Rapid Functional Deterioration Research Articles

Sex similarities and differences in the reverse and anti-remodeling effect of pressure unloading therapy in a rat model of aortic banding and debanding.

Investigating the effect of sex on pressure unloading therapy in a clinical scenario is limited by several nonstandardized factors. Hence, we sought to study sex-related similarities and differences under laboratory conditions. Pressure overload was induced in male and female rats by aortic banding (AB) for 6 and 12 wk. Age-matched sham-operated animals served as controls. Pressure unloading was performed by aortic debanding at week 6. Different aspects of myocardial remodeling were characterized by echocardiography, pressure-volume analysis, histology, qRT-PCR, and explorative proteomics. Hypertrophy, increased fetal gene expression, interstitial fibrosis, and prolonged active relaxation were noted in the AB groups at week 6 in both sexes. However, decompensation of systolic function and further deterioration of diastolic function only occurred in male AB rats at week 12. AB induced similar proteomic alterations in both sexes at week 6, whereas characteristic differences were found at week 12. After debanding, regression of hypertrophy and recovery of diastolic function took place to a similar extent in both sexes. Nevertheless, fibrosis, transcription of β-myosin-to-α-myosin heavy chain ratio, and myocardial proteomic alterations were reduced to a greater degree in females than in males. Debanding exposed anti-remodeling properties in both sexes and prevented the functional decline in males. Female sex is associated with greater reversibility of fibrosis, fetal gene expression, and proteomic alterations. Nevertheless, pressure unloading exposes a more pronounced anti-remodeling effect on the functional level in males, which is attributed to the more progressive functional deterioration in AB animals.NEW & NOTEWORTHY The present study is the first to assess the role of sex on pressure unloading-induced reverse and anti-remodeling in a rat model of aortic banding and debanding. Our data indicate that female sex is associated with a greater reversibility of fibrosis, fetal gene expression, and proteomic alterations compared with males. Nevertheless, pressure unloading exposes more anti-remodeling effect on the functional level in males, which is attributed to the more rapid functional deterioration in aortic-banded animals.

A Normal FGF23 Does Not Preclude Tumor-Induced Osteomalacia.

ABSTRACTTumor‐induced osteomalacia (TIO) is a rare cause of impaired bone mineralization mediated by the osteocyte‐derived, phosphaturic hormone: fibroblast growth factor 23 (FGF23). The case is presented of a previously healthy 45‐year‐old man who developed fragility fractures at multiple sites (initially metatarsals, eventually ribs, hips, spine, scapula, and sacrum) resulting in rapid functional deterioration, weakness, and the inability to bear weight and ambulate without a walker. Workup for secondary causes of bone loss was negative except for mild hypogonadotropic hypogonadism with normal pituitary MRI and hypophosphatemia that persisted despite aggressive supplementation. Testosterone was initiated but discontinued 6 months later because of deep vein thrombosis and pulmonary embolism, likely provoked by his new sedentary state, in addition to smoking history and possibly testosterone usage. Serum FGF23 was nonelevated at 138 mRU/mL (44–215). A genetic panel for OI variants was negative for a causal mutation. At the age of 48, 3 years after his initial fracture, he was referred to our academic endocrine clinic. We ruled out additional mutations that lead to hypophosphatemic rickets, including phosphate‐regulating endopeptidase homolog, X‐linked. PET/CT looking for a potential TIO locus revealed uptake in the left suprapatellar recess. Biopsy was consistent with a phosphaturic mesenchymal tumor. FGF23 was repeated for a preoperative baseline and now found to be elevated at 289 mRU/mL. In retrospect, it is likely that the initial level was inappropriately elevated for the degree of hypophosphatemia. After resection, he experienced marked improvement in physical function, decreased pain, and resolution of renal phosphate wasting. The principals of establishing a robust clinical diagnosis of TIO should be emphasized, excluding other entities and avoiding pitfalls in the interpretation of laboratory testing. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Patrones de detección del deterioro cognitivo leve en enfermería

