Intense chorus waves are the cause of flux-limiting in the heart of the outer radiation belt.

Chorus waves play a key role in outer Van Allen electron belt dynamics through cyclotron resonance. Here, we use Van Allen Probes data to reveal a new and distinct population of intense chorus waves excited in the heart of the radiation belt during the main phase of geomagnetic storms. The power of the waves is typically ~ 2-3 orders of magnitude greater than pre-storm levels, and are generated when fluxes of ~ 10-100 keV electrons approach or exceed the Kennel-Petschek limit. These intense chorus waves rapidly scatter electrons into the loss cone, capping the electron flux to a value close to the limit predicted by Kennel and Petschek over 50 years ago. Our results are crucial for understanding the limits to radiation belt fluxes, with accurate models likely requiring the inclusion of this chorus wave-driven flux-limiting process, that is independent of the acceleration mechanism or source responsible for enhancing the flux.

What effect do substorms have on the content of the radiation belts?

Substorms are fundamental and dynamic processes in the magnetosphere, converting captured solar wind magnetic energy into plasma energy. These substorms have been suggested to be a key driver of energetic electron enhancements in the outer radiation belts. Substorms inject a keV "seed" population into the inner magnetosphere which is subsequently energized through wave-particle interactions up to relativistic energies; however, the extent to which substorms enhance the radiation belts, either directly or indirectly, has never before been quantified. In this study, we examine increases and decreases in the total radiation belt electron content (TRBEC) following substorms and geomagnetically quiet intervals. Our results show that the radiation belts are inherently lossy, shown by a negative median change in TRBEC at all intervals following substorms and quiet intervals. However, there are up to 3 times as many increases in TRBEC following substorm intervals. There is a lag of 1-3 days between the substorm or quiet intervals and their greatest effect on radiation belt content, shown in the difference between the occurrence of increases and losses in TRBEC following substorms and quiet intervals, the mean change in TRBEC following substorms or quiet intervals, and the cross correlation between SuperMAG AL (SML) and TRBEC. However, there is a statistically significant effect on the occurrence of increases and decreases in TRBEC up to a lag of 6 days. Increases in radiation belt content show a significant correlation with SML and SYM-H, but decreases in the radiation belt show no apparent link with magnetospheric activity levels.

Evaluation of EGFR mutation status in cytology specimens: an institutional experience.

Epidermal growth factor receptor (EGFR) mutation status has been shown to predict response to anti-EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC). In patients with advanced-stage NSCLC, evaluation of mutational status is increasingly requested on biopsy or fine-needle aspiration specimens, which often have limited material. There are limited data on the suitability of cytology cell blocks (CB) for EGFR mutation testing. In this study, we report our institutional experience with cytology cell block material for EGFR mutation testing. We retrospectively reviewed EGFR mutation analyses performed on 234 surgical (SP) and cytology (CB) from October 2007 to May 2010. One hundred ninety-two SP specimens and 42 CB specimens were evaluated for EGFR mutation. CB specimens were evaluated for overall specimen size based on aggregate cellularity in comparison to small biopsy specimens, and percent tumor. Of the 192 SP and 42 CB specimens, 31 (16.1%) and 11 (26.2%) were positive for EGFR mutation, respectively; there does not appear to be an association between mutation detection rate and the source of the specimen (P = 0.124). Limited DNA was obtained from 70.0% (29/42), including 81.8% (9/11) of those which were mutation positive. Additionally, 45.4% (5/11) of mutation positive specimens had extremely low DNA yields. Although 16.6% (7/42) of CB specimens had <10% tumor, all 11 mutation positive CB cases had >10% tumor. These data indicate that CB specimens provide an alternative source for molecular evaluation of NSCLC, and that tumor percentage may be more important than specimen size and/or DNA yield in determining the suitability of these specimens for testing.

Impact of national guidelines on family history breast cancer surveillance.

The breast cancer risk of women already under family history surveillance was accurately assessed according to national guidelines in an attempt to rationalize the service. Women attending two breast units in Glasgow between November 2003 and February 2005 were included. One thousand and five women under annual surveillance were assessed and had their relatives diagnoses verified. Four hundred and ninety-seven women were at significantly increased risk and eligible for follow-up. Five hundred and eight (50%) women attending were not eligible for family history surveillance, and 498 (98%) of these women accepted discharge. In conclusion, national guidelines have helped to more clearly define women who should undergo surveillance. This avoids unnecessary and potentially harmful routine investigations, and the service has been improved.

Retinal remodeling in the Tg P347L rabbit, a large-eye model of retinal degeneration.

