Spontaneous subdural haemorrhage from an arachnoid cyst: a case report and literature review.

We discuss a spontaneous subdural haematoma (SDH) arising from an arachnoid cyst in a healthy adult male, presenting with headache and vomiting. Imaging revealed a large SDH communicating with an arachnoid cyst and intracystic haemorrhage. The patient fully recovered with surgical evacuation. We also discuss the causes of spontaneous SDH, and specific risk factors for bleeding in arachnoid cysts, as well as review the literature on spontaneous SDH from arachnoid cysts - a rare but serious complication.

Words will never hurt me? Preferred terms for describing obesity and binge eating.

OBJECTIVE: This study evaluated individuals' language preferences for discussing obesity and binge eating. METHOD: Participants (N = 817; 68.3% female) were an online community sample. They rated the desirability of terms related to obesity and binge eating, and also completed psychometrically established eating-disorder measures. In addition to examining participants' preferences, analyses explored whether preferences differed by socio-demographic variables, weight status and binge-eating status. RESULTS: Preferred obesity-related terms were weight and BMI, although women rated undesirable obesity-related terms even lower than did men. Participants with obesity and binge eating rated weight, BMI, unhealthy BMI and large size as less desirable than participants with obesity but not binge eating. Binge-related terms were generally ranked neutrally; preferred descriptions were kept eating even though not physically hungry and loss of control. CONCLUSIONS: Preferred terms were generally consistent across sex, weight status and binge-eating status. Using terms ranked more preferably and avoiding terms ranked more undesirably may enhance clinical interactions, particularly when discussing obesity with women and individuals reporting binge eating, as these groups had stronger aversion to some non-preferred terms. Findings that the selected binge-related descriptions were rated neutrally on average provide support for their use by clinicians.

Predictive significance of the overvaluation of shape/weight in obese patients with binge eating disorder: findings from a randomized controlled trial with 12-month follow-up.

BACKGROUND: Undue influence of body shape or weight on self-evaluation - referred to as overvaluation - is considered a core feature across eating disorders, but is not a diagnostic requirement for binge eating disorder (BED). This study examined the concurrent and predictive significance of overvaluation of shape/weight in obese patients with BED participating in a randomized clinical trial testing cognitive behavioral therapy (CBT) and behavioral weight loss (BWL). Method A total of 90 participants were randomly assigned to 6-month group treatments of CBT or BWL. Assessments were performed at baseline, throughout- and post-treatment, and at 6- and 12-month follow-ups after completing treatments with reliably administered semi-structured interviews and established measures. RESULTS: Participants categorized with overvaluation (n = 52, 58%) versus without overvaluation (n = 38, 42%) did not differ significantly in demographic features (age, gender and ethnicity), psychiatric co-morbidity, body mass index or binge eating frequency. The overvaluation group had significantly greater levels of eating disorder psychopathology and poorer psychological functioning (higher depression and lower self-esteem) than the non-overvaluation group. Overvaluation of shape/weight significantly predicted non-remission from binge eating and higher frequency of binge eating at the 12-month follow-up, even after adjusting for group differences in depression and self-esteem levels. CONCLUSIONS: Our findings suggest that overvaluation does not simply reflect concern commensurate with being obese or more frequent binge eating, but also is strongly associated with heightened eating-related psychopathology and psychological distress, and has negative prognostic significance for longer-term treatment outcomes. Overvaluation of shape/weight warrants consideration as a diagnostic specifier for BED as it provides important information about severity and treatment outcome.

A review of stream nutrient criteria development in the United States.

Elevated nutrients and sediments are the main factors contributing to the poor biological condition measured in over 40% of US waters, highlighting the need for criteria that can aid management efforts to protect or restore the quality of US waters. A large amount of literature on nutrient criteria has been generated since the USEPA called for their development in 1998. Our objective was to examine this peer-reviewed literature to evaluate two main approaches for criteria development in lotic ecosystems: percentile rank and bivariate predictive statistical analyses. The 25th percentile approach has been examined broadly across USEPA-aggregate nutrient ecoregions, and we found that USEPA-suggested criteria for these aggregate ecoregions were often more conservative than criteria estimated using more current regionally focused data based on our compiled data set. Furthermore, 25th percentile estimates were often less than 75th percentile estimates based on reference sites, suggesting that 75th percentile estimates were not more conservative than 25th percentile estimates. Predictive approaches have focused on establishing linear and nonlinear relationships between water quality and algae, macroinvertebrate, and fish communities; attributing causation; and determining whether threshold points exist that can aid in nutrient criteria development. Most of the predictive approaches have occurred at the state or watershed level and may not be directly comparable to USEPA aggregate ecoregions. However, percentile method estimates often fell within the confidence interval of biological threshold criteria estimates, suggesting overlap and some consensus between the two main approaches.

