Contrasting dynamic responses in vivo of the Bcl-xL and Bim erythropoietic survival pathways

Survival signaling by the erythropoietin (Epo) receptor (EpoR) is essential for erythropoiesis and for its acceleration in hypoxic stress. Several apparently redundant EpoR survival pathways were identified in vitro, raising the possibility of their functional specialization in vivo. Here we used mouse models of acute and chronic stress, including a hypoxic environment and β-thalassemia, to identify two markedly different response dynamics for two erythroblast survival pathways in vivo. Induction of the antiapoptotic protein Bcl-x(L) is rapid but transient, while suppression of the proapoptotic protein Bim is slower but persistent. Similar to sensory adaptation, however, the Bcl-x(L) pathway "resets," allowing it to respond afresh to acute stress superimposed on a chronic stress stimulus. Using "knock-in" mouse models expressing mutant EpoRs, we found that adaptation in the Bcl-x(L) response occurs because of adaptation of its upstream regulator Stat5, both requiring the EpoR distal cytoplasmic domain. We conclude that survival pathways show previously unsuspected functional specialization for the acute and chronic phases of the stress response. Bcl-x(L) induction provides a "stop-gap" in acute stress, until slower but permanent pathways are activated. Furthermore, pathologic elevation of Bcl-x(L) may be the result of impaired adaptation, with implications for myeloproliferative disease mechanisms.     

A model of the viscoelastic behavior of flowable resin composites prior to setting

Objective

The aim of this study is to develop fractional derivative models for the assessment of viscoelastic properties related to handling characteristics of dental resin composites belonging to two classes: flowable (Revolution Formula 2 and Filtek Ultimate) and posterior “bulk-fill” flowable base (Smart Dentin Replace).

Methods

Rheological measurements on all materials tested in this study were performed using dynamic oscillatory rheometer at temperature of 23 °C. A parallel plates module with a diameter of 20 mm was used to measure the properties of the resin composites tested. We developed two models to describe the obtained data: the generalized Newton model and the generalized Zener model (the so-called three parameter model). Both models contain fractional derivatives of Riemann–Liouville type. By determining the parameters of the model we were able to fit experimental data with high accuracy.

Results

Our results show that flowable “bulk-fill” resin-composite material (SDR) has distinct properties as compared to other two flowable resin composite materials (Revolution Formula 2 and Filtek Ultimate). Thus, previously found SDR properties as “bulk-fill” flowable base results in the fact that it is described by generalized Zener model (i.e., it has properties of solid like viscoelastic material).

Significance

Our model may be used to predict behavior of tested composites in different flow conditions. The SDR has initially small almost constant complex viscosity showing that it has good self-leveling property.     

Metastases of esophageal carcinoma to skeletal muscle: Single center experience

Metastases of esophageal carcinoma to the skeletal muscle are rare, but the incidence may be increasing because of better diagnosis resulting from widespread use of positron emission tomography/computed tomography (PET/CT). A cohort of 205 patients with esophageal carcinoma treated at our center who had PET/CT between 2006 and 2010 was retrospectively evaluated for the presence of skeletal muscle metastases. Four patients had skeletal muscle metastases of esophageal carcinoma, including two patients with squamous cell carcinoma. In another patient with squamous cell carcinoma of the esophagus and synchronous skeletal muscle metastases, muscle metastases were subsequently shown to be related to second primary pancreatic adenocarcinoma. In all cases, skeletal muscle metastases were the first manifestation of systemic disease. In three patients palliation was obtained with the combination of external beam radiation therapy, systemic chemotherapy or surgical resection. Skeletal muscle metastases are a rare complication of esophageal carcinoma.     

Correlation between atmospheric pressure changes and abdominal aortic aneurysm rupture: results of a single-center study

Purpose

There is much interest in all factors that influence the etiopathogenesis of abdominal aortic aneurysm (AAA) rupture. Apart from the well-established factors such as arterial hypertension, smoking, age, and genetic predisposition, less common factors that may play a role in the mechanism of the rupture are the subject of much discussion. These include atmospheric conditions, temperature, and atmospheric pressure. We conducted this study to investigate the effects of the absolute value of atmospheric pressure and its changes on the frequency of AAA rupture.