Mild cognitive impairment (MCI) is characterized by an acquired cognitive loss that places individuals, mainly older adults, in an intermediate stage between normal cognitive functioning and dementia. This impairment has a high risk of progression to dementia and is suitable for screening, which allows more effective early intervention. Nursing professionals, especially community-based primary care nurses, play an important role in the detection and follow-up of MCI and in interventions for this condition. The first step should be to take a thorough history from both the patient and his or her carers, which should assess the changes occurring in the patient's daily, family and social life through functional patterns. In subsequent assessment of cognitive function, brief screening tests can be used such as the Mini Mental State Examination (MMSE) or other similar tests. Special attention should be paid to the presence of affective or depressive symptoms, sensory deficits, polypharmacy, decompensated cardiovascular risk factors, and rapid functional deterioration, given their particular influence on MCI. Finally, various nurse-led, non-pharmacological interventions that are effective in MCI can be recommended, based on cardiovascular risk factor control, physical exercise, and cognitive and psychosocial interventions.

Longitudinal Memory Profiles in Behavioral-Variant Frontotemporal Dementia and Alzheimer’s Disease

Alzheimer's disease (AD) and behavioral-variant of frontotemporal dementia (bvFTD) can present with an overlapping neuropsychological profile, which often hinders their clinical differentiation. To compare changes over time in memory, general cognition tasks, and functional scales between bvFTD and AD. Consecutive cases diagnosed with probable bvFTD (n = 22) and typical AD (n = 31) with at least two clinical visits were selected. Of these, 13 (9 AD, 4 bvFTD) underwent Pittsburgh compound B PET scan, which supported the clinical diagnosis in all cases. Mixed-model regressions were used to estimate the differential rate of decline on selected tasks between cohorts. Analyses demonstrated that, despite equivalent baseline performance, bvFTD patients experienced a more rapid functional deterioration and a steeper decline in global cognition than AD patients. At baseline, both groups were impaired on executive function and memory tasks compared to controls, but these deficits were more marked in the bvFTD group. In addition, performance on these domains continued to decline more rapidly in this group. Neither the initial neuropsychological assessment nor projected performances can reliably distinguish the totality of bvFTD and AD individuals. Nevertheless, annual rates of progression on cognitive tasks provide valuable information and will potentially help establish the impact of future therapeutic treatments in these dementia syndromes.

Changes in Retinal Nerve Fiber Layer Reflectance Intensity as a Predictor of Functional Progression in Glaucoma.

PurposeWe determined whether longitudinal changes in retinal nerve fiber layer (RNFL) reflectance provide useful prognostic information about longitudinal changes in function in glaucoma.MethodsThe reflectance intensity of each pixel within spectral-domain optical coherence tomography (SD-OCT) circle scans was extracted by custom software. A repeatability cohort comprising 53 eyes of 27 participants (average visual field mean deviation [MD] −1.65 dB) was tested five times within a few weeks. To minimize test–retest variability in their data, a reflectance intensity ratio was defined as the mean reflectance intensity of pixels within the RNFL divided by the mean between the RNFL and RPE. This was measured in a separate longitudinal cohort comprising 310 eyes of 205 participants tested eight times at 6-month intervals (average MD, −0.99 dB; median rate of change, −0.09 dB/y). The rate of change of this ratio, together with the rate of RNFL thinning, and their interaction, were used to predict the rate of change of MD.ResultsIn univariate analyses, the rate of RNFL thinning was predictive of the rate of MD change (P < 0.0001), but the rate of change of reflectance intensity ratio was not (P = 0.116). However, in a multivariable model, the interaction between these two rates significantly improved upon predictions of the rate of functional change made using RNFL thickness alone (P = 0.038).ConclusionsFor a given rate of RNFL thinning, a reduction in the RNFL reflectance intensity ratio is associated with more rapid functional deterioration. Incorporating SD-OCT reflectance information may improve the structure–function relation in glaucoma.

