Alterations of p11 in brain tissue and peripheral blood leukocytes in Parkinson's disease.

Individuals with Parkinson's disease (PD) often suffer from comorbid depression. P11 (S100A10), a member of the S100 family of proteins, is expressed widely throughout the body and is involved in major depressive disorder and antidepressant response. Central p11 levels are reduced in postmortem tissue from depressed individuals; however, p11 has not yet been investigated in PD patients with depression or those without depression. We investigated p11 levels in postmortem PD brains and assessed whether peripheral p11 levels correlate with disease severity. Substantia nigra, putamen, and cortical p11 protein levels were assessed in postmortem brain samples from PD patients and matched controls. In a different set of postmortem brains, p11 mRNA expression was measured in dopaminergic cells from the substantia nigra. Both p11 protein and mRNA levels were decreased in PD patients. Peripheral p11 protein levels were investigated in distinct leukocyte populations from PD patients with depression and those without depression. Monocyte, natural killer (NK) cell, and cytotoxic T-cell p11 levels were positively associated with the severity of PD, and NK cell p11 levels were positively associated with depression scores. Given that inflammation plays a role in both PD and depression, it is intriguing that peripheral p11 levels are altered in immune cells in both conditions. Our data provide insight into the pathological alterations occurring centrally and peripherally in PD. Moreover, if replicated in other cohorts, p11 could be an easily accessible biomarker for monitoring the severity of PD, especially in the context of comorbid depression.

Desmoplastic Small Round Cell Tumor Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Results of a Phase 2 Trial.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma that primarily affects adolescents and young adults. Patients can present with many peritoneal implants. We conducted a phase 2 clinical trial utilizing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) with cisplatin for DSRCT and pediatric-type abdominal sarcomas. PATIENTS AND METHODS: A prospective cohort study was performed on 20 patients, who underwent CRS-HIPEC procedures, with cisplatin from 2012 to 2013. All patients were enrolled in the phase 2 clinical trial. Patients with extraabdominal disease and in whom complete cytoreduction (CCR0-1) could not be achieved were excluded. All outcomes were recorded. RESULTS: Fourteen patients had DSRCT, while five patients had other sarcomas. One patient had repeat HIPEC. Patients with DSRCT had significantly longer median overall survival after surgery than patients with other tumors (44.3 vs. 12.5 months, p = 0.0013). The 3-year overall survival from time of diagnosis for DSRCT patients was 79 %. Estimated median recurrence-free survival (RFS) was 14.0 months. However, RFS for patients with DSRCT was significantly longer than for non-DSRCT patients (14.9 vs. 4.5 months, p = 0.0012). Among DSRCT patients, those without hepatic or portal metastases had longer median RFS than those with tumors at these sites (37.9 vs. 14.3 months, p = 0.02). In 100 % of patients without hepatic or portal metastasis, there was no peritoneal disease recurrence after CRS-HIPEC. CONCLUSIONS: Complete CRS-HIPEC with cisplatin is effective in select DSRCT patients. DSRCT patients with hepatic or portal metastasis have poorer outcomes.

The Omega-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid (DHA) Reverses Corticosterone-Induced Changes in Cortical Neurons.

