Perisynaptic Schwann cells phagocytose nerve terminal debris in a mouse model of Guillain‐Barré syndrome

In mouse models of acute motor axonal neuropathy, anti‐ganglioside antibodies (AGAbs) bind to motor axons, notably the distal nerve, and activate the complement cascade. While complement activation is well studied in this model, the role of inflammatory cells is unknown. Herein we aimed to investigate the contribution of phagocytic cells including macrophages, neutrophils and perisynaptic Schwann cells (pSCs) to distal nerve pathology. To observe this, we first created a subacute injury model of sufficient duration to allow inflammatory cell recruitment. Mice were injected intraperitoneally with an anti‐GD1b monoclonal antibody that binds strongly to mouse motor nerve axons. Subsequently, mice received normal human serum as a source of complement. Dosing was titrated to allow humane survival of mice over a period of 3 days, yet still induce the characteristic neurological impairment. Behaviour and pathology were assessed in vivo using whole‐body plethysmography and post‐sacrifice by immunofluorescence and flow cytometry. ex vivo nerve‐muscle preparations were used to investigate the acute phagocytic role of pSCs following distal nerve injury. Following complement activation at distal intramuscular nerve sites in the diaphragm macrophage localisation or numbers are not altered, nor do they shift to a pro‐ or anti‐inflammatory phenotype. Similarly, neutrophils are not significantly recruited. Instead, ex vivo nerve‐muscle preparations exposed to AGAb plus complement reveal that pSCs rapidly become phagocytic and engulf axonal debris. These data suggest that pSCs, rather than inflammatory cells, are the major cellular vehicle for axonal debris clearance following distal nerve injury, in contrast to larger nerve bundles where macrophage‐mediated clearance predominates.     

The HIV-1 proviral landscape reveals that Nef contributes to HIV-1 persistence in effector memory CD4+ T cells

Despite long-term antiretroviral therapy (ART), HIV-1 persists within a reservoir of CD4⁺ T cells that contribute to viral rebound if treatment is interrupted. Identifying the cellular populations that contribute to the HIV-1 reservoir and understanding the mechanisms of viral persistence are necessary to achieve an effective cure. In this regard, through Full-Length Individual Proviral Sequencing, we observed that the HIV-1 proviral landscape was different and changed with time on ART across naive and memory CD4⁺ T cell subsets isolated from 24 participants. We found that the proportion of genetically intact HIV-1 proviruses was higher and persisted over time in effector memory CD4⁺ T cells when compared with naive, central, and transitional memory CD4⁺ T cells. Interestingly, we found that escape mutations remained stable over time within effector memory T cells during therapy. Finally, we provided evidence that Nef plays a role in the persistence of genetically intact HIV-1. These findings posit effector memory T cells as a key component of the HIV-1 reservoir and suggest Nef as an attractive therapeutic target.     

Coronary arteriography in the intact rabbit: demonstration of coronary vasomotor and electrocardiographic effects of ergonovine and indomethacin in rabbits after abrupt cessation of prolonged nitroglycerin treatment

Abrupt withdrawal of chronic nitroglycerin treatment may predispose the coronary circulation to spasm. To test this hypothesis directly, we developed a technique for performing selective coronary arteriography in the intact rabbit with images obtained by video-based methods or cineangiographic film. Experiments were then conducted in rabbits treated three times daily with topical nitroglycerin ointment for 6 weeks and in age- and sex-matched control animals. Forty hours after cessation of treatment, animals were anesthetized, and ECG and coronary vasoactive effects (determined by coronary arteriography) of ergonovine, 0.2 mg/kg (intravenous) and indomethacin, 25 mg/kg (intravenous) were assessed. Of six nitroglycerin-treated rabbits, one died of ventricular fibrillation prior to arteriographic study. The remaining five developed ECG abnormalities (single ventricular premature beats, nonsustained ventricular tachycardia, and ST segment deviation) upon challenge with ergonovine or indomethacin. Neither agent evoked ECG changes in control rabbits. In contrast, the degree of luminal diameter reduction in epicardial coronary arteries provoked by ergonovine or indomethacin did not differ between control and nitroglycerin-treated animals. Focal coronary artery spasm was not observed in any rabbit. Our results demonstrate that selective coronary arteriography in rabbits is feasible and that changes in vessel caliber may be assessed from images thus obtained. Data from this study indicate that ergonovine- and indomethacin-induced ECG abnormalities observed in nitroglycerin-treated rabbits cannot be ascribed to epicardial coronary artery spasm.     

