Trans-ocular brain impedance index for assessment of cerebral autoregulation in a porcine model of cerebral hemodynamic perturbation

Cerebrovascular autoregulation (CA) is often impaired following traumatic brain injury. Established technologies and metrics used to assess CA are invasive and conducive for measurement, but not for continuous monitoring. We developed a trans-ocular brain impedance (TOBI) method that may provide non-invasive and continuous indices to assess CA. In this study, we monitored impedance metrics such as respiratory-induced impedance amplitude changes (dz) as well as a novel impedance index (DZx), which is a moving Pearson correlation between mean arterial pressure (MAP) and dz. Yorkshire swine were instrumented to continuously record ICP, MAP, and cerebral blood flow (CBF). TOBI was recorded by placement of standard ECG electrodes on closed eyelids and connected to a data acquisition system. MAP, ICP and CBF were manipulated utilizing an intravenous vasopressor challenge. TOBI indices (dz and DZx) were compared to the hemodynamic indicators as well as pressure reactivity index (PRx). During the vasopressor challenge, dz was highly correlated with ICP, CPP, and CBF (r?=??<?? 0.49, p?<?0.0001). ICP, CPP, and CBF had a mean percent increase (standard deviation) from baseline of 29(23.2)%, 70(25)%, and 37(72.6)% respectively while dz decreased by 31(15.6)%. Receiver operator curve test showed high predictive performance of DZx when compared to PRx with area under the curve above 0.86, with high sensitivity and specificity. Impedance indices appear to track changes in PRx and hemodynamics that affect cerebral autoregulation. TOBI may be a suitable less invasive surrogate to PRx and capable of tracking cerebral autoregulation.

     

PMS2 mutations in childhood cancer

Until recently, the PMS2 DNA mismatch repair gene has only rarely been implicated as a cancer susceptibility locus. New studies have shown, however, that earlier analyses of this gene have had technical limitations and also that the genetic behavior of mutant PMS2 alleles is unusual, in that, unlike MLH1 or MSH2 mutations, PMS2 mutations show low heterozygote penetrance. As a result, a dominantly inherited cancer predisposition has not been a feature reported in families with PMS2 mutations. Such families have instead been ascertained through childhood-onset cancers in homozygotes or through apparently sporadic colorectal cancer in heterozygotes. We present further information on the phenotype associated with homozygous PMS2 deficiency in 13 patients from six families of Pakistani origin living in the United Kingdom. This syndrome is characterized by café-au-lait skin pigmentation and a characteristic tumor spectrum, including leukemias, lymphomas, cerebral malignancies (such as supratentorial primitive neuroectodermal tumors, astrocytomas, and glioblastomas), and colorectal neoplasia with an onset in early adult life. We present evidence for a founder effect in five families, all of which carried the same R802-->X mutation (i.e., arginine-802 to stop) in PMS2. This cancer syndrome can be mistaken for neurofibromatosis type 1, with important management implications including the risk of the disorder occurring in siblings and the likelihood of tumor development in affected individuals.     

Development and initial validation of a family appraisal of caregiving questionnaire for palliative care

This article describes the derivation and initial psychometric validation of a multi-dimensional Family Appraisal of Caregiving Questionnaire for Palliative Care (FACQ-PC). The 25-item measure consists of four theoretically derived subscales: (i) caregiver strain, (ii) positive caregiving appraisals, (iii) caregiver distress, and (iv) family well-being. Based on a sample of 160 family caregivers of a relative with cancer receiving palliative care, reliability analyses demonstrated the subscale scores to be internally consistent and factor analysis revealed evidence of factorial validity. Correlations of the four subscales with measures of family functioning, positive and negative affect, and subjective burden provided evidence of convergent and discriminant validity. The FACQ-PC provides a measure of the family's appraisal of caregiving that can be used in clinical assessment, and has potential utility for evaluating the effectiveness of palliative care interventions.     

Treatment of recurrent central nervous system primitive neuroectodermal tumours in children and adolescents: results of a Children's Cancer and Leukaemia Group study

Background

The treatment of previously irradiated patients with recurrent central nervous system primitive neuroectodermal tumours (PNETs) is a considerable challenge. A study was undertaken to attempt to improve the outcome for such patients using a high dose chemotherapy (HDCT) based strategy.