BACKGROUND: Chronic exposure to the glucocorticoid hormone corticosterone exerts cellular stress-induced toxic effects that have been associated with neurodegenerative and psychiatric disorders. Docosahexaenoic acid is a polyunsaturated fatty acid that has been shown to be of benefit in stress-related disorders, putatively through protective action in neurons. METHODS: We investigated the protective effect of docosahexaenoic acid against glucocorticoid hormone corticosterone-induced cellular changes in cortical cell cultures containing both astrocytes and neurons. RESULTS: We found that glucocorticoid hormone corticosterone (100, 150, 200 µM) at different time points (48 and 72 hours) induced a dose- and time-dependent reduction in cellular viability as assessed by methyl thiazolyl tetrazolium. Moreover, glucocorticoid hormone corticosterone (200 µM, 72 hours) decreased the percentage composition of neurons while increasing the percentage of astrocytes as assessed by ßIII-tubulin and glial fibrillary acidic protein immunostaining, respectively. In contrast, docosahexaenoic acid treatment (6 µM) increased docosahexaenoic acid content and attenuated glucocorticoid hormone corticosterone (200 µM)-induced cell death (72 hours) in cortical cultures. This translates into a capacity for docosahexaenoic acid to prevent neuronal death as well as astrocyte overgrowth following chronic exposure to glucocorticoid hormone corticosterone. Furthermore, docosahexaenoic acid (6 µM) reversed glucocorticoid hormone corticosterone-induced neuronal apoptosis as assessed by terminal deoxynucleotidyl transferase-mediated nick-end labeling and attenuated glucocorticoid hormone corticosterone-induced reductions in brain derived neurotrophic factor mRNA expression in these cultures. Finally, docosahexaenoic acid inhibited glucocorticoid hormone corticosterone-induced downregulation of glucocorticoid receptor expression on ßIII- tubulin-positive neurons. CONCLUSIONS: This work supports the view that docosahexaenoic acid may be beneficial in ameliorating stress-related cellular changes in the brain and may be of value in psychiatric disorders.

Surgical management for Hirschsprung disease: A review for primary care providers.

Primary care providers may encounter infants and children with Hirschsprung disease, a congenital colonic defect. Although primarily a surgical problem, the disease requires extensive supportive care and a multidisciplinary approach that often extends beyond surgical correction. This article reviews the management of Hirschsprung disease.

Cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for children, adolescents, and young adults: the first 50 cases.

BACKGROUND: Extensive peritoneal metastatic disease is rare in children. Although usually manifested as carcinomatosis in adults, sarcomatosis is more common in children. The authors began a pediatric hyperthermic intraperitoneal chemotherapy (HIPEC) program, and this report describes their initial results from the first 50 pediatric, adolescent, and young adult patients. METHODS: A single-institution, retrospective study investigated the first 50 cytoreductive surgeries and HIPEC by one surgeon for patients 3-21 years of age. The HIPEC was added to chemotherapy and radiotherapy treatment. Demographics, outcome, and complications were recorded. RESULTS: The median follow-up period for the surviving patients was 21.9 months. The most common diagnoses were desmoplastic small round cell tumor (n = 21), rhabdomyosarcoma (n = 7), mesothelioma (n = 4), and other carcinoma (n = 17). Multivariate analysis showed that patients treated with HIPEC and an incomplete cytoreduction had a greater risk for recurrence than those who had a complete cytoreduction (p = 0.0002). The patients with a higher peritoneal cancer index (PCI) (i.e., a large tumor burden) had a median overall survival (OS) time of 19.9 months relative to the patients with a lower PCI score, who had a median OS of 34 months (p = 0.049). The patients without complete cytoreduction had a median OS of 7.1 months compared with 31.4 months for the patients with complete cytoreduction (p = 0.012). No perioperative mortalities occurred. The incidence of major complications was 28 %. CONCLUSION: Cytoreductive surgery and HIPEC with a programmatic approach for patients 3-21 years of age is unique. The best outcome was experienced by patients with desmoplastic small round cell tumor and those with complete cytoreduction. Complete cytoreduction for patients without disease outside the abdominal cavity at the time of surgery affords the best outcome.

Complete cytoreduction and HIPEC improves survival in desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is a rare tumor of adolescents and young adults. Less than 100 cases per year are reported in North America. Extensive peritoneal metastases are characteristic of this disease. We performed cytoreductive surgery and hyperthermic peritoneal perfusion with chemotherapy (HIPEC) using cisplatin (CDDP) for DSRCT. METHODS: A retrospective cohort study was performed on 26 pediatric and adult patients who underwent cytoreduction/HIPEC using CDDP for DSRCT at a single cancer center. Neoadjuvant chemotherapy, adjuvant chemotherapy, and postoperative enteral nutrition were given to all patients. Postoperative radiation therapy was given to most patients. Follow-up was from 6 months to 6 years. Outcome variables were evaluated for disease-free and overall survival (OS). RESULTS: Five patients (19 %) were less than 12 years of age at surgery. Patients who had disease outside the abdomen at surgery had a larger risk of recurrence or death than those who did not (p = 0.0158, p = 0.0393 time from surgery to death respectively). Age, liver metastasis, and peritoneal cancer index level did not significantly predict disease-free or OS. Patients who had CR0 or CR1 and HIPEC had significantly longer median survival compared with patients who had HIPEC and CR2 cytoreduction (63.4 vs. 26.7 months). CONCLUSIONS: HIPEC may be an effective therapy for children and young adults with DSRCT. Patients with DSRCT require complete cytoreduction before HIPEC to optimize outcome. Patients with DSRCT and disease outside the abdomen at the time of surgery do not benefit from HIPEC.

