The natural history of isolated common femoral endarterectomy for chronic limb-threatening ischemia.

OBJECTIVE: Occlusive disease of the common femoral artery can generate profound lower extremity ischemia as the normal collateral pathways from the profunda to the superficial femoral artery cannot adequately develop. In patients with lifestyle-limiting claudication, isolated common femoral endarterectomy (CFE) is highly effective. Because CFE does not provide direct, in-line flow to the plantar arch, it has been felt to provide inadequate revascularization to patients with chronic limb-threatening ischemia (CLTI). The purpose of this retrospective clinical study was to report and assess the natural history of selected patients with CLTI treated with isolated CFE (without concomitant infrainguinal revascularization). METHODS: Consecutive CFEs performed in a large, urban hospital for CLTI between 2014 and 2021 were reviewed. Patient characteristics, limb, and anatomical stages using the Wound, Ischemia, foot Infection (WIfI) and Global Limb Anatomic Staging System were tabulated. Limb-specific and survival-related end points were analyzed. RESULTS: Fifty-eight patients presenting with CLTI underwent isolated CFE (mean age, 74 ± 10 years; 62% male, 90% current or prior smoker). Comorbidities included diabetes (52%), coronary artery disease (55%), congestive heart failure (22%), and end-stage renal failure on hemodialysis (5%). Patients presented with either rest pain (36%) or tissue loss (64%); the latter group exhibited advanced limb threat (68% in WIfI stage 3 or 4). The majority of patients had associated severe infrainguinal disease (50% Global Limb Anatomic Staging Systems 3). After a median follow-up of 17 months (range, 10-29 months), vascular reintervention was required in 7 patients (12%). One patient (2%) required major limb amputation after presentation in WIfI stage 4 (W3I3fI0). Indeed, WIfI stage 4 was a significant univariate predictor of the need for subsequent infrainguinal bypass (P = .034). CONCLUSIONS: Isolated CFE as primary therapy in highly selected patients with CLTI was safe and effective. Index limb stage is predictive of the need for associated infrainguinal revascularization in this complex population.

Prophylactic Enoxaparin Dosing Using Anti-Factor Xa Levels in Hepatic Surgery Patients: A Pilot Study.

This study examines the safety and efficacy of using peak anti-Xa levels to achieve prophylactic enoxaparin (Lovenox, Sanofi-Aventis) levels in patients who underwent hepatic surgery. Prospectively enrolled patients undergoing major and minor hepatic procedures received postoperative enoxaparin dosing. The enoxaparin dose was adjusted to attain a peak anti-Xa level ≥ 0.20 U/ml. This group was compared to a historical cohort of patients who underwent similar procedures and received standard postoperative VTE chemoprophylaxis dosing. Inpatient postoperative VTE rates were higher in the control group when compared to the experimental group (0 patients [0.00%] vs 4 patients [8.16%]; P = .035). There was no statistically significant difference in number of postoperative blood transfusions, discharge hemoglobin, or in-hospital bleeding events. Adjusting enoxaparin dosing to achieve prophylactic peak anti-Xa levels of ≥0.20 IU/ml was associated with a reduced incidence of symptomatic inpatient postoperative VTE in patients who underwent hepatic surgery without increasing postoperative bleeding events.

Morbidity and mortality of common femoral endarterectomy.

OBJECTIVE: Common femoral endarterectomy (CFE) comprises the current standard-of-care for symptomatic common femoral artery occlusive disease. Although it provides effective inflow revascularization via a single incision, it remains an invasive procedure in an often-frail patient population. The purpose of this retrospective clinical study was to assess the morbidity and mortality of CFE in a contemporary cohort. METHODS: Consecutive CFEs performed at a large, urban hospital were reviewed. Six-month mortality, local complications (hematoma, lymphatic leak, pseudoaneurysm, wound infection, and/or dehiscence), and systemic complications were analyzed using univariate and multivariate analyses. RESULTS: A total of 129 isolated CFEs were performed over 7 years for claudication (36%), rest pain (16%), tissue loss (29%), or acute on chronic limb ischemia (21%). Mean age was 75 ± 9 years, and 68% of patients were male. Comorbidities were prevalent, including coronary artery disease (54%), diabetes (41%), chronic pulmonary disease (25%), and congestive heart failure (22%). The majority of CFEs were performed under general anesthesia (98%) with patch angioplasty using bovine pericardium (73% vs 27% Dacron). Twenty-two patients (17%) sustained local complications following the procedure; their occurrence was significantly associated with obesity (P = .002) but no technical or operative factors. Nineteen patients (15%) sustained serious systemic complications; their occurrence was significantly associated with chronic limb-threatening ischemia (P < .001), and a high American Society of Anesthesiologists (ASA) class (P = .002). By 6 months, 17 patients (13%) had died. Being on dialysis, presenting with chronic limb-threatening ischemia, and being in a high ASA class at the time of operation were all associated with 6-month mortality; a high ASA class at the time of operation was independently predictive of mortality (odds ratio, 3.08; 95% confidence interval, 1.03-9.24; P = .044). CONCLUSIONS: Although commonly performed, CFE is not a benign vascular procedure. Disease presentation, anesthetic risk, and expected longevity play an important role in clinical outcomes. Evolving endovascular approaches to the common femoral artery could serve to reduce morbidity and mortality in the future.

