SMAD inhibition attenuates epithelial to mesenchymal transition by primary keratinocytes in vitro.

Epithelial to mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype and contribute directly to fibrotic disease. Recent studies support a role for EMT in cutaneous fibrotic diseases including scleroderma and hypertrophic scarring, although there is limited data on the cytokines and signalling mechanisms regulating cutaneous EMT. We investigated the ability of TGF-ß and TNF-α, both overexpressed in cutaneous scleroderma and central mediators of EMT in other epithelial cell types, to induce EMT in primary keratinocytes and studied the signalling mechanisms regulating this process. TGF-ß induced EMT in normal human epidermal keratinocytes (NHEK cells), and this process was enhanced by TNF-α. EMT was characterised by changes in morphology, proteome (down-regulation of E-cadherin and Zo-1 and up-regulation of vimentin and fibronectin), MMP secretion and COL1α1 mRNA expression. TGF-ß and TNF-α in combination activated SMAD and p38 signalling in NHEK cells. P38 inhibition with SB203580 partially attenuated EMT, whereas SMAD inhibition using SB431542 significantly inhibited EMT and also reversed established EMT. These data highlight the retained plasticity of adult keratinocytes and support further studies of EMT in clinically relevant in vivo models of cutaneous fibrosis and investigation of SMAD inhibition as a potential therapeutic intervention.

Evaluation of the Safety and Tolerability of Sodium-Glucose Co-transporter 2 Inhibitors in the Older Population: A Systematic Review.

Objective The objective of this systematic review was to evaluate adverse effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older people. Data Sources Articles in PubMed and EBSCOhost-Medline databases between January 2011 and 2021 were analyzed. Search terms were SGLT2 inhibitor, SGLT2 inhibitors, geriatric/elderly/older people, and safety/ adverse drug reaction/tolerability. Meta-analyses, systematic reviews, review articles, journal clubs, articles that did not address the research question, excluded patients 65 years of age and older, had an updated article available, did not stratify by age group, or were a commentary on a cohort study were excluded. Data Synthesis The search resulted in 113 articles. There were 62 duplicates removed, and 30 excluded based on the abstract. Of the 32 articles remaining, 19 were removed for not meeting the research question or meeting exclusion criteria. A total of 13 studies, including randomized controlled trials, cohort studies, and case reports, were assessed. Conclusion Current evidence demonstrates that patients taking SGLT2 inhibitors and diuretics were more likely to experience volume depletion. Findings suggest that risk of UTI was highest when the patient's age is 75 years or older. Some studies indicated that risk of genital mycotic infection is prevalent in older people. Use of SGLT2 inhibitors in the older population was not associated with a higher risk of developing diabetic ketoacidosis. Use of SGLT2 inhibitors appears to be relatively safe in older people. The risk of side effects may be decreased by considering concomitant medications. Randomized controlled trials assessing safety of SGLT2 inhibitors in the older population is still warranted.

Use of a Synthetic Dermal Matrix for Reconstruction of 55 Patients with Nongraftable Wounds and Management of Complications.

The aim of this study was to investigate the role of a completely synthetic dermal matrix (Biodegradable Temporizing Matrix [BTM]) for staged reconstruction of complex wounds. The authors defined complex wounds as wounds not amenable to reconstruction with skin grafting alone due to an inherent avascularity such as the presence of bare bone, tendinous, or neural structures. A retrospective review of a prospectively maintained database of complex wounds as defined above was carried out. Fifty-five patients were identified who underwent staged BTM and autologous skin graft reconstruction for complex wounds affecting a wide variety of patient demographics, treatment indications, and body sites. Wound etiology included burn injury and nonburn-related trauma such as degloving injury or infective complications. Caveats relating to the successful application of staged dermal matrix reconstruction, techniques, tips, prevention, and management of complications are outlined. This large consecutive case series demonstrates the integral role dermal substitutes play in providing biological wound cover for avascular wound beds which may otherwise require complex distant flap or free tissue transfer for reconstruction. Staged synthetic dermal matrix reconstruction has proven robustness in the face of unfavorable wounds compared with nonsynthetic dermal matrices, physiologically covering avascular structures, allowing for early graft take, expediting rehabilitation, and mobilization with good scar cosmesis and limited contracture formation.

Outpatient Opioid and Naloxone Prescribing Practices at an Academic Medical Center during the COVID-19 Pandemic.