The role of cell type-specific responses in IFN-ß therapy of multiple sclerosis.

The mechanism of IFN-ß therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-ß by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-κB in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i.m. injection of IFN-ß1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-κB in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-ß depends on the activation of p38 and NF-κB as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-κB and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-ß therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-α/ß in hepatitis and cancer.

A role for interleukin-1ß in determining the lineage fate of embryonic rat hippocampal neural precursor cells.

Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1ß (IL-1ß) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1ß on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1ß treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1ß, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1ß exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1ß signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

Urinary retention and mydriasis secondary to topical glycopyrronium for axillary hyperhidrosis.

PURPOSE: Glycopyrronium, also known as glycopyrrolate, is an antimuscarinic competitive inhibitor of acetylcholine widely utilized topically for its anticholinergic properties in dermatology. A single topical glycopyrronium tosylate (GT) formulation is available on the market, and prescription of this medication has become increasingly popular among dermatologists. This medication has a relatively notable adverse effect profile and carries risks that patients need to be counseled on before initiation. SUMMARY: A 22-year-old female presented to our emergency department (ED) with a chief complaint of difficulty urinating for 48 hours and blurred vision for 2 weeks. Over the course of a week, she visited the ED once and urgent care multiple times due to complications associated with combination use of GT and cetirizine. Although these clinical effects were reversible, the patient impact in our case was profound given the time, cost, and invasive nature of these visits. CONCLUSION: The notable adverse effects of GT should be considered when prescribing this agent.

Anesthetic management and renal function in pediatric patients undergoing cytoreductive surgery with continuous hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin.

BACKGROUND: Extensive tumor implants secondary to sarcoma, sarcomatosis, or mesothelioma in children is rare. We conducted the first phase 1 trial of escalating doses of cisplatin during hyperthermic intraperitoneal chemotherapy (HIPEC) in children with sarcomatosis. The most devastating complication of cisplatin therapy is nephrotoxicity. Here we present the anesthetic management and analysis of the impact of intraoperative fluid management on the incidence of renal failure. METHODS: Of the 10 patients under 18 years of age who underwent HIPEC in the context of our phase 1 trial, six patients were under the age of 10 years. We reviewed the anesthetic management, intraoperative fluid and blood administration, and postoperative renal function in these patients. RESULTS: The average age and weight were 6 years and 20.9 kg, respectively. To avoid renal toxicity, urine output was maintained at an average of 3 ml/kg/h. Crystalloid and colloid were transfused at an average rate of 9 ml/kg/h. Percentage increase in creatinine postoperatively varied from 33 to 500 %. Volume of fluid administered did not correlate with percentage increase in creatinine. All patients had a temporary increase in their serum creatinine, but none required dialysis. CONCLUSIONS: Fluid administration at an average rate of 9 ml/kg/h was required to maintain satisfactory urine output. This rate of intraoperative fluid administration is similar to what is provided to adult HIPEC patients. There was no significant correlation in the volume or type of fluid delivered and the increase in serum creatinine. More studies are needed to determine optimal fluid management in children undergoing HIPEC with cisplatin.

Plasma IL-6 and IL-17A Correlate with Severity of Motor and Non-Motor Symptoms in Parkinson's Disease.

