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Cockayne syndrome (CS) is a rare progeroid disorder characterized by multisystem degeneration, including neurological dysfunction, for which deep brain stimulation (DBS) is a proposed treatment. This study represents only the third case of DBS for CS-associated movement disorder and the first in which both proposed targets had devices implanted, allowing for direct comparison. A case of DBS for CS-associated movement disorder is presented. Previous literature documents two cases with one targeting the ventral intermediate nucleus of the thalamus (VIM) and the other targeting the globus pallidus interna (GPi). Our patient underwent stimulation of GPi nuclei followed by repositioning to VIM nuclei with improved symptom control using VIM stimulation. In all cases, there was a significant clinical benefit without off-target effects. CS-associated movement disorder exhibits phenotypic variability for which DBS is a viable treatment. Target selection should be driven by clinical phenotype.

Non-infectious peri-electrode edema is a rare complication after implantation of a deep brain stimulation (DBS) electrode. DBS is frequently used in the management of movement disorders with increasing interest surrounding its value in more rare disorders associated with movement abnormalities. This is the report of a 10-year-old male with Cockayne syndrome who acutely developed symptomatic non-infectious, non-hemorrhagic peri-electrode edema 18 days postoperatively from implantation of a DBS system targeting the bilateral globus pallidus internus. CT head confirmed extensive vasogenic edema along the entire length of the left electrode, and infectious workup was negative. The patient required admission to the pediatric intensive care unit for management utilizing steroid, hypertonic, and hyperosmolar therapy due to the amount of mass effect. Symptoms reduced over a 7-day hospital stay and were completely resolved at 1 month without removal of the DBS system. Management of this rare entity remains controversial and often involves the use of steroids and anti-epileptic prophylaxis. This represents the first case of non-infectious peri-electrode edema reported in a pediatric patient and is especially notable for its fulminant nature.

OBJECTIVEThe authors conducted a retrospective analysis of a consecutive series of children with intracranial subdural empyemas (SEs) and epidural abscesses (EAs) to highlight the important clinical difference between these two entities. They describe the delays and pitfalls in achieving accurate diagnoses and make treatment recommendations based on clinical and imaging findings.METHODSThey reviewed their experience with children who had presented with intracranial SE and/or EA in the period from January 2013 to May 2018. They recorded presenting complaint, date of presentation, age, neurological examination findings, time from presentation to diagnosis, any errors in initial image interpretation, timing from diagnosis to surgical intervention, type of surgical intervention, neurological outcome, and microbiology data. They aimed to assess possible causes of any delay in diagnosis or surgical intervention.RESULTSSixteen children with SE and/or EA had undergone evaluation by the authors’ neurosurgical service since 2013. Children with SE (n = 14) presented with unmistakable evidence of CNS involvement with only one exception. Children with EA alone (n = 2) had no evidence of CNS dysfunction. All children older than 1 year of age had sinusitis.The time from initial presentation to a physician to diagnosis ranged from 0 to 21 days with a mean and median of 4.5 and 6 days, respectively. The time from diagnosis to neurosurgical intervention ranged from 0 to 14 days with a mean and median of 3 and 1 day, respectively. Delay in treatment was due to misinterpretation of images, a failure to perform timely imaging, progression on imaging as an indication for surgical intervention, or the managing clinician’s preference. Among the 14 cases with SE, initial imaging studies in 6 were not interpreted as showing SE. Four SE collections were dictated as epidural even on MRI. The only fatality was associated with no surgical intervention. Endoscopic sinus surgery was not associated with reducing the need for repeat craniotomy.CONCLUSIONSRegardless of the initial imaging interpretation, any child presenting with focal neurological deficit or seizures and sinusitis should be assumed to have an SE or meningitis, and a careful review of high-resolution imaging, ideally MRI with contrast, should be performed. If an extraaxial collection is identified, surgical drainage should be performed expeditiously. Neurosurgical involvement and evaluation are imperative to achieve timely diagnoses and to guide management in these critically ill children.

