Widespread latent hyperactivity of nociceptors outlasts enhanced avoidance behavior following incision injury.

Nociceptors with somata in dorsal root ganglia (DRGs) exhibit an unusual readiness to switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Ongoing activity (OA) during this state is present in vivo in rats months after spinal cord injury (SCI), and has been causally linked to SCI pain. OA induced by various neuropathic conditions in rats, mice, and humans is retained in nociceptor somata after dissociation and culturing, providing a powerful tool for investigating its mechanisms and functions. An important question is whether similar nociceptor OA is induced by painful conditions other than neuropathy. The present study shows that probable nociceptors dissociated from DRGs of rats subjected to postsurgical pain (induced by plantar incision) exhibit OA. The OA was most apparent when the soma was artificially depolarized to a level within the normal range of membrane potentials where large, transient depolarizing spontaneous fluctuations (DSFs) can approach AP threshold. This latent hyperactivity persisted for at least 3 weeks, whereas behavioral indicators of affective pain - hindpaw guarding and increased avoidance of a noxious substrate in an operant conflict test - persisted for 1 week or less. An unexpected discovery was latent OA in neurons from thoracic DRGs that innervate dermatomes distant from the injured tissue. The most consistent electrophysiological alteration associated with OA was enhancement of DSFs. Potential in vivo functions of widespread, low-frequency nociceptor OA consistent with these and other findings are to amplify hyperalgesic priming and to drive anxiety-related hypervigilance.

Snip conjunctivoplasty associated with methylene blue staining for treatment of postoperative conjunctival chemosis.

Conjunctival chemosis usually undergoes spontaneous resolution; sometimes, it requires treatment. We present the case of a 43 years-old female patient who developed bilateral conjunctival chemosis following upper and lower blepharoplasty. Two months after the operation, patient underwent bilateral snip conjunctivoplasty with methylene blue demarcation of the chemotic conjunctiva.

Assessment of CD200R Activation in Combination with Doxycycline in a Model of Melioidosis.

Antimicrobial resistance continues to be a global issue. Pathogens, such as Burkholderia pseudomallei, have evolved mechanisms to efflux certain antibiotics and manipulate the host response. New treatment strategies are therefore required, such as a layered defense approach. Here, we demonstrate, using biosafety level 2 (BSL-2) and BSL-3 in vivo murine models, that combining the antibiotic doxycycline with an immunomodulatory drug that targets the CD200 axis is superior to antibiotic treatment in combination with an isotype control. CD200-Fc treatment alone significantly reduces bacterial burden in lung tissue in both the BSL-2 and BSL-3 models. When CD200-Fc treatment is combined with doxycycline to treat the acute BSL-3 model of melioidosis, there is a 50% increase in survival compared with relevant controls. This benefit is not due to increasing the area under the concentration-time curve (AUC) of the antibiotic, suggesting the immunomodulatory nature of CD200-Fc treatment is playing an important role by potentially controlling the overactive immune response seen with many lethal bacterial infections. IMPORTANCE Traditional treatments for infectious disease have focused on the use of antimicrobial compounds (e.g. antibiotics) that target the infecting organism. However, timely diagnosis and administration of antibiotics remain crucial to ensure efficacy of these treatments especially for the highly virulent biothreat organisms. The need for early antibiotic treatment, combined with the increasing emergence of antibiotic resistant bacteria, means that new therapeutic strategies are required for organisms that cause rapid, acute infections. Here, we show that a layered defense approach, where an immunomodulatory compound is combined with an antibiotic, is better than an antibiotic combined with a relevant isotype control following infection with the biothreat agent Burkholderia pseudomallei. This approach has the potential to be truly broad spectrum and since the strategy includes manipulation of the host response it's application could be used in the treatment of a wide range of diseases.

Amyotrophic lateral sclerosis: translating genetic discoveries into therapies.

Recent advances in sequencing technologies and collaborative efforts have led to substantial progress in identifying the genetic causes of amyotrophic lateral sclerosis (ALS). This momentum has, in turn, fostered the development of putative molecular therapies. In this Review, we outline the current genetic knowledge, emphasizing recent discoveries and emerging concepts such as the implication of distinct types of mutation, variability in mutated genes in diverse genetic ancestries and gene-environment interactions. We also propose a high-level model to synthesize the interdependent effects of genetics, environmental and lifestyle factors, and ageing into a unified theory of ALS. Furthermore, we summarize the current status of therapies developed on the basis of genetic knowledge established for ALS over the past 30 years, and we discuss how developing treatments for ALS will advance our understanding of targeting other neurological diseases.