Cell sources, liver support systems and liver tissue engineering: alternatives to liver transplantation.

The liver is the largest organ in the body; it has a complex architecture, wide range of functions and unique regenerative capacity. The growing incidence of liver diseases worldwide requires increased numbers of liver transplant and leads to an ongoing shortage of donor livers. To meet the huge demand, various alternative approaches are being investigated including, hepatic cell transplantation, artificial devices and bioprinting of the organ itself. Adult hepatocytes are the preferred cell sources, but they have limited availability, are difficult to isolate, propagate poor and undergo rapid functional deterioration in vitro. There have been efforts to overcome these drawbacks; by improving culture condition for hepatocytes, providing adequate extracellular matrix, co-culturing with extra-parenchymal cells and identifying other cell sources. Differentiation of human stem cells to hepatocytes has become a major interest in the field of stem cell research and has progressed greatly. At the same time, use of decellularized organ matrices and 3 D printing are emerging cutting-edge technologies for tissue engineering, opening up new paths for liver regenerative medicine. This review provides a compact summary of the issues, and the locations of liver support systems and tissue engineering, with an emphasis on reproducible and useful sources of hepatocytes including various candidates formed by differentiation from stem cells.

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study

ObjectiveTo investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS).MethodsA cross-sectional study involving 136...

Pathophysiology, Diagnosis and Clinical Management of Hepatorenal Syndrome: From Classic to New Drugs

Advanced cirrhosis is frequently associated with renal dysfunction. Hepatorenal syndrome (HRS) is characterized by the occurrence of kidney injury in cirrhotic patients in the absence of other identifiable causes. HRS is classified in 2 different types. Type 1 is characterized by acute renal failure and rapid functional deterioration of other organs, usually related to a precipitating event. Type 2 is characterized by slowly progressive renal failure and refractory ascites. Advanced liver disease induces the progression of hemodynamic alterations such as arterial vasodilation of splanchnic circulation and impairment of cardiac function. The resulting ineffective circulating blood volume promotes the activation of both the renin-angiotensin-aldosterone and sympathetic nervous system, by an increase of antidiuretic hormone activity, in an attempt to restore volemia. Despite fluid retention, ascites and dilutional hyponatremia, renal function is often initially preserved by renal production of vasodilators. However, further insults can lead to an imbalance between systemic vasoconstriction and local renal vasodilation, resulting in progressive renal failure. Over the last decade, clinical strategies to prevent HRS have been improved by a better understanding of the natural history of renal failure in cirrhosis, resulting in a reduction of HRS prevalence in cirrhotic patients. Vasoconstrictor drugs may improve renal function, but the effect on mortality has not yet been established. Vaptans, nonpeptide vasopressin receptor antagonists, may also reduce hyponatraemia and ascites, even if the clinical effects in HRS remain unknown. This review updates the pathophysiology, diagnosis and management of HRS.

Rapidly Destructive Inflammatory Arthritis of the Hip

Rapidly destructive coxarthrosis (RDC) is a rare syndrome that involves aggressive hip joint destruction within 6–12 months of symptom onset with no single diagnostic laboratory, pathological, or radiographic finding. We report an original case of RDC as an initial presentation of seronegative rheumatoid arthritis (RA) in a 57-year-old Caucasian woman presenting with 6 months of progressive right groin pain and no preceding trauma or chronic steroid use. Over 5 months, she was unable to ambulate and plain films showed complete resorption of the right femoral head and erosion of the acetabulum. There were inflammatory features seen on computed tomography (CT) and magnetic resonance imaging (MRI). She required a right total hip arthroplasty, but arthritis in other joints showed improvement with triple disease modifying antirheumatic drugs (DMARD) therapy and almost complete remission with the addition of adalimumab. We contrast our case of RDC as an initial presentation of RA to 8 RDC case reports of patients with established RA. Furthermore, this case highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration.

