Vascular Deficit Research Articles

Sulforaphane Attenuates Ethanol-Induced Teratogenesis and Dysangiogenesis in Zebrafish Embryos

Prenatal ethanol exposure can cause a broad range of abnormalities in newborns known as Fetal Alcohol Spectrum Disorder (FASD). Despite significant progress in understanding the disease mechanisms of FASD, there remains a strong global need for effective therapies. To evaluate the therapeutic potential of sulforaphane (SFN), an active compound extracted from cruciferous vegetables, in preventing FASD, ethanol-exposed zebrafish embryos were pretreated, co-treated, or post-treated with various concentrations of SFN. The FASD-like morphological features, survival rate, hatching rate, and vascular development were then assessed in the zebrafish embryos. It was found that pretreatment with 2 μM SFN during 3–24 hpf had no noticeable protective effects against teratogenicity induced by subsequent 1.5% ethanol exposure during 24–48 hpf. In contrast, co-treatment with 2 μM SFN and 1.5% ethanol during 3–24 hpf significantly alleviated a range of ethanol-induced malformations, including reduced body length, small eyes, reduced brain size, small otic vesicle, small jaw, and pericardial edema. Post-treatment with 3 μM SFN for 4 days following 1.5% ethanol exposure during 3–24 hpf also significantly reduced the characteristic features of FASD, decreasing the mortality rate and restoring body length, eye size, brain size, and otic vesicle circumference. Moreover, we found that ethanol, even at a low dose (0.5%), causes vascular development deficit in the zebrafish embryos, which were also largely rescued by SFN treatment. These data indicated that SFN has great potential to be used in the prevention and treatment of FASD.

Volar Lunate Dislocation: A Case Report

Introduction: Perilunate dislocations are rare high-energy injuries which may often have the potential to cause lifelong disability of the wrist if not addressed optimally. Hence, early recognition, diagnosis, and intervention are of paramount importance in the restoring function and prevention of morbidity. Lunate dislocations are the fourth and last stage of perilunate dislocations being extremely rare, with volar dislocations representing <3% of perilunate dislocations. Case Report: A 24-year-old man suffered from an alleged history of fall from a bike on an outstretched hand following which he developed complaints of pain and swelling in the right wrist. On examination, the patient has relative sensory loss over the lateral half of the palm with no vascular deficit. An accurate range of motion could not be documented due to severe pain. Standard digital X-rays revealed lunate displaced and angulated volarly with a typical “spilled teacup” appearance along with radial and ulnar styloid fractures. Management: The patient was initially given an attempt of closed reduction which was not successful and was followed with open reduction and internal fixation with both volar and dorsal approach with Kirschner wires. The patient’s wrist was immobilized for 6 weeks with below elbow cast with the removal of k wires at 8 weeks after which wrist ROM exercises were started. Results: The patient was followed up for 6 months and now has a functional range of motion of the wrist with no sensory deficit and is able to continue with his profession as a car mechanic. Conclusion: Mayfield progression Stage 4 perilunate dislocations are uncommon with a poor prognosis if not addressed timely. Hence, these injuries need to be identified early and optimally managed with surgical intervention for a favorable outcome. Keywords: Perilunate dislocation, carpal bones, avascular necrosis of lunate, wrist trauma, carpal instability

A rare case report: compartment syndrome after brachiocephalic arteriovenous fistula formation in a hemodialysis patient

Introduction: Acute compartment syndrome is a condition in which increased pressure in the tight fascia space reduces capillary perfusion below the level required for tissue viability. Very few cases of acute compartment syndrome associated with dialysis have been reported. It can lead to severe damage to the tissues of the arm. Case Illustration: A 47-year-old woman with end-stage renal failure presented to the emergency room with swelling and pain in the right upper extremity and has lasted for a day. Three days before admission, the patient underwent right brachiocephalic arteriovenous (AV) fistula surgery. Physical Examination showed a blackish bruise at the fossa cubiti, radial and ulnar artery were not palpable, but there is trill at AV fistula. Decreased motoric strength, reduced hand sensation and decreased capillary return in fingers. Oxygen blood saturation of the right fingers could not be read. Diagnosis of acute compartment syndrome was made. The patient was immediately taken to the operating room for decompression surgery. Emergency compartment fasciotomy was performed. After fasciotomy, necrotomy was performed. Furthermore, brachiocephalic AV fistula was ligated. Postoperative evaluation obtained good radial and ulnar artery. Six months after the surgery, the wound was fully healed and no sign of neuromuscular or vascular deficit. Conclusion: Compartment syndrome is a possible complication after AV fistula formation that can have disastrous consequences. However, it can be effectively treated if detected and treated early. Prognosis of compartment syndrome after fasciotomy depends on how quickly the condition is diagnosed and treated.