Non-infectious peri-electrode edema is a rare complication after implantation of a deep brain stimulation (DBS) electrode. DBS is frequently used in the management of movement disorders with increasing interest surrounding its value in more rare disorders associated with movement abnormalities. This is the report of a 10-year-old male with Cockayne syndrome who acutely developed symptomatic non-infectious, non-hemorrhagic peri-electrode edema 18 days postoperatively from implantation of a DBS system targeting the bilateral globus pallidus internus. CT head confirmed extensive vasogenic edema along the entire length of the left electrode, and infectious workup was negative. The patient required admission to the pediatric intensive care unit for management utilizing steroid, hypertonic, and hyperosmolar therapy due to the amount of mass effect. Symptoms reduced over a 7-day hospital stay and were completely resolved at 1 month without removal of the DBS system. Management of this rare entity remains controversial and often involves the use of steroids and anti-epileptic prophylaxis. This represents the first case of non-infectious peri-electrode edema reported in a pediatric patient and is especially notable for its fulminant nature.

Summary Purpose: The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years. Methods: We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system. Key Findings: Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome. Significance: Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

The authors present the case of a 26-year-old man with a 10–15-year history of worsening bilateral dystonia and baseline chorea occurring up to 20 times per day that was exacerbated by stress and anxiety and was refractory to medical management. Paroxysmal nonkinesigenic dyskinesia was diagnosed, which is a rare, hyperkinetic movement disorder that is episodic and does not respond to nonbenzodiazepine antiepileptics. The patient was significantly debilitated by his disease, lived in a group home, and suffered from frequent falls, necessitating the wearing of a protective helmet and face mask at all times. The patient underwent implantation of bilateral deep brain stimulation quadripolar electrodes in the globus pallidus internus with the aid of image-guided stereotactic neurosurgery and microelectrode recording without complication. At his 1-month postoperative follow-up, the patient reported a subjective 90% improvement in his symptoms; the only notable side effect was a slight increased slurring in his baseline dysarthria. Objective reporting and recording forms maintained by the patient's caretakers over the following 18 months suggested a significant and sustained improvement in his overall balance, ambulation, and gross motor function with a substantial decrease in the incidence of reported falls. The authors conclude that pallidal deep brain stimulation may be successfully applied to patients suffering from refractory paroxysmal nonkinesigenic dyskinesia with promising results. This treatment strategy deserves further prospective investigation, clinical consideration, and refinement.

The lined sea anemone Edwardsiella lineata has evolved a derived parasitic life history that includes a novel body plan adapted for life inside its ctenophore hosts. Reputedly its sole host is the sea walnut, Mnemiopsis leidyi, a voracious planktivore and a seasonally abundant member of many pelagic ecosystems. However, we have observed substantially higher E. lineata prevalence in a second ctenophore species, the ctenophore predator Beroë ovata. The interplay among these 3 species has important conservation consequences as M. leidyi introductions are thought to be responsible for the severe depletion of numerous commercial fisheries in the Mediterranean basin, and both E. lineata and B. ovata have been proposed as biological controls for invasive M. leidyi. Over a 3-yr period (2004-2006), we collected 8,253 ctenophores from Woods Hole, Massachusetts, including M. leidyi, B. ovata, and a third ctenophore, Pleurobrachia pileus, and we recorded E. lineata infection frequencies, parasite load, and parasite location. We also conducted laboratory experiments to determine the likely mechanisms for parasite introduction and the effect of each host on parasite development. We observed peak E. lineata infection frequencies of 0% in P. pileus, 59% in M. leidyi, and 100% in B. ovata, suggesting that B. ovata could be an important natural host for E. lineata. However, in laboratory experiments, E. lineata larvae proved far more successful at infecting M. leidyi than B. ovata, and E. lineata parasites excised from M. leidyi exhibited greater developmental competence than parasites excised from B. ovata. Although we show that E. lineata is efficiently transferred from M. leidyi to B. ovata when the latter preys upon the former, we conclude that E. lineata larvae are not well adapted for parasitizing the latter species and that the E. lineata parasite is not well adapted for feeding in B. ovata; these developmental and ecological factors underlie the host specificity of this recently evolved parasite.

