p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia

MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.     

The metastatic infiltration at the metastasis/brain parenchyma-interface is very heterogeneous and has a significant impact on survival in a prospective study

The current approach to brain metastases resection is macroscopic removal of metastasis until reaching the glial pseudo-capsule (gross total resection (GTR)). However, autopsy studies demonstrated infiltrating metastatic cells into the parenchyma at the metastasis/brain parenchyma (M/BP)-interface. Aims/Methods: To analyze the astrocyte reaction and metastatic infiltration pattern at the M/BP-interface with an organotypic brain slice coculture system. Secondly, to evaluate the significance of infiltrating metastatic tumor cells in a prospective biopsy study. Therefore, after GTR, biopsies were obtained from the brain parenchyma beyond the glial pseudo-capsule and analyzed histomorphologically. Results: The coculture revealed three types of cancer cell infiltration. Interestingly, the astrocyte reaction was significantly different in the coculture with a benign, neuroectodermal-derived cell line. In the prospective biopsy study 58/167 (34.7%) samples revealed infiltrating metastatic cells. Altogether, 25/39 patients (64.1%) had proven to exhibit infiltration in at least one biopsy specimen with significant impact on survival (OS) (3.4 HR; p = 0.009; 2-year OS was 6.6% versus 43.5%). Exceptionally, in the non-infiltrating cohort three patients were long-term survivors. Conclusions: Metastatic infiltration has a significant impact on prognosis. Secondly, the astrocyte reaction at the M/BP-interface is heterogeneous and supports our previous concept of the organ-specific defense against metastatic (organ-foreign) cells.     

Recent advances in the management of venous thromboembolism

Deep venous thrombosis and pulmonary embolism are frequently diagnosed in patients encountered in a primary-care practice. In the past 10 years, many important advances have been made regarding the management of these disorders. Risk factors have been better defined than in the past. Several new prophylactic measures--such as external pneumatic compression of the lower extremities, dihydroergotamine in combination with heparin, adjusted-dose heparin, and two-step warfarin therapy--can be used to help prevent deep venous thrombosis in surgical patients. The use of serial impedance plethysmography has expanded options for noninvasive diagnosis of deep venous thrombosis. Correlations between pulmonary embolism and ventilation-perfusion lung scan patterns have been clarified. Although much has been learned about heparin and warfarin that affect common management decisions, the indications for thrombolytic therapy for venous thromboembolism remain controversial. Finally, studies have shown that calf vein thrombi that are not detectable by impedance plethysmography and that show no evidence of proximal propagation by serial impedance plethysmography do not require treatment.     

Excessive release of endogenous neuropeptide Y into cerebrospinal fluid after treatment of spontaneous subarachnoid haemorrhage and its possible impact on self-reported neuropsychological performance – results of a prospective clinical pilot study on good-grade patients

ABSTRACT

Objectives: Neuropsychological dysfunction after treatment of spontaneous subarachnoid haemorrhage (sSAH) is common but underreported. The vasoconstrictor neuropeptide Y (NPY) is excessively released after sSAH and in psychiatric disorders. We prospectively analysed the treatment-specific differences in the secretion of endogenous cerebrospinal fluid (CSF) NPY during the acute stage after sSAH and its impact on cognitive processing.

Methods: A total of 26 consecutive patients (f:m = 13:8; mean age 50.6 years) with good-grade sSAH were enrolled (drop out n = 5): n = 9 underwent endovascular aneurysm occlusion, n = 6 microsurgery, and n = 6 patients with perimesencephalic SAH received standardized intensive medical care. Ventricular CSF was drawn daily from day 1–10. CSF NPY levels were determined with competitive enzyme immunoassay. All patients underwent neuropsychological self-report assessment [36-Item Short Form Health Survey (SF-36) and ICD-10-Symptom-Rating questionnaire (ISR)] after the onset of sSAH (day 11–35; t₁) and at the 6-month follow-up (t₂).

Results: At t₁, increased mean levels of NPY in CSF significantly correlated with impaired performance in most ISR scores (ISR total p = .018, depression p = .035, anxiety p = .008, nutrition disorder p = .047, supplementary items p = .038) and in several psychological SF-36 items (vitality p = .019, general mental health p = .001, mental component summary p = .025).

Discussion: To the best of our knowledge, this study is the first to correlate the levels of endogenous NPY in supratentorial CSF with cognitive outcome in good-grade sSAH patients. Excessive NPY release into CSF may have a short-term influence on the pathogenesis of neuropsychological deficits. The impact of cerebrovascular manipulation on NPY release has to be further elucidated.