Positive airway pressure therapy for post-stroke sleep disordered breathing: a systematic review, meta-analysis and meta-regression.

Sleep disordered breathing (SDB) is an under-recognised independent risk factor and a potential consequence of stroke. We systematically reviewed and meta-analysed the effectiveness of positive airway pressure (PAP) therapy in improving post-stroke outcomes. We searched CENTRAL, Embase, PubMed, CINAHL, PsycINFO, Scopus, ProQuest, Web of Science and CNKI (China National Knowledge Infrastructure) for randomised controlled trials comparing PAP therapy against a control or placebo group. We evaluated the pooled effects of PAP therapy on recurrent vascular events, neurological deficit, cognition, functional independence, daytime sleepiness and depression using random effects meta-analyses. We identified 24 studies. Our meta-analyses showed that PAP therapy reduced recurrent vascular events (risk ratio 0.47, 95% CI 0.28-0.78), and showed significant beneficial effects on neurological deficit (Hedges' g= -0.79, 95% CI -1.19- -0.39), cognition (g=0.85, 95% CI 0.04-1.65), functional independence (g=0.45, 95% CI 0.01-0.88) and daytime sleepiness (g= -0.96, 95% CI -1.56- -0.37). However, there was insignificant reduction in depression (g= -0.56, 95% CI -2.15-1.02). No publication bias was detected. Post-stroke patients with SDB benefited from PAP therapy. Prospective trials are needed to determine the ideal initiation period and the minimum effective therapeutic dose.

PS-B10-6: CAPILLARY-TO-ARTERIOLAR SIGNALLING, INFLAMMATION AND SMALL VESSEL DISEASE OF THE BRAIN

Objective: Chronic cerebral inflammation is thought to be a mechanism by which hypertension causes small vessel disease of the brain, leading to dementia. Mouse studies have demonstrated enhanced small resistance artery constriction and neurovascular uncoupling in hypertension. We wished to examine whether acute exposure to the predominant inflammatory driver in hypertension, interleukin-1β; (IL-1β;) could account for this dual vascular deficit. Design and method: Pressure myography of freshly isolated mouse posterior cerebellar pial arteries was used to assess contributions of the inwardly rectifying K+ 2.1 (KIR2.1) channel to vasodilation. In order to assess neurovascular coupling from a vascular perspective, we adopted a recently described approach: the Capillary to Parenchymal Arteriole (CaPA) preparation. In the CaPA preparation, penetrating arterioles (< 40ums) with attached capillary branches are isolated and pressurised. The capillary branch and arteriole are independently stimulated via a micropipette and arteriole diameter is recorded. This approach enables the retrograde hyperpolarising signal from the KIR2.1 channel, which propagates against the flow of blood in the brain, to be assessed both in terms of the extent of arteriole vasodilation and the speed of communication (video). In order to assess the effects of perivascular inflammation on cerebrovascular function, we incubated (in culture medium) small pial arteries with IL-1β; for 24 hours prior to study on a pressure myograph rig. KIR2.1 function was assessed using 10 mM exogenous K+. Cerebral arterioles with attached capillaries were incubated with IL-1β; for 2 hours prior to CaPA study. We then examined the capillary-to-arteriolar signalling mechanism via application of 10 mM K+ to the capillary. We also assessed arteriolar tone and reaction to directly applied K+, NS309 and U46619. Results: Preliminary data suggests that sub-acute incubation with exogenous IL-1β; had no effects on the degree of pressure induced constriction of either the pial artery or the arteriole. CaPA preparation showed that the KIR2.1 capillary-to-arteriolar signalling was preserved as well as arteriolar responses to direct K+, NS309 and U46619 following IL-1β; exposure. Conclusions: Whilst chronic cerebral inflammation in the setting of hypertension results in cerebrovascular deficits, sub-acute exposure with IL-1β; does not appear to significantly impair cerebral microvascular function. Precisely how chronic exposure to inflammation in hypertension induces neurovascular uncoupling is the subject of ongoing investigation.