Extracorporeal Lung Perfusion and Ventilation to Improve Donor Lung Function and Increase the Number of Organs Available for Transplantation

IntroductionEx vivo lung perfusion (EVLP) has been validated as a valuable technique to increase the pool of organs available for lung transplantation. Material and MethodsAfter a preclinical experience, we obtained permission from the Ethics Committee of our institution to transplant lungs after EVLP reconditioning. ABO compatibility, size match, and donor arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ≤ 300 mm Hg were considered to be inclusion criteria, whereas the presence of chest trauma and lung contusion, evidence of gastric content aspiration, pneumonia, sepsis, or systemic disease were exclusion criteria. We only considered subjects on an extra corporeal membrane oxygenation (ECMO) bridge to transplantation with rapid functional deterioration. Using Steen solution with packed red blood cells oxygenated with 21% O2, 5% to 7% CO2 was delivered, targeted with a blood flow of approximately 40% predicted cardiac output. Once normothermic, the lungs were ventilated with a tidal volume of 7 mL/kg a PEEP of 5 cmH2O and a respiratory rate of 7 bpm. Lungs were considered to be suitable for transplantation if well oxygenated [P(v-a) O2 > 350 mm Hg on FiO2 100%], in the absence of deterioration of pulmonary vascular resistance and lung mechanics over the perfusion time. ResultsFrom March to September 2011, six lung transplantations were performed, including two with EVLP. The functional outcomes were similar between groups: at T72 posttransplantation, the median PaO2/FiO2 were 306 mm Hg (range, 282 to 331 mm Hg) and 323 mm Hg (range, 270 to 396 mm Hg) (P = 1, EVLP versus conventional). Intensive care unit ICU and hospital length of stay were similar (P = .533 and P = .663, respectively) with no mortality at 60 days in both groups. EVLP donors were older (49 ± 6 y versus 21 ± 7 y, P < .05), less well oxygenated (184 ± 6 mm Hg versus 570 ± 30, P < .05), displaying higher Oto scores (9.5 ± 0.7 versus 1.7 ± 1.5, P < .05). ConclusionsThe first 6 months of the EVLP program allowed us to increase the number of organs available for transplantation with short-term outcomes comparable to conventional transplantations.

The Rehabilitation of Children with Anti–N-methyl-D-aspartate–Receptor Encephalitis

Anti-N-methyl-D-aspartate (NMDA)-receptor encephalitis is a serious, complex, and potentially fatal disease in children. Children with this condition frequently present with altered mental status, rapid functional deterioration, and seizures. Despite aggressive treatment with immune therapy such as corticosteroids, intravenous immunoglobin, and plasmapheresis, children often need extensive rehabilitative services and can be left with lasting deficits. In this case series, we report on six known consecutive pediatric cases of N-methyl-D-aspartate-receptor antibody encephalitis in Northern California requiring comprehensive inpatient rehabilitation. The children presented with a variety of symptoms and had waxing and waning clinical courses. All children progressed well through their rehabilitation programs but were discharged home with persistent functional deficits. At follow-up, all but one child had lasting deficits. Because of the complicated management and extensive rehabilitation needs of children with anti-N-methyl-D-aspartate-receptor encephalitis, physiatrists and other rehabilitation providers should be knowledgeable about this complex condition.