Time to diagnosis of paediatric posterior fossa tumours: an 11-year West of Scotland experience 2000-2011.

INTRODUCTION: Brain tumours are the most common solid childhood malignancy accounting for 20% of all paediatric cancers. Of these, posterior fossa tumours comprise approximately 60-70% of all brain tumours in children. Several studies have estimated the median pre-diagnostic interval (PSI) of paediatric brain tumours as approximately 60 days. OBJECTIVES: The objectives of this retrospective analysis were to (a) identify the common presenting symptoms of posterior fossa tumours, (b) determine the time interval from the first attributable symptom to the radiological diagnosis of a posterior fossa tumour, (c) compare the West of Scotland with other international centres and (d) identify which factors correlate with outcome for these children. MATERIALS AND METHODS: A retrospective case note review of 69 children diagnosed with posterior fossa tumours from January 2000 to September 2011. Of the 69 children diagnosed during this period, complete data were available for 66 children (M:F = 31:35, Mean age (SD): 7.50 + 4.53 years). Results. Nausea and vomiting (75.8%), headaches (63.6%) and incoordination (51.5%) were recorded as the most common presenting symptoms followed by lethargy (28.8%), cranial nerve palsy (25.8%) and diplopia (24.2%). Fifty-three of the sixty-six children (i.e., 80.3%) demonstrated radiological evidence of hydrocephalus on their initial scan. The majority of children were assessed by less than three specialists after a median PSI of 43.5 days. The only variable significantly associated with PSI was tumour grade (r = - 0.202, p = 0.036). Neither age at diagnosis, number of specialists seen, nor outcome was significantly correlated with PSI. The only factor associated with outcome was tumour grade (r = 0.337, p = 0.006). CONCLUSION: Despite recent reports indicating poor performance of the UK with respect to time to diagnosis of paediatric brain tumours, the present data indicate that the experience of this cohort is favourably comparable to international standards.

Absence of cancer-associated changes in human fibroblasts immortalized with telomerase.

The ectopic expression of telomerase in normal human cells results in an extended lifespan, indicating that telomere shortening regulates the timing of cellular senescence. As telomerase expression is a hallmark of cancer, we investigated the long-term effects of forced expression of human telomerase catalytic component (hTERT) in normal human fibroblasts. In vitro growth requirements, cell-cycle checkpoints and karyotypic stability in telomerase-expressing cells are similar to those of untransfected controls. In addition, co-expression of telomerase, the viral oncoproteins HPV16 E6/E7 (which inactivate p53 and pRB) and oncogenic HRAS does not result in growth in soft agar. Thus, although ectopic expression of telomerase in human fibroblasts is sufficient for immortalization, it does not result in changes typically associated with malignant transformation.

Rapid response predicts 12-month post-treatment outcomes in binge-eating disorder: theoretical and clinical implications.

