Developmental and Regional Studies of the Metabolism of Inositol 1,4,5-Trisphosphate in Rat Brain

Coupling of CNS receptors to phosphoinositide turnover has previously been found to vary with both age and brain region. To determine whether the metabolism of the second messenger inositol 1,4,5-trisphosphate also displays such variations, activities of inositol 1,4,5-trisphosphate 5′-phosphatase and 3′-kinase were measured in developing rat cerebral cortex and adult rat brain regions. The 5′-phosphatase activity was relatively high at birth (∼50% of adult values) and increased to adult levels by 2 weeks postnatal. In contrast, the 3′-kinase activity was low at birth and reached ∼50% of adult levels by 2 weeks postnatal. In the adult rat, activities of the 3′-kinase were comparable in the cerebral cortex, hippocampus, and cerebellum, whereas much lower activities were found in hypothalamus and pons/medulla. The 5′-phosphatase activities were similar in cerebral cortex, hippocampus, hypothalamus, and pons/medulla, whereas 5-to 10-fold higher activity was present in the cerebellum. The cerebellum is estimated to contain 50–60% of the total inositol 1,4,5-trisphosphate 5′-phosphatase activity present in whole adult rat brain. The localization of the enriched 5′-phosphatase activity within the cerebellum was examined. Application of a histochemical lead-trapping technique for phosphatase indicated a concentration of inositol 1,4,5-trisphosphate 5′-phosphatase activity in the cerebellar molecular layer. Further support for this conclusion was obtained from studies of Purkinje cell-deficient mutant mice, in which a marked decrement of cerebellar 5′-phosphatase was observed. These results suggest that the metabolic fate of inositol 1,4,5-trisphosphate depends on both brain region and stage of development.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65545/1/j.1471-4159.1990.tb01976.x.pd

Cholesterol Synthesis and Nerve Regeneration

In this report, we examine the requirement of cholesterol biosynthesis and its axonal transport for goldfish optic nerve regeneration. Cholesterol, labeled by intraocular injection of [ 3 H]mevalonolactone. exhibited a delayed appearance in the optic tectum. Squalene and other minor components were labeled but not transported. Following optic nerve crush, the amount of labeled cholesterol transport was elevated, while retinal labeling was not altered relative to control fish. A requirement for cholesterol biosynthesis is inferred from the inhibition of neurite outgrowth in retinal explants caused by the cholesterol synthesis inhibitor, 20, 25-diazacholes-terol. The inhibition of growth could be overcome by addition of mevalonolactone, but not cholesterol, to the medium. Intraperitoneal administration of 200 nmol of dia-zacholesterol resulted in 92-98% inhibition of retinal cholesterol synthesis and accumulation of labeled des-mosterol and other lipids in fish retina and brain which persisted for 2 weeks. Diazacholesterol-treated fish showed no reduction in the amount of lipid-soluble radioactivity transported following intraocular injection of [ 3 H]mevalonolactone, but there were alterations in the chromatographic pattern of the transported labeled lipids. In contrast to its effects on neurite outgrowth in vitro , diazacholesterol did not inhibit optic nerve regeneration in vivo , as measured both by arrival of labeled rapidly transported protein at the tectum and by time required for the return of visual function.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65710/1/j.1471-4159.1984.tb12701.x.pd

Properties of a CDP-Diglyceride Hydrolase from Guinea Pig Brain

Enzymatic hydrolysis of the pyrophosphate bond of CDP-diglyceride (CDP-DG), previously shown to occur in bacteria, is demonstrable in mammalian tissues. Activity was enriched in a lysosomal fraction obtained from guinea pig cerebral cortex and was purified 92-fold relative to the homogenate by a combination of XM-300 ultrafiltration and DEAE-cellulose column chromatography. When incubated with CDP-dipalmitin, the purified enzyme produced stoichiometric amounts of CMP and phosphatidate. dCDP-DG served as a substrate, while ADP-DG was an inhibitor, as were 5′-AMP and 5′-dAMP. CDP-DG hydrolysis was not affected by the presence of excess amounts of CDP-choline, CDP-glycerol, sodium pyrophosphate, or cyclic 3′,5′-AMP.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65407/1/j.1471-4159.1981.tb01691.x.pd

