Fundamental Neurochemistry Review: At the intersection between the brain and the immune system: Non-coding RNAs spanning learning, memory and adaptive immunity.

Non-coding RNAs (ncRNAs) are highly plastic RNA molecules that can sequester cellular proteins and other RNAs, serve as transporters of cellular cargo and provide spatiotemporal feedback to the genome. Mounting evidence indicates that ncRNAs are central to biology, and are critical for neuronal development, metabolism and intra- and intercellular communication in the brain. Their plasticity arises from state-dependent dynamic structure states that can be influenced by cell type and subcellular environment, which can subsequently enable the same ncRNA with discrete functions in different contexts. Here, we highlight different classes of brain-enriched ncRNAs, including microRNA, long non-coding RNA and other enigmatic ncRNAs, that are functionally important for both learning and memory and adaptive immunity, and describe how they may promote cross-talk between these two evolutionarily ancient biological systems.

Synapse-Enriched m6A-Modified Malat1 Interacts with the Novel m6A Reader, DPYSL2, and Is Required for Fear-Extinction Memory.

The RNA modification N6-methyladenosine (m6A) regulates the interaction between RNA and various RNA binding proteins within the nucleus and other subcellular compartments and has recently been shown to be involved in experience-dependent plasticity, learning, and memory. Using m6A RNA-sequencing, we have discovered a distinct population of learning-related m6A- modified RNAs at the synapse, which includes the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (Malat1). RNA immunoprecipitation and mass spectrometry revealed 12 new synapse-specific learning-induced m6A readers in the mPFC of male C57/BL6 mice, with m6A-modified Malat1 binding to a subset of these, including CYFIP2 and DPYSL2. In addition, a cell type- and synapse-specific, and state-dependent, reduction of m6A on Malat1 impairs fear-extinction memory; an effect that likely occurs through a disruption in the interaction between Malat1 and DPYSL2 and an associated decrease in dendritic spine formation. These findings highlight the critical role of m6A in regulating the functional state of RNA during the consolidation of fear-extinction memory, and expand the repertoire of experience-dependent m6A readers in the synaptic compartment.SIGNIFICANCE STATEMENT We have discovered that learning-induced m6A-modified RNA (including the long noncoding RNA, Malat1) accumulates in the synaptic compartment. We have identified several new m6A readers that are associated with fear extinction learning and demonstrate a causal relationship between m6A-modified Malat1 and the formation of fear-extinction memory. These findings highlight the role of m6A in regulating the functional state of an RNA during memory formation and expand the repertoire of experience-dependent m6A readers in the synaptic compartment.

Production of reactive oxygen species after reperfusion in vitro and in vivo: protective effect of nitric oxide.

OBJECT: Thrombolytic treatments for ischemic stroke can restore circulation, but reperfusion injury, mediated by oxygen free radicals, can limit their utility. The authors hypothesized that, during reperfusion, nitric oxide (NO) provides cytoprotection against oxygen free radical species. METHODS: Levels of NO and oxygen free radicals were determined in both reoxygenation in vitro and reperfusion in vivo models using an NO electrochemical probe and high-performance liquid chromatography with the 2,3- and 2,5-dihydroxybenzoic acid trapping method, before and after addition of the NO donor diethanolamine nitric oxide (DEA/NO). Reoxygenation after anoxia produced a twofold increase in NO release by human fetal astrocytes and cerebral endothelial cells (p < 0.005). In both cell lines, there was also a two- to threefold increase in oxygen free radical production (p < 0.005). In human fetal astrocytes and cerebral endothelial cells given a single dose of DEA/NO, free radical production dropped fivefold compared with peak ischemic levels (p < 0.001). In a study in which a rat global cerebral ischemia model was used, NO production in a vehicle-treated group increased 48 +/- 16% above baseline levels after reperfusion. After intravenous DEA/NO infusion, NO reached 1.6 times the concentration of the postischemic peak in vehicle-treated animals. In vehicle-treated animals during reperfusion, free radical production increased 4.5-fold over basal levels (p < 0.01). After intravenous DEA/NO infusion, free radical production dropped nearly 10-fold compared with peak levels in vehicle-treated animals (p < 0.006). The infarct volume in the vehicle-treated animals was 111 +/- 16.9 mm3; after DEA/NO infusion it was 64.8 +/- 23.4 mm3 (p < 0.01). CONCLUSIONS: The beneficial effect of early restoration of cerebral circulation after cerebral ischemia is limited by reperfusion injury. These results indicate that NO release and oxygen free radical production increase during reperfusion, and suggest a possible early treatment of reperfusion injury using NO donors.

