Comparative analysis of arterial compliance in mice genetically null for cathepsins K, L, or S.

Cysteine cathepsins are potent proteases implicated in cardiovascular disease for degrading extracellular matrix (ECM) whose structure and integrity determine the mechanical behavior of arteries. Cathepsin knockout mouse models fed atherogenic diets have been used to study their roles in cardiovascular disease, but the impacts of cathepsin knockout on non-atherosclerotic arterial mechanics are scarce. We examine arterial mechanics in several cathepsin knockout mouse lines (CatK-/-, CatL-/-ApoE-/- and CatS-/-ApoE-/-) and controls (C57/Bl6, apolipoprotein E-/-). Common carotid arteries of three month-old mice were isolated and underwent biaxial mechanical testing and opening angle tests. Measured wall thicknesses and pressure-diameter curves were fed into a 4-fiber constitutive model to assess differences in material properties. Pressure-diameter data revealed CatL-/-ApoE-/- arteries were smaller in caliber compared to CatK-/-, CatS-/-ApoE-/- and ApoE-/- controls and were less compliant than ApoE-/- and CatS-/-ApoE-/- arteries at lower pressures, where elastin governs the mechanical response. CatK-/- arteries showed increased in vivo axial stretches compared to CatL-/-ApoE-/- and CatS-/-ApoE-/- arteries. CatL-/-ApoE-/- arteries were less compliant than ApoE-/- and CatS-/-ApoE-/- arteries pressurized to sub-diastolic pressures. 4-fiber and unified fiber distribution models were able to capture arteries' nonlinear mechanical responses; calculated material parameters suggested that ApoE-/- arteries had increased axial parameters compared to CatL-/-ApoE-/- and CatS-/-ApoE-/- arteries. Taken together, the data suggests that loss of the potent collagenase catK increases axial and circumferential arterial compliance, while knockout of the elastase catL decreased circumferential arterial compliance, and knockout of the elastase catS showed no impact on carotid arterial mechanics.

Effects of acute exposures to carbon dioxide on decision making and cognition in astronaut-like subjects.

Acute exposure to carbon dioxide (CO2) concentrations below those found on the International Space Station are reported to deteriorate complex decision-making. Effective decision-making is critical to human spaceflight, especially during an emergency response. Therefore, effects of acutely elevated CO2 on decision-making competency and various cognitive domains were assessed in astronaut-like subjects by the Strategic Management Simulation (SMS) and Cognition test batteries. The double-blind cross-over study included 22 participants at the Johnson Space Center randomly assigned to one of four groups. Each group was exposed to a different sequence of four concentrations of CO2 (600, 1200, 2500, 5000 ppm). Subjects performed Cognition before entering the chamber, 15 min and 2.5 h after entering the chamber, and 15 min after exiting the chamber. The SMS was administered 30 min after subjects entered the chamber. There were no clear dose-response patterns for performance on either SMS or Cognition. Performance on most SMS measures and aggregate speed, accuracy, and efficiency scores across Cognition tests were lower at 1200 ppm than at baseline (600 ppm); however, at higher CO2 concentrations performance was similar to or exceeded baseline for most measures. These outcomes, which conflict with those of other studies, likely indicate differing characteristics of the various subject populations and differences in the aggregation of unrecognized stressors, in addition to CO2, are responsible for disparate outcomes among studies. Studies with longer exposure durations are needed to verify that cognitive impairment does not develop over time in crew-like subjects.

Thermal Regulation of Emergency Oxygen Supplies in Commercial Space Vehicles.