Origin of Elevated S-Glutathionylated GAPDH in Chronic Neurodegenerative Diseases.

H2O2-oxidized glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalytic cysteine residues (Cc(SH) undergo rapid S-glutathionylation. Restoration of the enzyme activity is accomplished by thiol/disulfide SN2 displacement (directly or enzymatically) forming glutathione disulfide (G(SS)G) and active enzyme, a process that should be facile as Cc(SH) reside on the subunit surface. As S-glutathionylated GAPDH accumulates following ischemic and/or oxidative stress, in vitro/silico approaches have been employed to address this paradox. Cc(SH) residues were selectively oxidized and S-glutathionylated. Kinetics of GAPDH dehydrogenase recovery demonstrated that glutathione is an ineffective reactivator of S-glutathionylated GAPDH compared to dithiothreitol. Molecular dynamic simulations (MDS) demonstrated strong binding interactions between local residues and S-glutathione. A second glutathione was accommodated for thiol/disulfide exchange forming a tightly bound glutathione disulfide G(SS)G. The proximal sulfur centers of G(SS)G and Cc(SH) remained within covalent bonding distance for thiol/disulfide exchange resonance. Both these factors predict inhibition of dissociation of G(SS)G, which was verified by biochemical analysis. MDS also revealed that both S-glutathionylation and bound G(SS)G significantly perturbed subunit secondary structure particularly within the S-loop, region which interacts with other cellular proteins and mediates NAD(P)+ binding specificity. Our data provides a molecular rationale for how oxidative stress elevates S-glutathionylated GAPDH in neurodegenerative diseases and implicates novel targets for therapeutic intervention.

Mechanism of GAPDH Redox Signaling by H2O2 Activation of a Two-Cysteine Switch.

Oxidation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by reactive oxygen species such as H2O2 activate pleiotropic signaling pathways is associated with pathophysiological cell fate decisions. Oxidized GAPDH binds chaperone proteins with translocation of the complex to the nucleus and mitochondria initiating autophagy and cellular apoptosis. In this study, we establish the mechanism by which H2O2-oxidized GAPDH subunits undergo a subunit conformational rearrangement. H2O2 oxidizes both the catalytic cysteine and a vicinal cysteine (four residues downstream) to their respective sulfenic acids. A 'two-cysteine switch' is activated, whereby the sulfenic acids irreversibly condense to an intrachain thiosulfinic ester resulting in a major metastable subunit conformational rearrangement. All four subunits of the homotetramer are uniformly and independently oxidized by H2O2, and the oxidized homotetramer is stabilized at low temperatures. Over time, subunits unfold forming disulfide-linked aggregates with the catalytic cysteine oxidized to a sulfinic acid, resulting from thiosulfinic ester hydrolysis via the highly reactive thiosulfonic ester intermediate. Molecular Dynamic Simulations provide additional mechanistic insights linking GAPDH subunit oxidation with generating a putative signaling conformer. The low-temperature stability of the H2O2-oxidized subunit conformer provides an operable framework to study mechanisms associated with gain-of-function activities of oxidized GAPDH to identify novel targets for the treatment of neurodegenerative diseases.

Transposition of left subclavian artery with reimplantation of isolated left vertebral artery before thoracic endovascular aneurysm repair for type B aortic dissection.

Understanding and recognizing anatomic anomalies of the aortic arch is important when planning extra-anatomic debranching before thoracic endovascular aortic repair. A rare anomaly is the left vertebral artery aberrantly arising from the aortic arch; found in ∼5% of adults. When present, the artery courses through the carotid sheath at a variable length before entering the third or fourth cervical transverse foramen. In the present report, we have described the case of a 49-year-old man with a symptomatic, enlarging type B aortic dissection with an aberrant left vertebral artery and the novel methods used to surgically correct his pathology.

Stewart-Treves Syndrome in Obesity-Associated Chronic Lymphedema: A Case Report.

