Models of respiratory rhythm generation in the pre-B?tzinger complex. III. Experimental tests of model predictions.

We used the testable predictions of mathematical models proposed by Butera et al. to evaluate cellular, synaptic, and population-level components of the hypothesis that respiratory rhythm in mammals is generated in vitro in the pre-B?tzinger complex (pre-B?tC) by a heterogeneous population of pacemaker neurons coupled by fast excitatory synapses. We prepared thin brain stem slices from neonatal rats that capture the pre-B?tC and maintain inspiratory-related motor activity in vitro. We recorded pacemaker neurons extracellularly and found: intrinsic bursting behavior that did not depend on Ca(2+) currents and persisted after blocking synaptic transmission; multistate behavior with transitions from quiescence to bursting and tonic spiking states as cellular excitability was increased via extracellular K(+) concentration ([K(+)](o)); a monotonic increase in burst frequency and decrease in burst duration with increasing [K(+)](o); heterogeneity among different cells sampled; and an increase in inspiratory burst duration and decrease in burst frequency by excitatory synaptic coupling in the respiratory network. These data affirm the basis for the network model, which is composed of heterogeneous pacemaker cells having a voltage-dependent burst-generating mechanism dominated by persistent Na(+) current (I(NaP)) and excitatory synaptic coupling that synchronizes cell activity. We investigated population-level activity in the pre-B?tC using local "macropatch" recordings and confirmed these model predictions: pre-B?tC activity preceded respiratory-related motor output by 100-400 ms, consistent with a heterogeneous pacemaker-cell population generating inspiratory rhythm in the pre-B?tC; pre-B?tC population burst amplitude decreased monotonically with increasing [K(+)](o) (while frequency increased), which can be attributed to pacemaker cell properties; and burst amplitude fluctuated from cycle to cycle after decreasing bilateral synaptic coupling surgically as predicted from stability analyses of the model. We conclude that the pacemaker cell and network models explain features of inspiratory rhythm generation in vitro.     

In memory of Prof. Dr. K. T. Friedhoff (* 05.06.1932 – † 02.09. 2018)

Parasitology Research -     

Strategies for management of axillary lymph nodes in breast cancer. Point of view of the Institut Bergonié.

Sentinel lymph node biopsy in breast cancer has changed pathology management of axillary lymph nodes by pathologists, but there is still no consensus either for serial sectioning nor for immunohistochemistry. We analyze: 1) data in the literature about the prognostic significance of micrometastases (pNlmi) and immunohistochemically detected infiltrating tumor cells (pN0(i+) in axillary lymph nodes. 2) management strategies at the Bergonié Institute and by other teams for axillary lymph nodes and sentinel lymph nodes. 3) questions and controversies on sentinel lymph node management and recommendations of the five main reference groups.     

Differentiation of Babesia bigemina, B. bovis, B. divergens and B. major by Western blotting—first report of B. bovis in Austrian cattle

To establish an assay for the serological differentiation of bovine Babesia species (B. bigemina, B. bovis, B. divergens and B. major), antigens from experimentally infected cattle were Western blotted and probed with homologous and heterologous sera. Varying antigen patterns for each species allowed the determination of species-specific diagnostic antigens. Blood samples from 36 naturally infected cattle from the province of Styria were tested by indirect immunofluorescence antibody test (IFAT) against B. divergens, as well as by Western blotting against B. bigemina, B. bovis, B. divergens and B. major, 3 weeks after clinical babesiosis was diagnosed by blood smears. All 36 cattle were B. divergens-positive when tested by IFAT. In four cases (11%), an infection with both B. bovis and B. divergens and in two cases a single infection with B. bovis were diagnosed when tested by Western blot. B. bigemina and B. major infections were not detected. These are the first serologically confirmed cases of B. bovis in Austrian cattle.     

Membranoproliferative glomerulonephritis. One of many diesases?

Membranoproliferative (mesangio-capillary) glomerulonephritis (MPGN) has been divided into two types: type 1, MPGN with subendothelial deposits; type 2, MPGN with intramembranous dense deposits. Although the types are clinically similar, the light, immunofluorescent, and electron microscopical data differ. The cause in the majority of the cases is unknown, but chronic antigenemia as a pathogenic mechanism is suggested in cases associated with chronic bacteremia, chronic hepatitis, parasitic infections, certain blood dyscrasias, and partiallipodystrophy. Both the classic and the alternate pathway of complement activation may be important. The mechanism of the formation of the dense intramembranous deposits is unknown, but activation of the alternate pathway of complement appears to be an important factor. It is emphasized that while there are two basic pathologic types of MPGN, there are diverse clinical syndromes associated with these lesions, the recognition of which is crucial.     

Models of respiratory rhythm generation in the pre-B?tzinger complex. I. Bursting pacemaker neurons.

A network of oscillatory bursting neurons with excitatory coupling is hypothesized to define the primary kernel for respiratory rhythm generation in the pre-B?tzinger complex (pre-B?tC) in mammals. Two minimal models of these neurons are proposed. In model 1, bursting arises via fast activation and slow inactivation of a persistent Na+ current INaP-h. In model 2, bursting arises via a fast-activating persistent Na+ current INaP and slow activation of a K+ current IKS. In both models, action potentials are generated via fast Na+ and K+ currents. The two models have few differences in parameters to facilitate a rigorous comparison of the two different burst-generating mechanisms. Both models are consistent with many of the dynamic features of electrophysiological recordings from pre-B?tC oscillatory bursting neurons in vitro, including voltage-dependent activity modes (silence, bursting, and beating), a voltage-dependent burst frequency that can vary from 0.05 to >1 Hz, and a decaying spike frequency during bursting. These results are robust and persist across a wide range of parameter values for both models. However, the dynamics of model 1 are more consistent with experimental data in that the burst duration decreases as the baseline membrane potential is depolarized and the model has a relatively flat membrane potential trajectory during the interburst interval. We propose several experimental tests to demonstrate the validity of either model and to differentiate between the two mechanisms.     

When are students most at risk of encountering academic difficulty? A study of the 1992 matriculants to U.S. medical schools.

The authors carried out the study reported here to assess which variables are most predictive of the risk of medical students' experiencing academic difficulties and to assess when these students are most susceptible to encountering those difficulties. The entering class of 1992 was chosen as the study population because it was the first matriculating class in which the majority of students (88%) applied to medical school with scores from the revised Medical College Admission Test (MCAT), first implemented in 1991. The primary event of interest in this study was the first occurrence of one of the following events because of academic difficulty: withdrawal, leave of absence, dismissal, or delay of graduation date. The variables examined were MCAT scores undergraduate science GPA, undergraduate institutional selectivity, undergraduate major, racial-ethnic background, sex, and age upon entering medical school. Survival analysis was used to assess which variables were most predictive of the risk of academic difficulty and when students with different characteristics were most at risk. The results of the survival analysis indicated that (1) while the risk and timing of academic difficulty varied across the groups studied, a majority of the students who experienced academic difficulty eventually graduated from medical school and (2) students with non-science undergraduate majors did not have a greater risk of academic difficulty. The results confirm previous findings that increased risk of academic difficulty is associated with low MCAT scores, low science GPA, low undergraduate institutional selectivity, being a woman, being a member of a racial-ethnic underrepresented minority, or being older. The study findings can be generalized to help in early identification of students who are more likely to be at risk of experiencing academic difficulty. Knowing when these students are more likely to be at risk can help medical schools develop targeted remedial and enrichment programs. Further studies are needed to investigate school-related factors associated with risk.