Histological Validation of Heart Slices as a Model in Cardiac Research

Recently vibratome-cut heart slices has been proposed as a new model in cardiac research, particularly in studying functional integration of transplanted donor stem cells into the host myocardium. This emerging model has, over co-culture models, a theoretical advantage in maintaining the 3-dimensional cardiac structure and physiological cell-cell connections; however, further validation is needed for this to be an established model. Particularly, the ability of cardiomyocytes in heart slices to connect with administered donor cells remains uncertain. Heart slices of 300 μm thickness were cut from adult and embryonic rat hearts using a vibratome and cultured. Adult heart slices maintained localized contraction for up to 3 days. Various histological studies demonstrated that the myocardial morphology was well preserved with necrotic cells being restricted to the edges of slices, but the number of apoptotic cells in the slices increased with culture periods (16.0 ± 3.2% at day 2 and 59.1 ± 8.3% at day 6). Importantly, immunohistolabeling and western blotting showed that connexin43 expression, which is a prerequisite for gap junction formation between donor-derived and host cardiomyocytes, was markedly diminished by 1 day in culture, suggesting rapid functional deterioration of adult heart slices. In contrast, embryonic heart slices remained contracting at least for 35 days with myocardial morphology and connexin43-involved gap junctions remaining intact, though in the embryonic, immature pattern. Collectively, both adult and embryonic rodent heart slices, in the current style, have critical limitations to assess integration between donor-derived and host cardiomyocytes. Further study to improve the quality of heart slices is warranted.

Wnt Signaling Molecules in Left Ventricular Remodeling

Under acute or chronic stresses, the adult heart undergoes a remodeling process that involves cardiomyocyte hypertrophy accompanied by apoptosis, necrosis, and fibrosis that lead to impaired cardiac contractility. The role of endogenous regeneration in this process is currently under investigation. Sustained deleterious stimuli will lead to a decompensated form of hypertrophy often culminating in heart failure.1 This form of hypertrophy is often referred to as “maladaptive.” When dealing with hypertrophy, it appears important to distinguish between the term being used on the cellular and molecular level (enlargement of individual cardiomyocytes and re-expression of fetal/embryonic genes) and the organ level (increased heart weight, left ventricular wall thickness, and functional diastolic and systolic impairment). In our view, these processes are certainly linked but not identical. Hypertrophy on the organ levels summarizes several independent cellular and molecular processes (see below), where cardiomyocyte growth is not necessarily the most important. Independent of its origin, cardiac hypertrophy is associated with alterations in cardiac geometry, mass, architecture, and function controlled by a complex network of interconnected and abundant signal-transduction pathways.2 New signaling molecules are emerging as possible targets to specifically attenuate maladaptive hypertrophy. Pathological, stress-induced growth of cardiomyocytes was shown to depend on Wnt/β-catenin nuclear signaling rather than its adhesive function in cell adhesion. However, the specificity of the cell type and the molecular mechanisms governing the Wnt signaling–dependent changes are currently unknown.3 In this issue of the Hypertension , the study by Malekar et al4 provides new evidences concerning the …

Natural History of Very Severe Aortic Stenosis

We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67 + or - 16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) > or = 5.0 m/s (average AV-Vel, 5.37 + or - 0.35 m/s; valve area, 0.63 + or - 0.12 cm(2)). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel > or = 5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel > or = 5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

10.4172/2329-9126.1000331

Background: Spinal Dural Arteriovenous Fistulae (SDAVF) cause usually slowly progressive myelopathy. Specific descriptions of SDAVF with rapid functional deterioration are still lacking in the literature and are purpose of this study. Material and Methods: We retrospectively evaluated data of 59 SDAVF patients who were treated in our institution between 2006 and 2016. Based on clinical course, we dichotomized our cohort in two groups; a) patients with rapid functional deterioration within a period of 0-6 months, b) patients with slowly progressive functional deterioration within a period of more than 6 months. Motor disabilities were rated according to the modified Aminoff- Longue disability score (AL-score) as follows: 1) mild: AL-score 0-1, 2) moderate: AL-score 2-3, 3) severe: AL-score 4-5. Alterations of the perimedullar veins were rated subjectively as absent, mild or prominent. Follow-up analysis was performed via telephone survey. Results: Complete data of forty patients was eligible for this analysis. Thirteen and twenty-seven patients were included in group (a) and (b) respectively. The durations of symptom differed significantly between both groups (p=0.02). AL-scores showed no significant differences between both groups at time of diagnosis. However, patients group (a) presented more prominent perimedullar veins at time of diagnosis and better outcome at the last follow-up. Conclusion: Early diagnosis and treatment of SDAVF might decrease the risk of further irreversible damages of the spinal cord and result in a better outcome regardless of the functional condition at time of diagnosis. Further histopathological studies are acquired to improve our understanding of this rare but serious disease.