Retinitis pigmentosa (RP) is an inherited blinding disease characterized by progressive loss of retinal photoreceptors. There are numerous rodent models of retinal degeneration, but most are poor platforms for interventions that will translate into clinical practice. The rabbit possesses a number of desirable qualities for a model of retinal disease including a large eye and an existing and substantial knowledge base in retinal circuitry, anatomy, and ophthalmology. We have analyzed degeneration, remodeling, and reprogramming in a rabbit model of retinal degeneration, expressing a rhodopsin proline 347 to leucine transgene in a TgP347L rabbit as a powerful model to study the pathophysiology and treatment of retinal degeneration. We show that disease progression in the TgP347L rabbit closely tracks human cone-sparing RP, including the cone-associated preservation of bipolar cell signaling and triggering of reprogramming. The relatively fast disease progression makes the TgP347L rabbit an excellent model for gene therapy, cell biological intervention, progenitor cell transplantation, surgical interventions, and bionic prosthetic studies.

Establishment of a standardized multiplex assay with the analytical performance required for quantitative measurement of BCR-ABL1 on the international reporting scale.

Accurate and standardized methods for the quantitative measurement of BCR-ABL1 are a prerequisite for monitoring of treatment response in t(9;22)-positive leukemia. Here, we describe a novel multiplex assay system based on the proven TaqMan and Armored RNA technologies and optimized for sensitive detection of three BCR-ABL1 fusion transcripts and ABL1 in a single reaction. Analytical experiments confirmed the absence of significant competition between the simultaneous amplification reactions and established the sensitivity, linearity and precision of the assay. Comparative studies with 115 clinical specimens resulted in high qualitative and quantitative agreement with independent singleplex laboratory-developed tests routinely used in clinical testing. Direct comparison with a reference laboratory calibrated to the international scale (IS) demonstrated minimal analytical bias between methods and an overall accuracy and precision within the performance range required for quantitative measurement of BCR-ABL1 on the IS. We conclude that detection of e1a2, b2a2, b3a2 and ABL1 can be achieved in a multiplex assay format compatible with IS reporting. Further clinical validation of the assay could improve the operational efficiency of clinical laboratories, increase their adherence to current recommendations for b2a2/b3a2 reporting on the IS and provide for the first time an opportunity to standardize e1a2-monitoring results.

On-site determination of formaldehyde: a low cost measurement device for museum environments.

A trapping reagent for formaldehyde, based on the pararosaniline reaction, was evaluated as a method of determination of formaldehyde in the aqueous or vapour phase. Collection of formaldehyde vapour relied upon passive diffusion of formaldehyde into the trapping media and quantitative results were obtained without the need for liquid impingers, bubblers or active sampling pumps. Moreover, a novel, hand-held absorption spectrophotometric measurement device was designed to provide on-site, quantitative measurements. It is proposed that the full measurement system devised would be ideally suited to specific sampling applications such as those found in museum enclosures.

Prospective surveillance of women with a family history of breast cancer: auditing the risk threshold.

To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services.

Is it worth pursuing surgery for epilepsy in patients with normal neuroimaging?

OBJECTIVE: To determine whether it is worth pursuing surgery for the treatment of epilepsy in patients with normal neuroimaging. METHODS: Two patient populations were studied: (1) 136 consecutive patients who were surgically treated; (2) 105 consecutive patients assessed with chronically implanted intracranial electrodes within the same period. Sixty patients belonged to both groups, and included all 21 patients who had normal neuroimaging. RESULTS: There were no differences in the proportion of patients with favourable outcome between those with normal and those with abnormal neuroimaging, irrespective of whether intracranial recordings were required. Among the 19 operated patients with normal neuroimaging, 74% had a favourable outcome (Engel's seizure outcome grades I and II), and among the 93 patients with abnormal neuroimaging, 73% had favourable outcome (p = 0.96). In patients with temporal resections, 92% of the 13 patients with normal neuroimaging had a favourable outcome, whereas among the 70 patients with abnormal neuroimaging, 80% had a favourable outcome (p = 0.44). In patients with extratemporal resections, two of the six patients with normal neuroimaging had a favourable outcome, while 12 of the 23 patients with abnormal neuroimaging had a favourable outcome (p = 0.65). Among the 105 patients studied with intracranial electrodes, five suffered transitory deficits as a result of implantation, and two suffered permanent deficits (one hemiplegia caused by haematoma and one mild dysphasia resulting from haemorrhage). CONCLUSIONS: It is worth pursuing surgery in patients with normal neuroimaging because it results in good seizure control and the incidence of permanent deficits associated with intracranial studies is low.

MOR-1-immunoreactive neurons in the dorsal horn of the rat spinal cord: evidence for nonsynaptic innervation by substance P-containing primary afferents and for selective activation by noxious thermal stimuli.