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS). OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID. We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability), also affects the vasa vasorum to impair the function of the capacitance vessels. In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.

Progressive Lacunar Strokes: A Predictive Score

Background and PurposeProgressive lacunar syndromes (PLS) occur in up to 20-30% of patients with lacunar strokes, increasing the risk of long term dependency. Our aim is to develop a predictive score to identify patients at high risk of presenting PLS. MethodsWe derived a risk score for PLS in a cohort of consecutive patients (n=187) presenting with one of the five classic lacunar syndromes (LS) and absence of vascular occlusion, perfusion deficit or symptomatic stenosis. A risk score was developed using the coefficients from the logistic regression model, and receiver operating characteristic (ROC) analysis was conducted to assess the prognostic value of the risk score. Sensitivity, specificity and accuracy were estimated for each total point score. ResultsOut of 187 patients included in our sample, 52 (27.8%) presented PLS. Previous history of diabetes mellitus (1 point), diastolic blood pressure at admission (2 points), clinical deficits consistent with a pure motor syndrome (1 point) and asymptomatic intracranial atheromatosis or stenosis in non-symptomatic territory (1 point) were independent predictors for PLS. The estimated area under the ROC curve for this model was 0.77 (95% CI,0.68 - 0.84). ConclusionThis score could be a useful tool in routine clinical practice to predict the occurrence of PLS, allowing the identification of those patients with LS who are at high risk of long term dependency due to early neurological worsening, and who would benefit the most from an intensive treatment.

Depletion of iNOS-positive inflammatory cells decelerates neuronal degeneration and alleviates cerebral ischemic damage by suppressing the inflammatory response

Ischemic stroke leads to neuronal damage and severe inflammation that activate iNOS expression in different cell types, especially inflammatory cells in the brain. It is shown that NO released from iNOS contributes to the pathological development of cerebral ischemia. However, the role of these iNOS-expressing inflammatory cells in ischemic stroke has not been fully elucidated. Our purpose is to test if ischemia-induced iNOS+ inflammatory cells may exaggerate cerebral inflammation to exacerbate neuronal deficit. We studied the dynamics of iNOS+ cells after stroke and found an early and sustained iNOS expression at lesion site. Since iNOS is highly expressed in inflammatory cells after injury, we depleted the iNOS + inflammatory cells via the selective scavenger GdCl3, and investigated its effect on stroke outcome, neuronal and vascular deficit, and inflammatory response. After GdCl3 treatment, half of iNOS+ inflammatory cells were depleted, including mainly activated microglia/macrophages and some astrocytes. Selective depletion of iNOS+ inflammatory cells resulted in a pronounced reduction in brain damage, resulting in improvement of motor ability. Histologic studies and in vivo two-photon imaging data revealed a slowdown of neuronal degeneration after the depletion of iNOS+ inflammatory cells. In contrast to iNOS inhibition alone, depletion of iNOS+ inflammatory cells profoundly altered the immune microenvironment profile, in addition to reducing NO production. qRT-PCR analysis showed that depletion of iNOS+ inflammatory cells significantly restrained the production of pro-inflammatory cytokines, which moderated the immune microenvironment at the lesion site. Taken together, our data demonstrate that depleting iNOS+ inflammatory cells prevents neuronal damage not only by inhibiting NO, but also importantly by suppressing the inflammatory response, which is beneficial to ischemic injury. These results provide evidence that iNOS+ inflammatory cells, as a vital source of pro-inflammatory cytokines, contribute to the development of ischemic damage and could be a potential therapeutic target for the treatment of ischemia.

