Stimulus-Specific Adaptation in Field Potentials and Neuronal Responses to Frequency-Modulated Tones in the Primary Auditory Cortex

In order to structure the sensory environment our brain needs to detect changes in the surrounding that might indicate events of presumed behavioral relevance. A characteristic brain response presumably related to the detection of such novel stimuli is termed mismatch negativity (MMN) observable in human scalp recordings. A candidate mechanism underlying MMN at the neuronal level is stimulus-specific adaptation (SSA) which has several characteristics in common. SSA is the specific decrease in the response to a frequent stimulus, which does not generalize to an interleaved rare stimulus in a sequence of events. SSA was so far mainly described for changes in the response to simple pure tone stimuli differing in tone frequency. In this study we provide data from the awake rat auditory cortex on adaptation in the responses to frequency-modulated tones (FM) with the deviating feature being the direction of FM modulation. Adaptation of cortical neurons to the direction of FM modulation was stronger for slow modulation than for faster modulation. In contrast to pure tone SSA which showed no stimulus preference, FM adaptation in neuronal data differed sometimes between upward and downward FM. This, however, was not the case in the local field potential data recorded simultaneously. Our findings support the role of the auditory cortex as the source for change-related activity induced by FM stimuli by showing that dynamic stimulus features such as FM modulation can evoke SSA in the rat in a way very similar to FM-induced MMN in the human auditory cortex.     

Cardiac troponin in ischemic cardiomyocytes: Intracellular decrease before onset of cell death

Aim

Cardiac troponin I (cTnI) and T (cTnT) are the most important biomarkers in the diagnosis of acute myocardial infarction (AMI). Nevertheless, they can be elevated in the absence of AMI. It is unclear if such elevations represent irreversible cardiomyocyte-damage or leakage from viable cardiomyocytes. Our objective is to evaluate whether cTn is released from viable cardiomyocytes in response to ischemia and to identify differences in the release of cTn and its molecular forms.

Methods and results

HL-1 cardiomyocytes (mouse) were subjected to ischemia (modeled by anoxia with glucose deprivation). The total contents and molecular forms of cTn were determined in culture media and cell lysates. Cell viability was assessed from the release of lactate dehydrogenase (LDH). Before the release of LDH, the intracellular cTn content in ischemic cells decreased significantly compared to control (52% for cTnI; 23% for cTnT) and was not matched by a cTn increase in the medium. cTnI decreased more rapidly than cTnT, resulting in an intracellular cTnT/cTnI ratio of 25.5 after 24 h of ischemia. Western blots revealed changes in the relative amounts of fragmented cTnI and cTnT in ischemic cells.

Conclusions

HL-1 cardiomyocytes subjected to simulated ischemia released cTnI and cTnT only in combination with the release of LDH. We find no evidence of cTn release from viable cardiomyocytes, but did observe a significant decrease in cTn content, before the onset of cell death. Intracellular decrease of cTn in viable cardiomyocytes can have important consequences for the interpretation of cTn values in clinical practice.     

The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4+ T‐cell compartment

Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8–12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4⁺ T‐cell dependent, since old (40–50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age‐related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4⁺ T cells that promote ANA production were radioresistant. Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T‐cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T‐cell homeostasis may drive the onset of some autoimmune features.     

IMPACT OF THE DARE TO BE YOU FAMILY SUPPORT PROGRAM: COLLABORATIVE REPLICATION IN RURAL COUNTIES

Rural families often have unmet needs for services to strengthen family functioning and promote optimal youth development. Community needs assessments conducted at 2 rural sites led to a community‐university collaboration that implemented the DARE to be You (DTBY) program for families and youth aged 9 years at one site and aged 13 years at the second site. Families in the DTBY intervention, in contrast to a matched comparison group, evinced significantly greater gains in parent self‐efficacy, effective child‐rearing practices (i.e., more democratic and less coercive), and positive parent‐child relationships. As well, changes to community assets were documented in the form of increased human services to strengthen families. The results are discussed in terms of the utility of community–university partnerships to help strengthen rural families and promote community social capital.     

Incidence of sickle cell disease in an unselected cohort of neonates born in Berlin,Germany

Sickle cell disease (SCD) does not occur in the indigenous German population. However, with the increasing numbers of immigrants its prevalence is steadily rising. Nevertheless, robust epidemiological data is not available for Germany and, consequently, the German newborn screening (NBS) program does not include SCD. Between 1 September 2011 and 30 November 2012, an unselected cohort of 34 084 Berlin newborns was tested for SCD. The results of 14 newborns were consistent with SCD and 265 babies were identified as hemoglobin S (Hb S) carriers. These data indicate a 95% probability that the incidence of SCD in Berlin is at least 2.5/10 000.     

