Development of donor specific antibodies after SARS-CoV-2 vaccination:What do we know so far?

Vaccination against Coronavirus disease-19(COVID-19)was pivotal to limit spread,morbidity and mortality.Our aim is to find out whether vaccines against COVID-19 lead to an immunological response stimulating the production of de novo donor specific antibodies(DSAs)or increase in mean fluorescence intensity(MFI)of pre-existing DSAs in kidney transplant recipients(KTRs).This study involved a detailed literature search through December 2nd,2023 using PubMed as the primary database.The search strategy incorporated a combination of relevant Medical Subject Headings terms and keywords:"COVID-19","SARS-CoV-2 Vaccination","Kidney,Renal Transplant",and"Donor specific antibodies".The results from related studies were collated and analyzed.A total of 6 studies were identified,encompassing 460 KTRs vaccinated against COVID-19.Immunological responses were detected in 8 KTRs of which 5 had increased MFIs,1 had de novo DSA,and 2 were categorized as either having de novo DSA or increased MFI.There were 48 KTRs with pre-existing DSAs prior to vaccination,but one study(Massa et al)did not report whether pre-existing DSAs were associated with post vaccination outcomes.Of the remaining 5 studies,35 KTRs with pre-existing DSAs were identified of which 7 KTRs(20%)developed de novo DSAs or increased MFIs.Overall,no immunological response was detected in 452(98.3%)KTRs.Our study affirms prior reports that COVID-19 vaccination is safe for KTRs,especially if there are no pre-existing DSAs.However,if KTRs have pre-existing DSAs,then an increased immunological risk may be present.These findings need to be taken cautiously as they are based on a limited number of patients so further studies are still needed for confirmation.

Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders

Deep brain stimulation(DBS) is emerging as a pow-erful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mecha-nisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative elec-troencephalography as well a intraoperative recordings have been utilized to attempt to understand the under-pinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomog-raphy and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activ-ity in a distributed neural network. These investigations are critical for advancing the field of invasive neuro-modulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroim-aging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed(Nucleus ac-cumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promis-ing area.

Neuroprotective effects of Alda-1 mitigate spinal cord injury in mice:involvement of Alda-1-induced ALDH2 activation-mediated suppression of reactive aldehyde mechanisms

Spinal cord injury(SCI)is associated with high production and excessive accumulation of pathological 4-hydroxy-trans-2-nonenal(4-HNE),a reactive aldehyde,formed by SCI-induced metabolic dysregulation of membrane lipids.Reactive aldehyde load causes redox alteration,neuroinflammation,neurodegeneration,pain-like behaviors,and locomotion deficits.Pharmacological scavenging of reactive aldehydes results in limited improved motor and sensory functions.In this study,we targeted the activity of mitochondrial enzyme aldehyde dehydrogenase 2(ALDH2)to detoxify 4-HNE for accelerated functional recovery and improved pain-like behavior in a male mouse model of contusion SCI.N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide(Alda-1),a selective activator of ALDH2,was used as a therapeutic tool to suppress the 4-HNE load.SCI was induced by an impactor at the T9–10 vertebral level.Injured animals were initially treated with Alda-1 at 2 hours after injury,followed by once-daily treatment with Alda-1 for 30 consecutive days.Locomotor function was evaluated by the Basso Mouse Scale,and pain-like behaviors were assessed by mechanical allodynia and thermal algesia.ALDH2 activity was measured by enzymatic assay.4-HNE protein adducts and enzyme/protein expression levels were determined by western blot analysis and histology/immunohistochemistry.SCI resulted in a sustained and prolonged overload of 4-HNE,which parallels with the decreased activity of ALDH2 and low functional recovery.Alda-1 treatment of SCI decreased 4-HNE load and enhanced the activity of ALDH2 in both the acute and the chronic phases of SCI.Furthermore,the treatment with Alda-1 reduced neuroinflammation,oxidative stress,and neuronal loss and increased adenosine 5′-triphosphate levels stimulated the neurorepair process and improved locomotor and sensory functions.Conclusively,the results provide evidence that enhancing the ALDH2 activity by Alda-1 treatment of SCI mice suppresses the 4-HNE load that attenuates neuroinflammation and neurodegeneration,promotes the neurorepair process,and improves functional outcomes.Consequently,we suggest that Alda-1 may have therapeutic potential for the treatment of human SCI.Animal procedures were approved by the Institutional Animal Care and Use Committee(IACUC)of MUSC(IACUC-2019-00864)on December 21,2019.

Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model

Bone wound healing is a highly dynamic and precisely controlled process through which damaged bone undergoes repair and complete regeneration. External factors can alter this process, leading to delayed or failed bone wound healing. The findings of recent studies suggest that the use of selective serotonin reuptake inhibitors(SSRIs) can reduce bone mass, precipitate osteoporotic fractures and increase the rate of dental implant failure. With 10% of Americans prescribed antidepressants, the potential of SSRIs to impair bone healing may adversely affect millions of patients’ ability to heal after sustaining trauma. Here, we investigate the effect of the SSRI sertraline on bone healing through pre-treatment with(10 mg·kg-1sertraline in drinking water, n = 26) or without(control, n = 30) SSRI followed by the creation of a 5-mm calvarial defect. Animals were randomized into three surgical groups:(a) empty/sham,(b) implanted with a DermaMatrix scaffold soak-loaded with sterile PBS or(c) DermaMatrix soak-loaded with542.5 ng BMP2. SSRI exposure continued until sacrifice in the exposed groups at 4 weeks after surgery. Sertraline exposure resulted in decreased bone healing with significant decreases in trabecular thickness, trabecular number and osteoclast dysfunction while significantly increasing mature collagen fiber formation. These findings indicate that sertraline exposure can impair bone wound healing through disruption of bone repair and regeneration while promoting or defaulting to scar formation within the defect site.

Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

Mild traumatic brain injury（TBI）, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide（NO）, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha（HIF-1α）, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione（GSNO） and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

Dual neuronal response to tumor necrosis factor-alpha following spinal cord injury

BACKGROUND： Numerous studies have shown that tumor necrosis factor α （TNF-α） is closely correlated with spinal cord injury （SCI）, but the mechanisms of TNF-α and therapeutic treatments for SCI are still poorly understood. OBJECTIVE： To determine the role of TNF-α in the pathogenesis of SCI. DESIGN, TIME AND SETTING： An in vivo experiment based on genetically engineered animals was performed at the Medical University of South Carolina, Charleston, South Carolina, USA, between June 2007 and October 2008. MATERIALS： TNF-α transgenic rats （Xenogen Biosciences in Cranbury, New Jersey, USA） were utilized in this study. METHODS： TNF-α transgenic （tg） and wild-type （WT） rats underwent a complete single-level laminectomy at the 10^th thoracic vertebra （T10）. MAIN OUTCOME MEASURES： Motor function of rat hindlimb was assessed using the Basso, Beattie, and Bresnahan hindlimb locomotor rating scale. Histological evaluation of spinal cord tissue loss was conducted. Immunohistochemistry for astrocytes, microglia/macrophages, and TNF receptors （TNFRs） was performed on spinal cord tissue sections. TNF-α mRNA expression was detected by real-time polymerase chain reaction. The concentrations of nerve growth factor （NGF） and brain-derived neurotrophic factor （BDNF） in the supernatant were determined using an enzyme-linked immunosorbent assay kit for rat NGF or BDNF, respectively. The rats were injected subcutaneously with etanercept to verify that TNF-α was the direct effect of the modulation of behavioral and neurodegenerative outcomes in the TNF-α tg rats. RESULTS： TNF-α tg rats showed higher expression of TNF-α mRNA in the spinal cord prior to SCI. TNF-α tg rats showed worse motor deficits than WT rats in the acute period （〈 3 days） after SCI （P 〈 0.01）, while in the chronic period, TNF-α tg rats exhibited persistent elevated baseline levels of TNF-α mRNA and improved recovery in motor function and tissue healing compared to WT rats （P 〈 0.01 ）. Following SCI, the number of microglia/macrophages in TNF-α tg rat was always greater than in WT rat （P 〈 0.01）. There were no significant differences in NGF and BDNF levels in the supernatant of spinal cord homogenates. TNFR1 expression was significantly greater in the TNF-α tg rats compared to the WT rats （P 〈 0.01）. However, TNFR2 expression did not reveal a significant increase in the TNF-α tg rats compared to the WT rats. Finally, treatment with etanercept reduced injury acutely, but exacerbated the injury chronically. CONCLUSION： Overexpression of TNF-α is deleterious in the acute phase, but beneficial in the chronic phase in the response to SCI. The role of TNF-α post-injury may depend on TNF-α expression in the spinal cord and its differential binding to TNFRI. Our observations may have clinical relevance that antagonists or inhibitors of TNF-α could be administered within the early time window post-injury, and appropriate amounts of TNF-α could be administered during the chronic stage, in order to improve the final neurological recovery in patients with SCI.