BACKGROUND: We examined rapid response in obese patients with binge-eating disorder (BED) in a clinical trial testing cognitive behavioral therapy (CBT) and behavioral weight loss (BWL). METHOD: Altogether, 90 participants were randomly assigned to CBT or BWL. Assessments were performed at baseline, throughout and post-treatment and at 6- and 12-month follow-ups. Rapid response, defined as 70% reduction in binge eating by week four, was determined by receiver operating characteristic curves and used to predict outcomes. RESULTS: Rapid response characterized 57% of participants (67% of CBT, 47% of BWL) and was unrelated to most baseline variables. Rapid response predicted greater improvements across outcomes but had different prognostic significance and distinct time courses for CBT versus BWL. Patients receiving CBT did comparably well regardless of rapid response in terms of reduced binge eating and eating disorder psychopathology but did not achieve weight loss. Among patients receiving BWL, those without rapid response failed to improve further. However, those with rapid response were significantly more likely to achieve binge-eating remission (62% v. 13%) and greater reductions in binge-eating frequency, eating disorder psychopathology and weight loss. CONCLUSIONS: Rapid response to treatment in BED has prognostic significance through 12-month follow-up, provides evidence for treatment specificity and has clinical implications for stepped-care treatment models for BED. Rapid responders who receive BWL benefit in terms of both binge eating and short-term weight loss. Collectively, these findings suggest that BWL might be a candidate for initial intervention in stepped-care models with an evaluation of progress after 1 month to identify non-rapid responders who could be advised to consider a switch to a specialized treatment.

Salty water and salty leaf litter alters riparian detrital processes: Evidence from sodium-addition laboratory mesocosm experiments.

Terrestrial and freshwater secondary salinization is a global phenomenon arising partially from anthropogenic activities. How low-level direct (e.g., sodium exposure through irrigation runoff) or indirect (e.g., sodium exposure through sodium-enriched leaves as riparian plants uptake sodium that via senescence enters detrital systems) impacts detrital processes in riparia have received little attention. Based on the sodium ecosystem respiration hypothesis, we predicted low-level salinization of an inland mesic riparia would result in increased detrital processing and increased leachate dissolved organic carbon (DOC) and conductivity. Two riparian soil mesocosm experiments tested how low-level salinization affects leachate chemistry and conductivity and riparian decomposition rates and detritivore community structure: 1) direct low-level NaCl deposition in water (weekly additions of 300 ml of 0.05% NaCl or just H2O (controls)), and 2) indirect low-level NaCl deposition through Na-enriched artificial litter (0.05% NaCl or just H2O (controls)). After three months, leachate Na+ concentrations were 12-fold and 1.5-fold higher in Na-addition than control mesocosms for direct and indirect Na-addition experiments, respectively. Contrary to predictions, decomposition rate was 1.3-fold lower in indirect Na-addition than control mesocosms but invertebrate communities were similar. Decomposition rate did not differ in direct Na-addition experiments, and although invertebrate abundance was lower, diversity was 1.4-fold higher in Na-addition than control mesocosms. Leachate DOC did not differ between Na-addition and control mesocosms for either direct or indirect Na-addition experiments. This study adds to the growing evidence that even low-level Na addition can stress inland mesic terrestrial systems and demonstrates that even Na-enriched detritus alone can induce salt-stress in riparian soil systems. These results suggest that even low-level salinization of riparia can impact riparian ecosystem function and leachate chemistry through direct exposure and indirectly through Na-enriched detritus, a previously overlooked pathway.

Robotic-assisted laparoscopic partial nephrectomy for a 7-cm mass in a renal allograft.

Treatment options for a suspicious renal mass in a renal allograft include radical nephrectomy or nephron-sparing surgery (NSS). To our knowledge robotic-assisted laparoscopic partial nephrectomy (RPN) as treatment for a renal mass in a transplant kidney has not been previously reported. We report the case of RPN for a 7-cm renal mass in a transplanted kidney. A 35-year-old female with reflux nephropathy received a living-related donor kidney transplant in 1986. At 24 years after transplantation she had a 7-cm Bosniak III cystic mass of the allograft detected on computerized tomography (CT) scan. Preoperative creatinine was 2.2 mg/dL with an estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m(2) . RPN was performed with bulldog clamping of the renal vessels, the graft was left in situ and immunosuppression was maintained postoperatively. Tumor diameter was 7.3 cm with a nephrometry score of 10a. Warm ischemia time (WIT) was 26.5 min. Estimated blood loss was 100 mL. There was no change between pre- and postoperative eGFR. There were no operative complications. Histology was papillary renal cell carcinoma type 1, nuclear grade 2. Margins were negative. RPN is a technically feasible treatment option for a suspicious renal mass in renal allografts.

Attitudes toward obesity in obese persons: a matched comparison of obese women with and without binge eating.