INTRODUCTION: While NASA requires that commercial spaceflight vehicles provide onboard emergency oxygen supplies for crew, there are currently no requirements in place regarding thermal constraints of delivered gas. The question has been raised whether or not onboard emergency oxygen supplies must be warmed prior to administration to the crew, as inclusion of warming capabilities will increase the complexity and mass of life support systems in the vehicle. We sought to identify the risk of various inhaled oxygen temperatures and resultant pulmonary inflammatory response in potentially injured crewmembers. METHODS: A systematic review of published literature was conducted concerning thermal regulation of inhaled gases, reactive airway response, and inflammatory reactions. In particular, we sought literature that correlated inhaled gas temperature to airway response to identify a temperature threshold that would avoid deleterious sequelae. RESULTS: Cold air inhalation can induce acute bronchoconstriction, increased respiratory rate, and associated dyspnea and hypoxia. Physiological response to cold air varies between healthy lungs and injured tissues, and increased inflammation is associated with increasing airway reactivity. Most studies suggest that inhaled gas temperatures below 10°C may induce deleterious physiological sequelae. DISCUSSION: Best practices would include maintenance of inhaled gas temperatures to >10°C to avoid poor physiological response, preferably as close to physiological norms as possible. Given that inhaled gas temperature may be altered by transit through an oxygen delivery system, measurement of actual delivered gas temperature should occur at the point of crewmember inhalation.Pattarini JM, Blue RS, Alexander DJ. Thermal regulation of emergency oxygen supplies in commercial space vehicles. Aerosp Med Hum Perform. 2018; 89(10):918-922.

A Comparison of Rodent and Nonrodent Laryngeal and Tracheal Bifurcation Sensitivities in Inhalation Toxicity Studies and Their Relevance for Human Exposure.

In inhalation toxicity studies, drug-induced lesions are frequently reported in the larynx and sometimes at the tracheal bifurcation (carina) in the rat, but less so in the dog or monkey, bringing into question the relevance of these rodent findings for humans. The rat larynx is widely considered to be more sensitive than that of the dog and monkey in its response to inhaled xenobiotics, although we could find no published data to support this. In this review, data from 52 inhalation studies involving rodent and nonrodent species were collated and reviewed. These data showed that the rodent larynx, and to a lesser extent the carina, was far more commonly affected by treatment than those of the nonrodent. This review indicates the greater susceptibility of the rodent larynx and carina and emphasizes their lack of relevance for man. Observations and data suggest that the human larynx is much closer to the beagle dog and cynomolgus monkey in its response to inhaled xenobiotics and that greater clinical relevance should be placed on any specific findings in these animal models.

Pitfalls in the interpretation of standardised quality of life instruments for individual patients? A qualitative study in colorectal cancer.

PURPOSE: Despite being readily available and practical to administer, standardised instruments are not widely used in clinical practice. Concerns have been raised about the validity of applying such data to individuals. The aim of this qualitative study was to explore the practical difficulties of interpreting standardised HrQoL data for individual patients. METHODS: A purposive sample of 20 patients with colorectal cancer was chosen from 210 participants in a prospective HrQoL study. In an in-depth interview, individual participants were asked about their experiences and to review the accuracy of their own HrQoL data, collected over preceding months using four different instruments (FACT-C QLQ-C30/CR38 SF12 and EQ-5D). A framework qualitative analysis was used to develop emerging themes. RESULTS: A number of themes emerged from the analysis to explain why disparity arose between the patients' experiences and the questionnaire data in certain situations. These included weakly worded items that over emphasised health problems, incongruous items within scales causing unpredictable scores, insufficient levels of response causing insensitivity, and unrecognised reversal of item direction causing contradictory scores. Exogenous factors such as mood and co-morbidities also influenced HrQoL reporting. CONCLUSIONS: Data from standardised instruments can be used to measure the HrQoL of individuals in clinical practice, but the instruments used need careful selection and interpretation. Appropriate guidance linked to the themes of this study is provided.

Association of Inhalation Toxicologists (AIT) working party recommendation for standard delivered dose calculation and expression in non-clinical aerosol inhalation toxicology studies with pharmaceuticals.

