Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia

A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).     

Suffocation and respiratory responses to carbon dioxide and breath holding challenges in individuals with panic disorder

OBJECTIVE: Findings showing that individuals with panic disorder (PD) are prone to experience panic attacks when inhaling CO2-enriched air have given rise to the hypothesis that physiological systems underlying the experience of suffocation may be important in the etiology of PD. In this study, we tested several predictions stemming from this view. METHODS: Forty individuals with PD and 32 controls underwent both a breath-holding challenge and a CO2 rebreathing challenge. A wide array of physiological and psychological responses, including continuous measurements of subjective suffocation, was recorded. RESULTS: Individuals with PD experienced elevated physiological reactivity to both challenges and greater levels of suffocation sensations during the rebreathing challenge. Furthermore, PD individuals who experienced a panic attack in response to the rebreathing challenge exhibited faster but shallower breathing during the challenge than did other PD individuals. CONCLUSION: Findings are consistent with theories linking PD to hypersensitive brain systems underlying the experience of suffocation. The possibility that subjective suffocation was in part mediated by peripheral interoceptive disturbances (vs. brainstem dysregulation) is discussed.     

WAY-318068: a novel, potent and selective noradrenaline re-uptake inhibitor with activity in rodent models of pain and depression

Background and purpose:

Antidepressants, which raise the CNS concentrations of 5-HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.

Experimental approach:

In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY-318068 (1-[(1S,2R)-1-(3,5-difluorophenyl)-2-hydroxy-3-(methylamino)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one).

Key results:

WAY-318068 is a potent and effective inhibitor of the NET with a K_i of 8.7 nM in a binding assay, and an IC₅₀ of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5-HT transporter, leading to a functional selectivity of greater than 2500-fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5-HT. WAY-318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.

Conclusions and implications:

Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.     

Metabolic and clinical correlates of acute ischemic infarction

We studied cerebral metabolism, anatomy, and clinical status in 36 patients with acute cerebral ischemia. Results from FDG-PET were compared with CT to find the relationships between the metabolic, anatomic, and clinical findings. Metabolic abnormalities seen on PET frequently were more extensive than the corresponding CT findings. The pattern of metabolic abnormality was significantly related to both the type of clinical syndrome and the degree of eventual recovery. No such relationships were found for the CT results. We conclude that studies of cerebral metabolism are of value in establishing prognosis after acute cerebral ischemia. Also, knowledge of the patterns of cerebral dysmetabolism provides a powerful means for the localization of clinical function.     

Local cerebral metabolic changes in acute ischemic strokes

Positron emission tomography (PET) studies with 18F deoxyglucose were completed in 35 patients with acute ischemic strokes. Twelve cases were studied within 72 h, 23 between 4 and 14 days. Results indicate the functional and prognostic significance of early tomography studies of metabolism, and anticipate possible use of metabolic imaging in the evaluation of treatment.     

Cerebral metabolism and patterned visual stimulation: a positron emission tomographic study of the human visual cortex

We studied the impact of visual stimulation upon cerebral metabolism in normal young men using FDG-PET. Results obtained from subjects receiving patterned visual stimulation while performing an ocular fixation task were compared with results from ocular fixation alone. Visual stimulation in the macular region of either hemifield produced significant increases in metabolism of the contralateral posterior striate cortex. Visual stimulation induced highly significant asymmetries in metabolism of the prefrontal and inferior parietal cortices. Metabolic activation in extrastriate areas tended to be right-sided. These findings support the classic notion of retinotopic organization within the primary visual sensory cortex. They also indicate that the patterns of cerebral metabolism are not equivalent between the two cerebral hemispheres. This latter finding suggests that in humans the right cerebral hemisphere may be specialized for visual processing.     

Behavioural assessment and treatment of chronic headaches in children

ABSTRACT This review explores advances in the behavioural assessment and treatment of childhood headaches. Behavioural assessment procedures are outlined including the behavioural interview, self-report questionnaires, self-monitoring and caregiver observations. We conclude that behavioural treatment strategies are effective in the management of childhood headaches, although most of the research support appears to be limited to relaxation training and biofeedback. Nonetheless, the behavioural assessment and treatment of childhood headaches appears to be a promising clinical and research direction.     

Validating studies for panic disorder in patients with angiographically normal coronary arteries

This article describes validating studies for diagnosing panic disorder in some patients with angiographically normal coronary arteries (NCA) and chest pain. Psychiatric interviews of 94 such patients showed that 34% met the diagnostic criteria for panic disorder. Further studies showed that NCA patients with panic disorder were more disabled at 3.5-year follow-up, had more relatives with panic disorder, were more likely to suffer from major depression, and were more likely to respond to 35% CO2 challenge with panic symptoms. Because panic disorder is highly disabling but responds well to psychological and pharmacologic treatments, screening NCA patients in the cardiology population for this disorder is recommended.     

Myeloablative combination chemotherapy without total body irradiation for neuroblastoma

Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1, hyperfractionated radiation (2,100 cGy) to the primary site and adjacent lymph nodes, carmustine (BCNU) 200 mg/m2 x 1, melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12), and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16, histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis, grade 1 to 2 diarrhea, and fevers. No patient required infusion of unpurged reserve autografts. At ABMT, 16 patients (group I) were progression-free 6.5 months to 14 months (median, 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median, 39 months) off therapy, six relapsed 4 months to 17 months post-ABMT, and three died of toxicity (candidiasis, metabolic derangement, and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT, including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy, four relapsed 3 months to 12 months post-ABMT, and three died of toxicity (aspergillosis, hemorrhagic cystitis, VOD). Only one of 10 relapses involved a primary site, suggesting a beneficial effect of local radiation. In terms of survival or toxicity, an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma, but concerns over late relapses and toxicity mandate continuing efforts to devise alternative, less risky, and more clearly beneficial approaches for definitive ablation of neuroblastoma.