While improving opioid safety has been a national priority, the coronavirus disease 2019 (COVID-19) pandemic has been associated with increased rates of opioid overdose. The present study characterized outpatient opioid and naloxone prescribing patterns during the COVID-19 pandemic. A retrospective chart review was conducted of adult patients receiving opioid therapy between August 2020 through October 2020 from outpatient clinics within a Texas health system. The primary outcome was naloxone co-prescription during the study period or within the year prior. During the study period, 1,368 patients received an opioid prescription, most of which were prescribed for chronic pain treatment (63.0%). Most opioid prescriptions (91.5%) were written for < 50 MME/day. For prescriptions written for acute pain, 78% were written for ≤ 10 days supply. While 31.1% of patients received gabapentinoid prescriptions, few (7.9%) received benzodiazepine or Z-hypnotic prescriptions. Twenty-two (1.6%) patients were co-prescribed naloxone. In this study, naloxone was rarely prescribed for outpatients receiving opioid prescriptions during the COVID-19 pandemic. Health systems should continue to prioritize adherence to evidence-based clinical guidelines and increase access to naloxone.

Posterior Antiglide Plating vs Lateral Neutralization Plating for Weber B Distal Fibular Fractures: A Systematic Review and Meta-analysis of Clinical and Biomechanical Studies.

BACKGROUND: Distal fibular fractures are extremely common, yet there remains controversy about which type of plating technique is the most appropriate. We aimed to compare clinical and biomechanical outcomes following posterior antiglide plating and lateral neutralization plating for Weber B distal fibular fractures. METHODS: A systematic review and meta-analysis of the literature was conducted by two independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We included all comparative studies of distal fibular fracture fixation with either a posterior antiglide plate or a lateral neutralization plate. Our primary outcome of interest was reoperation for hardware removal. Secondary outcomes included hardware discomfort, peroneal tendon irritation, infection, wound complications, and mechanical torque to failure. RESULTS: A total of 1122 patients with Weber B ankle fractures were included across nine eligible clinical studies, and 76 cadaveric ankles were subject to testing across three eligible biomechanical studies. Meta-analyses revealed a two-fold greater odds of requiring removal of hardware in the lateral plating group compared to the posterior plating group (odds ratio [OR] 2.48, 95% CI 1.58 to 3.91, P < .0001), and a three-fold greater odds of experiencing hardware discomfort in the lateral plating group compared to the posterior plating group (OR 2.96, 95% CI 1.83 to 4.80, P < .0001). There were no significant differences in rates of peroneal tendon irritation, infection, wound complications, operative time, and torque to failure when comparing the two plating methods. CONCLUSION: The results of this review indicate that using posterior antiglide plating for distal fibular Weber B-type fractures is associated with significantly fewer reoperations due to hardware complications and less hardware discomfort compared to lateral neutralization plating. This technique does not appear to increase the risk of peroneal tendon irritation or increase operative time.

Biodegradable Temporizing Matrix Reconstruction of Complex Perineal Burn Wound: A Case Report.

This case report details our experience using a two-stage Biodegradable Temporizing Matrix (NovoSorb® PolyNovo Ltd) and autograft for acute reconstruction of a complex perineal burn wound in an elderly comorbid patient. A 77-year-old man sustained 42% full-thickness burns extending circumferentially from bilateral thighs and buttocks, across the entire perineal and genital regions up to his mid-trunk, following self-immolation using an accelerant. Early total burn wound excision was carried out with acute application of Biodegradable Temporizing Matrix to all affected sites. Excellent integration and vascularization of Biodegradable Temporizing Matrix took place despite the challenge of intermittent fecal contamination affecting the perineal and buttock burn sites and matrix colonization with multidrug-resistant organisms. Delamination and serial split-thickness skin autografting were carried out 42 days after the first matrix application with complete and robust graft take. Perineal burns present a reconstructive challenge due to the proximity of specialized structures such as the genitalia, urethral, and anal orifices. Restoration of complex anatomy and function may be required after debridement with increased risks of infection, contracture formation, and mortality compared with burns affecting other anatomical sites. Two-stage Biodegradable Temporizing Matrix represents a reliable reconstruction option for complex extensive perineal wounds in frail elderly patients, despite an unfavorable local microbial environment.

A pilot study assessing the addition of a Quit and Win program to pharmacist-led intensive smoking cessation therapy in a predominantly underserved, minority population.

