NeuroDAC: an open-source arbitrary biosignal waveform generator.

Objective.Researchers are developing biomedical devices with embedded closed-loop algorithms for providing advanced adaptive therapies. As these devices become more capable and algorithms become more complex, tasked with integrating and interpreting multi-channel, multi-modal electrophysiological signals, there is a need for flexible bench-top testing and prototyping. We present a methodology for leveraging off-the-shelf audio equipment to construct a biosignal waveform generator capable of streaming pre-recorded biosignals from a host computer. By re-playing known, well-characterized, but physiologically relevant real-world biosignals into a device under test, researchers can evaluate their systems without the need for expensivein vivoexperiments.Approach.An open-source design based on the proposed methodology is described and validated, the NeuroDAC. NeuroDAC allows for 8 independent channels of biosignal playback using a simple, custom designed attenuation and buffering circuit. Applications can communicate with the device over a USB interface using standard audio drivers. On-board analog amplitude adjustment is used to maximize the dynamic range for a given signal and can be independently tuned for each channel.Main results.Low noise component selection yields a no-signal noise floor of just 5.35 ± 0.063. NeuroDAC's frequency response is characterized with a high pass -3 dB rolloff at 0.57 Hz, and is capable of accurately reproducing a wide assortment of biosignals ranging from EMG, EEG, and ECG to extracellularly recorded neural activity. We also present an application example using the device to test embedded algorithms on a closed-loop neural modulation device, the Medtronic RC+S.Significance.By making the design of NeuroDAC open-source we aim to present an accessible tool for rapidly prototyping new biomedical devices and algorithms than can be easily modified based on individual testing needs.ClinicalTrials.gov Identifiers: NCT04281134, NCT03437928, NCT03582891.

Macrophage migration inhibitory factor expression is increased in pituitary adenoma cell nuclei.

Macrophage migration inhibitory factor (MIF) is an essential regulator of the macrophage responses to endotoxin. MIF also has the ability to override the anti-inflammatory actions of glucocorticoids during an immune response, and is thus an important pro-inflammatory factor. The presence of MIF in cells of the anterior pituitary has been described, and high levels of MIF in other rapidly proliferating tIssues have also been demonstrated. It has been hypothesised that MIF release from these cells is influenced by the hypothalamo-pituitary-adrenal axis, and that ACTH and MIF are released simultaneously to exert counter-regulatory effects on cortisol. However, another intracellular role for MIF has also been suggested as it has been shown that MIF exerts an effect on the inhibitory cell cycle control protein p27 through an interaction with Jab1, a protein implicated in p27 degradation. We studied MIF expression in different normal and adenomatous human pituitary samples using immunohistochemistry and RT-PCR. There was evidence of co-immunoprecipitation of MIF with Jab1, suggesting an interaction of the two proteins. Our results showed that there is increased expression of MIF protein in the nuclei of all pituitary adenomas compared with normal tIssue (P=0.0067), but there was no statistically significant difference in nuclear MIF expression between the different adenoma types. Nuclear MIF expression correlated positively with p27 and its phosphorylated form in normal tIssue (P=0.0028 and P<0.0001); however, this relationship was not seen in the adenoma samples. Cytoplasmic expression of MIF was found to be variable both in normal and adenomatous samples, with no consistent pattern. MIF mRNA was demonstrated to be present in all tumour and normal samples studied. Somatotroph tumours showed higher MIF mRNA expression compared with normal pituitary or other types of adenomas. In conclusion, MIF is expressed in cell nuclei in pituitary adenomas to a greater extent than in normal pituitary tIssue. We speculate that it may play a role in the control of the cell cycle, but whether its higher level in adenomas is a cause or a consequence of the tumorigenic process remains to be clarified.

A workable solution for the pre-Medicare population.

Incremental reforms to expand health coverage among older Americans are justified by medical spending that increases with age and enrollment in employer insurance that decreases with age. Older Americans are also at risk of unexpected changes in health, access to health insurance, and earnings that could leave them poorly positioned financially for their retirement years. We propose offering universal access to Medicare at a community-rated premium, with premium vouchers for those with a history of low lifetime earnings and tax-preferred savings accounts to help everyone with the increased cost of insurance at older ages. These subsidies are available for coverage obtained from sources other than Medicare. We would set the eligibility age for the buy-in at 62. However, because enrollment in employer insurance does not drop precipitously at age 62, we regard the eligibility age as an adjustable design element that could resize the program to fit political and budgetary constraints.

