Magnetic Clouds: Solar Cycle Dependence, Sources, and Geomagnetic Impacts.

Magnetic clouds (MCs) are transient magnetic structures giving the strongest southward magnetic field (Bz south) in the solar wind. The sheath regions of MCs may also carry a southward magnetic field. The southward magnetic field is responsible for space-weather disturbances. We report a comprehensive analysis of MCs and Bz components in their sheath regions for 1995 to 2017. 85% of 303 MCs contain a south Bz up to 50 nT. Sheath Bz during the 23 years may reach as high as 40 nT. MCs of the strongest magnetic magnitude and Bz south occur in the declining phase of the solar cycle. Bipolar MCs depend on the solar cycle in their polarity, but not in the occurrence frequency. Unipolar MCs show solar-cycle dependence in their occurrence frequency, but not in their polarity. MCs with the highest speeds, the largest total- B magnitudes, and sheath Bz south originate from source regions closer to the solar disk center. About 80% of large Dst storms are caused by MC events. Combinations of a south Bz in the sheath and south-first MCs in close succession have caused the largest storms. The solar-cycle dependence of bipolar MCs is extended to 2017 and now spans 42 years. We find that the bipolar MC Bz polarity solar-cycle dependence is given by MCs that originated from quiescent filaments in decayed active regions and a group of weak MCs of unclear sources, while the polarity of bipolar MCs with active-region flares always has a mixed Bz polarity without solar-cycle dependence and is therefore the least predictable for Bz forecasting. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11207-018-1356-8) contains supplementary material, which is available to authorized users.

Correction to: Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

Due to a typesetting error the wrong Table 2 was used. The correct Table 2 is shown here.

Spectrum of movement disorders and neurotransmitter abnormalities in paediatric POLG disease.

OBJECTIVES: To describe the spectrum of movement disorders and cerebrospinal fluid (CSF) neurotransmitter profiles in paediatric patients with POLG disease. METHODS: We identified children with genetically confirmed POLG disease, in whom CSF neurotransmitter analysis had been undertaken. Clinical data were collected retrospectively. CSF neurotransmitter levels were compared to both standardised age-related reference ranges and to non-POLG patients presenting with status epilepticus. RESULTS: Forty-one patients with POLG disease were identified. Almost 50% of the patients had documented evidence of a movement disorder, including non-epileptic myoclonus, choreoathetosis and ataxia. CSF neurotransmitter analysis was undertaken in 15 cases and abnormalities were seen in the majority (87%) of cases tested. In many patients, distinctive patterns were evident, including raised neopterin, homovanillic acid and 5-hydroxyindoleacetic acid levels. CONCLUSIONS: Children with POLG mutations can manifest with a wide spectrum of abnormal movements, which are often prominent features of the clinical syndrome. Underlying pathophysiology is probably multifactorial, and aberrant monoamine metabolism is likely to play a role.

Three-Dimensional Simulations of Tearing and Intermittency in Coronal Jets.

Observations of coronal jets increasingly suggest that local fragmentation and intermittency play an important role in the dynamics of these events. In this work we investigate this fragmentation in high-resolution simulations of jets in the closed-field corona. We study two realizations of the embedded-bipole model, whereby impulsive helical outflows are driven by reconnection between twisted and untwisted field across the domed fan plane of a magnetic null. We find that the reconnection region fragments following the onset of a tearing-like instability, producing multiple magnetic null points and flux-rope structures within the current layer. The flux ropes formed within the weak-field region in the center of the current layer are associated with "blobs" of density enhancement that become filamentary threads as the flux ropes are ejected from the layer, whereupon new flux ropes form behind them. This repeated formation and ejection of flux ropes provides a natural explanation for the intermittent outflows, bright blobs of emission, and filamentary structure observed in some jets. Additional observational signatures of this process are discussed. Essentially all jet models invoke reconnection between regions of locally closed and locally open field as the jet-generation mechanism. Therefore, we suggest that this repeated tearing process should occur at the separatrix surface between the two flux systems in all jets. A schematic picture of tearing-mediated jet reconnection in three dimensions is outlined.

Infant botulism due to C. butyricum type E toxin: a novel environmental association with pet terrapins.