Hypopharyngeal carcinoma with skeletal muscle metastases: a rare clinical entity

The common sites of distant metastatic spread of head and neck malignant tumor are lungs, liver, and bones. Skeletal muscles metastases are extremely rare. We present a case of 61-year-old man who was previously treated with radical chemo radiotherapy for hypopharyngeal squamous cell carcinoma, stage T4bN2cM0. During surveillance follow up 21 months post treatment, he developed a right proximal arm mass. There were no neurological or vascular deficit. MRI revealed an irregular enhancing intramuscular soft tissue mass within the right triceps muscle, with widespread nodal and skeletal muscle metastases. Tissue biopsy revealed a metastatic carcinoma favoring poorly differentiated squamous cell carcinoma. He received palliative chemotherapy but died 4 months later. Skeletal muscle metastases must be high in the list of differential diagnosis in a head and neck cancer patient presented with a muscle mass, even though it is rather rare. Radiological imaging and tissue biopsy helped in the diagnosis and prompt management.

Reconstructive Surgical Management of Charcot Neuropathy of the Foot and Ankle: A Retrospective Study

Category:DiabetesIntroduction/Purpose:Treatment of Charcot neuropathy (CN) of the foot and ankle remains a challenge for both patient and surgeon. Non-operative treatment with immobilization in a cast/orthosis has long been the mainstay of treatment, but more recently surgical intervention-with attention to internal fixation-has gained interest because of the poor long-term outcomes with non-operative care.Methods:To assess long-term outcomes between CN patients managed with reconstructive surgeries at a tertiary referral center; a retrospective chart review analyzed comorbidities, demographics, and complications (ulceration, infection, and below the knee amputation).Results:Over the last 16 years, 31 patients with CN were treated with internal fixation (midfoot fusion, open reduction, or hindfoot fusion nail). Average BMI was 33.5, average number of comorbidities was 2.93, and the percentage of patients with a vascular deficit was 19.3%. The rate of infection and ulceration prior to surgery was 19.4% (6/31 patients) and 45.2% (14/31 patients) respectively. After surgery, the rate of new infections was 38.7% (12/31 patients). The rate of new ulcerations was 41.9% (13/31 patients). The rates of below the knee amputation was 19.4% (6/31 patients).Conclusion:A 16-year retrospective review of operative management of Charcot neuropathy in 31 patients at a tertiary referral center found high rates of ulceration, infection, and amputation in patients treated with internal fixation. This study could prove valuable in counseling CN patients regarding reconstructive surgery.

Značaj multidetektorske kompjuterizovane tomografije u otkrivanju, praćenju i izboru terapije kod akutnog moždanog udara

Introduction: A stroke is a sudden, focal nonconvulsive neurological dysfunction which occurs due to vascular damage. Aim: The aim of the study was monitoring all patients who reported to the Emergency Center due to some neurological deficit, within a particular period of time. Materials and methods: For a period of one month, we monitored 123 patients who were admitted to the Department of Emergency Diagnostics with some form of neurological deficit and who underwent a native computed tomography (CT) scan and/or angiographic examination of the endocranium. All examinations were performed with the GE BrightSpeed 16 Slice CT scanner (USA). After initial native CT diagnostics, depending on the finding, the examination was either stopped, or the contrast dye was administered and postcontrast examination was performed or CT angiography was carried out. Results: Most of the patients with vascular neurological deficit were between 50 and 59 years old, while a smaller number of patients was registered in the age group of persons younger than 40 years. Most of the female patients were in the 50 - 59 age group, while most of the male patients were between 40 and 49 years old. Of the 94 patients who developed stroke, 78 (83%) patients had ischemic stroke, while 16 (17%) patients suffered hemorrhagic stroke. There is no statistically significant difference in the occurrence of intracerebral hemorrhage and subarachnoid hemorrhage between the sexes. The localization of ischemic brain infarction was in the vascular territory of the anterior cerebral artery (ACA) - 3.2% of the cases, the middle cerebral artery (MCA) - in 38.9% of the cases, the internal carotid artery (ICA) - in 8.4% of the patients, the basilar artery (BA) - in 13.7% of the cases, the posterior cerebral artery (PCA) - in 7.4% of the patients, the vertebral artery (VA) - 9.5% of the cases, and the supratentorial watershed areas of arterial irrigation - in 11.7% of the patients. Conclusion: Native CT examination is the golden standard for the triage of patients with acute stroke. The advantages of using a CT scan in the assessment of patients with acute stroke are that it is practical, precise, quick and available. CT imaging has prognostic value as well, as it can predict the response to the administered thrombolytic therapy.