Attachment Ligands of Viable Toxoplasma gondii Induce Soluble Immunosuppressive Factors in Human Monocytes

Previous studies have demonstrated that surface antigen proteins, in particular SAG-1, of Toxoplasma gondii are important to this parasite as attachment ligands for the host cell. An in vitro assay was developed to test whether these ligands and other secretory proteins are involved in the immune response of human cells to toxoplasma. Human monocytes were infected with tachyzoites in the presence of antiparasite antibodies, and their effect on mitogen-induced lymphoproliferation was examined. The presence of antibody to either parasite-excreted proteins (MIC-1 and MIC-2) or surface proteins (SAG-1 and SAG-2) during infection neutralized the marked decrease seen in mitogen-induced lymphoproliferation in the presence of infected monocytes. Conversely, antibodies to other secreted proteins (ROP-1) and cytoplasmic molecules had no effect on parasite-induced, monocyte-mediated downregulation. Fluorescence microscope analysis detected microneme and surface antigen proteins on the monocyte cell surface during infection. These results suggest that microneme and surface antigen proteins trigger monocytes to downregulate mitogen-induced lymphoproliferation

Measurement of Receptor-Activated Phosphoinositide Turnover in Rat Brain: Nonequivalence of Inositol Phosphate and CDP-Diacylglycerol Formation

Two methods for the measurement of receptor-activated phosphoinositide turnover were evaluated for their degree of correspondence in slices of rat brain; they involved the Li + -dependent accumulations of either [ 3 H]-inositol-labeled inositol phosphates or [ 3 H]cytidine-labeled CDP-diacylglycerol. In contrast to the expectation that the ratio of these two responses would remain approximately constant, varying degrees of correspondence were obtained. The two extremes are exemplified by carbachol, which elicited large increases in both inositol phosphate and CDP-diacylglycerol labeling, and endothelin, which gave a robust inositol phosphate response with little or no accumulation of 3 H-CDP-diacylglycerol. No instance of the presence of the latter response in the absence of 3 H-inositol phosphate accumulation was observed. Measurement of 3 H-CDP-diacylglycerol accumulation thus may add additional insight into the regulation of phosphoinositide turnover and the complex actions of Li + .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66135/1/j.1471-4159.1993.tb03258.x.pd

Correction to: Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma: final update of the pivotal ERIVANCE BCC study

Following publication of the original article [1], it was reported that the legend for Fig. 1 was incomplete. The complete figure legend is:https://deepblue.lib.umich.edu/bitstream/2027.42/148648/1/12885_2019_Article_5568.pd

A multicomponent intervention for the management of chronic pain in older adults: study protocol for a randomized controlled trial

Background: Studies have shown that physical interventions and psychological methods based on the cognitive behavioral approach are efficacious in alleviating pain and that combining both tends to yield more benefits than either intervention alone. In view of the aging population with chronic pain and the lack of evidence-based pain management programs locally, we developed a multicomponent intervention incorporating physical exercise and cognitive behavioral techniques and examined its long-term effects against treatment as usual (i.e., pain education) in older adults with chronic musculoskeletal pain in Hong Kong. Methods/design: We are conducting a double-blind, cluster-randomized controlled trial. A sample of 160 participants aged ≥ 60 years will be recruited from social centers or outpatient clinics and will be randomized on the basis of center/clinic to either the multicomponent intervention or the pain education program. Both interventions consist of ten weekly sessions of 90 minutes each. The primary outcome is pain intensity, and the secondary outcomes include pain interference, pain persistence, pain self-efficacy, pain coping, pain catastrophizing cognitions, health-related quality of life, depressive symptoms, and hip and knee muscle strength. All outcome measures will be collected at baseline, postintervention, and at 3 and 6 months follow-up. Intention-to-treat analysis will be performed using mixed-effects regression to see whether the multicomponent intervention alleviates pain intensity and associated outcomes over and above the effects of pain education (i.e., a treatment × time intervention effect). Discussion: Because the activities included in the multicomponent intervention were carefully selected for ready implementation by allied health professionals in general, the results of this study, if positive, will make available an efficacious, nonpharmacological pain management program that can be widely adopted in clinical and social service settings and will hence improve older people’s access to pain management services

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease