Sut-6/NIPP1 modulates tau toxicity.

Neurodegenerative diseases exhibiting the pathological accumulation of tau such as Alzheimer's disease and related disorders still have no disease-modifying treatments and the molecular mechanisms of neurodegeneration remain unclear. To discover additional suppressor of tauopathy (sut) genes that mediate or modulate the toxicity of pathological tau, we performed a classical genetic screen using a tau transgenic Caenorhabditis elegans model. From this screen, we identified the suppressing mutation W292X in sut-6, the C. elegans homolog of human NIPP1, which truncates the C-terminal RNA-binding domain. Using CRISPR-based genome editing approaches, we generated null and additional C-terminally truncated alleles in sut-6 and found that loss of sut-6 or sut-6(W292X) suppresses tau-induced behavioral locomotor deficits, tau protein accumulation and neuron loss. The sut-6(W292X) mutation showed stronger and semi-dominant suppression of tau toxicity while sut-6 deletion acted recessively. Neuronal overexpression of SUT-6 protein did not significantly alter tau toxicity, but neuronal overexpression of SUT-6 W292X mutant protein reduced tau-mediated deficits. Epistasis studies showed tauopathy suppression by sut-6 occurs independent of other known nuclear speckle-localized suppressors of tau such as sut-2, aly-1/aly-3 and spop-1. In summary, we have shown that sut-6/NIPP1 modulates tau toxicity and found a dominant mutation in the RNA-binding domain of sut-6 which strongly suppresses tau toxicity. This suggests that altering RNA-related functions of SUT-6/NIPP1 instead of complete loss of SUT-6/NIPP1 will provide the strongest suppression of tau.

Thermal effects of a novel electrosurgical device for focused preparation in breast surgery tested in a specified porcine tissue ex vivo breast model using infrared measurement.

PURPOSE: This article investigates the qualities and thermal effects of a novel electrosurgical device (PT) which has been designed by ERBE Elektromedizin GmbH, Germany, for the preparation of critical locations such as in skin-sparing or nipple-sparing techniques and compares it to a standard device (SD) in a porcine ex vivo breast model using an heat map generated by infrared thermography. METHODS: In total, 42 abdominal wall specimens of porcine tissue consisting of the skin and the underlying subcutaneous and muscle layer were alternately dissected using one of the devices and pre-settings. During the preparation with the two devices, the epicutaneous temperature was measured by an infrared camera (VarioCam, Jenoptik, Germany) and the maximum temperature as well as the slope of the temperature rise was analysed. RESULTS: The use of PT shows significantly lower values for [Formula: see text] compared to SD. This effect was independent from the chosen mode. Using the same instrument in different modes, the use of AutoCut mode showed a significant reduction of [Formula: see text] at all indicated time points (SD: p < 0.0001 and PT: p < 0.0001). In summary, the combination of AutoCut + PT showed the lowest rise in temperature, whereas the combination of DryCut + SD led to the highest rise in temperature. The temperature difference between these two settings was 13.84 °C, which means a possible temperature reduction of 67% can be achieved by the right choice of device and its tailored mode. CONCLUSIONS: The novel PT shows a significant reduction in epicutaneous temperature and a significant reduction of the slope of temperature rise most probably by a more focused application of energy compared to SD.

Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

The biological functions and signaling mechanisms of the p75 neurotrophin receptor.

The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including programmed cell death, axonal growth and degeneration, cell proliferation, myelination, and synaptic plasticity. The multiplicity of cellular functions governed by the receptor arises from the variety of ligands and co-receptors which associate with p75(NTR) and regulate its signaling. P75(NTR) promotes survival through interactions with Trk receptors, inhibits axonal regeneration via partnerships with Nogo receptor (Nogo-R) and Lingo-1, and promotes apoptosis through association with Sortilin. Signals downstream of these interactions are further modulated through regulated intramembrane proteolysis (RIP) of p75(NTR) and by interactions with numerous cytosolic partners. In this chapter, we discuss the intricate signaling mechanisms of p75(NTR), emphasizing how these signals are differentially regulated to mediate these diverse cellular functions.

Clinical characteristics, pathological reevaluation, surgical management and adjuvant therapy of patients with endometrial stromal tumors.

