Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease

Copper influences the pathogenesis of prion disease, but whether it is beneficial or detrimental remains controversial. Copper homeostasis is also essential for normal physiology, as highlighted by the spectrum of diseases caused by disruption of the copper transporting enzymes ATP7A and ATP7B. Here, by using a forward genetics approach in mice, we describe the isolation of three alleles of Atp7a, each with different phenotypic consequences. The mildest of the three, Atp7a(brown), was insufficient to cause lethality in hemizygotes or mottling of the coat in heterozygotes, but did lead to coat hypopigmentation and reduced copper content in the brains of hemizygous males. When challenged with Rocky Mountain Laboratory scrapie, the onset of prion disease was delayed in Atp7a(brown) mice, and significantly less proteinase-resistant prion protein was found in the brains of moribund Atp7a(brown) mice compared with WT littermates. Our results establish that ATP7A-mediated copper homeostasis is important for the formation of pathogenic proteinase-resistant prion protein.     

Immunopathology of exercise-induced bronchoconstriction in athletes — A new modified inflammatory hypothesis

Elite athletes have a higher prevalence of exercise-induced bronchoconstriction than the general population. The pathogenesis of exercise-induced bronchoconstriction is not fully elucidated. Increasing evidence suggests that airway inflammation plays a major role in the immunopathogenesis of exercise-induced bronchoconstriction. The aim of our review is to discuss existing evidence and to present a new, modified inflammatory hypothesis of exercise-induced bronchoconstriction. Exercise alters the number and function of circulating immune cells. Episodes of upper respiratory symptoms in elite athletes do not follow the usual seasonal patterns. Moreover, they have an unusual short-term duration, which suggests a non-infectious etiology. If the pro-inflammatory response to exercise has the potential to induce symptoms that mimic respiratory tract infection, it definitely up-regulates pro-inflammatory cytokine expression in the airways. We can conclude that exercise up-regulates airway cytokine expression in a way that favors inflammation and allergic reactions in bronchi and lowers the threshold for bronchoconstriction to different stimuli like cool, dry air, allergens, and pollutants.     

Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia

Purpose

Intractable neuropathic dynamic allodynia remains one of the major symptoms of human trigeminal neuropathy and is commonly accepted to be the most excruciatingly painful condition known to humankind. At present, a validated animal model of this disorder is necessary for efficient and effective development of novel drug treatments. Intracisternal strychnine in rats has been shown to result in localized trigeminal dynamic allodynia, thus representing a possible model of trigeminal neuralgia. The purpose of this study was to validate a mouse model of trigeminal glycinergic inhibitory dysfunction using established positive (carbamazepine epoxide) and negative (morphine) controls.

Methods

The actions of conventional first-line treatment (carbamazepine epoxide [CBZe]) and clinically ineffective morphine were tested for trigeminal dynamic mechanical allodynia produced by intracisternal strychnine. In mice under halothane anesthesia, we injected either strychnine (0.3 μg), strychnine with CBZe (4 ng), or artificial cerebrospinal fluid (aCSF) intracisternally (i.c.). In a separate set of experiments, subcutaneous morphine (3 mg·kg^?1 sc) was injected with intracisternal strychnine. Dynamic mechanical allodynia was induced by stroking the fur with polyethylene (PE-10) tubing. The response of each mouse was rated to determine its allodynia score, and scores of each group were compared. In addition, in a separate dichotomous disequilibrium study, pairs of mice were injected with strychnine/saline, strychnine/strychnine-CBZe, or strychnine/strychnine-morphine. A blinded observer recorded which mouse of each pair had the greater global pain behaviour.