Although most patients with sagittal craniosynostosis are recognized and treated in infancy, some children are not referred to craniofacial centers until later in childhood. In this paper the authors describe a novel operative technique for calvarial reconstruction in older children with previously untreated sagittal craniosynostosis.The authors report a clinical series of eight patients who were treated using novel single-stage calvarial reconstruction, and they assess the complications and outcomes. The patient is placed supine for the procedure, which consists of a coronal incision, bifrontal craniotomy without orbital osteotomy, and multiple interlocking midline parietooccipital osteotomies and recontouring. Fixation is achieved using a bioabsorbable plate system. Cranial indices were calculated from measurements obtained before and after the reconstructive procedures. Preoperative, intraoperative, and postoperative photographs and three-dimensional computed tomography scans are presented for review. Between November 2003 and April 2005, the authors treated seven boys (age range approximately 1-10 years, mean age 4.2 years) with uncorrected sagittal craniosynostosis and one with bicoronal and sagittal synostosis. The mean operating time was 5.13 hours (range 4.3-8 hours), with a mean blood loss of 425 ml (range 200-800 ml). As a percentage of the estimated circulating blood volume, the mean operative blood loss was 33.5% (range 17-57%). The mean hospital stay was 4.9 days. The cranial index significantly improved from a mean of 65.6 to 71.3% (p = 0.001). No acute or delayed complications have been noted. Follow-up examinations performed at an average of 12 months (range 1-17 months) have confirmed early patient and family satisfaction.An approach of aggressive calvarial reconstruction with multiple interleaving osteotomies crossing the midline achieves improvements in biparietal narrowing. Combined with a bifrontal reconstruction, early outcomes are excellent, with an acceptable amount of intraoperative blood loss and no significant complications.

A novel Helicobacter species Helicobacter japonicum was isolated from the stomach and intestines of clinically normal mice received from three institutes from Japan. The novel Helicobacter sp. was microaerobic, grew at 37°C and 42°C, was catalase and oxidase positive, but urease negative. It is most closely related to the 16S rRNA gene of H.muridarum (98.6%); to the 23S rRNA gene of H.hepaticus (97.9%); to the hsp60 gene of H.typhlonius (87%). The novel Helicobacter sp. has in vitro cytolethal distending toxin (CDT) activity; its cdtB gene sequence has 83.8% identity with that of H.hepaticus The whole genome sequence of H.japonicum MIT 01-6451 has a 2.06-Mb genome length with a 37.5% G + C content. When the organism was inoculated into C57BL/129 IL10-/- mice, it was cultured from the stomach, colon and cecum of infected mice at 6 and 10 weeks post-infection. The cecum had the highest H.japonicum colonization levels by quantitative PCR. The histopathology of the lower bowel was characterized by moderate to severe inflammation, mild edema, epithelial defects, mild to severe hyperplasia, dysplasia and carcinoma. Inflammatory cytokines IFNγ, TNFα and IL17a, as well as iNOS were significantly upregulated in the cecal tissue of infected mice. These results demonstrate that the novel H.japonicum can induce inflammatory bowel disease and carcinoma in IL10-/- mice and highlights the importance of identifying novel Helicobacter spp. especially when they are introduced from outside mouse colonies from different geographic locations.

The short-term efficacy and safety of epilepsy surgery relative to medical therapy has been established, but it remains underutilized. There is a lack of data regarding the long-term seizure-control rates and quality of life outcomes after epilepsy surgery. This study represents the longest follow-up study to date, with a mean follow-up duration of 26 years.We studied the seizure and health-related quality of life outcomes of patients who underwent epilepsy surgery by Dr. Sidney Goldring from 1967 to 1990. Retrospective clinical chart reviews gathered perioperative data and surveys obtained follow-up data. Seizure outcome was evaluated using the Engel classification system.Of 361 patients, 117 (32.4%) completed follow-up interviews. Fifty-six patients (48%) were Engel class I. Mean overall Quality of Life in Epilepsy (QOLIE-31) questionnaire score for the cohort was 68.2 ± 16. Eighty percent of patients reported their overall quality of life now as being better than before surgery. Seizure freedom was associated with better quality of life. We did not observe a statistically significant association between postoperative complications and long-term outcome. Patients who underwent temporal lobe resection achieved better seizure outcomes than those who underwent other types of procedures. Astatic seizures and bilateral surgery were associated with a worse Engel class outcome.Our study demonstrates that the beneficial effects of epilepsy surgery are sustained over decades, and that these beneficial effects are correlated with an improved quality of life. The confirmation of its durability makes us optimistic that the outcomes from modern epilepsy surgery will be even better and that our present enthusiasm for this treatment modality is not misplaced.

