Hyperpolarization-activated (I) currents in auditory brainstem neurons of normal and congenitally deaf mice

We have investigated the membrane properties of brainstem auditory neurons in a mouse model of congenital deafness (dn/dn). Whole-cell recordings were made from visualized neurons in slices of the medial nucleus of the trapezoid body (MNTB) and anteroventral cochlear nucleus (AVCN). We have recently demonstrated that MNTB neurons in deaf mice are more excitable than in normal mice, due in part to a reduced expression of low-threshold potassium currents. In this study, we have examined the contribution of hyperpolarization-activated (Ih) channels to the membrane properties of MNTB and AVCN neurons. Our results show that Ih is larger in MNTB neurons from deaf mice than in normal mice. In contrast, no significant differences were found in Ih or excitability between AVCN bushy cells from dn/dn and normal mice. Experimental evidence and neuronal modelling suggests that, in the MNTB of normal mice, a small contribution of Ih helps to reduce temporal summation of synaptic potentials. A larger Ih in neurons from deaf mice has a much greater effect in reducing temporal summation of synaptic potentials, counteracting to some extent the greater excitability of these cells. Our results provide further insight into the role of activity during development in regulating the membrane and firing properties of central neurons.     

Detection of small implanted tumors growing during repeated magnetic resonance imaging of the rabbit liver: application of an interpretation model

Purpose: To apply experimentally and further develop a new image interpretation model based on repeated imaging and aimed at improving assessments of technical efficacy and diagnostic accuracy in the detection of small lesions.

Material and Methods: VX2 carcinoma was implanted in the liver of 14 rabbits as two 1.1-1.7 mm³ cores. Magnetic resonance imaging was performed before and 4 days after implantation and then every second day up to the 14th to 20th day. One T2-weighted sequence (TSE T2) and three T1-weighted sequences (SE T1, GE T1, and TFL T1) were used. Interpretation was performed stepwise: three readers independently interpreted image sequences chronologically (step 1). Tumors were included at the last examination (step 2). By concurrent interpretation of repeated examinations, the earliest day at which tumors became visible and tumor size were recorded (step 3). Records were corrected (step 4) and autopsy was performed (step 5). Two procedures for use in calculating repeated detection rates of tumors with different magnetic resonance imaging sequences are presented and discussed.

Results: Of 40 macroscopic tumors, 34 were included. They were mainly small (size range SE T1: 1-3 mm, TSE T2: 1.5-5 mm) when they became visible as determined at step 3, which was consistently earlier than observed at step 1. TSE T2, SE T1, and GE T1 did not differ significantly regarding earliest day of detection (step 3), while TFL T1 revealed the tumors later. The initial repeated detection rates were higher with TSE T2 than with the other sequences. Frequency of false positives varied over time, indicating fluctuating criteria for reporting tumors.

Conclusion: A theoretical image interpretation model previously described proved to be applicable for detection of experimental liver tumors. The model was improved by introducing calculations of repeated detection rates for initial image interpretation using an imaging reference standard.     

Dose reduction and its influence on diagnostic accuracy and radiation risk in digital mammography: an observer performance study using an anthropomorphic breast phantom

This study aimed to investigate the effect of dose reduction on diagnostic accuracy and radiation risk in digital mammography. Simulated masses and microcalcifications were positioned in an anthropomorphic breast phantom. Thirty digital images, 14 with lesions, 16 without, were acquired of the phantom using a Mammomat Novation (Siemens, Erlangen, Germany) at each of three dose levels. These corresponded to 100%, 50% and 30% of the normally used average glandular dose (AGD; 1.3 mGy for a standard breast). Eight observers interpreted the 90 unprocessed images in a free response study, and the data were analysed with the jackknife free response receiver operating characteristic (JAFROC) method. Observer performance was assessed using the JAFROC figure of merit (FOM). The benefit of radiation risk reduction was estimated based on several risk models. There was no statistically significant difference in performance, as described by the FOM, between the 100% and the 50% dose levels. However, the FOMs for both the 100% and the 50% dose were significantly different from the corresponding quantity for the 30% dose level (F-statistic = 4.95, p-value = 0.01). A dose reduction of 50% would result in three to nine fewer breast cancer fatalities per 100,000 women undergoing annual screening from the age of 40 to 49 years. The results of the study indicate a possibility of reducing the dose to the breast to half the dose level currently used. This has to be confirmed in clinical studies, and possible differences depending on lesion type should be examined further.     

