Automated protocols for delineating human hippocampal subfields from 3 Tesla and 7 Tesla magnetic resonance imaging data.

Researchers who study the human hippocampus are naturally interested in how its subfields function. However, many researchers are precluded from examining subfields because their manual delineation from magnetic resonance imaging (MRI) scans (still the gold standard approach) is time consuming and requires significant expertise. To help ameliorate this issue, we present here two protocols, one for 3T MRI and the other for 7T MRI, that permit automated hippocampus segmentation into six subregions, namely dentate gyrus/cornu ammonis (CA)4, CA2/3, CA1, subiculum, pre/parasubiculum, and uncus along the entire length of the hippocampus. These protocols are particularly notable relative to existing resources in that they were trained and tested using large numbers of healthy young adults (n = 140 at 3T, n = 40 at 7T) whose hippocampi were manually segmented by experts from MRI scans. Using inter-rater reliability analyses, we showed that the quality of automated segmentations produced by these protocols was high and comparable to expert manual segmenters. We provide full open access to the automated protocols, and anticipate they will save hippocampus researchers a significant amount of time. They could also help to catalyze subfield research, which is essential for gaining a full understanding of how the hippocampus functions.

Laterally Placed Expandable Interbody Spacers With and Without Adjustable Lordosis Improve Radiographic and Clinical Outcomes: A Two-Year Follow-Up Study.

Introduction Interbody spacers are necessary for achieving disc height restoration when surgical intervention is used for the treatment of severe degenerative disc disease. Minimally invasive lateral lumbar interbody fusion (MIS LLIF) is a popular surgical approach that historically uses large static interbody spacers through a lateral approach. However, static spacers have been associated with iatrogenic distraction and excessive impaction forces, which may increase the risk of subsidence and loss of lordosis, compromising stability. Expandable interbody spacers with or without adjustable lordosis may help address these concerns by maximizing segmental lordosis and aiding in sagittal balance correction. This study describes the clinical and radiographic outcomes of patients treated with expandable interbody spacers with or without adjustable lordosis, for MIS LLIF. Materials and methods This is retrospective, single-surgeon Institutional Review Board-exempt chart review was of 103 consecutive patients who had undergone MIS LLIF at one to two contiguous level(s) utilizing expandable interbody spacers with or without adjustable lordosis (66/103 patients had adjustable lordosis spacers). Collection of clinical and radiographic functional outcomes occurred at preoperative and postoperative time points through 24 months. Results One-hundred and three consecutive patients were evaluated-average age, 58.2 ± 12.1 years; 42.1% (45/107) were female. There were 78.6% (81/103) one-level cases and 21.4% (22/103) two-level cases for a total of 125 levels; 44.8% (56/125) were performed at L4-5 and 34.4% (43/125) at L3-4. The average estimated blood loss was 24.6 ± 12.3cc. Mean operative time was 61.0 ± 19.1 min, and mean fluoroscopic time was 28.2 ± 14.6 sec. Visual Analog Scale (VAS) back and leg pain scores decreased significantly by an average of 7.1 ± 1.0 points at 24 months (p<0.001). Oswestry Disability Index (ODI) scores significantly decreased by a mean of 67.4 ± 8.9 points at 24 months (p<0.001). Lumbar lordosis significantly improved by a mean of 3.1 ± 8.8° at 24 months (p=0.001). Anterior, middle, and posterior disc height significantly increased at 24 months by averages of 4.7 ± 3.1, 4.0 ± 3.0, and 2.1 ± 2.2mm, respectively (p<0.001). Neuroforaminal height had significantly increased at 24 months by a mean of 3.0 ± 3.6mm (p<0.001). Segmental lordosis significantly improved by 3.7 ± 2.9° at 24 months (p<0.001). There were 51 patients with abnormal preoperative Pelvic Incidence-Lumbar Lordosis (PI-LL) measurements that significantly improved by 9.1 ± 4.9° (p<0.001) and 52 patients with normal preoperative PI-LL measurements that improved by 0.2 ± 4.6° (p=0.748) at 24 months. One-hundred percent fusion occurred at all levels, and no findings of radiolucency were observed. One case of subsidence (1/125, 0.8%) was reported at 24 months. No implanted-related complications were reported, with 0% pseudoarthrosis and no secondary surgery required at the operative levels. Conclusion Indirect decompression and sagittal correction were achieved and maintained through a 24-month follow-up. Functional clinical outcomes significantly improved based on decreased VAS pain and ODI scores at 24 months. This study resulted in positive clinical and radiographic outcomes for patients who underwent MIS LLIF with expandable interbody spacers with or without adjustable lordosis.

