Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus,Respiratory Syncytial Virus and Influenza A Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca²⁺ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.     

Improved Synthesis of Biotinol-5′-AMP: Implications for Antibacterial Discovery

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Perspectives of Dutch Physiotherapists on Self-Management Support: A Q-Methodology Study

Self-management support programs are reported to have positive effects on the health and care of people with physical disabilities. It is unclear how physiotherapists (PTs) view self-management support. A cross-sectional study with mixed-methods design using Q-methodology was conducted to determine the perspectives of Dutch PTs on self-management support. PTs (n = 39) rank-ordered 37 validated statements about self-management support from “most disagree (?3)” to “most agree (+3).” Differences in perspectives on self-management support were explored in a by-person centroid factor analysis on the basis of the explained variance (R²). After having sorted the statements, PTs explained their ranking of ?3 and +3 statements in semi-structured interviews. All PTs recognized self-management support as intrinsic part of physiotherapy practice. Nevertheless, four particular perspectives could be identified: (1) the “externally driven educator” (R² = 14%), (2) “internally driven educator” (R² = 9%), (3) “client-centered coach” (R² = 13%), and (4) “client-initiated coach” perspective (R² = 15%). Each perspective reflects particular goals and perceptions of self-management support. Differences were identified with respect to the PTs’ role perception (educating or coaching), drive (external or internal), and collaboration with the patient (as partner or not). The identified perspectives can be used in the physiotherapy education curriculum to create awareness about the various ways of practicing self-management support and the skills needed to be able to tailor support to patient needs and to switch between perspectives.     

Complete cervical spinal cord injury above C6 predicts the need for tracheostomy

Background

Failed extubation and delayed tracheostomy contribute to poor outcomes in patients with a traumatic spinal cord injury (SCI). We determined if the level and completeness of SCI predict the need for tracheostomy.

Methods

Data from 256 patients with SCI between C1 and T3 with or without tracheostomy were retrospectively analyzed. Logistic regression identified predictors for tracheostomy. Data are presented as raw percentage or odds ratio (OR) with 95% confidence interval. P < .05 indicates significance.

Results

Complete spinal cord injuries were common in patients requiring tracheostomy (55% vs 18%, P < .05), and predicted the need for tracheostomy (OR: 6.4 (3.1 to 13.5), P < .05). An injury above C6 predicted the need for tracheostomy in patients with complete injury (OR: 3.7 (1 to 11.9), P < .05), but not incomplete injury (OR: .7 (.3 to 1.9); P = .53).

Conclusion

Tracheostomy is unlikely in patients with incomplete SCI, regardless of the level of injury. Patients with complete SCI above C6 are likely to require tracheostomy.     

The Bolognese surgeon Giuseppe Ruggi: how and why the aseptic surgery was introduced in Bologna in the middle half of the XIX century

Background

The first reliable statistic data about perioperatory mortality were published in 1841 by the French Joseph-Francois Malgaigne (1806–1863): he referred to a mean mortality of 60% for amputations and this bad result was to be attributed mainly to hospital acquired diseases. The idea of “hospital acquired disease” although vague, included five infective nosologic entities, which at that time were diagnosed more frequently: erysipelas, tetan, pyemia, septicemia, and gangrene. Nonetheless, the suppuration with pus production was considered from most of the surgeons and doctors of that time as a necessary and unavoidable step in the process of wound healing. During the end of the eighteenth century, hospitals of the main European cities were transforming into aggregations of several wards, where the high concentration of patients created poor sanitary conditions and a consistent increase of perioperatory mortality. In 1865, Lister applied his first antiseptic dressing on the surface of an exposed fracture. These experimental attempts lead to an effective reduction of wound infections respect to the dressing with strings used previously.

Discussion

Lister's innovations in the field of wound treatment were based on two brand new concepts: germs causing rot were ubiquitarious and the wound infection was not a normal step in the process of wound healing. The concept of antisepsis was hardly accepted in the European surgical world: “Of all countries, Italy is the most indifferent and uninterested in experimenting this method, which has been so favorably judged from the greatest surgical societies in Germany”. This quotation from the young surgeon Giuseppe Ruggi (1844–1925) from Bologna comes from his article where he presented his first experiences on aseptic medications started the previous year in the Surgical Department of Maggiore Hospital in Bologna. In his report, Ruggi described the adopted technique and suggested that the medication should be extended to all the surgical patients of the hospital:“… this is needed to totally remove from the hospital all those elements of infection which grow in the wounds dressed with the old method”. The experimentation of this new dressing for the few treated cases was rigorous and concerned both the sterilization of surgical tools with the fenic acid (5%) and the shaving of the skin. Ruggi also observed that there was no correlation between the seriousness of the wound and its extension or way of healing: when “simple” cases that “should heal without complication” showed fever he often realized that “it was often due to a medication performed without following the rules for an accurate disinfection and dressing”. Ruggi thought that the fever was connected to “reabsorption of pyrogenic substances, which can be removed cleaning and disinfecting the wound” in cases of wounds not accurately dressed and rarely medicated. Frequent postoperative medications of the wound were able to eliminate the fever within 2 h. Ruggi's attitude toward the fine reasoning lead him to introduce the concept of immunodeficiency related to physical deterioration: “… patients treated for surgical disease may sometimes suffer from complications of medical conditions, which initially escape the most accurate investigations… The surgical operation could, in some cases, hold the balance of power”.