Betwixt and between: targeting coverage reforms to those approaching Medicare.

Recent Medicare buy-in proposals agree on setting eligibility at age sixty-two but disagree on linking eligibility to loss of employer insurance or ability to pay. We examine arguments for targeting incremental coverage for older Americans in these ways. While access to retiree health insurance is declining, we question whether targeting loss of employer insurance can address many older Americans' insurance problems. Furthermore, focusing on persons ages sixty-two to sixty-four misses a large group of persons in poor health with limited resources. Efforts to improve coverage for older Americans should consider trade-offs between defining eligibility by age versus ability to pay.

Haemangioblastoma of a cervical sensory nerve root in Von Hippel-Lindau syndrome.

Spinal haemangioblastomas are rare, accounting for only about 7% of all central nervous system cases. The case of a 40-year-old woman with a haemangioblastoma arising solely from a cervical sensory nerve root is presented. At operation via a cervical laminectomy, it was possible to resect the tumour en masse with the sensory ramus, by extending the laminectomy through the exit foramen for C6. Haemangioblastomas are commonly intramedullary, and have only been reported in this location on one previous occasion. The patient has Von Hippel-Lindau syndrome and a history of multiple solid tumours. The possible role of the Von Hippel-Lindau tumour suppressor gene in the pathogenesis of these neoplasms is discussed.

Spinal intradural tumours: Part I--Extramedullary.

Sixty-six patients had surgery for an intramedullary nerve sheath tumour under the care of one surgical team in a 16-year period. Surgery concentrated on radical intra- and extradural excision combined if necessary with vertebral column reconstruction. Ninety procedures were used in 35 males and 30 females with an age range 12-81 years. Forty-five per cent were located in the cervical, 26% in the thoracic and 29% in the lumbosacral region. Eighteen patients had NF1 and two patients NF2. Sixty-five per cent were schwannomas, 27% were mixed histology and 6% malignant. In terms of functional outcome, 37 patients improved by one or more Frankel grades, three deteriorated by one Frankel grade and no one who presented with symptoms alone deteriorated. There were no operative deaths; no instrumentation failures and five patients developed a CSF leak.

Spinal intradural tumours: Part II--Intramedullary.

The results of surgical management in 54 patients with intramedullary spinal cord tumours are presented. Cervical tumours were most frequent (25/54) followed by thoracic (16/54) and then lumbar (14/54). Ependymomas and astrocytomas were the most common tumour types. Total tumour removal was possible in just over half of the cases. Surgical complications included: two deaths, six patients with CSF leaks and one with wound infection. Postoperatively three patients had worsening of their motor deficit (unable to walk) and three patients had worsening of urinary sphincter function. Conversely, three patients who were unable to walk preoperatively were able to walk postoperatively, whilst four patients with sphincter disturbance showed improvement. Total tumour removal was not associated with increased risk of postoperative neurological deficit. Long-term follow up (2-18 years) was possible in 40 patients; 90% were still independently mobile. Our results compare favourably with other European studies and data from the North American units which have pioneered this surgery.

Neuronal nitric oxide synthase gene expression in human pituitary tumours: a possible association with somatotroph adenomas and growth hormone-releasing hormone gene expression.

