Influence of ventricular pacing on myocardial oxygen tension

INTRODUCTION: The influence of heart rate on cardiac output, oxygen consumption, and myocardial activity has been widely investigated. However, the influence of heart rate on myocardial oxygen tension (pO2) remains unclear. Since the introduction of flexible pO2 micro catheters to measure partial oxygen tension in a working muscle, it is possible to investigate the influence of heart rate on myocardial oxygen tension. METHODS: Intraoperatively, a flexible pO2 micro catheter was positioned in the mid-myocardium of 8 male farm pigs. The heart rate was varied via an external pacer from base rate up to fibrillation and the corresponding myocardial pO2 was measured. RESULTS: Within 2 min, the myocardial pO2 adjusted to a change in heart rate. In this animal model, an optimal myocardial pO2 was observed at 109 bpm. A further increase in heart rate led to a decrease in myocardial pO2. When the heart rate was reaching the level of a fibrillation, pO2 dropped to zero. CONCLUSION: In young healthy pigs--with a normal blood vessel regulation and the pharmacologic and experimental conditions used in this study--a significant relation between myocardial pO2 and heart rate was observed. Myocardial oxygen tension increased during cardiac pacing until a heart rate of 109 bpm. Thereafter a decline of pO2 occurred. Each change in heart rate resulted in a corresponding change of pO2 within roughly 2 min.     

Fluid therapy and acute kidney injury in cardiogenic shock after cardiac arrest

Aim of the study

It has recently been suggested that acute kidney injury (AKI) may strongly be influenced by post-resuscitation disease and cardiogenic shock (CS), and may not just be a consequence of cardiac arrest and time without spontaneous circulation. AKI also has been suggested as a strong independent predictor of in-hospital mortality. Therefore the present study aimed at investigating the effect of fluid management on the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated by mild therapeutic hypothermia.

Methods

Fluid therapy and the incidence of acute kidney injury (AKI) was retrospectively reviewed in 51 patients with cardiogenic shock after cardiac arrest comparing patients with and without hemodynamic (PPV, SVV) and volumetric (ELWI, GEDI) monitoring.

Results

There was no significant difference in baseline or cardiac arrest characteristics between hemodynamic monitored patients and conventional monitored patients. 28 patients were monitored by standard monitoring, in 23 patients monitoring was complemented by a PICCO system. In the first 24 h of treatment the total amount of fluid was significantly higher in patients under PICCO monitoring compared to conventional monitoring (4375 ± 1285 ml vs. 5449 ± 1438 ml, p = 0.007). This was associated with a significant reduction in the incidence of AKI (RIFLE ‘I’/‘F’: PICCO-group: 1 (4.3%) vs. conventional group 8 (28.6%), p = 0.03).

Conclusion

The presented data suggest that volume therapy guided by volumetric (ELWI, GEDI) and arterial waveform derived variables (PPV, SVV) can reduce the incidence of AKI in patients with cardiogenic shock after cardiac arrest treated with mild therapeutic hypothermia.     

Molecular biomarkers have the potential to improve the diagnostic work-up of pancreatic cystic lesions

Pancreatic cysts are increasingly diagnosed due to the widespread use of cross-sectional imaging, and some of these lesions harbor malignant potential. Mucinous cystic neoplasms and intraductal papillary mucinous neoplasms are the major premalignant cystic neoplasms of the pancreas. A variety of diagnostic tools are used to predict the malignant potential of these cysts, but specificity and sensitivity are limited. Thus, many patients undergo unnecessary operations for benign cysts. Balancing the risks of watchful waiting with those of operative management is key in managing these lesions. During the last decade, genetic changes of pancreatic cysts have been examined extensively to estimate their malignant potential. In this review, we provide an overview of the latest molecular and genetic aspects of pancreatic cysts and how they may contribute to the differential diagnosis in patients with pancreatic cystic neoplasms.     

Large-scale determinants of intestinal schistosomiasis and intermediate host snail distribution across Africa: does climate matter?

The geographical ranges of most species, including many infectious disease agents and their vectors and intermediate hosts, are assumed to be constrained by climatic tolerances, mainly temperature. It has been suggested that global warming will cause an expansion of the areas potentially suitable for infectious disease transmission. However, the transmission of infectious diseases is governed by a myriad of ecological, economic, evolutionary and social factors. Hence, a deeper understanding of the total disease system (pathogens, vectors and hosts) and its drivers is important for predicting responses to climate change. Here, we combine a growing degree day model for Schistosoma mansoni with species distribution models for the intermediate host snail (Biomphalaria spp.) to investigate large-scale environmental determinants of the distribution of the African S. mansoni-Biomphalaria system and potential impacts of climatic changes. Snail species distribution models included several combinations of climatic and habitat-related predictors; the latter divided into “natural” and “human-impacted” habitat variables to measure anthropogenic influence. The predictive performance of the combined snail–parasite model was evaluated against a comprehensive compilation of historical S. mansoni parasitological survey records, and then examined for two climate change scenarios of increasing severity for 2080. Future projections indicate that while the potential S. mansoni transmission area expands, the snail ranges are more likely to contract and/or move into cooler areas in the south and east. Importantly, we also note that even though climate per se matters, the impact of humans on habitat play a crucial role in determining the distribution of the intermediate host snails in Africa. Thus, a future contraction in the geographical range size of the intermediate host snails caused by climatic changes does not necessarily translate into a decrease or zero-sum change in human schistosomiasis prevalence.     