Methods

Between 2000 and 2007, 40 patients with relapsed medulloblastoma (MB) and 5 with relapsed supratentorial PNETs (StPNETs) were accrued. All but one had received prior craniospinal radiotherapy. Patients were initially treated with cyclophosphamide (4 g/m²) together with surgery or local radiotherapy where appropriate. If complete or near complete remission was achieved, the patient proceeded to receive two sequential courses of HDCT with stem cell rescue. The first course consisted of thiotepa (900 mg/m²) and the second carboplatin (AUC 21).

Results

All five patients with StPNET died of tumour progression with a median OS of 0.4 years. Nineteen of the 40 patients with relapsed MB underwent surgery. Radiotherapy was administered to eight patients. All patients received at least one course of cyclophosphamide. Only 22 MB patients progressed to the HDCT phase; 10 patients received thiotepa only and 12 thiotepa and carboplatin. At a median follow-up of 7.4 years (Range 2.8-8.2 years), only three MB patients are still alive, one following a further relapse. Three and 5 year OS was 22.0% and 8.2%, respectively and 3 and 5 year EFS was 14.6% and 8.7%, respectively.

Conclusion

This national study based on a strategy including a particular tandem HDCT regimen showed no benefit for previously irradiated patients with relapsed StPNET and very limited benefit for patients with relapsed medulloblastoma.     

Epidemiology of leukaemia and lymphoma in children and young adults from the north of England, 1990–2002

AimWe aimed to describe and contrast the epidemiology of haematological malignancies among 0–14 and 15–24-year-olds in northern England from 1990 to 2002 and compare clinical trial entry by age group.Patients and methodsIncidence rates were examined by age, sex and period of diagnosis and differences were tested using Poisson regression. Differences and trends in survival were assessed using Cox regression.Results1680 subjects were included comprising 948 leukaemias and 732 lymphomas. Incidence rates for acute lymphoblastic leukaemia were significantly higher for 0–14 compared to 15–24-year-olds, whilst Hodgkin lymphoma showed the reverse. No significant changes in incidence were observed. 60% of leukaemia patients aged 15–24 years entered trials compared to 92% of 0–14-year-olds. Survival rates were significantly lower and improved less markedly over time for 15–24 compared to 0–14-year-olds, particularly for leukaemia.ConclusionsTrial accrual rates need to be improved amongst 15–24-year-olds and a more structured follow-up approach adopted for this unique population.     

Human cortical responses to the speech envelope

OBJECTIVE: To evaluate the response of the human auditory cortex to the temporal amplitude-envelope of speech. Responses to the speech envelope could be useful for validating the neural encoding of intelligible speech, particularly during hearing aid fittings--because hearing aid gain and compression characteristics for ongoing speech should more closely resemble real world performance than for isolated brief syllables. DESIGN: The speech envelope comprises energy changes corresponding to phonemic and syllabic transitions. Envelope frequencies between 2 and 20 Hz are important for speech intelligibility. Human event-related potentials were recorded to six different sentences and the sources of these potentials in the auditory cortex were determined. To improve the signal to noise ratio over ongoing electroencephalographic recordings, we averaged the responses over multiple presentations, and derived source waveforms from multichannel scalp recordings. Source analysis led to bilateral, symmetrical, vertical, and horizontal dipoles in the posterior auditory cortices. The source waveforms were then cross-correlated with the low frequency log-envelopes of the sentences. The significance and latency of the maximum correlation for each sentence demonstrated the presence and latency of the brain's response. The source waveforms were also cross-correlated with a simple model based on a series of overlapping transient responses to stimulus change (the derivative of the log-envelope). RESULTS: Correlations between the log-envelope and vertical dipole source waveforms were significant for all sentences and for all but one of the participants (mean r = 0.35), at an average delay of 175 (left) to 180 (right) msec. Correlations between the transient response model (P1 at 68 msec, N1 at 124 msec, and P2 at 208 msec) and the vertical dipole source waveforms were detected for all sentences and all participants (mean r = 0.30), at an average delay of 6 (right) to 10 (left) msec. CONCLUSIONS: These results show that the human auditory cortex either directly follows the speech envelope or consistently reacts to changes in this envelope. The delay between the envelope and the response is approximately 180 msec.