Taking health care to factory floor proves smart move for growing Ontario company.

A fully equipped, state-of-the-art wellness centre that employs physicians and other health care providers to meet the health needs of more than 1200 employees is being credited with giving a Canadian company a leg up on the competition.

Selective excision of adenomas originating in or extending into the pituitary stalk with preservation of pituitary function.

When the surgeon identifies an adenoma within the gland and selectively excises it, endocrine-active pituitary tumors are usually cured and pituitary function is preserved. Occasionally ectopic adenomas arise primarily in the pituitary stalk or arise superiorly in the midportion of the anterior lobe and extend upward within the stalk. To determine if these tumors can be selectively excised with preservation of pituitary function, the authors examined the outcome of selective adenomectomy in 10 patients with Cushing's disease with an ectopic adenoma originating in, and confined to, the stalk (four microadenomas) or an adenoma extending superiorly through the diaphragma sella and into the stalk (five microadenomas and one macroadenoma) from an operative series of 516 patients with Cushing's disease. To reach the adenoma transsphenoidally in these patients, the diaphragma sella was incised anteroposteriorly in the midline to the anterior edge of the stalk, the suprasellar cistern was entered, and the adenoma was selectively excised using care to limit injury to the infundibulum. After selective adenomectomy, Cushing's disease remitted in all patients. All patients were hypocortisolemic immediately after surgery and required hydrocortisone for up to 21 months. Apart from the adrenal axis, pituitary function was normal in five patients in the immediate postoperative period, including two patients with tumors confined to the stalk and three patients with preoperative hypothyroidism (one patient) and/or hypogonadism (three patients). Three others with transient postoperative hypothyroidism (one patient) or diabetes insipidus (two patients) had normal pituitary function within 7 months of surgery. One patient with hypothyroidism and one with hypogonadism before surgery had panhypopituitarism postoperatively. A patient with a microadenoma located high in the stalk next to the optic chiasm had bitemporal hemianopsia postoperatively. These results demonstrate the feasibility of achieving curative transsphenoidal resection and preservation of pituitary function in cases of pituitary adenomas that are confined to the pituitary stalk or tumors that extend superiorly within the stalk from an intrasellar origin.

Dr. James MacCallum: patron and friend of Canada's Group of Seven.

In the early part of this century, Toronto eye specialist Dr. James M. MacCallum's keen delight in painting and in helping artists expanded the borders of Canadian art. As friend, patron and confidant to the members of the Group of Seven, he encouraged some of the most recognizable and evocative art ever painted in this country.

Traumatic peroneal tendon instability.

To investigate the causes of, pathologic changes associated with, and treatment results after traumatic peroneal tendon subluxation or dislocation, we reviewed 11 cases in 10 patients at a mean followup of 29 months. We also describe a technique of superior peroneal retinacular repair combined with fibular rotational osteotomy. Excellent clinical and functional results were achieved in 9 of the 11 cases, enabling the patients to return to previous competitive sports by 3 months. There was one persisting subluxation that required further surgery. Another ankle, with chronic sepsis from previous surgery and documented degeneration of the ankle joint, had a recurrence of the infection and sequestration of the osteotomized fragment. The personal tendons, however, remained stabilized by the resultant scar tissue. We conclude that superior peroneal retinacular repair, with or without fibular rotational osteotomy, is a successful technique in treating both acute and recurrent instability of the peroneal tendons. It can be combined with a Bröstrom repair when there is concurrent peroneal tendon and anterolateral ankle instability. Peroneal tenosynovitis and tendon splitting were commonly found at operation, especially in cases of recurrent instability. The degree of pathologic change in the tendon did not affect the clinical result.