Characterization of the sensitizing potential of chemicals by in vitro analysis of dendritic cell activation and skin penetration

Development of in vitro models to identify sensitizing chemicals receives public interest since animal testing should be avoided whenever possible. In this article we analyze two essential properties of sensitizing chemicals: skin penetration and dendritic cell (DC) activation. Activation of immature DC derived from peripheral blood monocytes was evaluated by flow cytometric analysis of CD86 positive cells and quantitative measurement of interleukin-1beta and aquaporin P3 gene expression. The sensitizer 2,4,6-trinitrobenzenesulfonic acid induced a concentration-dependent response for all parameters, whereas the irritant sodium lauryl sulfate did not. When two related aromatic amines, p-toluylenediamine (PTD) and hydroxyethyl-p-phenylenediamine (HE-PPD) were tested, both induced substantial DC activation indicating their potential sensitizing properties. These findings contrasted with in vivo results: in murine local lymph node assays (LLNA) PTD, but not HE-PPD, was sensitizing using acetone/aqua/olive oil as vehicle. Skin penetration measurement revealed that this was due to bioavailability differences. On retesting HE-PPD in the LLNA using the penetration enhancer dimethylsulfoxide as vehicle, it induced a specific response. We conclude that in vitro analysis of DC activation capability of the two selected chemicals demonstrates that prediction of skin sensitization potential is possible provided that skin penetration data indicate sufficient bioavailability of the test compound.     

The tumor gene survivin is highly expressed in adult renal tubular cells: implications for a pathophysiological role in the kidney

The inhibitor of apoptosis protein survivin is of critical importance for regulation of cellular division and survival. Published data point to a restricted function of survivin in embryonic development and cancer; thus survivin has been broadly proposed as an ideal molecular target for specific anti-cancer therapy. In contrast to this paradigm, we report here broad expression of survivin in adult differentiated tissues, as demonstrated at the mRNA and protein levels. Focusing on the kidney, survivin is strongly expressed in proximal tubuli, particularly at the apical membrane, which can be verified in rat, mouse, and human kidneys. In the latter, survivin expression seems to be even stronger in proximal tubuli than in adjacent cancerous tissue. Primary and immortalized human renal tubular cells also showed high levels of survivin protein expression, and RNA interference resulted in a partial G(2)/M arrest of the cell cycle and increased rate of apoptosis. In conclusion, survivin may be of importance for renal pathophysiology and pathology. The predominant apical expression of survivin may indicate a further, yet unknown, function. Interventional strategies to inhibit survivin's function in malignancy need to be carefully (re)evaluated for renal side effects, as well as for other possible organ dysfunctions.     

Characterization and investigation of single nucleotide polymorphisms and a novel TLR2 mutation in the human TLR2 gene

In the innate immune system, TLR2 plays a central role for the response to a wide variety of microbial and endogenous danger signals. A considerable number of genetic polymorphisms within the human TLR2 gene have been reported in non-coding and coding sequences. Except for the Arg753Gln variant, however, their clinical relevance is unclear and the assessment of the effects of amino acid substitutions on receptor function is lacking. In the present study, we have characterized all known single nucleotide polymorphisms (SNPs) of TLR2 for their functional relevance in transiently transfected HEK293 cells subsequently exposed to a specific stimulus. Among the known non-synonymous SNPs in the TLR2 coding sequence, four SNPs (Thr411Ile, Tyr715stop, Tyr715Lys and Arg753Gln) were found to be functionally relevant in our experimental setting. In addition, we identified a new mutation Arg447stop leading to a premature stop codon in the extracellular portion of the receptor. TLR2-specific stimulation of whole blood from two heterozygote donors of this mutation resulted in a reduced secretion of pro-inflammatory cytokines. Finally, we tested the prevalence of these functional genetic variants in 169 healthy individuals of Caucasian origin for the mutations in the extracellular domain and 106 individuals for the mutations in the intracellular domain of the receptor. Except for 10 heterozygote donors of the Arg753Gln variant determined to be prevalent in 9.4% of the tested individuals, none of the other SNPs was found in this population.     

Skin sensitization to p-phenylenediamine: the diverging roles of oxidation and N-acetylation for dendritic cell activation and the immune response

Skin is a target of allergic reactions to aromatic amine hair dye precursors, such as p-phenylenediamine (PPD). As conversion of PPD on or in the skin is expected to be required for the induction of allergic contact dermatitis, we analyzed the role of oxidation and N-acetylation as major transformation steps. PPD and its oxidative and N-acetylated derivatives were tested for their sensitizing potential in vitro using a dendritic cell (DC) activation assay and in vivo using the local lymph node assay (LLNA). PPD did not induce relevant DC activation but induced a positive LLNA response. In contrast, DC activation was obtained when PPD was chemically pre-oxidized or after air oxygen exposure. Under both conditions, the potent sensitizing PPD oxidation product Bandrowski's base was identified along with other di- and trimeric species, indicating that PPD oxidation products provide an effective immune stimulation (danger signal). In contrast mono- and diacetylated PPD did not induce DC activation or a positive LLNA response. We conclude that dermal N-acetylation of PPD competes with the formation of oxidized PPD whereas skin exposure conditions allowing auto-oxidation, as in the LLNA, provide an effective danger signal necessary to induce skin sensitization to PPD.