Letter to the Editor Regarding “Traumatic Brain Injury–Related Pediatric Mortality and Morbidity in Low- and Middle-Income Countries: A Systematic Review”

Cervical pedicle screws (CPS) in the subaxial cervical spine (C3-C6) are faced with high incidence of perforating the lateral pedicular cortex endangering the vertebral artery (VA). The present study analyzes the pedicle width (PW) from C3 to C6 and defines the relation of VA with regard to pedicle and transverse foramen (TF) to determine the safety margin in cases of lateral pedicular breach.Computed tomography angiograms of 500 patients were retrospectively studied to identify the pedicle width (PW), VA area, TF area, and the lateral pedicle to vertebral artery distance (LPVA). Occupancy ratio (OR; the percentage area of transverse foramen occupied by VA) and safety margin (SM; permissible displacement of VA in TF), along with LPVA were considered to be protective parameters against VA injury if lateral pedicle breach happens.PW was 4.7 mm at C3, 4.83 mm at C4, 5.26 mm at C5 and 5.41 mm at C6. Mean LPVA at different levels was between 0.97 mm and 1.15 mm, OR was around 20% at all levels, and mean SM was between 2.34 mm and 2.92 at various levels. Sex differences were statistically significant for PW but not for LPVA, SM, or OR.This study gives us an idea about the various parameters in placement of cervical pedicle screw in subaxial cervical spine and the probable reasons there are few vertebral artery injuries despite high incidence of cervical pedicle breach. LPVA, safety margin, and OR may explain why even very significant CPS misplacement does not lead to vascular injury or neurologic deficit.

Hemiballism a Case Report and Literature Review

The term ballism derives from the Greek word ballistēs which translates as throw. Ballism is one of the abnormal movements reported in the medical literature, characterized by the involuntary, non-purposeful action of a limb, in a repetitive, sudden, centrifugal way, and when it affects the upper and lower limbs together ipsilaterally in a patient is called hemiballism, this neurological manifestation is part of the so-called abnormal hyperkinetic movements. The objective of our report is to present the clinical picture of a patient with hemiballism who jointly presents cerebrovascular alterations and the use of dopaminergic drugs. He is a male of 79 years old, with a history of chronic degenerative diseases such as, systemic hypertension, diabetes mellitus type II, cerebrovascular disease, hyperlipidemia, vascular cognitive deficit and apparently Parkinson's disease, which presented abnormal movements of sudden onset, of insidious progression, to the left side of the uncoordinated type, abrupt, thick, centrifugal, causing disability in their bodily functioning and deteriorating their quality of life. This picture began after the increase in the medicines used for the diagnosis of Parkinson's disease. The diagnosis of Hemiballism was established and medical treatment based on Haloperidol and reduction of the antiparkinsonic drug was provided, showing an important improvement evidenced in the attached video. A review of the anatomical, histological, physiological and pathophysiological aspects related to this type of pathology is made emphasizing the relationship of the direct and indirect pathways of the extrapyramidal system used for the modulation of the corporal movement by the primary motor system.

Meningovascular syphilis in recurrent stroke: A case report

Syphilis is a known cause of tardive vasculitis which has preference over aortic and intracranial vessels. It may lead to vascular deficit and subsequent stroke.

Determination of Availability of Safety Margin for Placement of C3-C6 Pedicle Screw on CT Angiography