Abbreviations: ANOVA: analysis of variance; aSAH: aneurysmal subarachnoid haemorrhage; AUC: area under the curve; CBF: cerebral blood flow; CSF: cerebrospinal fluid; CT (scan): computed tomography (scan); CV: cerebral vasospasm; DIND: delayed ischemic neurological deficit; DSA: digital subtraction angiography; EIA: enzyme immunoassay; EV: endovascular aneurysm occlusion; EVD: external ventricular drainage; FU: 6-month follow-up; GCS: Glasgow Coma Scale; Ghp: general health perceptions; GOS: Glasgow Outcome Scale; h: hour/s; HH: Hunt and Hess; ICU: intensive care unit; ISR: ICD-10-Symptom-Rating questionnaire; MCS: mental component summary; Mhi: general mental health; min: minute/s; min-max: minimum – maximum; ml: millilitre; mRS: modified Ranking Scale; MS: microsurgical clipping, microsurgical aneurysm occlusion; ng: nanograms; no. [n]: number; NPY: Neuropeptide Y; p: p value; Pain: bodily pain; PCS: physical component summary; Pfi: physical functioning; pSAH: perimesencephalic subarachnoid haemorrhage; PTSD: posttraumatic stress disorder; QoL: quality of life; Rawhtran: health transition item; Rolem: role limitations because of emotional problems; Rolph: role limitations due to physical health problems; SAH: subarachnoid haemorrhage; SD: standard deviation; SF-36: 36-Item Short Form Health Survey; Social: social functioning; sSAH: spontaneous subarachnoid haemorrhage; TCD: trans-cranial Doppler ultrasound; (test) t₁: test in the sub-acute phase after the onset of bleeding (between day 11 and 35 after subarachnoid haemorrhage); (test) t₂: test in the short-term (chronic phase) after treatment at 6-month follow-up; test t₁ - t₂: intergroup development from t₁ to t₂; Vital: vitality; vs: versus.     

Behavioral Intervention Technologies: Evidence review and recommendations for future research in mental health

Objective

A technical expert panel convened by the Agency for Healthcare Research and Quality and the National Institute of Mental Health was charged with reviewing the state of research on behavioral intervention technologies (BITs) in mental health and identifying the top research priorities. BITs refers to behavioral and psychological interventions that use information and communication technology features to address behavioral and mental health outcomes.

Method

This study on the findings of the technical expert panel.

Results

Videoconferencing and standard telephone technologies to deliver psychotherapy have been well validated. Web-based interventions have shown efficacy across a broad range of mental health outcomes. Social media such as online support groups have produced disappointing outcomes when used alone. Mobile technologies have received limited attention for mental health outcomes. Virtual reality has shown good efficacy for anxiety and pediatric disorders. Serious gaming has received little work in mental health.

Conclusion

Research focused on understanding reach, adherence, barriers and cost is recommended. Improvements in the collection, storage, analysis and visualization of big data will be required. New theoretical models and evaluation strategies will be required. Finally, for BITs to have a public health impact, research on implementation and application to prevention is required.     

Plasma β-amyloid peptides in canine aging and cognitive dysfunction as a model of Alzheimer's disease

Aging dogs naturally demonstrate cognitive impairment and neuropathology that model early Alzheimer's disease (AD). In particular, there is evidence that canine cognitive dysfunction syndrome (CDS) in aged dogs is accompanied by cortical deposition of Aβ peptides and neurodegeneration. Plasma Aβ levels have been examined in humans as putative biomarkers for AD, but to date, no similar studies have been conducted for canine dementia. The aim of the present study was to assess plasma Aβ1-42 and Aβ1-40 levels in a blind study using pet dogs that were either successfully aging or exhibiting CDS. The severity of cognitive impairment was assessed using an owner-based questionnaire. On average, young dogs presented significantly higher plasma levels of Aβ1-42 and Aβ1-40 than aged, cognitively unimpaired dogs. Notably, among aged dogs, the levels of Aβ1-42 and the Aβ42/40 ratio were significantly higher in those showing mild cognitive impairment than in either cognitively unimpaired or severely affected dogs. These results suggest that increased plasma Aβ1-42 levels and Aβ42/40 ratio could be a biomarker for canine cognitive dysfunction, which is considered an excellent natural model of early AD.     

Correction to: Henoch-Schönlein purpura nephritis: initial risk factors and outcomes in a Latin American tertiary center

Clinical Rheumatology - One of the author’s name on this article was incorrectly spelled as “Sylvia C. L. Fahrat” . The correct spelling is “Sylvia C. L. Farhat” and...     

Annual Meeting Scientific Program August 7-10, 2003

Abstract

Gabrielle Weiss and Lily T. Hechtman, Hyperactive Children Grown Up: Empirical Findings and Theoretical Considerations. New York: Guilford Press, 1986, 367 pp., ISBN 0-89862-66 1-7, $32.50 (US)     

Association Notes

Neurologic evaluation during the first year of life serves to separate infants into normal and abnormal groups and to identify those who should be carefully watched. The evaluation must reflect physical findings as well as neurologic status, and emphasize the patterned and stereotyped responses characteristic of certain periods of infancy.