Thermomechanical performance of continuous carbon fibre composite materials produced by a modified 3D printer.

First of all, this article aimed to evidence the role of a modified printer developed for continuous carbon fibre reinforced PolyAmide (cCF/PA6-I) together with the use of a fully open slicing step on the printing quality and the longitudinal/transverse tensile and in-plane shear properties. A comprehensive assessment of the microstructure and properties with a similar material (cCF/PA6-I), but produced with a commercial printer (i.e., Markforged® MarkTwo) has been achieved. Our customised printer and the open slicer used have made possible to better control the print conditions (i.e., layer height and distance between filaments), to reduce the porosity from more than 10% to about 2% and improve the mechanical properties. Moreover, the understanding of the behaviour of these 3D printed composites with wide-ranging external temperatures is mandatory for future use in a severe environment and/or development of new thermally active 4D printed composites. The 3D printed cCF/PA6-I composites have been then thermomechanically characterised along different printing directions (0, 90 and ± 45°) from -55 to +100 °C. Unlike the longitudinal properties that hardly change with temperature, the transverse and in-plane shear stiffness and strength of these 3D printed composites were particularly sensitive to temperature variations, with decreases of 25-30% and 30-55%, respectively. This was due to the high sensitivity of the polymer matrix, the fibre/matrix and interfilament interfaces when the composites were loaded along those directions, because damages induced by internal thermal stresses. Fractography has also been carried out to reveal damage mechanisms.

The impact of COVID-19 pandemic on breast surgery in Italy: a multi-centric retrospective observational study.

COVID-19 pandemic had an impact on surgical activities. The aim of this multi-centric, retrospective study was to evaluate the impact of the COVID-19 pandemic on breast surgery. The patients who operated during the pre-pandemic year 2019 were compared to those operated in 2020. Fourteen Breast Care Units provided data on breast surgical procedures performed in 2020 and 2019: total number of breast-conserving surgery (BCS), number of 1st level oncoplastic breast surgery (OBS), number of 2nd level OBS; total number of mastectomies, mastectomies without reconstruction, mastectomies with a tissue expander, mastectomies with direct to implant (DTI) reconstruction, mastectomies with immediate flap reconstruction; total number of delayed reconstructions, number of expanders to implant reconstructions, number of delayed flap reconstructions. Overall 20.684 patients were included: 10.850 (52.5%) operated during 2019, and 9.834 (47.5%) during 2020. The overall number of breast oncologic surgical procedures in all centers in 2020 was 8.509, compared to 9.383 in 2019 (- 9%). BCS decreased by 744 cases (- 13%), the overall number of mastectomies decreased by 130 cases (- 3.5%); mastectomy-BCS ratio was 39-61% in 2019, and 42-58% in 2020. Regarding immediate reconstructive procedures mastectomies with DTI reconstruction increased by 166 cases (+ 15%) and mastectomies with immediate expander reconstruction decreased by 297 cases (- 20%). Breast-delayed reconstructive procedures in all centers in 2020 were 142 less than in 2019 (- 10%). The outburst of the COVID-19 pandemic in 2020 determined an implemented number of mastectomies compared to BCS, an implemented number of immediate breast reconstructions, mainly DTI, and a reduction of expander reconstruction.

Clinical and echocardiographic outcomes after percutaneous closure of patent foramen ovale: a single center experience.

