Transmission of amyloid-βpathology in humans:a perspective on clinical evidence

Transmission of misfolded amyloid-β(Aβ)aggregates between human subjects:Protein misfolding disorders are a family of diseases characterized by the accumulation of misfolded protein aggregates.These proteinaceous structures,also known as amyloids,are key drivers of fatal neurodegenerative disorders such as prion diseases,Alzheimer’s disease(AD),Parkinson’s disease,and others.

Glial progenitor heterogeneity and plasticity in the adult spinal cord

Glial progenitor cells were reported to have the capacity to generate various types of cells in both the central nervous system(CNS)and peripheral nervous system.Glial progenitor cells can respond to diverse environmental signals and transform into distinct populations,each serving specific functions.Notably,the adult spinal cord hosts various populations of glial progenitors,a region integral to the central nervous system.During development,glial progenitors express glial fibrillary acidic protein(GFAP;Dimou and Gotz,2014).However,the specific identities of GFAP-expressing progenitors in the adult spinal cord were not thoroughly investigated.

Reinforced tissue matrix to strengthen the abdominal wall following reversal of temporary ostomies or to treat incisional hernias

BACKGROUND Abdominal wall deficiencies or weakness are a common complication of tem-porary ostomies,and incisional hernias frequently develop after colostomy or ileostomy takedown.The use of synthetic meshes to reinforce the abdominal wall has reduced hernia occurrence.Biologic meshes have also been used to enhance healing,particularly in contaminated conditions.Reinforced tissue matrices(R-TMs),which include a biologic scaffold of native extracellular matrix and a syn-thetic component for added strength/durability,are designed to take advantage of aspects of both synthetic and biologic materials.To date,RTMs have not been reported to reinforce the abdominal wall following stoma reversal.METHODS Twenty-eight patients were selected with a parastomal and/or incisional hernia who had received a temporary ileostomy or colostomy for fecal diversion after rectal cancer treatment or trauma.Following hernia repair and proximal stoma closure,RTM(OviTex®1S permanent or OviTex®LPR)was placed to reinforce the abdominal wall using a laparoscopic,robotic,or open surgical approach.Post-operative follow-up was performed at 1 month and 1 year.Hernia recurrence was determined by physical examination and,when necessary,via computed tomo-graphy scan.Secondary endpoints included length of hospital stay,time to return to work,and hospital readmissions.Evaluated complications of the wound/repair site included presence of surgical site infection,seroma,hematoma,wound dehiscence,or fistula formation.RESULTS The observational study cohort included 16 male and 12 female patients with average age of 58.5 years±16.3 years and average body mass index of 26.2 kg/m^(2)±4.1 kg/m^(2).Patients presented with a parastomal hernia(75.0%),in-cisional hernia(14.3%),or combined parastomal/incisional hernia(10.7%).Using a laparoscopic(53.6%),robotic(35.7%),or open(10.7%)technique,RTMs(OviTex®LPR:82.1%,OviTex®1S:17.9%)were placed using sublay(82.1%)or intraperitoneal onlay(IPOM;17.9%)mesh positioning.At 1-month and 1-year follow-ups,there were no hernia recurrences(0%).Average hospital stays were 2.1 d±1.2 d and return to work occurred at 8.3 post-operative days±3.0 post-operative days.Three patients(10.7%)were readmitted before the 1-month follow up due to mesh infection and/or gastrointestinal issues.Fistula and mesh infection were observed in two patients each(7.1%),leading to partial mesh removal in one patient(3.6%).There were no complications between 1 month and 1 year(0%).CONCLUSION RTMs were used successfully to treat parastomal and incisional hernias at ileostomy reversal,with no hernia recurrences and favorable outcomes after 1-month and 1-year.