Conclusions

The obtained results, published in 1879, appear extremely interesting. As he wrote in 1898, for the presentation of his case record of more than 1000 laparotomies, he had started “… operating as a young surgeon without any tutor, helped only by his mind and what he could deduce from publications existing at the moment …”.     

Infección de sitio quirúrgico tras apendicectomía urgente: tasa global y tipo según la vía de abordaje (abierta/laparoscópica)

Objective

To compare the incidence and profile of surgical site infection (SSI) after laparoscopic (LA) or open (OA) appendicectomy.

Material and method

Observational and analytical study was conducted on patients older than 14 years-old with suspected acute appendicitis operated on within a 4-year period (2007-2010) at a third level hospital (n = 868). They were divided in two groups according to the type of appendicectomy (LA, study group, 135; OA, control group, 733). The primary endpoint was a surgical site infection (SSI), and to determine the overall rate and types (incisional/organ-space). The risk of SSI was stratified by: i) National Nosocomial Infection Surveillance (NNIS) index (low risk: 0E, 0 and 1; high risk: 2 and 3); ii) status on presentation (low risk: normal or phlegmonous; high risk: gangrenous or perforated). The statistical analysis was performed using the software SPSS. The main result and stratified analysis was determined with χ², and the risk parameters using OR and Mantel-Haenszel OR with 95%CI, accepting statistical significance with P < .05.

Results

Age, gender, ASA index and incidence of advanced cases were similar in both groups. The overall SSI rate was 13.4% (more than a half of them detected during follow-up after discharge). Type of SSI: OA, 13% (superficial 9%, deep 2%, organ-space 2%); AL, 14% (superficial 5%, deep 1%, organ-space 8%) (overall: not significant; distribution: P < .000). Stratified analysis showed that there is an association between incisional SSI/OA and organ-space SSI/LA, and is particularly stronger in those patients with high risk of postoperative SSI (high risk NNIS or gangrenous-perforated presentation).

Conclusion

OA and LA are associated with a higher rate of incisional and organ-space SSI respectively. This is particularly evident in patients with high risk of SSI.     

Subpicomolar diphenyleneiodonium inhibits microglial NADPH oxidase with high specificity and shows great potential as a therapeutic agent for neurodegenerative diseases

Activation of microglial NADPH oxidase (NOX2) plays a critical role in mediating neuroinflammation, which is closely linked with the pathogenesis of a variety of neurodegenerative diseases, including Parkinson's disease (PD). The inhibition of NOX2‐generated superoxide has become an effective strategy for developing disease‐modifying therapies for PD. However, the lack of specific and potent NOX2 inhibitors has hampered the progress of this approach. Diphenyleneiodonium (DPI) is a widely used, long‐acting NOX2 inhibitor. However, due to its non‐specificity for NOX2 and high cytotoxicity at standard doses (µM), DPI has been precluded from human studies. In this study, using ultra‐low doses of DPI, we aimed to: (1) investigate whether these problems could be circumvented and (2) determine whether ultra‐low doses of DPI were able to preserve its utility as a potent NOX2 inhibitor. We found that DPI at subpicomolar concentrations (10^?14 and 10^?13 M) displays no toxicity in primary midbrain neuron‐glia cultures. More importantly, we observed that subpicomolar DPI inhibited phorbol myristate acetate (PMA)‐induced activation of NOX2. The same concentrations of DPI did not inhibit the activities of a series of flavoprotein‐containing enzymes. Furthermore, potent neuroprotective efficacy was demonstrated in a post‐treatment study. When subpicomolar DPI was added to neuron‐glia cultures pretreated with lipopolysaccharide, 1‐methyl‐4‐phenylpyridinium or rotenone, it potently protected the dopaminergic neurons. In summary, DPI's unique combination of high specificity toward NOX2, low cytotoxicity and potent neuroprotective efficacy in post‐treatment regimens suggests that subpicomolar DPI may be an ideal candidate for further animal studies and potential clinical trials. GLIA 2014;62:2034–2043