Long-term differences in urinary, bowel and sexual function among men treated with surgery versus radiation for prostate cancer

surgery and radiation have both been shown to increase the longterm diseasespecific survival rate for men with din icaUy localized prostate cancer. Although both modalities have demonstrated favor able effects on cancer control, questions regarding quality of life （QoL） and func tional outcomes remain incompletely answered. To date, no randomized prospective trials have been performed comparing the two treatment modalities and so indirect compar isons of longterm functional outcomes have served as a substitute to aid in patient coun seling and decisionmaking. As there is a pau city of longterm data comparing functional outcomes after radical prostatectomy and external beam radiation therapy, a recent art icle by Resnick et al.,1 has attempted to pro vide additional information about this topic in terms of continence, erectile function and bowel function. Utilizing the Prostate Cancer Outcomes Study cohort, a populationbased cohort of men diagnosed with prostate cancer in the pro statespecific antigen （PSA） era, the authors compared rates of urinary incontinence, erect ile dysfunction, and bowel urgency at 2, 5 and 15 years after primary therapy. They showed that men undergoing prostatectomy had higher rates of incontinence and erectile dys function at 2 and 5 years, but these rates were similar to those in the radiotherapy group at 15 years. More specifically, men were approxi mately five times more likely to have urinary continence issues if they underwent prostatec tomv versus radiotherapy and almost three anda half times more likely to develop erectile dys function in the short to intermediateterm following primary treatment. As expected, rates of bowel urgency were higher in the radio therapy group at 2 and 5 years, but not sig nificantly different from the surgery group at 15 years. In addition, the authors note that the rate of incontinence and erectile function pro gressively worsened over time, regardless of primary treatment modality. At 15 years of followup, the prevalence of erectile dysfunc tion was approximately 87% in the prosta tectomy group, and 94% in the radiotherapy group, a nonsignificant difference. Interes tingly, only approximately 40% of patients in either group reported being bothered by this. Without an appropriate control group, it is hard to distinguish the relative contribution of inter vention or age to the overall decline in sexual function. Shortterm studies have shown that men undergoing prostatectomy have larger declines in sexual and urinary function than agematched controls,2 but no such untreated control cohort was present in this study. The effects on sexual, urinary and bowel function are critical issues to address when counseling patients regarding prostate cancer treatment. Rather than looking at specific points in time, the overall decrement in each QoL domain can be evaluated as the area under the curve for each treatment type. Therefore, while values generally are similar at 15 years, men have a cumulative difference in preserved erectile and urinary function over that period that can be compared by area under the curve measurement. A calculation of the relative decrement in each domain over time would be valuable for patient counsel ing, but these are not provided by the authors. In addition, the generalizability of the authors＇ findings may be limited by thedramatic refinement of treatment modalities since study enrollment in the mid1990s. Robotassisted laparoscopic radical prostatect only is now the primary surgical therapy for prostate cancer, with a much smaller propor tion of prostatectomies being performed at lowvolume centers and those not offering robotic surgery.3 As the shift to higher volume surgeons has progressed, it is reasonable to con sider that the improvements in lengths of stay and shortterm outcomes after robotic surgery could be extrapolated to the continence and sexual function domains.4 Additionally, the advent of image modulation in radiotherapy has reduced late toxicity rates and, in the cur rent era, may lower the reported rates of erec tile dysfimction, urinary incontinence and bowel dysfunction reported in this study.5 Any assessment of QoL following prostate cancer treatment merits discussion of the overdiagnosis and overtreatment of clinically insignificant cancers. Less than 10% of patients in either cohort had a Gleason score /〉 8 and less than a third of patients had a PSA level 〉 10 ng ml 1. There has been an increas ing view that some Gleason 6 prostate cancers do not have metastatic potential. As such, active surveillance in men with lowrisk dis ease is an appropriate choice and minimizes treatmentspecific issues with the QoL para meters considered in this study.6 Selection of only those men who have a high likelihood of benefiting from treatment may have the most significant effect in reducing treatment related sexual, bladder and bowel dysfunction.7 The Prostate Cancer Research International Active Surveillance Project is the largest obser vational prospective study evaluating active surveillance as an alternative to radical treat ment for lowrisk prostate cancer. Their data show that surveillance is a feasible strategy that does not compromise cancer cure.