Bystanders or not?Microglia and lymphocytes in aging and stroke

As the average age of the world population increases,more people will face debilitating aging-associated conditions,including dementia and stroke.Not only does the incidence of these conditions increase with age,but the recovery afterward is often worse in older patients.Researchers and health professionals must unveil and understand the factors behind age-associated diseases to develop a therapy for older patients.Aging causes profound changes in the immune system including the activation of microglia in the brain.Activated microglia promote T lymphocyte transmigration leading to an increase in neuroinflammation,white matter damage,and cognitive impairment in both older humans and rodents.The presence of T and B lymphocytes is observed in the aged brain and correlates with worse stroke outcomes.Preclinical strategies in stroke target either microglia or the lymphocytes or the communications between them to promote functional recovery in aged subjects.In this review,we examine the role of the microglia and T and B lymphocytes in aging and how they contribute to cognitive impairment.Additionally,we provide an important update on the contribution of these cells and their interactions in preclinical aged stroke.

Sex-biased autophagy as a potential mechanism mediating sex differences in ischemic stroke outcome

Stroke is the second leading cause of death and a major cause of disability worldwide,and biological sex is an important determining factor in stroke incidence and pathology.From childhood through adulthood,men have a higher incidence of stroke compared with women.Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke.Autophagy is a self-degrading cellular process orchestrated by multiple core proteins,which leads to the engulfment of cytoplasmic material and degradation of cargo after autophagy vesicles fuse with lysosomes or endosomes.The levels and the activity of components of these signaling pathways and of autophagy-related proteins can be altered during ischemic insults.Ischemic stroke activates autophagy,however,whether inhibiting autophagy after stroke is beneficial in the brain is still under a debate.Autophagy is a potential mechanism that may contribute to differences in stroke progression between the sexes.Furthermore,the effects of manipulating autophagy may also differ between the sexes.Mechanisms that regulate autophagy in a sex-dependent manner in ischemic stroke remain unexplored.In this review,we summarize clinical and pre-clinical evidence for sex differences in stroke.We briefly introduce the autophagy process and summarize the effects of gonadal hormones in autophagy in the brain and discuss X-linked genes that could potentially regulate brain autophagy.Finally,we review pre-clinical studies that address the mechanisms that could mediate sex differences in brain autophagy after stroke.

Functional phenotyping of microglia highlights the dark relationship between chronic traumatic brain injury and normal age-related pathology

Traumatic brain injury(TBI) is a major cause of death and disability worldwide. Age-related TBI differences demonstrate the third peak of prevalence and incidence of TBI within the elderly population. This is due to the elderly being at a higher risk of sustaining falls, which have been identified as the main cause(40–50%) of TBI.

Renin-angiotensin system in the central nervous system:focus on Huntington’s disease

The renin-angiotensin system(RAS)was originally conceived as a circulating hormonal system involved in the regulation of cardiovascular and renal homeostasis.With the discovery of local RAS components in diverse organs,including the brain,and related biologically active peptides.

Outcomes of severe sepsis and septic shock patients after stratifi cation by initial lactate value

BACKGROUND: In the setting of severe sepsis and septic shock, mortality increases when lactate levels are ≥ 4 mmol/L. However, the consequences of lower lactate levels in this population are not well understood. The study aimed to determine the in-hospital mortality associated with severe sepsis and septic shock when initial lactate levels are < 4 mmol/L.METHODS: This is a retrospective cohort study of septic patients admitted over a 40-month period. Totally 338 patients were divided into three groups based on initial lactate values. Group 1 had lactate levels < 2 mmol/L; group 2: 2–4 mmol/L; and group 3: ≥ 4 mmol/L. The primary outcome was in-hospital mortality.RESULTS: There were 111 patients in group 1, 96 patients in group 2, and 131 in group 3. The mortality rates were 21.6%, 35.4%, and 51.9% respectively. Univariate analysis revealed the mortality differences to be statistically significant. Multivariate logistic regression demonstrated higher odds of death with higher lactate tier group, however the findings did not reach statistical significance.CONCLUSION: This study found that only assignment to group 3, initial lactic acid level of ≥ 4 mmol/L, was independently associated with increased mortality after correcting for underlying severity of illness and organ dysfunction. However, rising lactate levels in the other two groups were associated with increased severity of illness and were inversely proportional to prognosis.