The nature of the inflammatory response in Parkinson's disease (PD) remains to be better understood. Here, we used highly sensitive Single Molecule Array (SIMOA) technology to measure the levels of the inflammatory mediators Interleukin 6 (IL-6), Interleukin 17A (IL-17A), Tumour Necrosis Factor α (TNFα) and Transforming Growth Factor ß (TGFß) in plasma from PD patients and age- and gender-matched healthy controls. We report that IL-17A correlates with non-motor symptoms (NMS) scores, while IL-6 positively correlates with motor scores. We found no correlations between cytokines and disease duration suggesting that IL-6 and IL-17A are associated with disease severity rather than disease duration in this cohort, furthermore IL-17A may be involved in the underlying pathophysiology of NMS in PD.

Novel Treatment Opportunities Against Cognitive Impairment in Parkinson's Disease with an Emphasis on Diabetes-Related Pathways.

Cognitive impairment is highly prevalent in patients with Parkinson's disease (PD) and causes adverse health outcomes. Novel procognitive therapies are needed to address this unmet need. It is now established that there is an increased risk of dementia in patients with type 2 diabetes mellitus (T2DM) and, moreover, T2DM and PD may have common underlying biological mechanisms. As such, T2DM medications are emerging as potential therapies in the context of PD dementia (PDD). In this review, we provide an update on pathophysiological mechanisms underlying cognitive impairments and PDD, focusing on diabetes-related pathways. Finally, we have conducted a review of ongoing clinical trials in PD patients with dementia, highlighting the multiple pharmacological mechanisms that are targeted to achieve cognitive enhancement.

Breast tissue, oral and urinary microbiomes in breast cancer.

It has long been proposed that the gut microbiome contributes to breast carcinogenesis by modifying systemic estrogen levels. This is often cited as a possible mechanism linking breast cancer and high-fat, low-fiber diets as well as antibiotic exposure, associations previously identified in population-based studies. More recently, a distinct microbiome has been identified within breast milk and tissue, but few studies have characterized differences in the breast tissue microbiota of patients with and without cancer, and none have investigated distant body-site microbiomes outside of the gut. We hypothesize that cancerous breast tissue is associated with a microbiomic profile distinct from that of benign breast tissue, and that microbiomes of more distant sites, the oral cavity and urinary tract, will reflect dysbiosis as well. Fifty-seven women with invasive breast cancer undergoing mastectomy and 21 healthy women undergoing cosmetic breast surgery were enrolled. The bacterial 16S rRNA gene was amplified from urine, oral rinse and surgically collected breast tissue, sequenced, and processed through a QIIME-based bioinformatics pipeline. Cancer patient breast tissue microbiomes clustered significantly differently from non-cancer patients (p=0.03), largely driven by decreased relative abundance of Methylobacterium in cancer patients (median 0.10 vs. 0.24, p=0.03). There were no significant differences in oral rinse samples. Differences in urinary microbiomes were largely explained by menopausal status, with peri/postmenopausal women showing decreased levels of Lactobacillus. Independent of menopausal status, however, cancer patients had increased levels of gram-positive organisms including Corynebacterium (p<0.01), Staphylococcus (p=0.02), Actinomyces (p<0.01), and Propionibacteriaceae (p<0.01). Our observations suggest that the local breast microbiota differ in patients with and without breast cancer. Cancer patient urinary microbiomes were characterized by increased levels of gram-positive organisms in this study, but need to be further studied in larger cohorts.

Treatment of carcinomatosis using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in adolescents and young adults.

BACKGROUND: Among colorectal carcinoma patients, approximately 150 patients/year are age 25 years old or younger according to Surveillance, Epidemiology, and End Results Program statistics. Because of lack of screening in their age group, they are at risk to have more advanced disease and have been largely unstudied. OBJECTIVE: To determine outcome of colon cancer adolescent and young adult patients. METHODS: Patients under the age of 26 were retrospectively reviewed from a single institution. RESULTS: The 5-year overall survival rate from the time of the first surgery was .45 (95% confidence interval .17 to .70). The median overall survival for the cohort was 2.98 years. Patients aged 15 to 21 years had a poorer overall survival than patients aged 22 to 25 years (82% survival vs 100% at 2 years and zero vs 56% at 5 years). Five patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Three are alive at 82, 36, and 16 weeks after hyperthermic intraperitoneal chemotherapy. CONCLUSIONS: Patients less than 21 years with nonsyndromic colorectal carcinoma may have a poorer outcome. Novel, more aggressive therapy may be necessary in these patients.