Cervical pedicle screws (CPS) in the subaxial cervical spine (C3-C6) are faced with high incidence of perforating the lateral pedicular cortex endangering the vertebral artery (VA). The present study analyzes the pedicle width (PW) from C3 to C6 and defines the relation of VA with regard to pedicle and transverse foramen (TF) to determine the safety margin in cases of lateral pedicular breach. Computed tomography angiograms of 500 patients were retrospectively studied to identify the pedicle width (PW), VA area, TF area, and the lateral pedicle to vertebral artery distance (LPVA). Occupancy ratio (OR; the percentage area of transverse foramen occupied by VA) and safety margin (SM; permissible displacement of VA in TF), along with LPVA were considered to be protective parameters against VA injury if lateral pedicle breach happens. PW was 4.7 mm at C3, 4.83 mm at C4, 5.26 mm at C5 and 5.41 mm at C6. Mean LPVA at different levels was between 0.97 mm and 1.15 mm, OR was around 20% at all levels, and mean SM was between 2.34 mm and 2.92 at various levels. Sex differences were statistically significant for PW but not for LPVA, SM, or OR. This study gives us an idea about the various parameters in placement of cervical pedicle screw in subaxial cervical spine and the probable reasons there are few vertebral artery injuries despite high incidence of cervical pedicle breach. LPVA, safety margin, and OR may explain why even very significant CPS misplacement does not lead to vascular injury or neurologic deficit.

Outer retina dysfunction and choriocapillaris impairment in type 1 diabetes

To study the outer retina morpho-functional characteristics and the choriocapillaris (CC) features in type 1 diabetic (T1D) patients, with and without signs of diabetic retinopathy (NPDR and NoDR). Twenty-five NPDR and 18 NoDR eyes were imaged by Optical Coherence Tomography Angiography. Ellipsoid zone (EZ) “normalized” reflectivity and CC perfusion density parameters, as flow deficits number (FDn), flow deficit average area (FDa) and flow deficit percentage (FD%), were analysed. Multifocal electroretinogram (mfERG) response amplitude densities (RADs) were measured. Mean EZ “normalized” reflectivity, CC FDn and FD% values, were similar (p > 0.05) in both groups, FDa was significant greater (p > 0.05) in NPDR compared with NoDR eyes. MfERG-RADs were similar in both groups. NPDR eyes showed a significant (p < 0.05) linear correlation between RADs and both, CC FDa and FD%. The EZ “normalized” reflectivity was negatively correlated with CC FD% in NoDR eyes. In NPDR T1D eyes a significant relationship between abnormal outer retina functional responses and CC impairment was observed, while in NoDR eyes the photoreceptor reflectivity was correlated to CC abnormalities. The outer retina dysfunction in NPDR correlated to CC drop-out let hypothesize that the outer retinal elements are functionally impaired in proportion to the CC vascular supply deficit.

Carfilzomib-Induced Hypertension Is Mediated By Ion Channel Dysregulation in the Kidneys; The Potent Role of AMP-Activated Kinase α