There are many ways in which the dose can be expressed in inhalation toxicology studies. This can lead to confusion when comparing results from studies performed in different laboratories. A working party of the Association of Inhalation Toxicologists has reviewed this subject in detail and has collected data from 10 inhalation laboratories and used these data to determine a new algorithm for the calculation of Respiratory Minute Volume (RMV), one of the most important factors in the calculation of delivered dose. The recommendations of the working party for regulatory inhalation toxicology studies with pharmaceuticals are as follows: 1. The dose should be reported as the delivered dose calculated according to the formula: DD = C x RMV x D(xIF)/BW, where DD = delivered dose (mg/Kg); C = concentration of substance in air (mg/L); RMV =respiratory minute volume or the volume of air inhaled in one minute (L/min); D = duration of exposure (min); IF = proportion by weight of particles that are inhalable by the test species, the inhalable fraction (inclusion of this parameter is not essential provided that the aerosol has reasonable respirability for the intended species. If it is included, the way in which it is determined should be clearly stated); BW = bodyweight (Kg). 2. The RMV for mice, rats, dogs and cynomolgus monkeys should be calculated according to the formula:RMV(L/min) = 0.608 x BW(Kg)(0.852). 3. If deposited dose or the amount of material actually retained inthe respiratory tract is presented as supplementary information,the way in which it is calculated should be clearly stated.4. Dose should always be presented in mg/Kg but may also bepresented in other ways, such as mg/unit body surface area, as supplementary information.

Presentation and management of perirectal sepsis.

Perirectal sepsis is a potentially severe complication which may follow minor anorectal intervention and be slow to be diagnosed and treated. We report the presentation and outcome of three patients with perirectal sepsis of differing aetiologies. Awareness of the possible diagnosis, urgent investigation with cross-sectional imaging and immediate treatment with broad-spectrum antibiotics is vital. However, radical surgical intervention may be necessary. This report highlights the importance of investigating patients with persistent pelvic pain after minor anorectal procedures or trauma and maintaining a high index of suspicion for this important complication.

Short-term and long-term outcomes of the cleft lift procedure in the management of nonacute pilonidal disorders.

PURPOSE: We report the results of the cleft lift procedure in the management of nonacute pilonidal sinus disorders. METHODS: Seventy consecutive patients who underwent a cleft lift for nonacute pilonidal sinus were evaluated prospectively. Responses to a postal questionnaire were analyzed for long-term outcome. RESULTS: All patients who fulfilled the criteria for day-case were operated on as such. Sixty-six patients achieved complete wound healing within six weeks. Delayed wound healing occurred in three patients and nonhealing occurred in one. Fourteen patients had one or more complications: wound breakdown, superficial (n = 7) and deep (n = 1); wound infection (n = 5); wound seroma (n = 4); and early recurrence (n = 1). The median time off work and to return to normal activities was two and four weeks, respectively (range, 0.5-12). Forty-seven patients completed the questionnaire at a median follow-up of 24 months: five patients reported minimal tenderness in the sacral region; none reported recurrence of pilonidal symptoms; and all were satisfied. CONCLUSIONS: The cleft lift procedure is easy to perform as a day-case procedure. It is associated with high rates of primary healing, durable low recurrence rates, and early functional recovery. This technique may be the procedure of choice in the surgical management of nonacute pilonidal disorders.

Measurement of health-related quality of life in the early follow-up of colon and rectal cancer.

PURPOSE: Little is known about factors that affect health-related quality of life during the early follow-up of colorectal cancer. This study was designed to identify the factors that contribute to poor health-related quality of life after six weeks of follow-up and to compare the relative performance of instruments best suited to measure it. METHODS: A single-center, prospective study was designed to examine health-related quality of life after potentially curative surgery for colorectal cancer. Two condition-specific and two generic instruments (QLQ-C30, FACT-C, SF12 and EQ-5D) measured quality of life six weeks after discharge. Univariate and multivariate analyses were used to assess the impact of 16 treatment factors, demographic variables, and symptoms on seven global health-related quality of life scores. RESULTS: Questionnaires were obtained from 201 consecutive patients. Five factors were associated with poor health-related quality of life scores at six-week follow-up in the multivariate analysis: reduced preoperative performance status, stomas, diarrhea, constipation, and younger than aged 65 years. No instrument out performed the others. However, condition-specific instruments and those in which patients subjectively rated their overall health-related quality of life were better suited to detect health-related quality of life differences relating to the effects of colorectal cancer treatment. CONCLUSIONS: Younger patients, those with stomas, and those suffering from diarrhea or constipation are more likely to report poor health-related quality of life at six-week follow-up. The routine measurement of health-related quality of life using an instrument that includes a patient-rated scale together with condition-specific items could be used to detect patients at risk of poorer short-term health-related quality of life outcomes.