Results

Strychnine (i.c.) produced higher quantitative allodynia scores in the trigeminal distribution (mean 81.5%; 95% confidence interval [CI] 76.4 to 86.6) vs the aCSF group (mean 11.3%; 95% CI 8.1 to 14.4) (P < 0.0001). Carbamazepine epoxide (i.c.) completely abolished allodynia when co-injected with strychnine (mean 83.2%; 95% CI 78.1 to 88.4) vs strychnine alone (mean 3.2%; 95% CI ?0.9 to 7.2) (P < 0.0001). Morphine co-injected with strychnine did not result in reduced allodynia (mean 65.7%; 95% CI 42.0 to 89.4) compared with strychnine alone (mean 87.6%; 95% CI 77.6 to 97.6) (P = 0.16). In a further global allodynia assessment, strychnine (i.c.) produced greater allodynia than both aCSF and strychnine administered with CBZe (P = 0.03). Morphine (ip) administered with strychnine did not result in reduced global allodynia compared with strychnine administered alone (P = 1.0).

Conclusion

In this study, we have developed and validated a novel murine model of trigeminal dynamic allodynia induced by intracisternal strychnine. The use of mice to study trigeminal allodynia has many benefits, including access to a vast repository of transgenic mouse variants, ease of handling, low cost, and minimal variance of results. The present model may have utility in screening drug treatments for dynamic mechanical allodynia resulting from trigeminal neuropathies.     

Major Perioperative Morbidity Does Not Affect Long-Term Survival in Patients Undergoing Esophagectomy for Cancer of the Esophagus or Gastroesophageal Junction

Introduction

The incidence of cancer of the esophagus/GE junction is dramatically increasing but continues to have a dismal prognosis. Esophagectomy provides the best opportunity for long-term cure but is hampered by increased rates of perioperative morbidity. We reviewed our large institutional experience to evaluate the impact of postoperative complications on the long-term survival of patients undergoing resection for curative intent.

Methods

We identified 237 patients who underwent esophagogastrectomy, with curative intent, for cancer between 1994 and 2008. Complications were graded using the previously published Clavien scale. Survival was calculated using Kaplan–Meier methodology and survival curves were compared using log-rank tests. Multivariate analysis was performed with continuous and categorical variables as predictors of survival, and examined with logistic regression and odds ratio confidence intervals.

Results

There were 12 (5 %) perioperative deaths. The average age of all patients was 62 years, and the majority (82 %) was male. Complication grade did not significantly affect long-term survival, although patients with grade IV (serious) complications did have a decreased survival (p = 0.15). Predictors of survival showed that the minimally invasive type esophagectomy (p = 0.0004) and pathologic stage (p = 0.0007) were determining factors. There was a significant difference in overall survival among patients who experienced pneumonia (p = 0.00016) and respiratory complications (p = 0.0004), but this was not significant on multivariate analysis.

Conclusions

In this single-institution series, we found that major perioperative morbidity did not have a negative impact on long-term survival which is different than previous series. The impact of tumor characteristics at time of resection on long-term survival is of most importance.     

Characteristics of Asthma Patients Admitted to an Intermediate Respiratory Care Unit

IntroductionIntermediate respiratory care units (IRCU) provide continuous monitoring and non-invasive mechanical ventilation (NIMV) in patients with severe respiratory failure who are usually admitted to intensive care units (ICUs). The usefulness of IRCU in managing severe asthma exacerbations has never been evaluated.MethodsClinical data were prospectively and systematically compiled from patients admitted to the IRCU with a principal diagnosis of bronchial asthma exacerbation. We assessed therapeutic failure (intubation or exitus) and patient evolution up until 6 months after discharge compared with a group of patients admitted to a conventional hospital ward, paired for age and sex, and with the same principal diagnosis.ResultsA total of 74 asthma patients were included (37 admitted to IRCU and 37 to the hospital ward) with a mean age (±SD) of 58 ± 20, who were predominantly women (67%), with previous diagnosis of asthma and persistent asthma treatment. The main cause of admittance to the IRCU was severe respiratory failure. The patients who were admitted to the IRCU presented more radiological affectation (alveolar infiltrates) and had significantly higher pCO₂. Ten patients admitted to the IRCU required non-invasive mechanical ventilation (NIMV). There were no differences between the two groups regarding either therapeutic failure or the 6-month follow-up after discharge.ConclusionsPatients with severe asthma exacerbations can be managed in an IRCU while avoiding hospitalization in an ICU and demonstrating a prognosis similar to milder exacerbations treated in conventional hospital wards.     