No research has compared expressions of weight bias across different subgroups of obese individuals. This study compared attitudes toward and beliefs about obesity in women with and without binge eating disorder (BED) and examined whether these attitudes are related to psychological factors. Fifty obese women with BED were compared with an age- and body mass index (BMI)-matched group of 50 obese women without BED on a battery of established measures of anti-fat attitudes and beliefs about weight controllability and psychological factors (self-esteem, depression, and eating disorder features). The ageand BMI-matched groups did not differ with respect to beliefs about obesity or attitudes toward obese persons, or in self-esteem or depression. Correlational analyses conducted separately within each group revealed that women with BED who reported more favorable attitudes towards obese persons had higher self-esteem and lower levels of depression, whereas there were no significant associations between these variables among women without BED. In addition, weight controllability beliefs and eating disorder features were unrelated to self-esteem and depression in both groups. These findings suggest that stigmatizing attitudes endorsed by obese persons are neither tempered nor worsened by psychological distress or eating pathology. Given that stigmatizing attitudes did not differ between obese women with and without BED, it may be that obesity itself, rather than psychological features or disordered eating, increases vulnerability to negative weight-based attitudes. Potential implications for stigma reduction efforts and clinical practice are discussed.

Stimulation of membrane ruffling and MAP kinase activation by distinct effectors of RAS.

The RAS guanine nucleotide binding proteins activate multiple signaling events that regulate cell growth and differentiation. In quiescent fibroblasts, ectopic expression of activated H-RAS (H-RASV12, where V12 indicates valine-12) induces membrane ruffling, mitogen-activated protein (MAP) kinase activation, and stimulation of DNA synthesis. A mutant of activated H-RAS, H-RASV12C40 (where C40 indicates cysteine-40), was identified that was defective for MAP kinase activation and stimulation of DNA synthesis, but retained the ability to induce membrane ruffling. Another mutant of activated H-RAS, H-RASV12S35 (where S35 indicates serine-35), which activates MAP kinase, was defective for stimulation of membrane ruffling and induction of DNA synthesis. Expression of both mutants resulted in a stimulation of DNA synthesis that was comparable to that induced by H-RASV12. These results indicate that membrane ruffling and activation of MAP kinase represent distinct RAS effector pathways and that input from both pathways is required for the mitogenic activity of RAS.

Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.

Mitogen stimulation of cytoskeletal changes and c-jun amino-terminal kinases is mediated by Rac small guanine nucleotide-binding proteins. Vav, a guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange factor for Rac that stimulates the exchange of bound GDP for GTP, bound to and was directly controlled by substrates and products of phosphoinositide (PI) 3-kinase. The PI 3-kinase substrate phosphatidylinositol-4,5-bisphosphate inhibited activation of Vav by the tyrosine kinase Lck, whereas the product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav by Lck. Control of Vav in response to mitogens by the products of PI 3-kinase suggests a mechanism for Ras-dependent activation of Rac.

A constitutively active and nuclear form of the MAP kinase ERK2 is sufficient for neurite outgrowth and cell transformation.

BACKGROUND: Mitogen-activated protein (MAP) kinases are ubiquitous components of many signal transduction pathways. Constitutively active variants have been isolated for every component of the extracellular-signal-regulated kinase 1 (ERK1) and ERK2 MAP kinase pathway except for the ERK itself. RESULTS: To create an activated ERK2 variant, we fused ERK2 to the low activity form of its upstream regulator, the MAP kinase kinase MEK1. The ERK2 in this fusion protein was active in the absence of extracellular signals. Expression of the fusion protein in mammalian cells did not activate endogenous ERK1 or ERK2. It was sufficient, however, to induce activation of the transcription factors Elk-1 and AP-1, neurite extension in PC12 cells in the absence of nerve growth factor, and foci of morphologically and growth-transformed NIH3T3 cells, if the fusion protein was localized to the nucleus. A cytoplasmic fusion protein was without effect. CONCLUSIONS: Activation of ERK2 is sufficient to cause several transcriptional and phenotypic responses in mammalian cells. Nuclear localization of activated ERK2 is required to induce these events.

Signaling through mitogen-activated protein kinase and Rac/Rho does not duplicate the effects of activated Ras on skeletal myogenesis.