BACKGROUND: Patent foramen ovale (PFO) has a high estimated prevalence (25% of the general population) and has been implicated in the pathogenesis of cryptogenic stroke and transient ischemic attack (TIA), as well as in the pathogenesis of migraine headache. This study evaluated the effectiveness of percutaneous transcatheter PFO closure with Amplatzer™ (Abbott Laboratories, Abbott Park, IL, USA) devices, from a large single-center experience. METHODS: From January 1998 to December 2014, 577 patients (243 males and 334 females, mean age 50 years, range 11-82 years) with documented PFO and history of at least one episode of cryptogenic stroke/TIA (N.=356) or occasional finding of previous ischemic lesions on MRI (N.=221) underwent percutaneous transcatheter closure of PFO using an Amplatzer™ Occluder (Abbott Laboratories). All the procedures were performed under general anesthesia or mild sedation and were assisted by transesophageal or intracardiac echocardiography. RESULTS: Procedural success was 100%. After a median follow-up period of 2.7 years with echocardiographic evaluations, the rate of recurrent adverse cerebral events was 0.4%. Two patients (0.4%) required a secondary procedure for significant residual shunt. Of 36 patients with minor residual shunt, 30 (83%) showed spontaneous shunt regression at follow-up. There was a consistent decrease after procedure in headache migraine, platypnea-orthodeoxia, fainting episodes, syncope, and coenesthesia phenomena. CONCLUSIONS: Transcatheter PFO closure is an effective and safe therapy for the prevention of thromboembolic events in the patients with cryptogenic stroke/TIA or an occasional finding of a positive cerebral MRI. Late follow-up shows device stability and clinical improvement in the majority of patients.

Gastroepiploic vascularized lymph node transfer for extremities' lymphedema: Is two better than one? A retrospective case-control study.

Single (SG-VLN) and double gastroepiploic vascularized lymph node transfer (DG-VLN) have shown promising results for the treatment of extremities' lymphedema. The literature search yields only few other cases describing outcomes following double VLN transfers, but no comparative studies have been produced so far. The aim of this study was to retrospectively examine and compare the effects of SG-VLN versus DG-VLN transfer. All patients diagnosed with extremities' stage II and III lymphedema who had undergone SG-VLN or DG-VLN between January 2012 and December 2018 were identified from two institutions' databases. Demographic and surgical data were collected. The primary endpoint was the comparison of the reduction in limb circumference (CRR) within 12 months post-surgery. Secondary endpoints included the reduction of cellulitis episodes and patients' quality of life improvement. Eighty-nine patients met the inclusion criteria. At 12 months of follow-up, higher CRR values were observed in the double inset group (p<0.05*) both at above elbow/above knee (AE/AK) level (SG-VLN: 70.6% ± 0.6%; DG-VLN: 72.2% ± 0.7%) and at below elbow/below knee level (SG-VLN: 59.1% ± 1.3%; DG-VLN: 61.6% ± 3.7%). Subgroup analyses of the involved limb (upper vs lower) were consistent with the primary treatment effects. The reduction of cellulitis episodes did not differ between the two groups, while the DG-VLN group showed better results in the overall satisfaction function, symptoms, and mood domains of the LYMQoL questionnaire (p=0.04). The study suggests that either single or double transfer can produce excellent results, but double inset of the gastroepiploic VLNT flap may produce greater volume reductions both at 12 and 24 months. Further studies with a larger sample size are warranted to corroborate our results.

Outer retinal transduction by AAV2-7m8 following intravitreal injection in a sheep model of CNGA3 achromatopsia.

Sheep carrying a mutated CNGA3 gene exhibit diminished cone function and provide a naturally occurring large animal model of achromatopsia. Subretinal injection of a vector carrying the CNGA3 transgene resulted in long-term recovery of cone function and photopic vision in these sheep. Research is underway to develop efficacious vectors that would enable safer transgene delivery, while avoiding potential drawbacks of subretinal injections. The current study evaluated two modified vectors, adeno-associated virus 2-7m8 (AAV2-7m8) and AAV9-7m8. Intravitreal injection of AAV2-7m8 carrying enhanced green fluorescent protein under a cone-specific promoter resulted in moderate photoreceptor transduction in wild-type sheep, whereas peripheral subretinal delivery of AAV9-7m8 resulted in the radial spread of the vector beyond the point of deposition. Intravitreal injection of AAV2-7m8 carrying human CNGA3 in mutant sheep resulted in mild photoreceptor transduction, but did not lead to the clinical rescue of photopic vision, while day-blind sheep treated with a subretinal injection exhibited functional recovery of photopic vision. Transgene messenger RNA levels in retinas of intravitreally treated eyes amounted to 4-23% of the endogenous CNGA3 levels, indicating that expression levels >23% are needed to achieve clinical rescue. Overall, our results indicate intravitreal injections of AAV2.7m8 transduce ovine photoreceptors, but not with sufficient efficacy to achieve clinical rescue in CNGA3 mutant sheep.