PURPOSE: To review a single-center experience over a 27-year period in the management of endometrial stromal sarcoma (ESS) and undifferentiated endometrial sarcoma (UES) for insight into clinical characteristics, pathological diagnosis, surgical practice, adjuvant therapy and clinical outcome. MATERIALS AND METHODS: This was a retrospective study of women with histologically proven ESS and UES who were treated at the Department of Obstetrics and Gynecology, University of Tuebingen, Germany, between 1983 and 2010. Available tumor tissue, as well as inpatient and ambulatory records were reviewed; follow-up and survival data were ascertained. RESULTS: The study sample comprised ten patients with ESS and seven patients with UES. Primary surgical treatment consisted of total hysterectomy in nine patients (90.0 %) with ESS and six patients (85.7 %) with UES; one patient (10.0 %) with ESS and one patient (14.3 %) with UES underwent debulking surgery. All patients (100 %) from the ESS group and six patients (85.7 %) from the UES group underwent bilateral salpingo-oophorectomy. Seven women (70.0 %) with ESS and six women (85.7 %) with UES underwent lymphadenectomy. Median DFS was 83.8 months (95 % CI 80.6-87.0) and median OS was 232.6 (95 % CI 49.3-415.9) for patients with ESS; median DFS was 12.9 months (95 % CI 0-284.1) and median OS was 17.6 (95 % CI 0-37.0) for patients with UES. There was no significant difference in DFS between patients with ESS as compared with patients with UES. However, patients with ESS had a significantly better OS when compared to patients with UES (p = 0.011). CONCLUSION: ESS and UES are very rare uterine neoplasms. Surgery consisting of total hysterectomy with or without bilateral salpingo-oophorectomy is the most important treatment-element in patients with ESS or UES.

Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease.

A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.

Rethinking discretization to advance limnology amid the ongoing information explosion.

Limnologists often adhere to a discretized view of waterbodies-they classify them, divide them into zones, promote discrete management targets, and use research tools, experimental designs, and statistical analyses focused on discretization. By offering useful shortcuts, this approach to limnology has profoundly benefited the way we understand, manage, and communicate about waterbodies. But the research questions and the research tools in limnology are changing rapidly in the era of big data, with consequences for the relevance of our current discretization schemes. Here, I examine how and why we discretize and argue that selectively rethinking the extent to which we must discretize gives us an exceptional chance to advance limnology in new ways. To help us decide when to discretize, I offer a framework (discretization evaluation framework) that can be used to compare the usefulness of various discretization approaches to an alternative which relies less on discretization. This framework, together with a keen awareness of discretization's advantages and disadvantages, may help limnologists benefit from the ongoing information explosion.

Stage I carcinoma of the Bartholin's gland managed with the detection of inguinal and pelvic sentinel lymph node.

BACKGROUND: Primary carcinoma of the Bartholin's gland is rare, consequently standard management is not clear. Although the sentinel concept has gained popularity for other malignancies of the female reproductive tract, the literature lacks reports of this approach for carcinomas of the Bartholin's gland. CASE: We present a patient with stage I adenocarcinoma of the Bartholin's gland. She was managed with wide excision and inguinal and laparoscopic pelvic sentinel lymphadenectomy followed by complete pelvic lymphadenectomy. We discuss the rationale for the sentinel concept. CONCLUSION: As for other gynaecological malignancies the sentinel lymphadenectomy seems to be an appropriate and feasible surgical approach for early stage carcinomas of the Bartholin's gland.

Risk-benefit analysis of preoperative breast MRI in patients with primary breast cancer.