Methods

We retrospectively examined 54 patients who underwent treatment for a ruptured AAA at the Clinic of Surgery in the University Hospital in Pilsen between 1 January 2005 and 31 December 2009. We collected data on the atmospheric pressure in this period from the Czech Hydrometeorological Institute in Pilsen.

Results

We did not find a significant difference in atmospheric pressure values between the days when the rupture occurred versus the other days (p < 0.5888). Moreover, we did not find significant changes in the atmospheric pressure during the 48 h preceding the rupture (Student’s test p < 0.4434) versus the day of rupture or in the mean atmospheric pressure in that month.

Conclusion

These findings suggest that atmospheric pressure and its changes do not affect the pathogenesis of AAA rupture.     

Acidiella bohemica gen. et sp. nov. and Acidomyces spp. (Teratosphaeriaceae), the indigenous inhabitants of extremely acidic soils in Europe

Extremely acidic soils (pH?<?3) harbour mycobiota that are different from less acidic habitats and are dominated by a small number of fungal species. During investigation of the mycobiota of highly acidic soils in the Czech Republic and Iceland, a group of melanised fungal isolates was obtained. Based on phenotype and nuclear ribosomal DNA sequences (ITS region, SSU, LSU), the isolates were accommodated by three phylogenetic lineages within the family Teratosphaeriaceae (Capnodiales, Dothideomycetes). The first lineage is here described as a new acidotolerant genus and species Acidiella bohemica gen. nov. et sp. nov. The most closely related species to this new clade are other extremotolerant fungi isolated from rocks and lichens collected in the Alps and Antarctica as well as leaf-spotting species and opportunistic human pathogens. The isolates belonging to the second and the third lineages were identified as the recently described acidophilic fungi Acidomyces acidophilus and Teratosphaeria acidotherma, respectively. The taxonomic status of both sister species is discussed and the latter species is ascribed here to the genus Acidomyces.     

A case report of rapid spontaneous redistribution of acute supratentorial subdural hematoma to the entire spinal subdural space presenting as a Pourfour du Petit Syndrome and review of the literature

Objective

This report illustrates the rare rapid spontaneous redistribution of an acute intracranial supratentorial subdural hematoma (AISSDH) to the entire spinal subdural space (SSS). The study is also unique in that the spinal subdural hematoma (SSH) manifested by the extremely rare Pourfour du Petit Syndrome (PPS).

Methods

A 66-year-old man sustained blunt head trauma. On admission to the regional hospital, he scored 6 on GCS and his pupils were of equal size reacting to light. Initial computed tomography (CT) scan showed a unilateral AISSDH. The patient was referred to our department and arrived 16 h following the accident, at which time a repeat CT scan revealed almost complete resolution of the AISSDH without clinical improvement. On the 9th postinjury day transient anisocoria and tachycardia without spinal symptomatology developed. Since neither neurological examination nor follow-up CT scans showed intracranial pathology explaining the anisocoria, the patient was treated further conservatively. During the next 3 days circulatory instability developed and the patient succumbed to primary traumatic injury. Autopsy revealed a SSH occupying the entire SSS.

Conclusion

This case calls attention to the unique combination of the displacement of an AISSDH to the SSS and the presentation of this clinical entity by the PPS.     

Validation of flavonoids as potential dipeptidyl peptidase III inhibitors: Experimental and computational approach

Fifteen flavonoids were studied for their inhibitory activity against human dipeptidyl peptidase III (hDPP III) combining an in vitro assay with an in silico molecular modeling study. All analyzed flavonoids showed inhibitory effects against hDPP III with the IC₅₀ values ranging from 22.0 to 437.2 μm . Our 3D QSAR studies indicate that the presence of hydrophilic regions at a flavonoid molecule increases its inhibitory activity, while the higher percentage of hydrophobic surfaces has negative impact on enzyme inhibition. Furthermore, molecular dynamics (MD) simulations of the complex of hDPP III with one of the most potent inhibitors, luteolin, were performed, and binding mode analysis revealed that the 3′ and 4′ hydroxyl group on B‐ring as well as 5 and 7 hydroxyl group on A‐ring helps luteolin to interact with the Asn391, Asn406, Tyr417, His450, Glu451, Val447, Glu512, Asn545, Gln566, and Arg572 residues. The MD results clearly provide valuable information explaining the importance of flavonoid hydroxyl groups in the mechanism for the binding pattern at the active site of hDPP III.