Shoulder Muscular Demand During Lever-Activated Vs Pushrim Wheelchair Propulsion In Persons With Spinal Cord Injury

Background/Objective: The high demand on the upper limbs during manual wheelchair (WC) use contributes to a high prevalence of shoulder pathology in people with spinal cord injury (SCI). Leveractivated (LEVER) WCs have been presented as a less demanding alternative mode of manual WC propulsion. The objective of this study was to evaluate the shoulder muscle electromyographic activity and propulsion characteristics in manual WC users with SCI propelling a standard pushrim (ST) and LEVER WC design.

Methods: Twenty men with complete injuries (ASIA A or B) and tetraplegia (C6, n = 5; C7, n = 7) or paraplegia (n = 8) secondary to SCI propelled STand LEVER WCs at 3 propulsion conditions on a stationary ergometer: self-selected free, self-selected fast, and simulated graded resistance. Average velocity, cycle distance, and cadence; median and peak electromyographic intensity; and duration of electromyography of anterior deltoid, pectoralis major, supraspinatus, and infraspinatus muscles were compared between LEVER and ST WC propulsion .

Results: Sign ificant decreases in pectoralis major and supraspinatus activity were recorded during LEVER compared with ST WC propulsion. However, anterior deltoid and infraspinatus intensities tended to increase during LEVER WC propulsion. Participants with tetraplegia had similar or greater anterior deltoid, pectoralis major, and infraspinatus activity for both ST and LEVER WC propulsion compared with the men with paraplegia.

Conclusions: Use of the LEVER WC reduced and shifted the shoulder muscular demands in individuals with paraplegia and tetraplegia. Further studies are needed to determine the impact of LEVER WC propulsion on long-term shoulder function.     

Preoperative Imaging for Resectable Periampullary Cancer: Clinicopathologic Implications of Reported Radiographic Findings

Background

High-resolution, multiphase, computed tomography (CT) is a standard preoperative test prior to pancreatectomy, yet the clinical significance of routinely reported findings remains unknown.

Methods

We identified patients who underwent a pancreaticoduodenectomy for a periampullary adenocarcinoma (PA) over the previous 5 years and had a pancreas protocol CT at our institution. Clinicopathologic implications of reported CT findings were evaluated.

Results

There were 155 pancreatic ductal adenocarcinomas (PDA) and 47 non-pancreatic PAs. No mass was visualized on CT in 6 % of PDAs and 23 % of non-pancreatic PA. A size discrepancy of ≥1 cm between radiographic and pathologic tumor diameters was observed in 40 % of PAs, with CT underestimating the size in most instances (75 %). Radiographically enlarged lymph nodes were not associated with true lymph node metastases in PDAs (70 % lymph node positive cases were enlarged on CT vs 74 % lymph node negative, p = 0.5), but were associated with a preoperatively placed biliary endoprosthesis (63 % with endoprosthesis were enlarged vs 37 % no endoprosthesis, p = 0.013). Major visceral vessel involvement on CT was not associated with a vascular resection (3 % with CT vessel involvement vs 2 % without, p = 0.8) or a positive uncinate resection margin (24 vs 20 %, respectively, p = 0.6).

Discussion

While dedicated pancreas protocol CT provides unprecedented detail, the test may lead to overinterpretation of the extent of disease in some instances. A radiographic suggestion of enlarged lymph nodes and vascular involvement does not necessarily preclude exploration with curative intent. CTs with local disease should be reported in an objective template and carefully reviewed by a multidisciplinary group of surgeons, radiologists, and oncologists to avoid missing an opportunity for neoadjuvant therapy or cure by resection.