The chromatin remodelers ISWI and ACF1 directly repress Wingless transcriptional targets.

The highly conserved Wingless/Wnt signaling pathway controls many developmental processes by regulating the expression of target genes, most often through members of the TCF family of DNA-binding proteins. In the absence of signaling, many of these targets are silenced, by mechanisms involving TCFs that are not fully understood. Here we report that the chromatin remodeling proteins ISWI and ACF1 are required for basal repression of WG target genes in Drosophila. This regulation is not due to global repression by ISWI and ACF1 and is distinct from their previously reported role in chromatin assembly. While ISWI is localized to the same regions of Wingless target gene chromatin as TCF, we find that ACF1 binds much more broadly to target loci. This broad distribution of ACF1 is dependent on ISWI. ISWI and ACF1 are required for TCF binding to chromatin, while a TCF-independent role of ISWI-ACF1 in repression of Wingless targets is also observed. Finally, we show that Wingless signaling reduces ACF1 binding to WG targets, and ISWI and ACF1 regulate repression by antagonizing histone H4 acetylation. Our results argue that WG signaling activates target gene expression partly by overcoming the chromatin barrier maintained by ISWI and ACF1.

Wnt signaling: complexity at the surface.

Wnts are secreted proteins that are essential for a wide array of developmental and physiological processes. They signal across the plasma membrane by interacting with serpentine receptors of the Frizzled (Fz) family and members of the low-density-lipoprotein-related protein (LRP) family. Activation of Fz-LRP promotes the stability and nuclear localization of beta-catenin by compromising the ability of a multiprotein complex containing axin, adenomatosis polyposis coli (APC) and glycogen synthase kinase 3 (GSK3) to target it for degradation and block its nuclear import. The Fz-LRP receptor complex probably accomplishes this by generating multiple signals in the cytoplasm. These involve activation of Dishevelled (Dsh), possibly through trimeric G proteins and LRP-mediated axin binding and/or degradation. However, individual Wnts and Fzs can activate both beta-catenin-dependent and -independent pathways, and Fz co-receptors such as LRP probably provide some of this specificity. Additional, conflicting data concern the role of the atypical receptor tyrosine kinase Ryk, which might mediate Wnt signaling independently of Fz and/or function as a Fz co-receptor in some cells.

Ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop.

Cancer cells of different solid and hematopoietic tumors express growth factors in respective stages of tumor progression, which by autocrine and paracrine effects enable them to grow autonomously. Here we show that the murine B16 melanoma cell line and two human primary cultures of stomach adenocarcinoma and glioblastoma multiforme (GBM) constitutively secrete interleukin (IL)-10 in an autocrine/paracrine manner. This cytokine is essential for tumor cell proliferation because its neutralization decreases clonogenicity of malignant cells, whereas addition of recombinant IL-10 increases cell proliferation. The immunomodulator ammonium trichloro(dioxoethylene-o,o')tellurate (AS101) decreased cell proliferation by inhibiting IL-10. This activity was abrogated by exogenous addition of recombinant IL-10. IL-10 inhibition by AS101 results in dephosphorylation of Stat3, followed by reduced expression of Bcl-2. Moreover, these activities of AS101 are associated with sensitization of tumor cells to chemotherapeutic drugs, resulting in their increased apoptosis. More importantly, AS101 sensitizes the human aggressive GBM tumor to paclitaxel both in vitro and in vivo by virtue of IL-10 inhibition. AS101 sensitizes GBM cells to paclitaxel at concentrations that do not affect tumor cells. This sensitization can also be obtained by transfection of GBM cells with IL-10 antisense oligonucleotides. Sensitization of GBM tumors to paclitaxel (Taxol) in vivo was obtained by either AS101 or by implantation of antisense IL-10-transfected cells. The results indicate that the IL-10 autocrine/paracrine loop plays an important role in the resistance of certain tumors to chemotherapeutic drugs. Therefore, anti-IL-10 treatment modalities with compounds such as AS101, combined with chemotherapy, may be effective in the treatment of certain malignancies.