Renin angiotensin system in liver diseases: Friend or foe?

In the last three decades,the understanding of the renin angiotensin system(RAS)has been changed by the discoveries of functional local systems,novel biologically active peptides,additional specific receptors,alternative pathways of angiotensin(Ang)?Ⅱ?generation,and new roles for enzymes and precursor components other than those in Ang?Ⅱ?synthesis.In this regard,the discovery that Ang-(1-7)opposes the pressor,proliferative,pro-fibrotic,and pro-inflammatory effects mediated by Ang?Ⅱ?has contributed to the realization that the RAS is composed of two axes.The first axis consists of the angiotensin-converting enzyme(ACE),with Ang?Ⅱ?as the end product,and the angiotensin type 1(AT1)receptor as the main effector mediating the biological actions of Ang?Ⅱ.The second axis results from ACE2-mediated hydrolysis of Ang?Ⅱ,leading to the production of Ang-(1-7),with the Mas receptor as the main effector conveying the vasodilatory,antiproliferative,anti-fibrotic,and anti-inflammatory effects of Ang-(1-7).Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases.In this manuscript,we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications,including hemodynamic changes and hepatorenal syndrome.The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.

Novel technique for anastomotic salvage using transanal minimally invasive surgery:A case report

Anastomotic leak(AL)after low anterior resection(LAR)can be a highly morbid complication.The incidence of AL ranges from 5%to 20%depending on patient characteristics and the distance of the anastomosis from the anal verge.Low anastomoses and leaks pose technical challenges for endoscopic treatment.The aim of this report was to describe the use of a commercially available laparoscopic energy device through a transanal minimally invasive surgery(TAMIS)port for the management of a symptomatic leak not requiring relaparotomy(grade B)after a LAR with diverting loop ileostomy.CASE SUMMARY A TAMIS GelPOINT Path port was inserted into the anus to access the distal rectum.Pneumorectum was achieved with AirSeal insufflation and a 30 degree laparoscope was introduced through a trocar.A LigaSureTM Retractable L-Hook device was then used to perform a septotomy of the chronic sinus tract identified posterior to the coloproctostomy.The procedure was then repeated twice in three weeks intervals with ultimate resolution of the chronic leak cavity.Several months after serial TAMIS septotomies,barium enema demonstrated a patent anastomosis with no evidence of persistent leak or stricture.The patient subsequently underwent ileostomy reversal and has had no significant postoperative issues.CONCLUSION TAMIS septotomy with the LigaSureTM Retractable L-Hook is a feasible and effective,minimally invasive salvage technique for the treatment of grade B ALs.Larger studies are needed to assess the generalizability and long-term results of this technique.

MMP-1 Over-expression Promotes Malignancy and Stem-Like Properties of Human Osteosarcoma MG-63 Cells In Vitro