INTRODUCTION: Quit and Win programs (Q&W) have been shown to improve smoking cessation rates by offering potential rewards to encourage smoking cessation. However, few studies have combined Q&W with intensive smoking cessation programs including behavioral counseling and pharmacotherapy, or studied Q&W in underserved, minority populations. This study was conducted to assess the impact on smoking cessation rates of adding a Q&W to intensive smoking cessation therapy in a largely underserved, minority population. METHODS: This was a single-center, prospective, open-label controlled study. Current smokers received pharmacist-led behavioral counseling and smoking cessation pharmacotherapy. Intervention group patients who successfully quit (verified by self-report and exhaled carbon monoxide) at 1 month and 3 months post-quit date were entered into a draw for $1000. The control group received the same smoking cessation services, but without a monetary incentive. RESULTS: Enrollment was 111 patients (N=85 in the intervention group), made up of predominantly underserved (82% had annual household income <$25000), minority (69.1%), and female (58%) patients. Groups were similar except the intervention group had lower educational and income levels, while the control group was more likely to smoke more than 1 pack per day. Quit rates at 3 months were 27% and 19% in the intervention and control groups, respectively (p=0.22). Female gender (OR=2.84; p=0.04) and Fagerström score (OR=0.71; p<0.01) were significant predictors of quitting. CONCLUSIONS: The addition of Q&W to intensive smoking cessation services increased clinic referrals and numerically improved cessation rates, although this difference was not statistically significant, possibly due to high attrition of the study.

A Synthetic Biodegradable Temporising Matrix in Degloving Lower Extremity Trauma Reconstruction: A Case Report.

Presented is the case of an obese, 72 year-old diabetic man with a dorsal foot de-gloving injury. Whilst the tendons of extensor hallucis longus, extensor digitorum longus to all digits, and extensor digitorum brevis to hallux and second toe were intact after surgical debridement, none had any covering paratenon. The joint between the medial cuneiform and first metatarsal was open. Reconstructive options were limited by his age and co-morbidities. A novel, completely synthetic dermal matrix (NovoSorb BTM) was applied, after which the patient was discharged home to attend for dressings and review of integration progress as an outpatient. He was allowed to mobilise without limitation. Because of the poor quality of the wound bed (and patient), the material integrated slowly over 9 weeks. Delamination of the matrix, and definitive closure by application of sheet split skin autograft, produced a robust, soft, mobile and excellent aesthetic result, over which he could wear footwear immediately. Clinically, the paratenon-denuded tendons glided under the neo-dermis without tethering to the overlying integrated matrix, allowing a full range of digital movement. This was confirmed on ultrasound examination, which also demonstrated no inflammation or oedema. Already proven in extensive burns, necrotising fasciitis and complex surgical wounds, BTM represents a useful addition to the reconstructive surgeon's toolbox.

Detection of Hepatozoon felis in Ticks Collected from Free-Ranging Amur Tigers ( Panthera tigris altaica), Russian Far East, 2002-12.

We collected 69 ticks from nine, free-ranging Amur tigers ( Panthera tigris altaica) between 2002 and 2011 and investigated them for tick-borne pathogens. DNA was extracted using alkaline digestion and PCR was performed to detect apicomplexan organisms. Partial 18S rDNA amplification products were obtained from 14 ticks from four tigers, of which 13 yielded unambiguous nucleotide sequence data. Comparative sequence analysis revealed all 13 partial 18S rDNA sequences were most similar to those belonging to strains of Hepatozoon felis (>564/572 base-pair identity, >99% sequence similarity). Although this tick-borne protozoon pathogen has been detected in wild felids from many parts of the world, this is the first record from the Russian Far East.

Laparoscopy complicating abdominal wall plastic surgery.

Abdominoplasty is often requested by patients following massive weight loss or multi-gravida. We report the cases of three patients who had incidental asymptomatic hernias diagnosed intra-operatively during abdominoplasty. All patients had previously undergone laparoscopic procedures and two had subsequent massive weight loss. Routine pre-operative clinical examination may not identify a small trocar related hernia. Prior knowledge of such hernias would aid in operative planning and reduce the risk of potential complications.

The impact of emergency nurse practitioners on referrals to a tertiary hand trauma service: a pilot of referral quality scoring system.

Hand injuries account for 2000 referrals to the Northern Ireland plastic surgery trauma service each year. Emergency nurse practitioners are increasingly utilised to assess and manage minor injuries and independently refer patients to the hand trauma service. This paper uses a newly developed scoring system to assess the impact of varying grades of referring practitioner on the quality and appropriateness of referral.