Caring for the child with fetal alcohol syndrome.

Physical and behavioral difficulties can beset the child exposed to alcohol in utero. Timely intervention can lessen their severity.

Inflammation and the developing brain: consequences for hippocampal neurogenesis and behavior.

While the detrimental impact of inflammation on adult hippocampal neurogenesis and associated behaviors has recently gained credence, the effects of inflammation on the developing brain is an area of research which is quickly gaining momentum, and a growing number of research articles on this topic have been published in recent years. Indeed, we now know that pro-inflammatory mediators negatively influence both hippocampal neurogenesis and neuronal cytoarchitecture during brain development. Here we present a comprehensive review of the current literature on inflammation-induced changes in hippocampal neurogenesis during early life and the consequent behavioral deficits which may ensue in later life. We also offer insights into the cellular and molecular mechanisms underlying the hippocampal-dependant behavioral changes observed in neurodevelopmental disorders, particularly in those where cognitive dysfunction plays a major role. We further consider whether early-life inflammation-induced changes in hippocampal neurogenesis may contribute to the onset of mood and cognitive deficits in later life.

GSK-3 mediates the release of IL-1ß, TNF-α and IL-10 from cortical glia.

Neuroinflammation has been shown to contribute to neurodegenerative and psychiatric disorders such as Alzheimer's disease and major depression due to the inappropriate release of pro-inflammatory cytokines from activated microglia. The precise molecular events that mediate cytokine release from glia remain unknown but we suggest that the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) may be involved. The aim of this study therefore was to investigate the effect of lipopolysaccharide (LPS) on expression and activity of the GSK-3ß isoform in glia, and to assess if GSK-3 mediates the LPS-induced change in inflammatory cytokine levels in culture medium from rat glial-enriched cortical cultures. GSK-3ß was expressed in microglia and astrocytes, and stimulation of these cultures with LPS induced an increase in GSK-3ß expression and activity, and in pro-inflammatory cytokine levels in culture media. We show that GSK-3 inhibition using a small molecule inhibitor SB216763 or the mood stabiliser lithium chloride reduced the LPS-induced elevated levels of pro-inflammatory cytokines present in culture media from rat glial-enriched cortical cultures. These results demonstrate a role for GSK-3 as a modulator of inflammatory cytokine levels in the brain, and contribute to a mechanistic insight into neurological disorders in which neuroinflammation is a characteristic feature.

Unusual cases: melanomatosis and nephroblastomatosis treated with hyperthermic intraperitoneal chemotherapy.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-established therapy for carcinomas, mesotheliomas, and some sarcomas. However, HIPEC has not been reported in melanomatosis or nephroblastomatosis. Here we present 2 unique cases of cytoreductive surgery and HIPEC. Cytoreductive surgery followed by HIPEC was performed in a 4-year old with melanomatosis and a 12-year old with nephroblastomatosis. A 4-year-old girl presented with leptomeningeal melanoma that metastasized from a congenital nevus. She had a ventricular peritoneal shunt placed as an infant. Melanomatosis involving the meninges and peritoneal surfaces was identified by positron emission tomographic scan imaging. Extensive plaques of melanoma were removed at the time of surgery, followed by HIPEC. She had no significant postoperative complications. Her abdomen remained free of disease 7 months after treatment. A 13-year-old girl presented with a Wilms' tumor at age 10 years. She then presented to us at the second local recurrence with multiple intraabdominal tumor implants (ie, nephroblastomatosis). We performed cytoreductive surgery followed by HIPEC. She had no postoperative complications and, at 1 year post-HIPEC, had no abdominal recurrence. We conclude that HIPEC can be performed safely for rare diseases such as melanomatosis and nephroblastomatosis. Although abdominal disease control can be realized, further systemic treatment options are necessary. A review of indications for HIPEC is included.