Educational Interventions for Promoting Food Literacy and Patient Engagement in Preventing Complications of Type 2 Diabetes: A Systematic Review.

The present review aims to map the current literature on educational interventions to promote food literacy in type 2 diabetes, with a particular focus on the concept of patient engagement. The systematic review was implemented on five databases with no restrictions on the publication year. The studies selected for the review were focused on patients with type 2 diabetes, ranging from 2003 to 2021 and published in 13 countries (44% USA). Thirty-three articles were analyzed. Twenty-seven articles targeted singular patients; fifteen articles conceptualized patient engagement as self-management. In seven articles, the provider is a multidisciplinary team. Twenty articles did not report a theoretical framework in the intervention development, and eleven did not use an intervention material. Twenty-six articles did not use a technology proxy. Outcome categories were narratively mapped into four areas: clinical, psychological, behavioral, and literacy. To date, most of the interventions are heterogeneous in the adopted methodology, measures, and outcomes considered. More attention should be given to the psychosocial characterization of patient engagement as well as the technological support. High-quality, randomized controlled trials and longitudinal studies are lacking and need to be conducted to verify the efficacy of these insights.

The Expander-Implant Breast Reconstruction in the COVID Era: Which is the "Unhappy" Tissue Expander Priority?

Breast surgeons seem to agree on the fact that a same-day surgery (mastectomy and breast reconstruction) protocol provides appropriate cancer treatment during times of unprecedented resource limitations, such as in the COVID era. In this scenario, pre-pectoral implant-based breast reconstruction can be definitively considered a sustainable technique. Nevertheless, the authors focus on the management of patients who had already undergone a same day procedure with two-stage breast reconstruction, implanting a breast tissue expander during the last two-year period and have been progressively delayed according to a surgical care based on priority. We coined the expression "unhappy tissue expander" to define all those symptomatic patients for which surgery should not be delayed even during an epidemic context.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Serotonin enhances depolarizing spontaneous fluctuations, excitability, and ongoing activity in isolated rat DRG neurons via 5-HT4 receptors and cAMP-dependent mechanisms.

Ongoing activity in nociceptors, a driver of spontaneous pain, can be generated in dorsal root ganglion neurons in the absence of sensory generator potentials if one or more of three neurophysiological alterations occur - prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Previous work showed that acute, sustained exposure to serotonin (5-HT) hyperpolarized AP threshold and potentiated DSFs, leading to ongoing activity if a separate source of maintained depolarization was present. Cellular signaling pathways that increase DSF amplitude and promote ongoing activity acutely in nociceptors are not known for any neuromodulator. Here, isolated DRG neurons from male rats were used to define the pathway by which low concentrations of 5-HT enhance DSFs, hyperpolarize AP threshold, and promote ongoing activity. A selective 5-HT4 receptor antagonist blocked these 5-HT-induced hyperexcitable effects, while a selective 5-HT4 agonist mimicked the effects of 5-HT. Inhibition of cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), attenuated 5-HT's hyperexcitable effects, but a blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels had no significant effect. 5-HT4-dependent PKA activation was specific to DRG neurons that bind isolectin B4 (a nonpeptidergic nociceptor marker). 5-HT's effects on AP threshold, DSFs, and ongoing activity were mimicked by a cAMP analog. Sustained exposure to 5-HT promotes ongoing activity in nonpeptidergic nociceptors through the Gs-coupled 5-HT4 receptor and downstream cAMP signaling involving both PKA and EPAC.

Lymphovenous anastomosis for the treatment of lymphedema: A systematic review of the literature and meta-analysis.