Radical subtotal pancreatic resection, including splenectomy, is an effective one-off treatment for infected pancreatic necrosis.

BACKGROUND: Pancreatic resection for severe acute necrotizing pancreatitis has been associated with prohibitive mortality rates and has been hence replaced by piecemeal debridement, either by the open or the laparoscopic technique. We report the results of deliberate subtotal pancreatectomy with splenectomy for infected pancreatic necrosis. MATERIALS AND METHODS: Six-year prospective audit of patients treated by a single surgeon, with an interest in pancreatic disease, within a Low Volume Hospital (LVH) setting. Results are presented as median (IQR). RESULTS: During the study period 18 patients (9 males) with complicated severe acute pancreatitis underwent radical pancreatic resection. The median age was 61 years (range 36-69). The median time to operation after presentation was 27 days (range 2-74). Microbiological culture confirmed infection in 14 (78%) patients. Three patients (17%) died within 30 days of operation. Twelve of the 15 survivors (80%) underwent a single operative procedure. Three patients required a further laparotomy, of whom 2 required colectomy for ischemia. Median hospital and ICU stays were 43 (range 30-57) and 5 (range 4-6) days respectively. Six patients (40% of survivors) developed an infection of the left half of the chevron incision; however, all wounds were fully healed within 3 months. Long-term follow-up of survivors (n=14) revealed 8 (57%) to need at least occasional pancreatic enzyme supplementation and 5 (36%) to have diabetes mellitus. Two patients (14%) developed an incisional hernia. CONCLUSIONS: Radical resection of pancreas and spleen, combined with postoperative irrigation, was associated with comparatively low rates of morbidity and mortality for patients with infected pancreatic necrosis in a LVH setting.

Maximising SHO training by inclusion of research fellows into a novel hybrid rota.

INTRODUCTION: As a result of current government legislation, junior surgical trainees are increasingly working in shift patterns. Night shifts provide few training opportunities and recent debate has focused on the most effective way of providing appropriate surgical training in the face of these working pattern restrictions. METHODS: At York Hospital, we have recently implemented a new hybrid rota in general surgery which uses research fellows to cover the majority of night-time shifts at SHO level. RESULTS & DISCUSSION: Surgical trainees have benefited by spending a much greater proportion of their time working with patients during the day where training is more continuous, better supervised and more uniform. Research fellows have benefited in being able to maintain their clinical skills whilst having sufficient free time to pursue research during the day. Extending the role of the research fellow at night to include registrar duties could also release higher surgical trainees from some night-time service commitments and allow them to benefit from more day-time training.

Heat shock protein 70 in the rat nasal cavity: localisation and response to hyperthermia.

Heat shock proteins (HSPs) are a group of proteins that are rapidly induced in response to physiological stress, including hyperthermia and exposure to toxicants. Thus they may provide a useful index of toxicity in in vitro systems for screening for toxicity. We have recently developed a rat nasal explant system for investigating upper respiratory tract toxicity, and the aims of this study were to localise HSP70 within the rat nasal cavity and to characterise its response to hyperthermia. Constitutively, HSP70 was found to be predominantly localised to the sustentacular cells, basal cells and Bowman's glands of the olfactory epithelium (OE), with the most intense immunohistochemical staining at levels 3 and 4 of the posterior of the rat nasal cavity. Ethmoturbinates (ETs) and liver slices were exposed to heat shock (37 degrees and 43 degrees C, respectively) for 45 min and then returned to normal culture temperatures (31 degrees and 37 degrees C, respectively) for 24 h. In ETs, HSP72 was maximally induced 4-fold at 4 h after heat shock, and levels then returned to those of control tissue. ATP concentrations were markedly decreased up to 4 h after heat shock and then returned to control levels. In contrast, HSP72 levels in liver slices increased and ATP levels decreased steadily throughout the 24 h culture period. ETs were also able to withstand a 45-min heat shock at 43 degrees C, that is 12 degrees C above normal culture temperature. Incubation of ETs with cycloheximide prior to heat shock reduced the ability of the OE to recover from heat shock at 37 degrees C. Thus the OE of the rat nasal cavity expresses HSP72, and this protein appears to play an important role in the ability of the tissue to withstand hyperthermia.