Introduction: Carfilzomib (Cfz), an irreversible proteasome inhibitor (PI), is an approved agent against relapsed/refractory multiple myeloma (R/R MM). Cfz is associated with high incidence of cardiovascular adverse effects. Hypertension stands as the most frequent cardiovascular complication of Cfz. Even though thrombotic microangiopathy (TMA) is inculpated of Cfz's hypertensive phenotype, its exact pathophysiology is still elusive. In our previous work, we showed that Cfz establishes cardiotoxicity in vivo in a Protein Phosphatase 2A (PP2A)-AMP-activated kinase α (AMPKα)-dependent manner (Efentakis P et al. Blood. 2019;133(7):710-723) but does not lead to a permanent vascular deficit, indicating that hypertension is not vascular derived [Efentakis P et al. IJMS 2020;21(15):E5185]. Taking under consideration that renal homeostasis plays an important role in blood pressure regulation we sought to (i) characterize the dose-dependent manifestation of Cfz-induced hypertension; (ii) investigate the molecular signaling of Cfz in the kidneys by proteomic and immunoblotting analyses and (iii) study the renal ion channels regulation. Methods: Forty C57Bl/6 mice (12-14 weeks of age) were randomly assigned to: (i) Acute Protocol: a. Control [Normal Saline (N/S) 0.9%] and b. Cfz (8mg/kg) for two days and (ii) Sub-acute Protocol: a) Control (N/S 0.9%,) and b) Cfz (8mg/kg) for seven days. Intraperitoneal administration of N/S 0.9% and Cfz was performed at two consecutive and on alternate days for the acute and sub-acute protocols respectively. At baseline and endpoint of the experiments, systolic (SBP) and diastolic blood pressure (DBP) were measured, and subsequently mice were sacrificed for the collection of blood and renal samples. Blood samples were collected in citrate buffer for hematological/coagulation profiling [prothrombin time (PT) and INR estimation] and for cleaved Von Willebrand Factor (cl. VWF) immunoblotting assessment as well as for blood testing of white blood cells (WBCs) and platelets. Renal samples underwent histological proteomic and molecular analyses. Results: SBP and DBP were found to be elevated in Cfz group only in the sub-acute protocol compared to control (SBP: 78.5±2.0 vs 68.2±0.7, p&amp;lt;0.01 and DBP: 104.1±2.3 vs 97.4±2.4, p&amp;lt;0.05, respectively). Neutrophil count in the whole blood was elevated both in the acute and sub-acute protocols, while platelet count was decreased in the acute protocol and restored after sub-acute Cfz administration. Mice presented a thrombotic phenotype characterized by increased PT and INR and decreased cl. VWF after acute Cfz treatment, and a hemorrhagic phenotype with restored cl. VWF after sub-acute Cfz administration. However, the presence of TMA was not confirmed by histological evaluation of the kidneys in any of the protocols. Nonetheless histological evaluation of the kidneys revealed inflammation of the perirenal adipose tissue only in the sub-acute protocol. Proteomic analysis presented that proteasome regulation, metabolism and transport of organic anion processes are affected by Cfz administration. Molecular analysis of the renal tissue showed that Cfz induced an increase in the inducible nitric oxide synthase (iNOS) and microtubule-associated proteins 1A/1B light chain 3B (LC3-B) expression and a decreased AMPKα phosphorylation. Moreover, RT-PCR analysis of the renal samples revealed that collecting duct ion channels epithelial Na+ channel (ENaC), Na+/K+/ATPase and urea transporter 1 (UTA-1) mRNA levels were increased in Cfz group. Conclusion: Sub-acute Cfz treatment establishes a renal-derived hypertensive phenotype and a circulating inflammatory phenotype as indicated by the increased neutrophil and WBCs count in the blood. TMA does not seem to be implicated with the observed phenotype in vivo as investigated molecularly and histologically. Cfz-induced dephosphorylation of AMPKα and the subsequent dysregulation of the collecting duct renal ion channel homeostasis is found to be responsible for the observed effect. Therefore, Cfz seems to induce hypertension by a dysregulation of water-ion re-absorbance leading to increased cardiac preload. The latter comes in agreement with clinical data showing that some Cfz-treated patients present with fluid retention, which can be attributed to the aforementioned renal effects of the drug. Disclosures Efentakis: Amgen: Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Dimopoulos:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. Andreadou:Amgen: Research Funding. Terpos:Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Sanofi: Honoraria; BMS: Honoraria.