Stewart-Treves syndrome (STS) is defined as the development of cutaneous angiosarcoma in the presence of long-standing lymphedema and is a rare disease with only about 400 cases reported in world literature. We report a case of a 63-year-old morbidly obese woman with a long-standing history of lymphedema who developed angiosarcoma of the right lower extremity with metastasis and presented with acute respiratory distress. The patient underwent a thorough laboratory workup with a chest X-ray showing bilateral effusions. The hematology-oncology service was consulted and found the patient to have significant progression of angiosarcoma causing respiratory failure and cardiac instability. A decision to transition to hospice care was made and the patient eventually passed away in the intensive care unit. We present this case to raise awareness of STS in medical literature to understand its clinical manifestations better. Early detection is imperative as angiosarcoma is commonly an aggressive disease.

Syncope as the Initial Manifestation of a Late-Stage Renal Cell Carcinoma With Metastasis to the Brain.

Renal cell carcinoma (RCC) is the most common neoplasm that arises from renal parenchyma. About one-third of patients with RCC develop metastatic spread, with common sites including the lung, liver, bone, adrenal gland, and brain. Distant metastases can be difficult to detect unless symptoms appear. We report a case of a 56-year-old female who presented to the emergency department with the unresponsiveness of unknown duration. She underwent a thorough laboratory workup, and the computed tomography (CT) scan revealed a retroperitoneal mass originating from the right kidney and a large hemorrhagic brain mass in the left frontal lobe. The patient underwent emergent full craniotomy for tumor removal, and histology confirmed metastatic RCC. Since several patients with RCC are asymptomatic, the slow growth of tumors leading to distant metastasis can be overlooked. Thus, this case demonstrates the importance of early detection of RCC to help prevent or delay further disease progression.

Chronic Idiopathic Intestinal Pseudo-Obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially debilitating gastrointestinal (GI) condition characterized by symptoms of intestinal obstruction with the absence of anatomic lesions. In this report, we present a case of an 86-year-old female who presented with severe abdominal discomfort, nausea, and vomiting for two weeks prior to presentation. Imaging studies revealed severe gastric distension with a lack of anatomic lesions. The patient was ultimately diagnosed with chronic idiopathic intestinal pseudo-obstruction (CIIP). The purpose of this case report is to raise awareness of this condition in the medical literature and discuss the epidemiology, pathophysiology, clinical manifestations, diagnostic workup, and treatment options of this disorder.

Deglutition Syncope Due to Exaggerated Vagal Reflex.

Swallow or deglutition syncope is an uncommon cause of syncope associated with bradyarrhythmia and hypotension during food swallowing. Early recognition of this condition is imperative but challenging. We report a case of a 60-year-old female who presented with a complaint of intermittent lightheadedness after swallowing food. An episode of presyncope was observed and a reduced pulse rate from baseline was noted when she was instructed to eat a candy bar in the clinic. Further workup revealed normal in-office electrocardiogram, bilateral carotid ultrasound, transthoracic echocardiogram, and videofluoroscopic swallow study. Our goal in presenting this case is to raise awareness of the condition in medical literature and provide a good understanding of its clinical manifestation to prevent life-threatening events.

Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins.

Numerous pathological amyloid proteins spread from cell to cell during neurodegenerative disease, facilitating the propagation of cellular pathology and disease progression. Understanding the mechanism by which disease-associated amyloid protein assemblies enter target cells and induce cellular dysfunction is, therefore, key to understanding the progressive nature of such neurodegenerative diseases. In this study, we utilized an imaging-based assay to monitor the ability of disease-associated amyloid assemblies to rupture intracellular vesicles following endocytosis. We observe that the ability to induce vesicle rupture is a common feature of α-synuclein (α-syn) assemblies, as assemblies derived from WT or familial disease-associated mutant α-syn all exhibited the ability to induce vesicle rupture. Similarly, different conformational strains of WT α-syn assemblies, but not monomeric or oligomeric forms, efficiently induced vesicle rupture following endocytosis. The ability to induce vesicle rupture was not specific to α-syn, as amyloid assemblies of tau and huntingtin Exon1 with pathologic polyglutamine repeats also exhibited the ability to induce vesicle rupture. We also observe that vesicles ruptured by α-syn are positive for the autophagic marker LC3 and can accumulate and fuse into large, intracellular structures resembling Lewy bodies in vitro. Finally, we show that the same markers of vesicle rupture surround Lewy bodies in brain sections from PD patients. These data underscore the importance of this conserved endocytic vesicle rupture event as a damaging mechanism of cellular invasion by amyloid assemblies of multiple neurodegenerative disease-associated proteins, and suggest that proteinaceous inclusions such as Lewy bodies form as a consequence of continued fusion of autophagic vesicles in cells unable to degrade ruptured vesicles and their amyloid contents.