AIM: To analyse and compare the risks and benefits of preoperative breast MRI (BMRI) in patients with primary breast cancer (PBC), and to determine the influence of mammographic breast density (BD) and histological tumour type (TT). MATERIALS AND METHODS: One hundred and nineteen patients who underwent preoperative bilateral breast MRI for staging of PBC during a 1-year period from July 2005 to August 2006 were prospectively evaluated. Changes in clinical management due to BMRI findings were recorded. MRI-detected lesions were correlated with histology. Additional MRI-detected malignant lesions and spared additional biopsies because of negative MRI in case of unclear ultrasound findings were determined as beneficial for the patient. Biopsies of benign MRI detected lesions were defined as disadvantageous. The influence of BD (ACR 1-4) and TT on the change in clinical management and patient benefit was evaluated. RESULTS: The findings of the BMRI examinations changed the clinical management in 48 patients (40.3%). Seventeen women underwent mastectomy instead of breast conservation, eight patients underwent extended excision, 21 additional lesions were clarified by MRI intervention, and two ultrasound-detected lesions were not biopsied because of negative MRI. Histologically malignant additional or extended biopsies (n=34) and two cases of spared biopsies resulted in 36 (30.3%) women who benefited from preoperative BMRI. Twelve patients (10.1%) had additional biopsies of MRI-detected benign lesions, and therefore, had an unfavourable outcome due to BMRI. The change in clinical management and patient benefit were independent of BD and TT (p>0.05). CONCLUSION: Preoperative BMRI was beneficial for 30.3% of 119 patients with PBC. The percentage of additional biopsies of benign lesions (10.1%) seems acceptable.

Parents' mental health after the birth of an extremely preterm child: a comparison between bereaved and non-bereaved parents.

OBJECTIVE: To assess the impact of extremely preterm birth (24-26 weeks of gestation) on the mental health of parents two to six years after delivery, and to examine potential differences in post-traumatic growth between parents whose newborn infant died and those whose child survived. METHOD: A total of 54 parents who had lost their newborn and 38 parents whose preterm child survived were assessed by questionnaires with regard to depression and anxiety (HADS) and post-traumatic growth (PTGI). RESULTS: Neither group of parents had clinically relevant levels of depression and anxiety. Mothers showed higher levels of anxiety than fathers. Bereaved parents with no other, living child reported higher levels of depression than bereaved parents with one or more children. Mothers reported higher post-traumatic growth compared to fathers. In particular, bereaved mothers experienced the value and quality of their close social relationships more positively compared to the non-bereaved parents. CONCLUSION: In the long term, bereaved and non-bereaved parents cope reasonably well with an extremely preterm birth of a child. Post-traumatic growth appears to be positively related to bereavement, particularly in mothers.

NANOS-3 and FBF proteins physically interact to control the sperm-oocyte switch in Caenorhabditis elegans.

BACKGROUND: The Caenorhabditis elegans FBF protein and its Drosophila relative, Pumilio, define a large family of eukaryotic RNA-binding proteins. By binding regulatory elements in the 3' untranslated regions (UTRs) of their cognate RNAs, FBF and Pumilio have key post-transcriptional roles in early developmental decisions. In C. elegans, FBF is required for repression of fem-3 mRNA to achieve the hermaphrodite switch from spermatogenesis to oogenesis. RESULTS: We report here that FBF and NANOS-3 (NOS-3), one of three C. elegans Nanos homologs, interact with each other in both yeast two-hybrid and in vitro assays. We have delineated the portions of each protein required for this interaction. Worms lacking nanos function were derived either by RNA-mediated interference (nos-1 and nos-2) or by use of a deletion mutant (nos-3). The roles of the three nos genes overlap during germ-line development. In certain nos-deficient animals, the hermaphrodite sperm-oocyte switch was defective, leading to the production of excess sperm and no oocytes. In other nos-deficient animals, the entire germ line died during larval development. This germ-line death did not require CED-3, a protease required for apoptosis. CONCLUSIONS: The data suggest that NOS-3 participates in the sperm-oocyte switch through its physical interaction with FBF, forming a regulatory complex that controls fem-3 mRNA. NOS-1 and NOS-2 also function in the switch, but do not interact directly with FBF. The three C. elegans nanos genes, like Drosophila nanos, are also critical for germ-line survival. We propose that this may have been the primitive function of nanos genes.

Post-traumatic stress disorder in women with eating disorders.