Vascular graft infection: the role of indium scanning

Infection of a prosthetic graft is one of the most feared complications of vascular surgery. The difficulties of accurate, objective diagnosis are well recognised. We have used III Indium labelled white blood cell scans (InWBC) in two groups: 9 control patients who underwent uncomplicated aortic aneurysm surgery, and 23 patients with suspected graft sepsis. In the control group there was one positive scan in a patient with an inflammatory aneurysm. In the suspected sepsis group, 11 patients subsequently has proven graft sepsis. Nine were correctly predicted by Indium scanning. Ten of 12 patients who did not have proven graft sepsis had negative scans. There was a total of 5 inflammatory aneurysms in the control and suspected sepsis groups, of whom two had positive scans. False positive scans were not present in the early postoperative period i patients without inflammatory aneurysms. In our experience Indium labelled WBC scanning for suspected graft sepsis has a accuracy of 83% a negative predictive value of 83% and a positive predictive value of 82%. These results suggest that Indium white cell labelling techniques which do not involve substantial cross-labelling of platelets are the best objective methods of establishing the presence or absence of graft sepsis.     

A laboratory model for studying blast overpressure injury

Blast injury remains an important source of trauma in both civilian and military settings. We have studied a recently developed blast wave generator to evaluate its effectiveness for laboratory study of blast injury. In order to determine the reliability of the device and the pathology of the lesions caused by the short duration (0.5-1.0 msec), and high intensity (60-375 psi) pressure wave, laboratory rats were exposed to the pressure waves generated by the machine. The animals were divided into three groups: the first exposed to midthoracic blasts, the second to abdominal blasts, and a group of controls exposed to a gentle stream of gas. Group I showed gross and microscopic evidence of lung blast injury of "rib imprint" hemorrhages, intra-alveolar hemorrhage, marked increase in lung weight, prolonged apnea, and bradycardia. Group II showed typical blunt abdominal trauma at the closest ranges, but characteristic submucosal hemorrhages up to 4.0 cm from the blast nozzle. In both groups, a protective effect was seen in heavier animals. The blast wave generator permits reproducible blast injury in the laboratory that is safer and faster than current methods. The lung and bowel lesions induced are grossly and microscopically similar to injuries of blast exposure seen in clinical patients.     

Emergency department protocol for the diagnosis and evaluation of geriatric abuse

As the number of elderly persons in the United States continues to increase, geriatric abuse has become the most recent manifestation of domestic violence seen in the emergency department. Recent data suggest that 1 million elderly persons are battered, neglected, or exploited each year by family members or caretakers. This maltreatment may be more difficult to identify than child or spouse abuse because of the relative isolation of the victims and their reluctance to report abuse. Many of these cases involve only subtle signs and have a great potential to pass undetected. We summarize the current literature on geriatric abuse and describe an ED protocol for identifying and reporting suspected victims. We retrospectively reviewed the medical records of 36 elderly patients hospitalized with documented abuse or neglect. Physical maltreatment was evident in 29 patients (80%), and 16 of the cases (44%) involved psychological abuse. Key points in the history, physical examination, and psychosocial evaluation were analyzed to identify specific criteria used in the development of the protocol. This framework will aid the emergency physician in the crucial first steps of identifying abuse, obtaining evidence, and providing immediate treatment and crisis intervention. Awareness that the problem exists and improved detection and intervention procedures are needed to prevent abuse of elderly persons from becoming more widespread.     

Perspective on Cancer Control: Whither the Tobacco Endgame for Canada?

Aims: In 2014, in response to evidence that Canada’s tobacco use would lead, inexorably, to substantial morbidity and mortality for the foreseeable future, a group of experts convened to consider the development of a “Tobacco Endgame” for Canada. The “Tobacco Endgame” defines a time frame in which to eliminate structural, political, and social dynamics that sustain tobacco use, leading to improved population health. Strategies: A series of Background Papers describing possible measures that could contribute to the creation of a comprehensive endgame strategy for Canada was prepared in advance of the National Tobacco Endgame Summit hosted at Queen’s University in 2016. At the summit, agreement was reached to work together to achieve <5% tobacco use by 2035 (<5 by ’35). A report of the proceedings was shared widely. Achievements: Progress since 2016 has been mixed. The Summit report was followed by a national forum convened by Health Canada in March 2017, and in 2018, the Canadian Government adopted “<5 × ’35” tobacco use target in a renewed Canadian tobacco reduction strategy. Tobacco use has declined in the last 5 years, but at a rate slower than that which will be needed to achieve the <5 by ’35 goal. There remain > 5 million smokers in Canada, signaling that smoking-related diseases will continue to be an enormous health burden. Furthermore, the landscape of new products (e-cigarettes and cannabis) has created additional risks and opportunities. Future directions: A bold, reinvigorated tobacco control strategy is needed that significantly advances ongoing policy developments, including full implementation of the key demand-reduction policies of the WHO Framework Convention on Tobacco Control. Formidable, new disruptive policies and regulations will be needed to achieve Canada’s Endgame goal.