Osteosarcoma is the most common primary malignant bone tumor in childhood,and it maintains a high level of recurrence.Matrix metalloproteinase-1(MMP-1)was found to contribute to cancer progression.The present study was to investigate the in vitro effects of MMP-1 over-expression on the proliferation,invasion,metastasis and stem-like properties of osteosarcoma MG-63 cells.The MG-63 cells were cultured and had a full length MMP-1 cDNA inserted by the tentiviral vector (MG-63^MMP-1+).MG-63 negative control and MG-63 blank control groups were established as well.MMP-1 expression was detected in MG-63^MMP-1+,MG-63 negative control and MG-63 blank control cells using qPCR,Western blotting and immunofluorescence after 24h of culture. The cell proliferation assay was performed with a camera attached to a bioreactor,which was programmed to photograph five regions of each well every 10 min over a period of 48 h.The cell invasion assay was conducted with Matrigel to assess the invasive potential,of MG-63 cells over 24h,the qPCR analysis to measure stem cell markers,including Oct4, Sox-2,Nanog,and Pax-7,and Western blot analysis to detect invasive and metastatic potential markers TIMP-1,VEGF and BMP2/4,after 24h of culture.Immunofluorescence was used to investigate the presence of the stem cell marker Pax-7 after 24-h culture. The results showed that over-expression of MMP-1 after transfection could significantly increase minor cell proliferation and invasion (P<0.05,MG-63^MMP-1+ versus controls).Pax-7 was highly expressed in MG-63^MMP-1+ cells,with no significant changes of Oct-4,Sox-2, and Nanog observed (P<0.05).MG-63^MMP-1+ cells showed higher expression of VEGF and BMP 2/4 proteins and lower expression of TIMP-1 protein than controls (P<0.05).It was concluded that MMP-1 over-expression in MG-63 cells contributed to the proliferation, invasion,metastasis and stem-like properties of osteosarcoma cells.Future studies should focus on in vivo effects of MMP-1 over-expression and the application of MMP-1 and Pax-7 inhibition in vivo to osteosarcoma theraoies.

Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation

Human linkage studies suggest that craniofacial deformities result from either genetic mutations related to cholesterol metabolism or high-cholesterol maternal diets. However, little is known about the precise roles of intracellular cholesterol metabolism in the development of craniofacial bones, the majority of which are formed through intramembranous ossification. Here, we show that an altered cholesterol metabolic status results in abnormal osteogenesis through dysregulation of primary cilium formation during bone formation. We found that cholesterol metabolic aberrations, induced through disruption of either Dhcr7(which encodes an enzyme involved in cholesterol synthesis) or Insig1 and Insig2(which provide a negative feedback mechanism for cholesterol biosynthesis), result in osteoblast differentiation abnormalities. Notably, the primary cilia responsible for sensing extracellular cues were altered in number and length through dysregulated ciliary vesicle fusion in Dhcr7 and Insig1/2 mutant osteoblasts. As a consequence, WNT/β-catenin and hedgehog signaling activities were altered through dysregulated primary cilium formation.Strikingly, the normalization of defective cholesterol metabolism by simvastatin, a drug used in the treatment of cholesterol metabolic aberrations, rescued the abnormalities in both ciliogenesis and osteogenesis in vitro and in vivo. Thus, our results indicate that proper intracellular cholesterol status is crucial for primary cilium formation during skull formation and homeostasis.

Promises and pitfalls of immune-based strategies for Huntington's disease

Huntington＇s disease （HD） is an autosomal-dominant neurodegenerative disease characterized by the selec- tive loss of neurons in the striatum and cortex, leading to progressive motor dysfunction, cognitive decline and behavioral symptoms. HD is caused by a trinucleotide （CAG） repeat expansion in the gene encoding for huntingtin. Several studies have suggested that inflammation is an important feature of HD and it is already observed in the early stages of the disease. Recently, new molecules presenting anti-inflammatory and/or immunomodulatory have been investigated for HD. The objective of this review is to discuss the data obtained so far on the immune-based therapeutic strategies for HD.

Consumption of energy beverage is associated with attenuation of arterial endothelial flow-mediated dilatation