The ability of basic helix-loop-helix muscle regulatory factors (MRFs), such as MyoD, to convert nonmuscle cells to a myogenic lineage is regulated by numerous growth factor and oncoprotein signaling pathways. Previous studies have shown that H-Ras 12V inhibits differentiation to a skeletal muscle lineage by disrupting MRF function via a mechanism that is independent of the dimerization, DNA binding, and inherent transcriptional activation properties of the proteins. To investigate the intracellular signaling pathway(s) that mediates the inhibition of MRF-induced myogenesis by oncogenic Ras, we tested two transformation-defective H-Ras 12V effector domain variants for their ability to alter terminal differentiation. H-Ras 12V,35S retains the ability to activate the Raf/MEK/mitogen-activated protein (MAP) kinase cascade, whereas H-Ras 12V,40C is unable to interact directly with Raf-1 yet still influences other signaling intermediates, including Rac and Rho. Expression of each H-Ras 12V variant in C3H10T1/2 cells abrogates MyoD-induced activation of the complete myogenic program, suggesting that MAP kinase-dependent and -independent Ras signaling pathways individually block myogenesis in this model system. However, additional studies with constitutively activated Rac1 and RhoA proteins revealed no negative effects on MyoD-induced myogenesis. Similarly, treatment of Ras-inhibited myoblasts with the MEK1 inhibitor PD98059 revealed that elevated MAP kinase activity is not a significant contributor to the H-Ras 12V effect. These data suggest that an additional Ras pathway, distinct from the well-characterized MAP kinase and Rac/Rho pathways known to be important for the transforming function of activated Ras, is primarily responsible for the inhibition of myogenesis by H-Ras 12V.

Differential effects of protein kinase A on Ras effector pathways.

Ras mutants with the ability to interact with different effectors have played a critical role in the identification of Ras-dependent signaling pathways. We used two mutants, RasS35 and RasG37, which differ in their ability to bind Raf-1, to examine Ras-dependent signaling in thyroid epithelial cells. Wistar rat thyroid cells are dependent upon thyrotropin (TSH) for growth. Although TSH-stimulated mitogenesis requires Ras, TSH activates protein kinase A (PKA) and downregulates signaling through Raf and the mitogen-activated protein kinase (MAPK) cascade. Cells expressing RasS35, a mutant which binds Raf, or RasG37, a mutant which binds RalGDS, exhibited TSH-independent proliferation. RasS35 stimulated morphological transformation and anchorage-independent growth. RasG37 stimulated proliferation but not transformation as measured by these indices. TSH exerted markedly different effects on the Ras mutants and transiently repressed MAPK phosphorylation in RasS35-expressing cells. In contrast, TSH stimulated MAPK phosphorylation and growth in cells expressing RasG37. The Ras mutants, in turn, exerted differential effects on TSH signaling. RasS35 abolished TSH-stimulated changes in cell morphology and thyroglobulin expression, while RasG37 had no effect on these activities. Together, the data indicate that cross talk between Ras and PKA discriminates between distinct Ras effector pathways.

Ral GTPases contribute to regulation of cyclin D1 through activation of NF-kappaB.

Ral GTPases have been implicated as mediators of Ras-induced signal transduction from observations that Ral-specific guanine nucleotide exchange factors associate with Ras and are activated by Ras. The cellular role of Ral family proteins is unclear, as is the contribution that Ral may make to Ras-dependent signaling. Here we show that expression of activated Ral in quiescent rodent fibroblasts is sufficient to induce activation of NF-kappaB-dependent gene expression and cyclin D1 transcription, two key convergence points for mitogenic and survival signaling. The regulation of cyclin D1 transcription by Ral is dependent on NF-kappaB activation and is mediated through an NF-kappaB binding site in the cyclin D1 promoter. Ral activation of these responses is likely through an as yet uncharacterized effector pathway, as we find activation of NF-kappaB and the cyclin D1 promoter by Ral is independent of association of Ral with active phospholipase D1 or Ral-binding protein 1, two proteins proposed to mediate Ral function in cells.

Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation.