We describe two cases of infant botulism due to Clostridium butyricum producing botulinum type E neurotoxin (BoNT/E) and a previously unreported environmental source. The infants presented at age 11 days with poor feeding and lethargy, hypotonia, dilated pupils and absent reflexes. Faecal samples were positive for C. butyricum BoNT/E. The infants recovered after treatment including botulism immune globulin intravenous (BIG-IV). C. butyricum BoNT/E was isolated from water from tanks housing pet 'yellow-bellied' terrapins (Trachemys scripta scripta): in case A the terrapins were in the infant's home; in case B a relative fed the terrapin prior to holding and feeding the infant when both visited another relative. C. butyricum isolates from the infants and the respective terrapin tank waters were indistinguishable by molecular typing. Review of a case of C. butyricum BoNT/E botulism in the UK found that there was a pet terrapin where the infant was living. It is concluded that the C. butyricum-producing BoNT type E in these cases of infant botulism most likely originated from pet terrapins. These findings reinforce public health advice that reptiles, including terrapins, are not suitable pets for children aged <5 years, and highlight the importance of hand washing after handling these pets.

Elevations of DNA topoisomerase I in invasive carcinoma of the breast.

DNA topoisomerase I (topo I) is the molecular target of the camptothecin group of anticancer drugs. Laboratory experiments indicate that breast cancer cell lines are sensitive to these agents and recent clinical trials have suggested that some breast cancer patients may respond to drugs targeting topo I. Since it is known that cells responding to topo I-targeted drugs have elevated levels of topo I, these results suggest that some breast cancers may have elevated expression of the enzyme. To test this we used a new topo I monoclonal antibody to immunostain 22 primary breast cancers and 5 lymph nodes with metastatic disease. Tissue was fixed in formalin and paraffin embedded. Expression of topo I was subjectively determined by noting the intensity of the immunostain. We found increased expression of topo I in 41% (9/22) of the primary tumors. We conclude that immunohistochemical staining of breast cancers for topo I can be easily performed and may help in defining the molecular parameters of those neoplasms sensitive to drugs targeting the enzyme.

Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer.

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P: < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats.

MedAC: lobbying for good government.

Physicians feel the frustration of practicing medicine in today's ever-changing environment. The wheels of government turn slowly, but they do turn. And they are turning toward the physician community in an effort to provide help and support.

Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma.

New anticancer drugs that target DNA topoisomerase I (topo I) are showing activity against a wide variety of solid human neoplasms. These drugs work by a novel mechanism of action and cause topo I-mediated DNA breaks. These DNA breaks become lethal in cycling cells when they interact with the replication fork. Because of the challenges in treating metastatic malignant melanoma, we performed an immunohistochemical study of this group of neoplasms to search for the presence of molecular markers that might indicate tumor response to topo I active drugs. Using a new immunohistochemical stain for topo I, we found elevation of this protein in 10 of 24 cases (41.6%) of metastatic malignant melanoma. The metastatic tumors that showed increased expression of topo I (2+ or 3+) had statistically significant higher proliferation indices, measured by immunohistochemical staining for DNA topo II-alpha, than did metastatic lesions with no detectable topo I expression. The average topo II-alpha index of metastatic melanomas with 2+ topo I expression was 45.1 (SD = 17.9) and with 3+ topo I expression was 52.3 (SD = 32.5). These values were found to be statistically different (P = .05) than the average topo II-alpha index of 18.9 (SD = 17.7) found for metastatic melanomas without detectable topo I immunostaining. Immunohistochemical staining for p53 suggested abnormal p53 function in 6 of the 10 melanomas (60%), which showed elevations of topo I (2 to 3+ topo I immunostaining) but normal p53 function in all 14 metastatic lesions that showed normal topo I expression.

Pathobiologic characteristics of hereditary breast cancer.

Patients with hereditary breast cancer (HBC) present at a young age with breast cancers that show adverse pathological characteristics such as high nuclear grade, negative hormone receptor status, and high proliferation indices. Surprisingly, the clinical course has been reported to be comparable or improved compared with patients with nonhereditary breast cancer (non-HBC). To determine whether there are any molecular markers that might help explain this paradox between pathologically aggressive neoplasms in patients with HBC and the lack of extreme clinically aggressive disease, we studied several molecular parameters in a group of 34 breast cancer patients with mutations in either the BRCA1 or BRCA2 tumor suppressor genes and compared them with a group of 20 breast cancer patients with non-HBC. In general, patients with HBC had tumors that were of higher nuclear grade, contained a higher population of proliferating cells, showed increased expression of DNA topoisomerase II-alpha (topo II-alpha), lacked hormone receptors, and were more likely to show immunopositivity for the p53 tumor suppressor gene. Additionally, tumors from patients with HBC showed a decreased angiogenesis compared with controls. The decreased angiogenesis and the elevated expression of topo II-alpha (an anticancer drug target) may, in part, explain the lack of correlation between clinical course and histological characteristics in patients with HBC.

Human DNA topoisomerase II-alpha: a new marker of cell proliferation in invasive breast cancer.