Blockade of proteinase-activated receptor 4 inhibits neutrophil recruitment in experimental inflammation in mice

Objective and design

The activation of proteinase-activated receptors (PARs) has been implicated in the development of important hallmarks of inflammation, including in vivo leukocyte recruitment; however, its role in the regulation of leukocyte migration in response to inflammatory stimuli has not been elucidated until now. Here, we examined the effects of the PAR4 antagonist YPGKF-NH 2 (tcY-NH₂) on neutrophil recruitment in experimentally induced inflammation.

Methods

BALB/c mice were intrapleurally injected with tcY-NH₂ (40 ng/kg) prior to intrapleural injection of carrageenan (Cg) or neutrophil chemoattractant CXCL8; the number of infiltrating neutrophils was evaluated after 4 h, and KC production was assessed at different times after Cg injection. Neutrophil adhesion and rolling cells were studied using a brain circulation preparation 4 h after the Cg or CXCL8 challenge in tcY-NH₂-treated mice.

Results

PAR4 blockade inhibited CXCL8- and Cg-induced neutrophil migration into the pleural cavity of BALB/c mice and reduced neutrophil rolling and adherence. Surprisingly, PAR4 blockade increased the level of KC in response to carrageenan.

Conclusion

These results demonstrated that PAR4 blockade impairs neutrophil migration in vivo, suggesting that PAR4 plays an important role in the regulation of inflammation, at least in part because of its ability to inhibit the actions of the neutrophil chemoattractant CXCL8.     

In vivo CYP3A4 activity does not predict the magnitude of interaction between itraconazole and tacrolimus from an extended release formulation

The magnitude of interaction between the CYP3A4 substrate tacrolimus and various CYP3A4 inhibitors is highly unpredictable. We investigated whether an individual's baseline in vivo CYP3A4 activity, assessed using the oral midazolam (MDZ) probe, could be used to predict the magnitude of drug–drug interaction between tacrolimus and the potent CYP3A4 inhibitor itraconazole. In a prospective single‐arm open‐label study, 16 healthy volunteers were administered single doses of MDZ and tacrolimus before and after a 4‐day course of itraconazole. Itraconazole treatment resulted in a 9.0‐fold decrease in MDZ apparent oral clearance (CL/F) and a 3.3‐fold decrease in tacrolimus CL/F (P < 0.001 for each). MDZ CL/F and tacrolimus CL/F were positively correlated both at baseline (r = 0.582, P = 0.018) and after itraconazole (r = 0.811, P < 0.001). Furthermore, baseline MDZ CL/F was positively correlated to the fold change in MDZ CL/F resulting from CYP3A4 inhibition (r = 0.759, P = 0.001). However, no predictors of change in tacrolimus CL/F resulting from CYP3A4 inhibition were identified, including baseline MDZ CL/F (P = 0.453), baseline tacrolimus CL/F (P = 0.759) and fold change in MDZ CL/F between both phases (P = 0.274). In conclusion, baseline oral MDZ clearance does not predict the magnitude of interaction between tacrolimus and itraconazole.     

Age‐time risk patterns of solid cancers in 60 901 non‐Hodgkin lymphoma survivors from Finland,Norway and Sweden

Survival after non‐Hodgkin lymphoma (NHL) has increased thanks to improved treatment but NHL survivors have an increased risk of second neoplasms. The assessment of cancer risk patterns after NHL may help to quantify the late side‐effects of therapy. Poisson regression was used to estimate relative risks (RRs) and absolute incidence rates for nine solid tumours based on a nationwide cohort of 60 901 NHL survivors from Finland, Norway and Sweden. Patients were diagnosed between 1980 and 2006 and developed 6815 s neoplasms. NHL patients showed an increased risk of each of the nine investigated cancer sites: prostate and pancreas (both RRs 1·28), breast (1·37), colorectum (1·48), urinary bladder (1·52), stomach and lung (both RRs 1·87), skin (melanoma 2·27) and kidney (2·56). The RRs showed a U‐shaped relationship with time after NHL for all nine‐second cancer types. NHL diagnosis early in life was a risk factor for the development of second cancers with the exception of melanoma, but a risk excess was even observed in patients diagnosed with NHL at age 80+ years. The present study provides accurate estimates on the adverse late effects of NHL therapy, which should guide the establishment of cancer prevention strategies in NHL survivors.