A direct action of mu-opioid agonists on neurons in the spinal dorsal horn is thought to contribute to opiate-induced analgesia. In this study we have investigated neurons that express the mu-opioid receptor MOR-1 in rat spinal cord to provide further evidence about their role in nociceptive processing. MOR-1-immunoreactive cells were largely restricted to lamina II, where they comprised approximately 10% of the neuronal population. The cells received few contacts from nonpeptidergic unmyelinated afferents, but many from substance P-containing afferents. However, electron microscopy revealed that most of these contacts were not associated with synapses. None of the MOR-1 cells in lamina II expressed the neurokinin 1 receptor; however, the mu-selective opioid peptide endomorphin-2 was present in the majority (62-82%) of substance P axons that contacted them. Noxious thermal stimulation of the foot induced c-Fos expression in approximately 15% of MOR-1 cells in the medial third of the ipsilateral dorsal horn at mid-lumbar level. However, following pinching of the foot or intraplantar injection of formalin very few MOR-1 cells expressed c-Fos, and for intraplantar formalin injection this result was not altered significantly by pretreatment with systemic naloxone. Although these findings indicate that at least some of the neurons in lamina II with MOR-1 are activated by noxious thermal stimulation, the results do not support the hypothesis that the cells have a role in transmitting nociceptive information following acute mechanical or chemical noxious stimuli.

The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru.

Improved tuberculosis (TB) case detection and cure rates are expected to accelerate the decline in incidence of TB and to reduce TB-associated deaths. Time series analyses of case reports in Peru showed that the per capita TB incidence rate was probably steady before 1991. Case reports increased between 1990 and 1992 as a result of improved case detection. Although diagnostic efforts have continued to increase since 1993, the incidence of new pulmonary TB cases has declined in every department of the country, with a national rate of decline > or =5.8% per year (range, 1.9%-9.7%). This elevated rate of decline suggests that 27% (19%-34%) of cases (158,000) and 70% (63%-77%) of deaths (91,000) among smear-positive patients were averted between 1991 and 2000. This is the first demonstration that a significant number of TB cases can be prevented through intensive short-course chemotherapy in a high-burden country.

Do Colles' fracture patients benefit from routine referral to physiotherapy following cast removal?

Colles' fracture patients who received physiotherapy immediately following cast removal were compared with patients who received no active therapy following cast removal in a prospective randomised study. Patients who attended physiotherapy achieved significantly greater increases in wrist extension and grip strength after 6 weeks compared to patients who received no active therapy.

Should needle localization breast biopsy give way to the new technology; the advanced breast biopsy instrumentation.

Between July 1995 and June 1997, 114 consecutive women underwent 118 breast biopsies for nonpalpable lesions. A limited procedure room and local anesthesia were used in 96.5 per cent of patients. Intravenous access was not established in 95 per cent of patients. Oral diazepam was given to 51 per cent of patients. Needle localization technique was used with a success rate of 97.5 per cent and average operative time of 18 minutes. Breast carcinoma was found in 29 (24.6 per cent) biopsies. A review of 99 of the 118 mammograms showed only 45 per cent of the lesions being amenable to the new technology, the advanced breast biopsy instrumentation. Advantages of the needle localization include short operative time; supine position for the patient; easy access to control bleeding; ability to choose a cosmetic site for the skin incision; minimal tissue removal before reaching the lesion; ability to maintain a sterile field; and applicability to almost any mammographic lesion identified, whether single or multiple. Disadvantages include the need for a separate procedure to place the wire and potential of missing the lesion in 2.5 per cent, requiring additional surgery.

Long-term outcome after pulmonary thromboendarterectomy.

This study evaluated long-term outcome of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Survival, functional status, quality of life, health care utilization, and relationships between these parameters and postoperative pulmonary hemodynamics were assessed. Questionnaires were mailed to 420 patients who were more than 1 yr post-PTE; 308 responded (mean age, 56 yr [range, 19-89 yr]; mean years since PTE, 3.3 [range, 1- 16]). Survival after PTE was 75% at > 6 yr. After surgery, symptoms were markedly reduced. Median distance walked was 5,280 ft; 56 patients could walk "indefinitely." Of the working population, 62% of patients unemployed before PTE returned to work. Post-PTE patients scored several quality of life components of the Rand SF-36 slightly lower than reported normals but significantly higher than did pre-PTE patients. Ten percent of patients used oxygen. Ninety-three percent were in NYHA Class I or II. Disease-related hospitalizations/ER visits were minimal. A relationship was shown between 48 h postoperative pulmonary vascular resistance (PVR) and walking and stair-climbing ability, NYHA class, dyspnea scores, and the physical function and general health quality of life components. These data indicate that PTE offers most CTEPH patients substantial improvement in survival, function, and quality of life, with minimal disease-related health care utilization.

Awake patient monitoring to determine the need for shunting during carotid endarterectomy.