IgE and IgG antibodies to Malassezia spp. yeast extract in patients with atopic dermatitis.

The presence of immunoglobulins to Malassezia spp. surface proteins in the sera from patients with atopic dermatitis and healthy subjects was studied. It was found that 28% of 25 examined patients with atopic dermatitis had IgE antibodies to Malassezia spp. surface protein preparation. All patients and 5 healthy subjects had IgG antibodies to this preparation. The presence and concentration of specific IgE antibodies in patients with atopic dermatitis correlated with reverse titers of IgG antibodies to this preparation (r=0.782). The medians of values reciprocal to IgG antibody titers in patients with atopic dermatitis with and without specific IgE antibodies to the preparation and in healthy subjects were 64, 1024, and 16, respectively. The preparation derived from Candida albicans (candidine) and previously derived preparation from Malassezia did not cross-react. According to immunoblotting data, the preparation contains allergens presented by proteins with molecular weights 15, 36, 52-56, and 78.4 kDa.

A method for estimation of urease activity in gastric mucosa biopsy specimens and Helicobacter pylori cell suspensions.

A method for measuring urease activity in biopsy specimens and Helicobacter pylori cultures from these specimens is proposed. The method is based on measurement (with a portable pH-meter) of the rate of pH changes in a reaction mixture consisting of buffer, substrate (urea), and biopsy specimen or bacterial cells. This method revealed that urease activity of biopsy specimens correlated with that of H. pylori suspension in the same experiment. High urease activity was found in biopsy specimens containing the greatest number of Helicobacter cells; only one of 14 specimens free of H. pylori cells showed no urease activity. Introduction of this method into clinical practice will help to evaluate the contribution of H. pylori to the pathological process.

Preliminary results of medical investigations during piloted flights in the Salyut-6 program.

The changes observed during flight on the whole corresponded with the preflight prognosis and reflected the phase nature of the processes of adaptation. They were shown by blood redistribution symptoms, fluctuations in the main indices of hemodynamics at rest not going beyond the limits of the physiological norm, an increase in the pulse-filling of the head with blood, and a decrease in that of the shank. The reaction of the blood circulation to a physical load and the application of negative pressure varied, and in a number of investigations during flight it was more pronounced than on Earth. The changes observed after the flight appeared regular for the period of readaptation of the reactions of the organism. These reactions bore a functional nature and qualitatively did not differ from reactions observed after other flights, and after the 140-day flight they were, on the whole, less pronounced than after the 96-day flight. In the postflight period to accelerate the process of adaptation a complex of restorative-healing measures was carried out, including mainly a regulation of motor activity, restorative massage of the muscles, remedial physical culture and aquatic procedures. The flight lasting 140 days revealed no contraindications to a further regular increase in the time of cosmic flights and demonstrates once again the possibility of the planned control of the state of a healthy subject in flight and the readiness of the organism for a return to the terrestrial force of gravity.

Pattern of blood circulation in the brain during rest and functional tests by Salyut-4 space crewmen.

Changes in the rheoencephalogram (REG) obtained for cosmonauts on the first and second expeditions during their time aboard the orbiting station, Salyut-4, are described. REGs were recorded by a small apparatus, Levkoi-3, with subsequent transmittal of the information to Earth stations. It was established that during flight under conditions of negative pressure on the lower half of the body (NPLHB), there was a decrease, in all cases, in pulse filling of brain blood vessels and an improvement in venous outflow from the cranial cavity. This indicates the efficiency of the compensation-adaptation reaction of the system studied to the state of weightlessness and the positive effect of prophylactic measures taken during flight. REG changes in indices affected by negative pressure were mainly such as were observed in preflight investigations, but there were individual differences. It was discovered that in all cosmonauts during performance of functional tests on a veloergometer, there was a significant increase in indices of pulse filling of brain blood vessels in response to muscle load in comparison with preflight studies. Normalization of basic REG indices took 3-7 min after the work was concluded. Planimetric analysis with REGs registered under conditions of long flight disclosed a variety of reactions of different sections of the vascular channels in the brain. Data obtained indicated the value of the REG method for making observations on crew members of space ships during orbital flights.