Lymphovenous anastomosis (LVA) has been described as an effective treatment for early stages of lymphedema (LE). The aim of this study was to deepen the evaluation of the effectiveness of LVA by performing a metaanalysis to provide information about its utility in specific anatomical sites, clinical stages, duration of lymphedema, and surgical technique. A systematic literature search using PubMed/Medline, Google Scholar, and Cochrane Database was performed in November 2019. Only original studies in which exclusively LVA was performed for primary and/or secondary lymphedema in humans were eligible for data extraction. A meta-analysis was performed on articles with a well-defined endpoint and a subgroup analysis was conducted in relation to surgical technique, duration of lymphedema, stage of pathology. Forty-eight studies, including 6 clinical trials and 42 lowrisk bias observational studies were included in our meta-analysis. 1,281 subjects were included and the majority of articles reported a pre-post analysis. Lymphaticovenular anastomosis appears to result effectively in treatment of lymphedema with an odds ratio of 0.07 (CI: 0.04, 0.13, p<0.001). All subgroup metaanalyses were statistically significant for LVAs specifically with regard to anatomical site, clinical stage, duration of LE, or type of microsurgical procedure (p<0.05). Our meta-analysis confirmed the efficacy of LVAs for the treatment of lymphedema, even when subgroup analysis was performed for clinical stage, duration of pathology, anatomical site of lymphedema, or type of microsurgical procedure. Further prospective trials with a common clearly defined outcome measure are warranted for an unbiased evaluation.

Surgical treatment of Milroy disease.

BACKGROUND AND OBJECTIVES: Milroy disease is a form of congenital primary lymphedema affecting the lower limbs. When conservative management is ineffective, surgical treatment becomes necessary. The purpose of this study was to investigate the efficacy of vascularized lymph node transfer (VLNT) associated with extensive therapeutic lipectomy in the treatment of these patients. METHODS: In China Medical University Hospital, four patients have been diagnosed with Milroy disease and treated over an 8 year-period time. All patients presented with hereditary bilateral legs swelling since birth. All patients were treated with VLNT from the gastroepiploic region bilaterally associated with extensive therapeutic lipectomy. RESULTS: All procedures have been executed bilaterally and have been successful, without complications. The average follow-up of the patients was 20.2 ± 2.8 months. The limbs treated presented an average circumference reduction of a 4.0 ± 2.1 cm and patients did not experience cellulitis during follow-up. Patients expressed satisfaction with the procedure. CONCLUSIONS: VLNT together with therapeutic lipectomy proved to be a reliable technique in moderate cases of Milroy disease, providing an alternative path for lymph drainage, and reducing the lymph load and the excess of subcutaneous adipose tissues, thus improving patients' quality of life.

Treatment of finger degloving injury with acellular dermal matrices: Functional and aesthetic results.

INTRODUCTION: Finger degloving injuries (FDIs) represent a challenge in hand surgery. When replantation is not possible, several techniques including loco-regional flaps, pocket abdominal flaps and free flaps have been described as methods to provide skin cover and avoid finger shortening. The aim of this study is to present our experience with acellular dermal matrices (ADMs) in the treatment of FDI. MATERIALS AND METHODS: We retrospectively reviewed the charts of 18 patients who presented with FDI and were treated with ADM between December 2015 and July 2017. Surgical outcomes including complications were analysed, and patient-centred assessments were performed at 12 months of follow-up. RESULTS: The follow-up period ranged from 10 to 20 months. All patients showed good integration and vascularisation of the ADM. All the fingers covered with ADM were firm and soft, with a slim and satisfactory appearance at a mean follow-up of 12 months. No limitations in tendon sliding were observed at dynamic sonography one year after surgery. CONCLUSION: ADMs could be regarded as a viable option when dealing with FDIs, if replantation is not possible and finger length is to be preserved. On the basis of these results, the surgical treatment of FDI with ADM is a viable option that produces good functional outcomes and cosmetic appearance.

CD200R deletion promotes a neutrophil niche for Francisella tularensis and increases infectious burden and mortality.

Pulmonary immune control is crucial for protection against pathogens. Here we identify a pathway that promotes host responses during pulmonary bacterial infection; the expression of CD200 receptor (CD200R), which is known to dampen pulmonary immune responses, promotes effective clearance of the lethal intracellular bacterium Francisella tularensis. We show that depletion of CD200R in mice increases in vitro and in vivo infectious burden. In vivo, CD200R deficiency leads to enhanced bacterial burden in neutrophils, suggesting CD200R normally limits the neutrophil niche for infection. Indeed, depletion of this neutrophil niche in CD200R-/- mice restores F. tularensis infection to levels seen in wild-type mice. Mechanistically, CD200R-deficient neutrophils display significantly reduced reactive oxygen species production (ROS), suggesting that CD200R-mediated ROS production in neutrophils is necessary for limiting F. tularensis colonisation and proliferation. Overall, our data show that CD200R promotes the antimicrobial properties of neutrophils and may represent a novel antibacterial therapeutic target.