AIM To investigate whether consumption of an energy drink will acutely impair endothelial function in young healthy adults. METHODS Energy drinks are being consumed more and more worldwide, and have been associated with some deaths in adolescents and young adults, especially when consumed while exercising. After fasting and not smoking for at least 8 h prior, eleven medical students(9 males) received an electrocardiogram, blood pressure and pulse check, and underwent baseline testing(BL) of endothelial function using the technique of endothelium-dependent flow mediated dilatation(FMD) with high-resolution ultrasound(according to recommended guidelines of the University of Wisconsin Atherosclerosis Imaging Research Program Core Laboratory). The subjects then drank an energy beverage(EB), a 24-oz can of Monster Energy, and the above was repeated at 90 min after consumption. The relative FMD(%) was calculated as the ratio between the average post-cuff release and the baseline diameter. Each image was checked for quality control, and each artery diameter was measured from the media to media points by two experts, 3 measurements at the QRS complex, repeated on 3 separate beats, and then all were averaged.RESULTS Subjects characteristics averages(given with standard deviations) include: Age 24.5 ± 1.5 years, sex 9 male and 2 female, weight 71.0 ± 9.1 kg, height 176.4 ± 6.0 cm, BMI 22.8 ± 2.7 kg/m^2. The hemodynamics were as follows, BL vs EB group respectively(mean ± SD): Heart rate 65.2 ± 11.3 vs 68.2 ± 11.8 beats per minute, systolic blood pressure 114.0 ± 10.4 mmH g vs 114.1 ± 10.4 mmH g, diastolic blood pressure 68.8 ± 9.3 mmH g vs 70.6 ± 7.1 mmH g; all were not significantly different. However after drinking the EB, a significantly attenuated peak FMD response was measured(mean ± SD): BL group 5.9% ± 4.6% vs EB group 1.9% ± 2.1%; P = 0.03). Given the increased consumption of energy beverages associated with exercise in young adults, more research is needed.CONCLUSION Energy beverage consumption has a negative impact on arterial endothelial function in young healthy adults.

Ritalin Dose Response Effect on Medial Prefrontal Cortex and on Animal Behavior

The prefrontal cortex (PFC) is involved in complex planning, learning, memory, attention and integrates sensory information. It was reported that the PFC was dysfunctional in attention deficit hyperactivity disorder (ADHD). Methylphenidate (MPD), a drug often prescribed for the treatment of ADHD, has potential for abuse and misuse. Most MPD studies were completed in adult subjects;however, most users were adolescents. The objective of this study was to investigate the acute and chronic dose response characteristics of MPD on PFC neuronal activity recorded in freely behaving adolescent rats. Four groups of animals were used: saline (control), 0.6, 2.5, and 10 mg/kg MPD. Acute MPD elicited a dose response increase in animals’ locomotor activity. Rechallenge with MPD at experimental day (ED10) when compared to the effect of MPD at ED1 showed no significant differences. When the animals were divided into two groups based on their individual responses to chronic MPD exposure, some animals expressed behavioral tolerance and some expressed behavioral sensitization. Electrophysiologically, a dose response characteristic for acute and chronic MPD exposure was observed. With increasing MPD doses, more PFC units responded by changing their firing rate. Moreover, the neuronal responses to chronic MPD recorded from animals expressing behavioral tolerance were significantly different compared to the neuronal population responses recorded from animals expressing behavioral sensitization. The majority of the PFC units recorded from animals expressing behavioral tolerance responded to MPD predominately by decreasing their firing rates, whereas PFC units recorded from behaviorally sensitized animals mainly showed an increase in their firing rates.

A Cross-Sectional Survey to Determine the Prevalence of Cardiovascular Disease Risk Factors in an Understudied Population in Sierra Leone

To document the prevalence of risk factors for cardiovascular disease in an unstudied community, a survey of 130 participants from different areas of Sierra Leone was performed. The focus was on cardiovascular disease because its prevalence had not been studied and World Health Organization (WHO) reports on Non-Communicable Diseases (NCD) prevalence were extrapolations and not from actual data. Resting blood pressure, fasting blood glucose, fasting lipid levels and carotid intima media thickness (CIMT) were measured. Mean blood pressure in men was slightly lower than in women (132/87 mmHg and 139/90 mmHg respectively), mean fasting blood glucose levels were <100 mg/dL in both groups and mean fasting total cholesterol was higher in women than in men (206 mg versus 193.5 mg/dL). Mean fasting low density lipoprotein levels were similar in both groups, 129 mg/dL in men and 133 mg/dL in women. Mean fasting high density cholesterol was 47.2 mg/dL in men and 55.5 mg/dL in women and CIMT values were similar in both groups, with 60% above the 75th percentile. This study demonstrated a prevalence of cardiovascular risk factors in this population with mean BP placing both men and women in pre-hypertension or stage 1 hypertension ranges and elevated mean low density lipoprotein levels. Fasting total cholesterol, blood glucose and high density lipoprotein were within normal ranges. Mean CIMT values for men and women placed them at risk for subclinical atherosclerosis.