The authors present the case of a 26-year-old man with a 10-15-year history of worsening bilateral dystonia and baseline chorea occurring up to 20 times per day that was exacerbated by stress and anxiety and was refractory to medical management. Paroxysmal nonkinesigenic dyskinesia was diagnosed, which is a rare, hyperkinetic movement disorder that is episodic and does not respond to nonbenzodiazepine antiepileptics. The patient was significantly debilitated by his disease, lived in a group home, and suffered from frequent falls, necessitating the wearing of a protective helmet and face mask at all times. The patient underwent implantation of bilateral deep brain stimulation quadripolar electrodes in the globus pallidus internus with the aid of image-guided stereotactic neurosurgery and microelectrode recording without complication. At his 1-month postoperative follow-up, the patient reported a subjective 90% improvement in his symptoms; the only notable side effect was a slight increased slurring in his baseline dysarthria. Objective reporting and recording forms maintained by the patient's caretakers over the following 18 months suggested a significant and sustained improvement in his overall balance, ambulation, and gross motor function with a substantial decrease in the incidence of reported falls. The authors conclude that pallidal deep brain stimulation may be successfully applied to patients suffering from refractory paroxysmal nonkinesigenic dyskinesia with promising results. This treatment strategy deserves further prospective investigation, clinical consideration, and refinement.

The use of cyclosporine has been associated with an increased incidence of thrombosis and endothelial cell perturbation. To explore possible mechanisms involved, we examined the effects of CSA on the activation of protein C by thrombomodulin. Cultured bovine aortic endothelial cell monolayers were incubated for 24 hr with a wide range of CSA concentrations. After removal of CSA and incubation with thrombin and purified protein C, thrombomodulin-dependent protein C activation was measured with an S-2238-based kinetic chromogenic assay. As compared to control, a significant fall in thrombomodulin activity occurred after 24-hr incubation with 100 (70.8 +/- 15.8%, P less than 0.05), 1000 (64.9 +/- 16.6%, P less than 0.05), or 10,000 (28.9 +/- 12.3%, P less than 0.05) ng/ml of CSA. A comparable inhibition of thrombomodulin activity was also observed in cultured renal artery endothelial cells (67.5 +/- 12.6%, P less than 0.05), after 24-hr incubation with 5000 ng/ml CSA. In cells incubated with 5000 ng/ml of CSA for 4 hr, thrombomodulin activity fell by almost 15% (85.6 +/- 8.3%, P less than 0.05) and tended to plateau between 7 hr (73.8 +/- 12.7%, P less than 0.05), and 24 hr of incubation (72.7 +/- 8.9%, P less than 0.05). These results indicate that CSA produces a time- and dose-dependent reduction in thrombomodulin activity of cultured endothelial cells, downregulating the protein C anticoagulant pathway, thereby increasing the risk of thrombosis.

Introduction: Gastrointestinal (GI) tract dysbiosis and resulting inflammation are implicated in breast carcinogenesis. CD11b+GR1+ myeloid- derived suppressor cells (MDSCs) are important drivers of breast cancer. Here we report that in APCMin/+ mice treated with enteric Helicobacter hepaticus (H. hepaticus) MDSCs cells are dramatically expanded and, along with the pathogen H. hepaticus, are directly recruited to mammary gland lymph node, where they suppress anti-carcinogenic cytotoxic T-cells and promote procarcinogenic inflammation, respectively. Methods: In our H. hepaticus and specific pathogen free colony we inoculated female APCMin/+ mice with H. hepaticus and compared neoplastic and inflammatory outcomes to the non-infected controls. Results: Successful infection was confirmed by H. hepaticus specific qPCR and fluorescence in situ hybridization (FISH). H. hepaticus was identified not only within the small intestine but also within the mammary gland lymph node and mammary tumor tissue of the treated group. In APCMin/+ mice treated with chow diet, H. hepaticus-induced procarcinogenic CD11b+GR1+ cells within the lamina propria of the small intestine, the surrounding mesenteric lymph nodes, the spleen, peripheral blood and the mammary gland lymph nodes. In H. hepaticus infected mice, this was accompanied by increased splenic expression of IL-1β, IL-6 and GM-CSF and the increased expression of IL-1β, IL-6 and GM-CSF, IL-23a and IL-17a in the small intestine. Interestingly, adding high fat diet to H. hepaticus infected mice appeared to further promote the trafficking of MDSCs from the spleen into the peripheral blood and regional lymph nodes with increased serum inflammatory cytokines production cytokines, including IL-6. This appears to have been mediated, at least in part, by adipocyte signaling to myeloid precursors. Conclusions: We show the presence of H. hepaticus in mammary gland and intestine, which correlated with mammary gland tumor incidence and increased intestinal tumor multiplicity. The co-existence of enteric H. hepaticus infection appears to promote mammary tumorigenesis through upregulation of IL-1β, IL-6 and GM-CSF and the resulting trafficking of tumor promoting CD11b+GR1+ MDSCs. We are currently examining the route and broader relevance of H. hepaticus extra-intestinal translocation and whether this has direct effects on tumorigenesis, consistent with findings in other Helicobacter spp. Citation Format: Xiaowei Chen, Daniel L. Worthley, Zhongming Ge, Yagnesh Tailor, Christian Kaufman, Lenzie Cheaney, Lesley Kline, Gladys Y. Valeriano, Christoph B. Westphalen, Susan E. Erdman, James G. Fox, Timothy C. Wang. Helicobacter hepaticus contributes to mammary gland carcinogenesis through bacterial translocation and subsequent expansion of cancer-promoting myeloid-derived suppressor cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A100.