OBJECTIVE: Nitric oxide (NO) has been implicated in the control of the secretory response to growth hormone-releasing hormone (GHRH) and may also modify GH release in response to excitatory aminoacids. Although rat and mouse pituitary cell lines have been shown to express neuronal NO synthase (nNOS), there has until now been no information on nNOS gene expression in human pituitary adenomas. Our objective was to provide such data and correlate the presence of nNOS transcripts with GHRH transcripts. PATIENTS: Pituitary adenoma tissue was obtained from a random selection of 32 patients with somatotrophadenomas, 16 patients with corticotroph adenomas, 39 patients with endocrinologically inactive adenomas and nine patients with macroprolactinomas undergoing transsphenoidal hypophysectomy. MEASUREMENTS: Transcripts for nNOS and GHRH were identified in frozen tissue sections by in situ hybridization histochemistry using synthetic 35S-labelled oligodeoxynucleotide probes with 100% homology to the target transcript. RESULTS: Neuronal NOS transcripts were identified in one of 16 corticotroph adenomas (6%), one of nine macroprolactinomas (11%), six of 39 endocrinologically inactive adenomas (15%) and 13 of 32 somatotroph adenomas (41%). GHRH transcripts were found in a similar distribution to nNOS transcripts in 10 of the 13 nNOS-expressing somatotroph adenomas, and in three of the four remaining adenomas from which suitable tissue was available. Cross-hybridization of the nNOS and GHRH probes to the same target was excluded by including rat brain sections cut through the arcuate nucleus as hybridization controls. Furthermore, two different nNOS oligodeoxynucleotide probes complementary to different regions of the target transcript produced identical results. CONCLUSIONS: These results suggest that there is a close correlation between nNOS gene expression and 'ectopic' expression of GHRH in human pituitary tumours, especially somatotroph adenomas. The relevance of these findings from a functional or pathologenic viewpoint remains unclear, but the data again emphasize that it is not just GH secretion that distinguishes somatotroph adenomas from other pituitary tumours.

Methotrexate therapy for ectopic pregnancy in adolescents.

STUDY OBJECTIVE: To determine the suitability and efficacy of methotrexate (MTX) therapy for adolescent patients with ectopic pregnancy. MATERIALS: Patients with ectopic pregnancy were treated with methotrexate, 50 mg/m2 intramuscularly. Follow-up determinations of quantitative beta hCG levels were done on days 1, 4, and 7. They were then seen weekly until beta hCG levels were less than 15 mIU/ml. PARTICIPANTS: Adolescents with ectopic pregnancy (55 patients) received MTX therapy and comprised the study group. They were compared with 186 adults similarly treated. The groups were compared for treatment outcome and for compliance with the rigid protocol requirements. MAIN OUTCOME MEASURES: Treatment success was defined as a patient who required no surgical intervention and whose beta hCG levels declined to < 15 mIU/ml. RESULTS: 85% of patients required no surgical intervention following MTX injection. Surgical intervention rates were slightly higher and success rates slightly lower for adolescent patients, but these differences were not statistically significant (p = .71). Although adult patients were more likely to have a perfect compliance rating, comparison of all compliance categories showed no significant differences (p = .17). CONCLUSIONS: MTX therapy is satisfactory for adolescent patients. It is effective, and adolescent patients are able to comply with the requirements of a rigid protocol.

MRI of 'idiopathic' juvenile scoliosis. A prospective study.

In a prospective trial we performed MRI of the spine and hind brain in 31 patients with scoliosis of onset between the ages of four and 12 years. In eight patients (26%) there was a significant neuroanatomical abnormality; there were six cases of Chiari-1 malformation associated with a syrinx, one isolated Chiari-1 malformation and one astrocytoma of the cervical spine. Four of these patients had left-sided curves. There were no clinical features which could reliably identify those patients with abnormalities on MRI. In particular, the unilateral absence of abdominal reflexes was found to be non-specific (1 of 8 of patients with neuroanatomical abnormalities (12.5%) v 2 of 23 with normal scans (8.7%). In view of the established risks of surgical correction of scoliosis in the presence of undecompressed syringomyelia and the possible improvement that may follow decompression of the foramen magnum, we feel that MRI of all patients with scoliosis of juvenile onset should be obligatory.

Medical management of the patient with an ectopic pregnancy.

Ectopic pregnancies are the leading cause of pregnancy-related death during the first trimester. Historically, the treatment for an ectopic pregnancy was emergency laparotomy, which included salpingectomy. In 1987, research began at the Regional Medical Center at Memphis, in conjunction with the University of Tennessee, examining early detection and medical treatment for ectopic pregnancy. Pharmacologic management of an unruptured, size-appropriate ectopic pregnancy is now an established standard of care. The present protocol recommends single-dose methotrexate. This form of methotrexate has proven to be a successful, cost-effective alternative to traditional surgical management of ectopic pregnancies.

Impact of a natural disaster on preschool children: adjustment 14 months after a hurricane.