Emergent Properties of Microglia

More than 80 years ago, Pio Del Rio‐Hortega recognized that one of the “main controversial points in regard to the microglia” is “whether it belongs to the reticulo‐endothelial system [i.e. monocytes and macrophages] and possesses the ordinary characteristics of this system or has a more specialized function.” The notion of microglia having functions that are different from those of other macrophages has gained significant support in recent years. The brain represents a unique environment and shows species, developmental and regional specialization. Thus, any consideration of microglial activity has to be thought of in this tissue context. Contexts may be normal (health, physiology) or disease conditions showing either primary or secondary microglial involvement. Subclinical, reversible “soft pathologies” (Kreutzberg) such as pain that involves microglia also exist. Here, we examine a multilayered approach to understanding microglia that illustrates the emergent character of the microglial (population) phenotype. Accordingly, terms such as microglial “activation” and microgliosis, which are of increasing importance for our understanding of neurological disorders, need to be filled with refined meaning. It is suggested that the pathophysiological context guides nomenclatorial considerations; for example, development, trauma or pain‐associated microglia is preferred over the traditional but less distinctive “microglial activation.” This should also help to tease out the different functional subtypes currently hidden under the umbrella term “neuroinflammation,” which is being applied so widely that it has become effectively useless in practice and even inhibits research progress because both true and pseudo‐inflammation are covered by this term.     

Topographic organization in the auditory brainstem of juvenile mice is disrupted in congenital deafness

There is an orderly topographic arrangement of neurones within auditory brainstem nuclei based on sound frequency. Previous immunolabelling studies in the medial nucleus of the trapezoid body (MNTB) have suggested that there may be gradients of voltage-gated currents underlying this tonotopic arrangement. Here, our electrophysiological and immunolabelling results demonstrate that underlying the tonotopic organization of the MNTB is a combination of medio-lateral gradients of low-and high-threshold potassium currents and hyperpolarization-activated cation currents. Our results also show that the intrinsic membrane properties of MNTB neurones produce a topographic gradient of time delays, which may be relevant to sound localization, following previous demonstrations of the importance of the timing of inhibitory input from the MNTB to the medial superior olive (MSO). Most importantly, we demonstrate that, in the MNTB of congenitally deaf mice, which exhibit no spontaneous auditory nerve activity, the normal tonotopic gradients of neuronal properties are absent. Our results suggest an underlying mechanism for the observed topographic gradient of neuronal firing properties in the MNTB, show that an intrinsic neuronal mechanism is responsible for generating a topographic gradient of time-delays, and provide direct evidence that these gradients rely on spontaneous auditory nerve activity during development.     

Home care during the pancytopenic phase after allogeneic hematopoietic stem cell transplantation is advantageous compared with hospital care

After myeloablative treatment and allogeneic stem cell transplantation (SCT), patients are kept in isolation rooms in the hospital to prevent neutropenic infections. During a 3-year period, patients were given the option of treatment at home after SCT. Daily visits by an experienced nurse and daily phone calls from a physician from the unit were included in the protocol. We compared 36 patients who wished to be treated at home with 18 patients who chose hospital care (control group 1). A matched control group of 36 patients treated in the hospital served as control group 2. All home care patients had hematologic malignancies and 19 were in first remission or first chronic phase. Of the donors, 25 were unrelated. The patients spent a median of 16 days at home (range, 0-26 days). Before discharge to the outpatient clinic after SCT, patients spent a median of 4 days (range, 0-39 days) in the hospital. In the multivariate analysis, the home care patients were discharged earlier (relative risk [RR] 0.33, P =.03), had fewer days on total parenteral nutrition (RR 0.24, P <.01), less acute graft-versus-host disease (GVHD) grades II-IV (RR 0.25, P =.01), lower transplantation-related mortality rates (RR 0.22, P =.04), and lower costs (RR 0.37, P <.05), compared with the controls treated in the hospital. The 2-year survival rates were 70% in the home care group versus 51% and 57% (not significant) in the 2 control groups, respectively (P <.03). To conclude, home care after SCT is a novel and safe approach. This study found it to be advantageous, compared with hospital care.     