Acetylcholinesterase inhibitors: structure based design, synthesis, pharmacophore modeling, and virtual screening.

Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer's disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure-activity relationship (QSAR) studies using a training set of 20 known compounds for which IC50 values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC50 values for a test set of 20 independent compounds with measured IC50 values. A correlation analysis was carried out comparing the statistics of the measured IC50 values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a-6j) and 5H-thiazolo[3,2-a] pyrimidines (7a-7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD.

Structure-based design and synthesis of benzothiazole phosphonate analogues with inhibitors of human ABAD-Aß for treatment of Alzheimer's disease.

Amyloid binding alcohol dehydrogenase, a mitochondrial protein, is a cofactor facilitating amyloid-ß peptide (Aß) induced cell stress. Antagonizing Aß-ABAD interaction protects against aberrant mitochondrial and neuronal function and improves learning memory in the Alzheimer's disease mouse model. Therefore, it offers a potential target for Alzheimer's drug design, by identifying potential inhibitors of Aß-ABAD interaction. 2D QSAR methods were applied to novel compounds with known IC(50) values, which formed a training set. A correlation analysis was carried out comparing the statistics of the measured IC(50) with predicted values. These selectivity-determining descriptors were interpreted graphically in terms of principle component analyses, which are highly informative for the lead optimization process with respect to activity enhancement. A 3D pharmacophore model also was created. The 2D QSAR and 3D pharmacophore models will assist in high-throughput screening. In addition, ADME descriptors were also determined to study their pharmacokinetic properties. Finally, amyloid binding alcohol dehydrogenase molecular docking study of these novel molecules was undertaken to determine whether these compounds exhibit significant binding affinity with the binding site. We have synthesized only the compounds that have shown the best drug-like properties as candidates for further studies.

Azetidinones as vasopressin V1a antagonists.

The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values <1nM and brain levels after oral dosing approximately 100-fold higher than receptor affinities.

RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.

In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.

ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease.

Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.

Financial considerations insurance and coverage issues in intestinal transplantation.

OBJECTIVE: To increase healthcare workers' knowledge of reimbursement concerns. METHODS: Chronological survey of transplants reimbursed at the University of Nebraska Medical Center from December 1997 to October 2003, which include accounts of 30 patients who received intestine transplants. CONCLUSIONS: Gross billed hospital charges for the past 30 transplantations ranged from dollars 112094 to dollars 667597. Length of stay ranged from 18 to 119 days. Charges include organ procurement fees. All 30 intestine transplants were reimbursed by third-party healthcare coverage; combination of coverage; and/or patient and family payments, which resulted in adherence to financial guidelines prearranged by the hospital. Financial guidelines are usually cost plus a percentage. Thirteen transplantations occurred after April 2001, when Medicare made a national coverage decision to reimburse this form of transplantation. Since then, obtaining surgical authorization and reimbursement is easier. Most insurance companies and state public health agencies accept intestinal transplantations as a form of treatment. Researching transplant coverage before evaluation is essential to be compensated adequately. Financial guidelines will secure the fiscal success of the program. Educating patients to insurance and entitlements may reduce the out-of-pocket cost to patients. Transplant financial coordinators coordinate these efforts for the facility. The best coverage option for the patient and transplant programs is a combination of commercial healthcare coverage, secondary entitlement program, and fund-raising. With length of stay ranging up to 119 days and a lifetime of posttransplant outpatient follow-up care, it is beneficial for the facility to also have a fundraising program to assist patients.

A beta, aging, and Alzheimer's disease: a tale, models, and hypotheses.

In this paper we explore the potential functional role of the A beta peptides in the context of Alzheimer's disease (AD). We begin by defining the morphology of the amyloid deposits in relation to surrounding glial cells and, more importantly, in relation to the brain vasculature. Amyloid accumulation in the brain's microvasculature causes disturbances in the blood-brain barrier (BBB), and in larger arteries, impairment in control of regional cerebral blood flow due to myocyte degeneration. We postulate that the deposition of vascular amyloid may represent a hydrophobic protein plaster to seal leaks in the BBB, occasionally observed in aging and catastrophically common in AD. The vasoconstrictive activity of A beta may also be related to leaky vessels whereby decreasing the arterial diameter may also help to control breaches in the BBB. The admission of plasma neurotoxic proteins into the brain may be controlled by activation of microglia elicited by soluble A beta peptides creating a subtle, but permanent brain inflammatory reaction. We also delve into the influence that cholesterol metabolism may have in membrane topology and A beta production, and the close correlations that exist between cardiovascular disease and AD. Finally, we speculate about the possibility of a peripheral source of A beta that may, by crossing the BBB, contribute to the vascular and parenchymal deposits of A beta in the AD brain.