A New Model of Photochemically Induced Acute and Reversible Demyelination in the Peripheral Nervous System

Acute photochemical demyelination accompanied by minor axonal degeneration was produced in rat sciatic nerve after topical application of the photosensitive dye Rose Bengal and focal illumination with cold light. Animals were sacrificed at different time periods after challenge and the exposed nerves prepared for light microscopic and ultrastructural evaluation. Important structural changes were already observed at 4-6 h. These included endoneurial swelling, diapedesis of neutrophils and monocytes, vacuolization and vesicularization of Schwann cell cytoplasm, lamellar separation of myelin sheaths, disintegration of axonal microtubules, and accumulation of vesicular material and mitochondria in the axoplasm. Disrupted myelin fragments were phagocytosed by macrophages which penetrated Schwann tubes at Day 3. Schwann cells proliferated and started to enwrap denuded segments of the axon. They were surrounded by redundant basal lamina, thrown into deep folds. Axons remained partly hypertrophic and contained many neurofilaments. A minority showed signs of degeneration. At Days 5-7 denudation was almost complete in the light-exposed nerve area but also in small distal nerve fascicles. After 1 month, axons in the illuminated area and distal to it were completely remyelinated although they had thinner sheaths. Exposure to increased light intensity resulted in deeper lesions and more extended anterograde damage, which also recovered within 1 month. All animals showed rapid functional deterioration which correlated with the severity and extent of structural damage. Recovery was slow and also depended on the degree of histologic damage. Neither control nerves nor sham-exposed nerves revealed signs of structural or functional changes. The present photochemical neuropathy model may be valuable for the study of the pathophysiology of demyelination and remyelination and the pharmacology of therapeutic or symptomatic intervention.

THE SIGNIFICANCE OF THE ANTI–CLASS I RESPONSE

Although the ability of preformed anti-class I antibodies to mediate hyperacute rejection is well established, their pathogenic role in acute rejection remains ill-defined. We set out to identify patients with anti-class I against donor cells and to define the clinical and pathological features of such patients. We collected sera pretransplant and in the first 3 months posttransplant from 64 renal transplant recipients (59 cadaver donors and 5 one-haplotype matched living-related donors). We assayed the sera for class I-like antibody against donor T cells in complement-dependent microcytotoxicity, with crossmatches against autologous T cells to exclude auto-antibodies. All pretransplant sera were negative against donor T cells. Of the 797 sera tested posttransplant, 131/195 sera from 13 patients were positive, and 602 sera from 51 patients were negative. All patients who formed anti-class I underwent rejections compared with only 41% of patients with no anti-class I detected (P less than 0.0005). More rejections in patients with anti-class I were classed as severe (12/15 [80%] compared with 9/28 [32%] P less than 0.005), and graft loss was significantly higher (5/13 vs. 2/51; P less than 0.002). Rejections associated with anti-class I occurred earlier; more frequently developed oliguria (35% versus 10%) and required dialysis (40% versus 10%) and biopsies (10/13 vs. 6/28); and had a higher rate of rise in serum creatinine (249 versus 79 microns/L in the first 48 hr). Biopsies during anti-class I positive rejections more frequently displayed endothelial injury in the microcirculation, neutrophils in the glomeruli and/or peritubular capillaries, and fibrin deposition in glomeruli or blood vessels. The biopsies in anti-class I negative rejection episodes tended to have tubulitis, interstitial infiltration, and blasts, suggesting that these lesions reflect T-cell-mediated mechanisms. We conclude that patients with antibody against donor class I had more severe rejection, probably because anti-class I injuries the endothelium of small blood vessels of the graft, leading to rapid functional deterioration. We believe that anti-class I may be a major factor in some severe rejection episodes.