BACKGROUND: The indications for shunt placement to prevent cerebral ischemia during carotid endarterectomy have been controversial. Some investigators have recommended empiric shunting for patients presumed to be at higher risk for cerebral ischemia with a recent stroke or severe stenosis or occlusion of the contralateral internal carotid artery. METHODS: Carotid endarterectomy was performed in 81 cases with cervical block anesthetic, monitoring the awake patient for the development of cerebral ischemia (unresponsiveness or paralysis) during carotid clamping. The need for shunting (based on awake response) was compared in patients with the arbitrarily defined empiric indications for shunting (n = 29) versus those who did not have such clinical or anatomic findings (n = 52). RESULTS: Cerebral ischemia requiring shunting was observed in five (17.2%) of 29 cases with the defined indications for empiric shunting. This was not different than the need for shunting in the control group where cerebral ischemia was seen in eight (15.4%) of 52 cases. No intraoperative neurologic events occurred in any case, but one (1.2%) patient suffered a postoperative transient ischemia attack and another (1.2%) had a postoperative stroke. CONCLUSIONS: Empiric clinical or anatomic indications for shunting were not reliable predictors of cerebral ischemia that developed during carotid clamping in this study. Awake patient monitoring during carotid endarterectomy with regional anesthetic allowed prompt, accurate identification of patients with cerebral ischemia who would clearly benefit from placement of a shunt.

Changes in the choroid plexus, responses by intrinsic epiplexus cells and recruitment from monocytes after experimental head acceleration injury in the non-human primate.

We have examined, by scanning and transmission electron microscopy, morphological changes in the choroid plexus of the lateral ventricles of the non-human primate brain after lateral head acceleration. We demonstrate passage of plasma and blood cells either through tears in blood vessels and the choroidal epithelium, or through the cells of the choroidal epithelium, 20 min after injury, together with morphological changes in that epithelium. At 3 and 4 h small cells with a reniform nucleus accumulate in the connective tissue core of the choroid plexus. We suggest that these are monocytes. At 6 and 12 h cells can be seen in enlarged intercellular spaces within the choroidal epithelium. These cells possess surface ruffles and we suggest that they are monocytes differentiating into macrophages and epiplexus cells. Further evidence for transepithelial migration of monocytes/macrophages is obtained at 7 days. However, at 28 days all blood has been removed from the surface of the choroid plexus and epiplexus cells possess an appearance typical of that in uninjured animals. The possible sources of epiplexus cells are discussed with reference to studies of responses after brain insult and of development. We have obtained no evidence in support of emperipolesis by monocytes through the choroidal epithelium. We suggest that monocytes/macrophages migrate, via an intercellular route, to differentiate into epiplexus cells, thus providing additional numbers of epiplexus cells after head injury.

Localisation of calcium ions and calcium-ATPase activity within myelinated nerve fibres of the adult guinea-pig optic nerve.

There is no published description of the distribution of free Ca2+, nor of the distribution of Ca(2+)-ATPase activity associated with the maintenance of low axoplasmic Ca2+ concentrations, in normal central myelinated nerve fibres. We have used the oxalate-pyroantimonate technique to localise free Ca2+, together with the lead-citrate technique to localise Ca(2+)-ATPase activity within myelinated fibres from the adult guinea-pig optic nerve. Pyroantimonate precipitate occurred within the axoplasm at nodes of Ranvier and the internode, at areas of myelin disruption, within Schmidt-Lanterman incisures (SLI) and glial paranodal loops. But precipitate was absent from the axoplasm beneath SLI and at the paranode. Ca(2+)-ATPase activity was localised in axonal smooth endoplasmic reticulum (SER), the outer membrane of mitochondria, the nodal axolemma, the glial membranes of the paranodal loops, the SLI and the external aspect of the myelin sheath. We have demonstrated large domains within the axons of CNS fibres where calcium is present or absent. Moreover, we have shown that, where calcium is absent, there is localisation of Ca(2+)-ATPase activity, which would serve to remove calcium from the adjacent axoplasm. Our results are compared with information obtained from PNS fibres and some differences of distribution discussed.

The rabbit retina: a long-term model system for aluminum-induced neurofibrillary degeneration.

Aluminum (Al) was injected into the rabbit eye as a potential long-term model system for Al-induced neurofibrillary degeneration (NFD). Neurofibrillary tangles made up of 10 nm phosphorylated neurofilaments were observed in a subpopulation of retinal ganglion cells, located primarily in the peripheral retina. The distribution of affected cells suggested a differential susceptibility of ganglion cells to Al intoxication. Importantly, none of the animals demonstrated any of the central neurological dysfunctions characteristic of previous Al intoxication models. The retinal model should allow for long-term studies of Al intoxication and its potential relationship to neurofibrillary degenerative disorders such as Alzheimer's disease.