血糖控制良好患者发生糖尿病视网膜病变的生物标志物和治疗研究进展

Diabetic retinopathy(DR)has exhibited a disconcerting surge over the past decades.As of 2021,global statistics indicate that over 537 million individuals were living with DR[1].With the diabetic population continually expanding,it is foreseen that the incidence of DR will soar to an estimated 800 million individuals worldwide by the year 2045[2].

Value of phosphodiesterase 5 inhibitors as a combination therapy for treating erectile dysfunction:A literature review

Erectile dysfunction(ED)is increasing in prevalence,with estimates that 50%of men between 40 and 70 years of age suffer from the disease.Due to a wide array of available medical interventions,significant focus has been put on combination therapies that can treat ED refractory to first-line treatments such as phosphodiesterase 5 inhibitors(PDE5is).However,reviews evaluating monotherapy noninferiority and patient satisfaction of monotherapy versus combination therapy are lacking.A thorough PubMed search was performed to evaluate combination therapy in ED treatment.Articles published between January 2008 and June 2023 were reviewed,including randomized control trials,retrospective analyses,and cohort studies.Combination therapies included PDE5i plus another PDE5i,testosterone supplementation,α-blockers,vacuum erectile devices,intracavernosal injections,and low-intensity shockwave therapy.Based on this review,PDE5i monotherapy is not inferior to combination therapy and has increased satisfaction,convenience,and ease of use for patients with ED.Limitations of current literature on combination therapy include small sample size,limited data on patient satisfaction,possible biases,and limited follow-up time.Further studies will need larger randomized control trials with follow-up times greater than 1 year.

Shaping the future of men's sexual health:How artificial intelligence can assist in the management and treatment of erectile dysfunction

Artificial intelligence(AI)is a complex combination of multidisciplinary machines and systems that can replicate human-like cognitive tasks to execute capabilities such as pattern recognition,decision-making,and problem-solving.Dating back to the 2000s,AI has been utilized in the medical field,however the interest in this subject has sharply increased over the past several years.Erectile dysfunction(ED)is an increasingly pervasive issue as men age,affecting up to 150 million men worldwide.In the field of men's health,AI has been employed to assist physicians in the evaluation and management of ED.This article aims to summarize the ways in which AI has been utilized in the management of ED,as well as the considerations that must be made when implementing this technology.AI can be utilized for virtual health assistance to protect patient privacy and increase access to care.Augmented reality can aid surgeons in real-time during operations,as well as be utilized to prepare physicians for situations that they may encounter in the operating room.Pharmaceutical companies can benefit from AI in the interpretation of data,analysis of chemical compounds and in drug development.Additionally,AI can be used to assist patients in post-procedure recovery in the form of rehabilitation and post-treatment monitoring.While the utilization of AI in men's health is an exciting venture,there are tremendous ethical and practical considerations that have limited its use in the management of ED.

Innovative treatments for congenital heart defects

The past few decades have witnessed substantial advances in the treatment of complex congenital heart defects,with most significant advances in surgical treatment strategies and improved outcomes dependent upon well-educated and calculated risk-taking innovations.In the present surgical era,doing nothing for complex congenital heart defects is unacceptable,and pioneering surgeons are willing to under-take and accept the substantial risks of innovative pediatric cardiac surgery[1].