OBJECTIVE: The aim of the study was to assess the frequency of co-morbid post-traumatic stress disorders (PTSD) in women with eating disorders (ED). METHOD: 277 women aged 17 to 50 with a current DSM-IV ED were included. 84 were diagnosed with anorexia nervosa (AN), 152 with bulimia nervosa (BN) and 41 with ED not otherwise specified (EDNOS). Structured Clinical Interviews (SCID-I and SCID-II) were performed. RESULTS: Sixty-eight participants (24.5%) reported unwanted sexual experiences (USE). Fifty-two participants (18.8%) reported some form of childhood sexual abuse (CSA). Four participants (1.4%) met the criteria for PTSD according to the Diagnostic and Statistical Manual-IV (DSM-IV). Participants with a history of USE did not differ from those without USE with regard to ED diagnosis, but were diagnosed more often with any Axis I or Axis II disorder. CONCLUSIONS: The prevalence of PTSD in this sample of women with ED was low (1.4%), despite a USE rate of 24.5%.

Blast exposure causes dynamic microglial/macrophage responses and microdomains of brain microvessel dysfunction.

Exposure to blast overpressure (BOP) is associated with behavioral, cognitive, and neuroimaging abnormalities. We investigated the dynamic responses of cortical vasculature and its relation to microglia/macrophage activation in mice using intravital two-photon microscopy following mild blast exposure. We found that blast caused vascular dysfunction evidenced by microdomains of aberrant vascular permeability. Microglial/macrophage activation was specifically associated with these restricted microdomains, as evidenced by rapid microglial process retraction, increased ameboid morphology, and escape of blood-borne Q-dot tracers that were internalized in microglial/macrophage cell bodies and phagosome-like compartments. Microdomains of cortical vascular disruption and microglial/macrophage activation were also associated with aberrant tight junction morphology that was more prominent after repetitive (3×) blast exposure. Repetitive, but not single, BOPs also caused TNFα elevation two weeks post-blast. In addition, following a single BOP we found that aberrantly phosphorylated tau rapidly accumulated in perivascular domains, but cleared within four hours, suggesting it was removed from the perivascular area, degraded, and/or dephosphorylated. Taken together these findings argue that mild blast exposure causes an evolving CNS insult that is initiated by discrete disturbances of vascular function, thereby setting the stage for more protracted and more widespread neuroinflammatory responses.

Psychiatric comorbidity in gender identity disorder.

OBJECTIVE: Despite being recognized as an important prognostic factor for the outcome in gender identity disorder (GID), psychiatric comorbidity has rarely been assessed by means of standardized diagnostic instruments. The aim of this study was to assess current and lifetime psychiatric comorbidity in patients with GID. METHODS: A cross-sectional sample of 31 patients who were treated for GID was assessed by the structured clinical interview for Axis I and II (SCID-I/II) and the Hospital Anxiety and Depression Scale (HADS). RESULTS: Twenty-nine percent of the patients had no current or lifetime Axis I disorder; 39% fulfilled the criteria for current and 71% for current and/or lifetime Axis I diagnosis. Forty-two percent of the patients were diagnosed with one or more personality disorders. CONCLUSIONS: Lifetime psychiatric comorbidity in GID patients is high, and this should be taken into account in the assessment and treatment planning of GID patients.

Fibrosarcoma of ovary. A new component in the nevoid basal-cell carcinoma syndrome.

An 8-year-old child with nevoid basal-cell carcinoma syndrome who developed abdominal pain underwent exploratory laparotomy. Both ovaries were enlarged and replaced by fibroblastic proliferations having cellular foci with high mitotic indices (greater than 4 mitoses/10 high-power fields) diagnostic of fibrosarcoma. Two years following salpingo-oophorectomy, a metastasis was excised from one adnexa. Further recurrence or distant metastasis was not evident after 6 more years of follow-up. The association of fibrosarcoma of the ovary in a patient with nevoid basal-cell carcinoma further expands the multifarious nature of this syndrome.

A role for peripheral somatostatin receptors in counter-irritation-induced analgesia.