DNA topoisomerase II-alpha is the molecular target of doxorubicin, an active drug used in the therapy of breast cancer. From many in vitro studies, it is known that high levels of topo II-alpha expression correlate with drug sensitivity, and low levels of topo II-alpha correlate with drug resistance. In addition, the enzyme is known to be a marker of cell proliferation in normal tissues. Because the number of proliferating cells in a breast cancer has been shown to be prognostically important, and because doxorubicin is used in the treatment of breast cancer, we hypothesized that the measurement of topo II-alpha in breast cancer may not only give drug sensitivity information but also may yield important data on cell proliferation. In this study, formalin-fixed, paraffin-embedded tissue from 30 specimens of invasive breast cancer from 20 patients were immunohistochemically stained for topo II-alpha with a mouse monoclonal antibody. For each case, a topo II-alpha index was determined that represents the number of positive-staining tumor cells divided by the total number of tumor cells counted times 100. A similar index was determined for MIB1, a known cell proliferation marker. Each case was also graded according to the modified Bloom-Richardson criteria and evaluated for c-erbB-2 amplification, hormonal status, S-phase fraction, and mitotic index. The topo II-alpha index correlates better with the MIB1 index than with the S-phase fraction or mitotic index. The topo II-alpha expression in breast cancer ranges from low (topo II-alpha index <1) to high (topo II-alpha index = 86). Amplification of c-erbB-2 was observed in 4 of 28 cases (14%) but did not correlate with high topo II-alpha indices. We conclude that measurement of topo II-alpha in invasive breast cancer can be readily performed by immunohistochemical staining, and it gives information on the number of cycling tumor cells. In addition, because the enzyme is the molecular target of doxorubicin, the expression of the enzyme may relate also to the sensitivity or resistance of the tumor to doxorubicin-based chemotherapeutic protocols.

Dissociation between beta-adrenoceptor-mediated cyclic AMP accumulation and inhibition of histamine-stimulated phosphoinositide metabolism in airways smooth muscle.

Spasmogen-stimulated phosphoinositide hydrolysis represents one of the major signalling pathways mediating pharmacomechanical coupling in airways smooth muscle (ASM), and cyclic AMP-induced inhibition of phosphoinositidase C has been proposed as an important mechanism underlying the bronchodilator properties of beta2-adrenoceptor agonists. To examine this hypothesis in more detail we have undertaken a direct comparison of the effects of salbutamol and salmeterol, short- and long-acting beta2-adrenoceptor agonists respectively, on cyclic AMP accumulation and histamine-stimulated [3H]-inositol phospholipid hydrolysis in bovine tracheal smooth muscle (BTSM) slices. Although salmeterol displayed a similarly greater potency over salbutamol for both stimulation of cyclic AMP, and inhibition of [3H]-inositol phosphate accumulation, there was a clear disparity between these agents with respect to both their efficacies and the duration of their effects. Hence while salmeterol caused a more protracted, but initially smaller increase in cyclic AMP accumulation compared to salbutamol, the inhibition of histamine-stimulated [3H]-inositol phosphate accumulation observed with salmeterol was of identical duration to salbutamol and was more marked than that of salbutamol at early time points. These data suggest that cyclic AMP accumulation is not the sole mechanism responsible for beta2-adrenoceptor-induced inhibition of phosphoinositide turnover in BTSM, and would support a recent proposal that cyclic AMP-dependent inhibition of agonist-stimulated Ca2+ mobilization in ASM may be mediated by factors independent of inositol phosphate generation.

[3H]inositol polyphosphate metabolism in muscarinic cholinoceptor-stimulated airways smooth muscle: accumulation of [3H]inositol 4,5 bisphosphate via a lithium-sensitive inositol polyphosphate 1-phosphatase.