Seeing medicine through opera glasses.

Few opera buffs stop to consider how the illnesses suffered by opera's great heroes and heroines mirrored the medical treatments and public attitudes of their time. A Toronto physician and his wife, an English professor and literary critic, have written a book exploring how opera presents illnesses such as tuberculosis and syphilis.

Delayed diagnosis of large cerebello-pontine angle tumors, despite hearing conservation training.

Recently, at the National Naval Medical Center in Bethesda, Maryland, we have encountered several patients with large cerebello-pontine angle tumors. All were active duty and had evaded the military's stringent hearing screening program until the tumors were of life-threatening size. Early detection of these tumors can reduce overall morbidity and improve the patient's chances of returning to a normal lifestyle. We have analyzed each of these cases and discovered weaknesses in the program. The primary difficulty was in accurately following the algorithms set forth by military regulations. To that end we recommend: (1) establishing a cutoff for identification of those who should be evaluated after they obtain their enlistment/annual physical examinations; (2) specific training for hearing conservation program managers in the algorithms for hearing screening; (3) establishment of specific guidelines for primary care physicians for further evaluation of abnormal audiograms; and (4) reevaluation of form DD 2216.

The posteroanterior 45 degrees flexion weight-bearing radiograph of the knee.

Biomechanical studies suggest that radiographs of the osteoarthritic knee taken in 30 degrees to 60 degrees of flexion more accurately demonstrate the true degree of articular cartilage loss than radiographs taken with the knee in full extension. Conventional anteroposterior weight-bearing full-extension radiographs were compared with posteroanterior 45 degrees flexion weight-bearing radiographs of 35 patients with 45 symptomatic knees (90 compartments) presenting with suspected osteoarthritis. In 35 compartments, there was a 2-mm or greater loss of joint space in the 45 degrees flexion views compared with those taken in full extension. Also, in 11 compartments (10 knees), there was a normal joint space on the full extension radiographs, but marked narrowing on the flexion view. Both results are statistically significant. It is concluded that the posteroanterior 45 degrees flexion weight-bearing radiograph is a useful additional tool in the assessment of knees with early degenerative change.

Dental management of anticoagulated patients.

Today's trend toward ambulatory medical care will bring more pharmacological problems into the dental office. While the dental management of patients taking oral anticoagulants is controversial, current research supports the contention that they can be safely treated on an outpatient basis. The use of the International Normalized Ratio (INR) has made better estimates of prothrombin time possible, and patients can be maintained in a narrow therapeutic range. Postoperative hemorrhage can be avoided or controlled with local hemostatic agents.

Cyclic oxygen analogues of alkyl-lysophospholipids. Synthesis and neoplastic cell growth inhibitory properties.

Ether phospholipids have demonstrated both in vitro and in vivo activity against a wide variety of tumor cell lines. The known cyclic ether phospholipid, SRI 62-834, was used as the model to prepare eight novel phospholipids containing a cyclic ether. All of the compounds were as effective as ET-18-OCH3 in their ability to activate macrophage-induced cytotoxicity against the Abelson-8.1 tumor cell line but varied in their direct cytotoxic effects. One of the new compounds, SDZ 62-406, was selected for in vivo studies and showed oral and i.v. activity in the mouse MethA fibrosarcoma model in the same range as ET-18-OCH3. No correlation was found between the direct or macrophage-activated cytotoxicity and the ability of the compounds to inhibit or promote platelet-activating factor (PAF)-induced aggregation of human platelets.

Synthesis and antiinflammatory activity of trisubstituted pyrimidines and triazines.

A series of mono-, bi-, and tricyclic pyrimidines and as-triazines was prepared and their antiinflammatory activity measured against carrageenan-induced edema in the rat. The more active analogues (ED50), including 4-pyri-dylpyrimidines 4a (38), 4b (47), and 4g (49) and 2-hydroxypyrimidine 8r (43), were then tested against adjuvant-induced edema in the rat. None was active in the adjuvant arthritis model.