intracranial pressure (ICP). Facial dysmorphism (exhibited by all of the probands and many of the affected relatives) took the form of orbital hypertelorism, mild exorbitism and malar hypoplasia resembling Crouzon syndrome but, importantly, a Class I occlusal relationship. Speech delay, poor gross and/or fine motor control, hyperactivity and poor concentration were common. Cranial vault surgery for raised ICP and/or Chiari‐1 malformation was expected when multisutural synostosis was observed. Variable expressivity and nonpenetrance among genetically affected relatives was encountered. These observations form the most complete phenotypic and developmental profile of this recently identified craniosynostosis syndrome yet described and have important implications for surgical intervention and follow‐up.

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