Fourteen months after a hurricane, young children who had experienced the storm showed significantly higher anxiety and withdrawal and more behavior problems than did children who had not. Behavioral problems decreased steadily over the six months following the storm. Mothers' distress in the hurricane's aftermath was associated with the longevity of their children's emotional and behavioral difficulties.

Absent superficial abdominal reflexes in children with scoliosis. An early indicator of syringomyelia.

We describe 12 children with idiopathic scoliosis who had a persistent absent superficial abdominal reflex (SAR) on routine neurological examination. MRI showed syringomyelia to be present in ten. The average age at detection of the scoliosis was 4.3 years and at diagnosis of syringomyelia 6.6 years. In all ten children the SAR was consistently absent on the same side as the convexity of the curve. In two it was the only abnormal neurological sign. An absent SAR in patients with scoliosis is an indication for investigation for underlying syringomyelia. In the children with syringomyelia, six had thoracic and four thoracolumbar curves. The clinical features differed in the two groups. Patients with thoracic curves were generally asymptomatic. Their neurological signs were subtle and none had any motor signs. By contrast, patients with thoracolumbar curves had symptoms and neurological signs. Abnormal gait was present in all four patients with thoracolumbar curves. In three this was due to considerable motor weakness. In eight children syringomyelia was associated with a Chiari-I malformation. In seven the syrinx was treated surgically by decompression of the foramen magnum.

Stroke-induced cardiovascular changes: a rare cause of death from polyarteritis nodosa.

Polyarteritis nodosa (PAN) is an uncommon but well documented cause of subarachnoid haemorrhage (SAH). We report a case of SAH in a patient with PAN causing death indirectly from the effects of resultant cardiovascular changes upon other manifestations of PAN. Clinicians should be aware of the systemic effects of SAH in patients with known vasculitides.

Syrinx associated with intramedullary metastasis.

Two cases are reported of syrinx associated with an intramedullary metastasis. The first presented with hyperaesthesia in the right arm and bilateral pyramidal leg weakness, the second with a partial right sided Brown Sequard syndrome with a sensory level at D6. A possible pathological mechanism for the development of such syrinxes is discussed.

Behavior of an extradural pressure monitor in clinical use. Comparison of extradural with intraventricular pressure in patients with acute and chronically raised intracranial pressure.

A comparison of intraventricular pressure (IVP) and extradural pressure (EDP) was carried out in 17 patients being investigated for normal-pressure hydrocephalus, and in six patients with acutely raised intracranial pressure following events such as head injury or intracerebral hematoma. Extradural pressure was measured using the CardioSearch monitor. There was a reasonably good correlation between EDP and IVP in the chronic stable group with pressures up to 25 mm Hg. In the acute group there was no predictable relationship between EDP and IVP, and during a 24-hour period the pressures could vary by as much as 30 mm Hg. Subdural pressure, measured with the same instruments, was compared to IVP in both acute and stable situations in eight other patients: there was a close and constant correlation between pressures in these two spaces. The authors conclude that misleading information may be obtained from EDP monitoring, and erroneous management decisions may result from dependence on such a technique. Possible explanations for this are discussed.

Isodense colloid cysts of the third ventricle: a diagnostic and therapeutic problem resolved by ventriculoscopy.

Eighteen patients with a colloid cyst of the 3rd ventricle presented to the Frenchay Hospital Neurosurgery Unit. The investigations included computed tomography (CT). Of these patients, 9 had radiographically isodense cysts that caused considerable diagnostic difficulties, being described only as an anterior 3rd ventricular space-occupying lesion and lateral ventricular dilatation in all but 2 cases. The clinical findings are described and the CT appearance is discussed. The new use of ventriculoscopy may resolve the problem rapidly; ventriculoscopy made the diagnosis in 5 cases and confirmed a CT diagnosis in 3 others. (It has also confirmed the diagnosis in 2 cases of hyperdense cysts.) Lately, it has been possible to aspirate the cyst contents endoscopically or, if the colloid is too viscous, to remove it with endoscopic rongeurs. After either of these procedures, the cyst wall can be coagulated with diathermy endoscopically. The method is described, and the advantages over other investigations and treatment are discussed.