D1 priming enhances both D1- and D2-mediated rotational behavior and striatal Fos expression in 6-hydroxydopamine lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions exhibit behavioral sensitization upon repeated treatment with dopamine agonists, a phenomenon called 'priming'. We examined the effectiveness of priming with D1 or D2 agonists on rotational behavior and striatal Fos expression following challenge with D1 or D2 agonists. Twenty-one days post-lesion, rats received three priming injections, spaced 3-6days apart, with water, D1 agonist SKF38393 (10mg/kg) or D2 agonist quinpirole (1mg/kg). One week later, 6-OHDA rats were challenged with water, SKF38393 (1 or 10mg/kg) or quinpirole (0.25mg/kg). 6-OHDA rats challenged with SKF38393 (1mg/kg) showed no contralateral rotational behavior, but robust striatal Fos expression in D1-primed animals. Challenge with SKF38393 (10mg/kg) led to pronounced contralateral rotational behavior and striatal Fos expression in all priming groups - with the largest behavioral response in D1- and D2-primed rats. Quinpirole challenge (0.25mg/kg) led to robust contralateral rotational behavior and striatal Fos expression in D1-primed animals, but only mild rotational behavior and baseline levels of striatal Fos expression in D2-primed animals. These data suggest that D1- or D2-priming enhances rotational behavior following challenge with D1 or D2 agonist, but only D1-priming enhances D1- and D2-mediated striatal Fos expression in 6-OHDA rats.

Assessing the effects of diurnal variation on the composition of human parotid saliva: quantitative analysis of native peptides using iTRAQ reagents.

Changes in salivary composition correlate with disease susceptibility, disease state, or both. However, use of saliva for diagnostic purposes is complicated by the gland-specific effects of circadian rhythm or diurnal variation. We recently characterized a suite of peptides in the < or =10-kDa fraction of human parotid saliva that included many novel species. In this study, we used novel iTRAQ labeling chemistry to investigate possible diurnal effects on peptide generation. We collected samples produced by gustatory stimulation as the ductal secretions at four time points under conditions that minimized proteolysis, pooled them according to collection time, and isolated the LMW fractions. Samples collected at each collection time were derivatized with a different isobaric iTRAQ reagent. The labeled samples were combined, separated by reversed-phase HPLC, co-spotted with matrix on MALDI targets, and analyzed by MALDI TOF/TOF mass spectrometry. With this approach, we achieved relative quantification of the parotid peptides at four time points. In several cases, abundance during the day changed dramatically. iTRAQ tagging improved the efficiency of MS/MS fragmentation, which in turn allowed the identification of several novel peptides. Our results demonstrated both the utility of this method and the importance of diurnal effects on the composition of the human parotid saliva peptidome.

Toward defining the human parotid gland salivary proteome and peptidome: identification and characterization using 2D SDS-PAGE, ultrafiltration, HPLC, and mass spectrometry.

Saliva plays many biological roles, from lubrication and digestion to regulating bacterial and leukocyte adhesion. To understand the functions of individual components and families of molecules, it is important to identify as many salivary proteins as possible. Toward this goal, we used a proteomic approach as the first step in a global analysis of this important body fluid. We collected parotid saliva as the ductal secretion from three human donors and separated the protein components by two-dimensional SDS-polyacrylamide gel electrophoresis (2D SDS-PAGE). Proteins in gel spots were identified by peptide mass fingerprinting, and the results were confirmed by tandem mass spectrometry of selected peptides. Complementing this approach we used ultrafiltration to prepare a low-molecular-weight fraction of parotid saliva, which was analyzed directly or after reversed phase high-performance liquid chromatography separation by using mass spectrometric approaches. MS analyses of 2D SDS-PAGE spots revealed known components of saliva, including cystatins, histatins, lysozyme, and isoforms and/or fragments of alpha-amylase, albumin, and proline-rich proteins. We also discovered novel proteins, such as several isoforms of Zn-alpha-2-glycoprotein and secretory actin-binding protein. MS analyses of the ultrafiltrate showed that the low-molecular-weight fraction of parotid saliva was peptide-rich, with novel fragments of proline-rich proteins and histatins in abundance. Experiments using Candida albicans as the test organism showed that at least one of the novel peptides had antifungal activity. Our results show that saliva is a rich source of proteins and peptides that are potential diagnostic and therapeutic targets.