Agonist-stimulated phosphoinositide hydrolysis is the principal mechanism underlying pharmacomechanical coupling in airways smooth muscle. In bovine tracheal smooth muscle, activation of muscarinic cholinoceptors results in sustained phospholipase C-mediated PtdIns(4,5)P2 hydrolysis but transient Ins(1,4,5)P3 accumulation, which implies agonist-stimulated metabolism of Ins(1,4,5)P3. To investigate the metabolic fate of Ins(1,4,5)P3 in bovine tracheal smooth muscle, we developed a [3H]inositol-labeling protocol wherein more than 98% of the [3H]inositol polyphosphates that accumulated over a 0 to 30-min incubation with 100 microM carbachol in the presence of 5 mM LiCl were derived from [3H]Ins(1,4,5)P3 and wherein the Ins(1,4,5)P3 3-kinase (EC 2.7.1.127) and 5-phosphatase (EC 3.1.3.56) pathways generated a set of mutually exclusive [3H]-inositol polyphosphate isomers. Under these conditions, the 5-phosphatase pathway was shown to be the dominant route for [3H]Ins(1,4,5)P3 metabolism at all time intervals measured, especially at early times (0-300 sec), where it accounted for more than 85% of [H]Ins(1,4,5)P3 metabolism. We also observed accumulation of a novel agonist and LiCl-sensitive [3H]InsP2 isomer identified as [3H]Ins(4,5)P2. The presence of a LiCI-sensitive inositol polyphosphate 1-phosphatase (EC 3.1.3.57) was demonstrated, and high LiCl concentrations (30 mM) caused a significant enhancement of [3H]Ins(1,4)P2 accumulation and a corresponding decline in [3H]Ins4P levels. Because nearly identical bell-shaped LiCl concentration-response curves were obtained for [H]Ins4P and [3H]Ins(4,5)P2 accumulation, and [3H]Ins(4,5)P2 was not generated under conditions expected to stimulate phospholipase D, these data suggest that the most likely precurser of [3H]Ins(4,5)P2 is [3H]Ins(1,4,5)P3. This is the first demonstration of Ins(4,5)P2 accumulation in a non-neuronal cell type, and the foregoing data suggest a novel route of formation via an Ins(1,4,5)P3 1-phosphatase, which would represent an additional pathway for [H]Ins(1,4,5)P3 removal.

Correlation of 99mTc-HMPAO SPECT with EEG monitoring: prognostic value for outcome of epilepsy surgery in children.

Sixteen children who had focal cortical resections for medically intractable epilepsy were preoperatively evaluated with 99mtechnetium-labelled hexamethylpropyleneamineoxime single photon emission computed tomography (99mTc-HMPAO SPECT). Video-EEG monitoring was performed in all patients. Outcome was assessed according to the criteria of Engel et al. [1], at a mean follow up length of 13.4 +/- 8.7 months, in all patients. Interictal SPECT showed appropriate localization in 11/15 cases, of whom nine had a class 1 outcome and two had class 2 and 4 outcomes. Interictal SPECT did not correlate with ictal EEG in 4/15 patients, of whom two had a class 1 outcome, and two had class 3 and 4 outcomes. Two postictal studies obtained in group I showed good correlation with the area of ictal EEG onset, and both patients had a class 1 outcome. Interictal HMPAO SPECT imaging, when positively correlated with the ictal EEG focus or with the site of surgery determined by other means, may have prognostic value for outcome of cortical resections for epilepsy in children. The use of ictal and post-ictal studies shows promise for further improving prognostic information in this population.

Postoperative medical management following pediatric epilepsy surgery.

Medical management of the post-epilepsy surgery patient depends on careful preoperative consideration of that patient's medical, social, cognitive, and emotional status. Outcome expectations should be realistic. Families should be warned that existing cognitive and psychobehavioral problems may not be following surgery, even if seizures are well controlled. As criteria for surgery and surgical techniques continue to evolve, epilepsy centers have an ongoing responsibility to provide objective assessment of outcome. Prospective multicenter studies are required to address these issues adequately.

Neurologic complications of pediatric heart transplantation.

OBJECTIVE: To determine the type and frequency of acquired neurologic complications in survivors of pediatric heart transplantation (HT). DESIGN: Retrospective study. SETTING: Tertiary care children's hospital. PARTICIPANTS: Fourteen survivors of 17 consecutive patients who underwent HT during a 60-month period beginning in January 1986. INTERVENTIONS: None. MEASUREMENTS OR MAIN RESULTS: Three distinct subgroups of patients who had undergone HT were identified: six infants with uncorrected hypoplastic left heart syndrome (HLHS), three infants with HLHS who had undergone previous stage 1 Norwood repair, and eight older children with end-stage cardiomyopathy. Fourteen (82%) of 17 children were alive at follow-up. Only one patient (7%) had a significant acquired neurologic deficit (left temporal lobe stroke with subsequent seizures in an infant with uncorrected HLHS). The remaining subjects had normal results of post-HT neurologic examinations (n = 7), minor post-HT neurologic abnormalities (n = 3), no significant change in preexisting neurologic abnormalities (n = 1), or normal neurologic status by report (n = 2). The minor neurologic abnormalities noted post-HT were dysmetria, tremor, and absent reflexes. No episodes of choreoathetosis or cyclosporine-related seizures were seen. CONCLUSIONS: Pediatric HT is associated with both a high survival rate and a low incidence of severe acquired neurologic deficits despite a significant incidence of severe systemic and metabolic derangements in the pretransplantation and posttransplantation periods. In infants with HLHS, HT seems to carry a lower incidence of severe neurologic morbidity (12%) than other surgical treatments.