Substantial evidence supports a critical role for the activation of the Raf-1/MEK/mitogen-activated protein kinase pathway in oncogenic Ras-mediated transformation. For example, dominant negative mutants of Raf-1, MEK, and mitogen-activated protein kinase all inhibit Ras transformation. Furthermore, the observation that plasma membrane-localized Raf-1 exhibits the same transforming potency as oncogenic Ras suggests that Raf-1 activation alone is sufficient to mediate full Ras transforming activity. However, the recent identification of other candidate Ras effectors (e.g., RalGDS and phosphatidylinositol-3 kinase) suggests that activation of other downstream effector-mediated signaling pathways may also mediate Ras transforming activity. In support of this, two H-Ras effector domain mutants, H-Ras(12V, 37G) and H-Ras(12V, 40C), which are defective for Raf binding and activation, induced potent tumorigenic transformation of some strains of NIH 3T3 fibroblasts. These Raf-binding defective mutants of H-Ras induced a transformed morphology that was indistinguishable from that induced by activated members of Rho family proteins. Furthermore, the transforming activities of both of these mutants were synergistically enhanced by activated Raf-1 and inhibited by the dominant negative RhoA(19N) mutant, indicating that Ras may cause transformation that occurs via coordinate activation of Raf-dependent and -independent pathways that involves Rho family proteins. Finally, cotransfection of H-Ras(12V, 37G) and H-Ras(12V, 40C) resulted in synergistic cooperation of their focus-forming activities, indicating that Ras activates at least two Raf-independent, Ras effector-mediated signaling events.

Raf-induced transformation requires an interleukin 1 autocrine loop.

The c-Raf-1 serine/threonine protein kinase plays a critical role in the proliferation of most cell types that have been examined. As such, the Raf proto-oncogene is thought to play a central role in the development of human tumors. Although the c-raf-1 gene itself rarely appears to be mutated in human tumors, the kinase activity of Raf is frequently found to be more active in tumor cells, likely through constitutive activation of upstream activators of Raf. The downstream events triggered by Raf that are involved in transformation have been studied less extensively. We show in this study that Raf-induced transformation of NIH 3T3 cells requires the activation of the ubiquitously expressed transcription factor, nuclear factor-kappaB, by Raf. Furthermore, through the use of CrmA, interleukin 1 (IL-1) receptor antagonist, and a dominant-negative form of TRAF6, we demonstrate a requirement for IL-1 production and signaling from the IL-1 receptor as necessary components of Raf-induced transformation. These results indicate that IL-1 may be used as an autocrine growth factor by a number of tumors in which activation of Raf plays an important role in transformation and suggest that blockade of IL-1 signaling may be an approach to limiting the growth of certain tumors.

Structural and functional linkages between subunit interfaces in mammalian pyruvate kinase.

Mammalian pyruvate kinase (PK) is a four-domain enzyme that is active as a homo-tetramer. Tissue-specific isozymes of PK exhibit distinct levels of allosteric regulation. PK expressed in muscle tissue (M1-PK) shows hyperbolic steady-state kinetics, whereas PK expressed in kidney tissue (M2-PK) displays sigmoidal kinetics. Rabbit M1 and M2-PK are isozymes whose sequences differ in only 22 out of 530 residues per subunit, and these changes are localized in an inter-subunit interface. Previous studies have shown that a single amino acid mutation to M1-PK at either the Y (S402P) or Z (T340 M) subunit interface can confer a level of allosteric regulation that is intermediate to M1-PK and M2-PK. In an effort to elucidate the roles of the inter-subunit interaction in signal transmission and the functional/structural connectivity between these interfaces, the S402P mutant of M1-PK was crystallized and its structure resolved to 2.8 A. Although the overall S402P M1-PK structure is nearly identical with the wild-type structure within experimental error, significant differences in the conformation of the backbone are found at the site of mutation along the Y interface. In addition, there is a significant change along the Z interface, namely, a loss of an inter-subunit salt-bridge between Asp177 of domain B and Arg341 of domain A of the opposing subunit. Concurrent with the loss of the salt-bridge is an increase in the degree of rotational flexibility of domain B that constitutes the active site. Comparison of previous PK structures shows a correlation between an increase in this domain movement with the loss of the Asp177: Arg341 salt-bridge. These results identify the structural linkages between the Y and Z interfaces in regulating the interconversion of conformational states of rabbit M1-PK.