An intervention to reduce psychosocial and biological indicators of stress in African American lupus patients: The balancing lupus experiences with stress strategies study

Objective: Very little is known about the impact of psychosocial stress on African American lupus patients. Due to the exposure of African Americans to a unique trajectory of stressors throughout life, it may be critical to understand the relationship between psychosocial stress and underlying biological mechanisms that influence disease activity and pathology in this high risk group. Methods: The Balancing Lupus Experiences with Stress Strategies (BLESS) study piloted the validated “Better Choices, Better Health” Chronic Disease Self-Management Program (CDSMP) in 30 African-American lupus patients participating in the SLE Clinic Database Project at the Medical University of South Carolina (MUSC). Measures of psychosocial and biological indicators of stress were collected in all of the patients in each of the study conditions before and after intervention activities, as well as four months’ post-intervention, to assess the effectiveness of the program in reducing perceived and biological indicators of stress. Results: Participation in the workshops had large effects upon depression (d = 1.63 and d = 1.68), social/role activities limitations (d =1.15), health distress (d = 1.13 and d = 0.78), fatigue (d = 1.03), pain (d = 0.96), and lupus self-efficacy (d = 0.85). Neither the differences in cortisol or DHEA levels pre- and post-intervention were found to be significantly different between intervention participants and controls. Conclusion: The intervention workshops acted to reduce perceived stress and improve quality of life. Our findings imply that comparable, if not more significant gains in relevant health indicators are possible in African American patients when provided the opportunity to participate in CDSMP’s.

Hypertension and obesity in living kidney donors

Over the past few decades,the shortage in the kidney donor pool as compared to the increasing number of candidates on the kidney transplant waitlist led to loosening of kidney donors’acceptance criteria.Hypertension and obesity represent risk factors for chronic kidney disease,both in native kidneys and those in kidney transplant recipients.While great progress has been made in kidney transplantation from living donors to benefit the recipient survival and quality of life,progress has been slow to fully risk-characterize the donors.This review critically reassesses the current state of understanding regarding the risk of endstage kidney disease in those donors with obesity,hypertension or both.Accurate risk assessment tools need to be developed urgently to fully understand the risk glomerular filtration rate compensation failure in the remaining kidney of the donors.

Identification of microbial contaminants in sinus rinse squeeze bottles used by allergic rhinitis patients

Objective:To identify whether irrigation devices become contaminated when used by patients with allergic rhinitis (AR).Methods:Ten AR patients with no clinical or endoscopic evidence of active sinonasal infection were given a sinus rinse system and instructed on its proper use,cleaning,and storage.Two squeeze bottles (bottle A and bottle B) were given to each patient for twice-a-day rinsing.Bottle A was used in the morning and analyzed after four weeks.Bottle B was used in the evening and analyzed after 8 weeks of use.Microbial contaminants were cultured from the nose pieces and the inner surface of the bottles obtained from patients.Results:Seventeen sinus rinse devices (17/20) from all individuals in this study grew bacteria commonly in the nozzles.Twenty-four bacterial isolates consisting of 14 different species were cultured and identified with most common organisms being bacilli and staphylococcus.In addition,no correlation was apparent between the length of bottle use and the degree of contamination (r =0.13,p =0.76).During the study period,no patient developed acute sinus infections.Conclusion:Microbial contamination of the sinus rinse system occurs commonly,even in uninfected AR patients;however no evidence exists linking this to clinically relevant sinus infections.

Microelectrode Array-evaluation of Neurotoxic Effects of Magnesium as an Implantable Biomaterial

Magnesium （Mg）-based biomaterials have shown great potential in clinical applications. However, the cytotoxic effects of excessive Mg2. and the corrosion products from Mg-based biomaterials, particularly their effects on neurons, have been little studied. Although viability tests are most commonly used, a functional evaluation is critically needed. Here, both methyl thiazolyl tetrazolium （MTT） and lactate de- hydrogenase （LDH） assays were used to test the effect of Mg2. and Mg-extract solution on neuronal viability. Microelectrode arrays （MEAs）, which provide long-term, real-time recording of extracellular electro- physiological signals of in vitro neuronal networks, were used to test for toxic effects. The minimum effective concentrations （ECmin） of Mg2. from the MTr and LDH assays were 3 mmol/L and 100 mmol/L respec- tively, while the ECmin obtained from the MEA assay was 0.1 mmol/L MEA data revealed significant loss of neuronal network activity when the culture was exposed to 25% Mg-extract solution, a concentra- tion that did not affect neuronal viability. For evaluating the biocompatibility of Mg-based biomaterials with neurons, MEA electrophysiological testing is a more precise method than basic cell-viability testing.