Long-term follow-up of patients treated at home during the pancytopenic phase after allogeneic haematopoietic stem cell transplantation

To prevent neutropenic infections, patients are kept in isolation rooms after allogeneic haematopoietic stem cell transplantation (ASCT). Patients living within one hours' driving distance from our unit were given the opportunity of treatment at home after ASCT during the pancytopenic phase. We compared 36 patients treated at home during March 1998 until December 2000, with 54 controls treated in the hospital during September 1995 and September 2001. The incidence of grades II-IV acute graft-versus-host disease (GVHD) was lower in the home care group compared to the controls, that is, 17 vs 44% (P < 0.01). The cumulative incidence of chronic GVHD was 52% in the home care group, compared to 57% in the controls. Transplant-related mortality (TRM) was 13% in the home care patients vs 44% in the controls (P = 0.002). The probability of relapse was similar in the two groups. The 4-year survival was 63% in the home care patients compared to 44% in the controls (P = 0.04). Home care after ASCT is a novel approach that resulted in less TRM, similar incidence of chronic GVHD and relapse, and improved long-term survival compared to controls treated in the hospital.     

Homozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population

Interferon-gamma (IFN-gamma) mediates the final damage of the stem cell compartment in Aplastic Anaemia (AA). Normal subjects homozygous for 12 (CA) repeats of polymorphism variable number of dinucleotide (CA) repeat (VNDR) in position 1349 of the IFN-gamma gene (IFNG) were shown to overproduce IFN-gammain vitro. We studied the distribution of polymorphism VNDR 1349 of IFNG in 67 Caucasian AA patients and in normal controls. Genotype (CA)12-12, (homozygosis for allele 2) and the single allele 12 were significantly more frequent (P = 0.005 and 0.004 respectively) in patients versus controls. The polymorphism was equally distributed in AA patients regardless of their response to immunosuppression. Homozygosity for 12 (CA) repeats of polymorphism VNDR 1349 of IFNG is strongly associated with the risk of AA in Caucasian subjects.     

Increased costs after allogeneic haematopoietic SCT are associated with major complications and re-transplantation

We wanted to evaluate factors associated with high costs after allogeneic haematopoietic SCT (HSCT). We collected all in-patient and outpatient costs during the first year after HSCT over 5 years, from 2003 to 2007. Mean 1-year costs per patient were \[euro]141,493 (95% confidence interval (95% CI)=125,019-157,967). Patients treated with non-myeloablative conditioning (NMC) had reduced costs, but patients treated with reduced-intensity or myeloablative conditioning had similar 1-year costs. Multivariate analysis showed that increased 1-year costs were seen in post-transplant complications: rejection (relative hazard (RH) 1.24, P<0.001), acute GVHD of grades III-IV (1.31, P<0.001) and invasive fungal infection (1.15, P=0.02). In addition, increased costs were associated with re-transplantation (1.21, P=0.001), mesenchymal stem-cell therapy (1.26, P<0.001), unrelated donor transplants (1.20, P=0.002) and the need for G-CSF treatment due to poor engraftment (1.12, P=0.047). In patients without any of these risk factors, mean 1-year costs were \[euro]84,773 (95% CI=71,145-98,400) (n=51). With three risk factors, the cost increased to \[euro]249,775 (95% CI=166,824-332,727) (n=14). To conclude, major complications increased the costs of HSCT. Unrelated donor transplants were more expensive than HLA-identical sibling transplants. Costs were reduced in patients treated with NMC.