Natural history and outcome of neonatal hypocalcemic and hypomagnesemic seizures.

The clinical characteristics and neurologic outcome of 15 newborn infants with seizures due to hypocalcemia and hypomagnesemia have been studied with careful exclusion of those patients who had other possible etiologies for seizures. Associated diagnoses included severe congenital heart disease in 7 of 15 (47%) patients. Possible causes for this association with congenital heart disease include a forme fruste of DiGeorge syndrome, hypocalcemia and hypomagnesemia due to critical illness, and subtle embolic cerebral ischemia. In contrast with previous studies, no abnormalities of formula milk feeding were observed. Five patients (36%) died of causes unrelated to seizures. Follow-up in 8 of 9 patients who had no cerebral insults other than neonatal seizures at a mean age of 57.8 +/- 10.5 months found neurologic abnormalities in 2 (22%), both with an endocrine etiology for hypocalcemia. We conclude that infants with severe congenital heart disease should be investigated for hypocalcemia and hypomagnesemia. Previous observations of a universally favorable neurologic outcome in newborns with hypocalcemic or hypomagnesemic seizures may be valid for those who have a nutritional etiology for the metabolic disturbance but are less relevant to the current population in whom hypocalcemia or hypomagnesemia due to errors in formula milk feeding is seldom observed. In this group, neurologic prognosis may be more related to associated medical conditions.

Effects of membrane depolarization and changes in intra- and extracellular calcium concentration on phosphoinositide hydrolysis in bovine tracheal smooth muscle.

Agonist-stimulated phosphoinositide metabolism plays a central role in pharmacomechanical coupling in airways smooth muscle (ASM). In many other tissues and cells, most noteably excitable cells, membrane depolarization or an increase in intracellular Ca2+ ([Ca2+]i) generated by inositol 1,4,5-trisphosphate (Ins(1,4,5)P3)-induced Ca2+ release or agonist-mediated Ca2+ influx is able to trigger or augment phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis and/or initiate PtdIns4P/PtdIns hydrolysis by direct stimulation of PIC. To assess the importance of these mechanisms in ASM the effects of KCl-induced membrane depolarization, extracellular Ca2+ ([Ca2+]e) chelation, and addition of ionomycin to elevate [Ca2+]i on basal and agonist-stimulated Ins(1,4,5)P3 concentration and [3H]-InsPx accumulation have been examined. Reducing [Ca2+]e from 1.8 mM to 6 or 0.8 microM caused a progressive inhibition of agonist-stimulated [3H]inositol polyphosphate accumulation over 30 min with the histamine-stimulated response being significantly more sensitive to [Ca2+]e chelation than the response to carbachol. In contrast, the initial accumulation of Ins(1,4,5)P3 was completely unaffected by such reductions in [Ca2+]e. Incubation of [3H]inositol-prelabelled BTSM slices with buffer containing 80 mM KCl failed to stimulate [3H]InsPx accumulation, causing instead a small inhibition of carbachol-stimulated [3H]InsPx accumulation with a similar effect seen with respect to Ins(1,4,5)P3 accumulation. Addition of 5 microM ionomycin to BTSM slices similarly did not stimulate Ins(1,4,5)P3 generation and only increased [3H]InsPx accumulation after prolonged stimulation in the presence of high (mM) [Ca2+]e. These data indicated that in ASM, membrane depolarization or physiological increases in [Ca2+]i did not result in either independent activation of PIC or augmentation of initial agonist-stimulated PtdIns(4,5)P2 hydrolysis. However, while the initial agonist-stimulated generation of Ins(1,4,5)P3 was not dependent on [Ca2+]e, a normal plasmalemmal Ca2+ gradient was required to sustain maximal rates of agonist-stimulated PtdIns(4,5)P2 hydrolysis.

Phosphoinositide metabolism in airway smooth muscle.

Agonist-stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphate, which generates inositol 1,4,5-trisphosphate and sn-1,2-diacylglycerol, is thought to be one of the major mechanisms underlying pharmacomechanical coupling in airway smooth muscle. This article is a review of the currently available information on phosphoinositide and inositol 1,4,5-trisphosphate metabolism in this tissue and includes data on inositol 1,4,5-trisphosphate-induced Ca2+ release and the receptor mediating this effect. The final section outlines the potential mechanisms underlying physiological regulation of phosphoinositide metabolism by other second-messenger pathways operative in this tissue.