Our hypothesis is that peripheral somatostatin (SRIF) has a role in counter-irritation-induced analgesia. Our paradigm involves the reduction of nociceptive behaviors produced by primary noxious stimuli (formalin or complete Freund's adjuvant [CFA] in the rat hind paw) by a counter-irritating stimulus (capsaicin [CAP] in the tail or muzzle). Activation of peripheral SRIF receptors is key since an SRIF receptor antagonist cyclo-somatostatin (c-SOM) and SRIF antibodies in the hind paw attenuate the counter-irritation-induced analgesia of both formalin and more persistent CFA nociception. Specificity of c-SOM is shown by reversal of its effects with octreotide, a SRIF analog. Injection of formalin in one hind paw and c-SOM in the other does not reduce the counter-irritation analgesia demonstrating local action of the c-SOM. Approximately 33% of peripheral sensory axons contain SRIF, which could release the peptide to activate SRIF receptors on cutaneous axons. Intraplantar naloxone has no effect on the counter-irritation analgesia indicating that SRIF is not activating opioid receptors. These results indicate that in addition to the classic central descending noxious inhibitory control systems that underlie counter-irritation-induced analgesia, there is a peripheral contribution arising from activation of SRIF receptors. Identifying a peripheral contribution of SRIF to mechanisms of counter-irritation analgesia offers opportunities for peripheral therapy.

DNA ploidy by image cytometry and karyotype in spontaneous abortion.

We compared the DNA content (DI) by cell image analysis with the karyotype and morphological phenotype of paraffin-embedded tissues from 51 spontaneous abortions. The study included 21 cases with triploid, 19 cases with diploid, and 11 cases with aneuploid (monosomic, trisomic, or mosaic) karyotype. Measurements were performed by image analysis on the trophoblastic and stromal cells of chorionic villi using 5-microm-thick, Feulgen-stained sections. At least 200 cells were analyzed. Results were interpreted using DI ranges of 1.3 to 1.7 for triploid and 0.9 to 1.1 for a diploid profile. All 21 cases with a cytogenetically confirmed triploid karyotype had DI values within the triploid range, and all 19 cases with a diploid karyotype had DI values within the diploid range. All of the trisomies and monosomies also had a DNA mass within the diploid range. However, eight cases with a triploid karyotype also had a peak in the diploid range: one case with a diploid karyotype and one case with a trisomic karyotype each had an additional peak in the triploid range. We did not find a morphological correlation either with image analysis or with karyotype. We conclude that cell image analysis is a reliable method for detection of triploidy in spontaneous abortions. This relatively rapid method allows visual discrimination of the areas to be analyzed, avoids the problem of maternal cell contamination, and may unmask mosaic karyotypes that would go unrecognized by cytogenetic studies alone.

Binary nature and radiographic identifiability of craniosynostosis.

RATIONALE AND OBJECTIVES: Two independent gold standards and diagnoses from three-dimensional computed tomography (CT) images were used to examine the possibility that craniosynostosis is a binary abnormality that potentially may be diagnosed without error. METHODS: Surgical reports, histology of excised sutures, and three-dimensional CT images were compared for 25 children undergoing surgical management of craniosynostosis. Surgical reports identified sutures as normal or abnormal. Histology reported suture closure on a 5-point scale. Four radiologists used three-dimensional CT images to diagnose sutures on a 6-point rated response scale. RESULTS: Sutures with histology 0, 1, or 2 were normal on surgical reports, and those with histology 3 or 4 were abnormal. Most readers achieved nearly perfect sensitivity and specificity. Reader confidence was unrelated to degree of pathology. CONCLUSION: Craniosynostosis appears to be binary in our sample. Surgical reports, pathology results, and three-dimensional CT images read by experienced viewers achieved nearly perfect agreement.

Bacterial infection stimulating granulocytic sarcoma of the small bowel.

A 57-year-old white man who had abdominal pain and distension, died after a short hospitalization for increasing ascites, anorexia, and deteriorating mental status. At autopsy, the principal gross finding was a dilated, hyperemic, thickened proximal jejunum that by light microscopy consisted of a transmural infiltrate of large mononuclear cells. Intense naphthol AS-D chloroacetate esterase (NASD) positivity was observed within most of the cells, suggesting granulocytic sarcoma. However, bacterial strains and electron-microscopic examination revealed that the massive jejunal infiltrate was composed of macrophages containing numerous phagocytosed bacteria. Although occasional cells had primary and secondary granules characteristic of myeloid precursors present within their cytoplasm, most cells lacked specific granules. Attempts to reproduce this markedly enhanced NASD result experimentally in peritoneal macrophages of mice were unsuccessful. This case shows that intense NASD cytoplasmic staining may occasionally occur macrophages that have phagocytosed large numbers of bacteria.