The study objective was to investigate further the potential role of long-term exposure to hydrocarbons (HCs) in the development of idiopathic chronic glomerulopathy (ICG) using a more refined measurement of HC exposure. A total of 321 pairs of cases and controls, matched by age, gender, and geographical area, were assembled. A detailed questionnaire was blindly administered to cases and controls to collect information on occupational and medical history and sociodemographic data. By integrating quantified measurements of HC exposure from a variety of sources with each subject's occupational history, a lifetime HC exposure score could be estimated and expressed in parts per million (ppm). Cases had an hydrocarbon exposure mean score of 165 ppm (median 48 ppm) as compared to 162 ppm (median 43 ppm) for controls (P = 0.757). When using hydrocarbon exposure as a dichotomous variable with a cutoff point at 100 ppm, cases had a higher proportion of exposed than controls, but the difference was not statistically significant at the 0.05 level, even after controlling for possible confounders through logistic regression. Subgroup analyses showed mixed results. In most subgroups differences between cases and controls tended to become significant when hydrocarbon was used as a dichotomous variable. Results from this study do not sufficiently support the hypothesized association of HC exposure and ICG in general. Subgroup analyses need further investigations. Efforts to generate accurate estimates of lifetime HC exposure should be emphasized for future investigations.

Fasting serum gastrin levels greater than 1000 pg/ml are said to establish the diagnosis of gastrinoma in a patient with peptic ulcer disease. The authors observed a patient with recurrent peptic ulcer disease, diarrhea, and a fasting serum gastrin of 1044 pg/ml who had a gastrocolic fistula, not the Zollinger-Ellison syndrome. The provocative tests of gastrin secretion, including secretin infusion and standard meal test, were helpful in ruling out a gastrinoma. This is the first reported association of gastrocolic fistula and hypergastrinemia. The patient demonstrates that the differential diagnosis of markedly elevated serum gastrin should be expanded to include gastrocolic fistula.

Fractional excretion of filtered sodium (FENa) is typically elevated (greater than 3%) in acute tubular necrosis and decreased (less than 1%) with volume depletion. We describe a patient who developed acute tubular necrosis with a FENa of 13%. Four weeks later, he was still oliguric but had also become volume-depleted. FENa was 0.4% to 0.8%, considerably lower than FENa's measured in eight nonvolume-depleted patients in acute renal failure. Vigorous intravenous fluid therapy in this patient produced a prompt increase in urine volume and improvement in renal function. We conclude the following: (1) a marked decrease in FENa in a patient with acute tubular necrosis should suggest the development of a superimposed sodium-retaining state such as volume depletion, and (2) severe volume depletion may delay or mask recovery from acute tubular necrosis.

Generalized edema, a cardinal feature of the nephrotic syndrome, may be associated with a low, normal, or high blood volume. Symptoms can usually be improved by a regimen that includes rest, proper diet, and careful use of diuretic agents. Hypovolemic patients are particularly prone to complications of diuretic therapy, which are the major source of the electrolyte disturbances encountered in patients being treated for nephrotic syndrome.

Transfusion of blood products containing immunocompetent lymphocytes may cause graft-versus-host disease (GVHD) in immunosuppressed recipients. We describe fatal GVHD which occurred in a 30-year-old renal transplant patient 2 weeks after transfusion of 1.0 x 10 8 lymphocytes/kilogram. In addition to typical cutaneous and gastrointestinal manifestations, she developed irreversible bone marrow failure, Acute GVHD following blood product transfusion from normal donors has a mortality of 88%. Treatment is unsatisfactory, but irradiation of blood products prior to administration is preventive.

Clearance studies were performed in awake dogs, before and after thyroparathy- roidectomy (TPX). Following TPX, mean plasma calcium decreased from 10.18 to 6.08 mg/100 ml (p 0.7). These data suggest that the TPX resulted in sustained renal vaso- dilatation. (Endocrinology 89: 909, 1971)