P1501KIDNEY FAILURE AND BRAIN FUNCTION DECLINE

Abstract Background and Aims: Chronic kidney disease (CKD) and cognitive impairment (CI) are two major health problems in an aging population, and both carry out negative prognostic implications. Prevalence in general population appears to be around 22.2% and recent analysis indicates that CI and frailty can be more prevalent in individuals undergoing hemodialysis (HD). Many causes can contribute to this higher prevalence, from vascular calcification to cerebral hypoperfusion, oxidative damage and uremic toxins. Both frailty and CI can lead to an increase morbimortality. Montreal Cognitive Assessment (MoCA) and Mini Mental State Examination (MMSE) are two screening instruments with a good application profile for cognitive evaluation, as well as the Frailty Clinical Scale (FCS). However, there are few studies using these scales on HD patients and demonstrating association between frailty, cognitive impairment and their clinical characteristics. The aim of this study is to investigate the prevalence of coexisting cognitive impairment and frailty in our center hemodialysis patients and its association with clinical characteristics and outcomes. Method: Thirty-two patients undergoing hospital hemodialysis program were assessed. The MoCA scale, MMSE and FCS were applied. Data were analyzed using appropriate statistical methods, using SPSS ® version 22.0. The significance level considered was 5%. Results: Thirty-two patients aged between 30 and 90 years were evaluated, with a mean of 61.63 years (SD ± 18.26), without gender predominance. The prevalence of deficits was 78.1% and 37,5% in MoCA and MMSE, respectively, without differences between gender. The prevalence of frailty (≥3) was 43.8%. Patients with deficit assessed by MoCA and MMSE were on average 15 years and 20 years older, respectively, than patients without deficit (p = 0.002). We found a statistically significant association between deficit measured by MMSE and frailty (p &amp;lt;.001), with higher prevalence of frailty (83.3%) in individuals with deficit compared to individuals without deficit, where the prevalence of frailty was 20.0%. The deficit assessed by MMSE was also associated with time on dialysis (p = .029). No statistically significant associations were detected between MoCA and frailty over time on dialysis or between deficit measured by MoCA and frailty. Regarding patients’ comorbidities, there were no statistically significant differences between deficit assessed by MoCA and MMSE and presence of diabetes mellitus, hypertension and dyslipidemia. Deficits assessed by MoCA, MMSE, and Frailty were not associated with phosphoremia and also there was no association between presence of significative hypotension episodes during HD and these scales. Dialysis efficacy (kt/v) was not statistically associated with MoCA and MMSE deficits. Similarly, no association was found between Kt / v and frailty. Conclusion: In our study, prevalence of CI and frailty in hemodialysis patients was high. Time on dialysis program was related in a statistically significant way with CI and there was higher prevalence of frailty in individuals with deficit measured by MMSE. However, we did not find a correlation between dialysis efficacy, comorbidities and vascular risk factors and cognitive deficit or frailty score. The epidemiology and natural history of cognitive impairment and its association with frailty are important to understand among patients on HD for early intervention and management.

Nandrolone decanoate in induced fracture nonunion with vascular deficit in rat model: morphological aspects.

The nonunion fracture is a relatively frequent complication in both human and veterinary medicine. Specifically, atrophic fracture nonunions are difficult to treat, with revision surgery usually providing the best prognosis. Anabolic steroids, such as nandrolone decanoate (ND), have been reported to have beneficial clinical effects on bone mass gain during osteoporosis; however, their utility in promoting regeneration in atrophic nonunions has not been documented. Our objective was to examine morphological changes induced by the ND in experimental fracture nonunion with vascular deficit in the rat model. Fourteen adult Wistar rats had an atrophic fracture nonunion induced in the diaphysis of their left femur. Rats were allocated into two groups: control group and nandrolone decanoate group. Rats in the latter group were given nandrolone decanoate (1.5mg/kg IM, once a week, during 4weeks after confirmation of fracture nonunion radiographically). Radiographic and anatomopathological examination, micro-tomography and histological analysis were assessed to characterize the morphological changes promoted by the nandrolone decanoate use. Based on radiology, anatomopathological evaluation, computed micro-tomography and conventional microscopy, nandrolone decanoate promoted bone regeneration at the fracture nonunion site by increasing the cellularity at the fracture site. Percentage of collagen was not significantly different between groups, consistent with high-quality regenerated bone. The anabolic steroid nandrolone decanoate improved bone mass and regeneration without affecting collagen production and therefore has potential for improving outcomes for atrophic fracture nonunion.

Efficacy of PASS Reading Enhancement Programme on Neuropsychological Functions of a Child with Mild Vascular Neurocognitive Disorder and Comorbid Attention Deficit Hyperactivity Disorder: A Case Study.

Background:PASS Reading Enhancement Programme (PREP), a reading enhancement tool focusing on successive and simultaneous processing tasks, has been used successfully to improve the information processing strategies that underlie reading. The study explored the effects of training with successive processing task of PREP on various cognitive and neuropsychological functioning of an 8-year-old child with mild vascular neurocognitive disorder with comorbid attention deficit hyperactivity disorder.Materials and Methods:A pre–post intervention single case design was used. AIIMS Comprehensive Neuropsychological Battery in Hindi, Children's Form was used to assess the baseline performance on various neuropsychological domains. After 25 sessions of weekly outpatient-based training with PREP, reassessment was done using the same test battery.Results:Results indicated posttraining global improvement in the neuropsychological functioning like receptive and expressive speech, intellectual processes, memory, and reading and writing abilities.Conclusion:Cognitive remediation programs focusing on training in successive processing could be used in the enhancement of overall neuropsychological functioning in children with neurocognitive disorder.