Pseudoaneurysm of the Dorsalis Pedis Artery Following Open Reduction Internal Fixation of a Second Metatarsal Fracture: A Case Study.

Pseudoaneurysms are created by a traumatic or iatrogenic perforation of an artery, resulting in accumulation of blood between the two outermost layers of a blood vessel, the tunica media and tunica adventitia. Pedal artery pseudoaneurysms are an extremely uncommon complication of foot and ankle surgery; therefore, few cases have been reported in the literature. Early diagnosis is important to ensure timely treatment of this condition. Once clinical suspicion has been established, urgent referral to vascular surgery for prompt surgical evaluation is required to prevent potentially harmful sequalae. We present the case of a 70-year-old female who developed a pseudoaneurysm of the dorsalis pedis artery 33 days after undergoing open reduction internal fixation (ORIF) of a second metatarsal fracture. Her treatment included urgent referral to vascular surgery with subsequent surgical repair of the pseudoaneurysm via ligation of the medial dorsal branch of the dorsalis pedis artery. At 10-month follow-up, she denied any pain, sensory deficits, or functional disability and had returned to all preinjury activities with no recurrence of the pseudoaneurysm. Our case study demonstrates early diagnosis and successful treatment of a pseudoaneurysm of the dorsalis pedis artery that developed shorty after ORIF of a second metatarsal fracture.

Case Report of a Diabetic Foot Infection Caused by Staphylococcus pseudintermedius, a Zoonotic Pathogen of Canine Origin.

Staphylococcus pseudintermedius is an emerging zoonotic pathogen that is very similar to human Staphylococcus pathogens, particularly multidrug-resistant Staphylococcus aureus. Recent reports have indicated that S pseudintermedius is easily transmitted between pets (mainly dogs) and owners because of these similarities. Although this pathogen has been associated with diabetic foot infections, it has not yet been described in the podiatric medical literature. In this case report, we present a diabetic foot infection in a 61-year-old man that was refractory to multiple rounds of antibiotic drug therapy. Deep wound cultures eventually grew S pseudintermedius, which was the first known case of this pathogen reported in our hospital system.

Utilization of Fluorescence Microangiography in Pediatric Acute Compartment Syndrome: A Case Report.

Acute compartment syndrome is a critical condition, most commonly arising as the result of high-energy trauma, fracture, and crush injury. Early diagnosis and treatment are imperative to avoid permanent functional damage to the affected extremity. Although isolated pedal compartment syndrome is well studied in adults, in the pediatric population, it has been seldom reported. Pediatric patients pose a unique challenge when diagnosing compartment syndrome. Their inability to appropriately verbalize symptoms and participate in physical examinations often causes a delay in diagnosis. We present the case of a 5-year-old female who developed compartment syndrome of her left foot 26 hours after sustaining an isolated crush injury to the distal forefoot. Her treatment included emergent fasciotomy in combination with 20 hyperbaric oxygen therapy treatments. The progression of her acute digital ischemia was monitored by using serial fluorescence microangiography studies performed at 17 hours, 7 days, and 3 weeks postinjury. Throughout these serial studies, improvement in hypofluorescence was noted involving the dorsolateral midfoot, as well as digits 3, 4, and 5, which correlated with physical examination. The patient went on to uneventfully autoamputate the distal aspects of digits 4 and 5 within 4 months of injury. At the 12-month follow-up visit, she denied any pain, sensory deficits, or functional disability and had returned to all preinjury activities. Our case study demonstrates the use of serial microangiography to monitor progression of acute ischemia associated with acute pediatric compartment syndrome and discusses prognostic capabilities.

Intestine-Specific Overexpression of LDLR Enhances Cholesterol Excretion and Induces Metabolic Changes in Male Mice.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most effective treatment options for severe obesity and related comorbidities, including hyperlipidemia, a well-established risk factor of cardiovascular diseases. Elucidating the molecular mechanisms underlying the beneficial effects of RYGB may facilitate development of equally effective, but less invasive, treatments. Recent studies have revealed that RYGB increases low-density lipoprotein receptor (LDLR) expression in the intestine of rodents. Therefore, in this study we first examined the effects of RYGB on intestinal cholesterol metabolism in human patients, and we show that they also exhibit profound changes and increased LDLR expression. We then hypothesized that the upregulation of intestinal LDLR may be sufficient to decrease circulating cholesterol levels. To this end, we generated and studied mice that overexpress human LDLR specifically in the intestine. This perturbation significantly affected intestinal metabolism, augmented fecal cholesterol excretion, and induced a reciprocal suppression of the machinery related to luminal cholesterol absorption and bile acid synthesis. Circulating cholesterol levels were significantly decreased and, remarkably, several other metabolic effects were similar to those observed in RYGB-treated rodents and patients, including improved glucose metabolism. These data highlight the importance of intestinal cholesterol metabolism for the beneficial metabolic effects of RYGB and for the treatment of hyperlipidemia.

Reprogramming of intestinal glucose metabolism and glycemic control in rats after gastric bypass.

The resolution of type 2 diabetes after Roux-en-Y gastric bypass (RYGB) attests to the important role of the gastrointestinal tract in glucose homeostasis. Previous studies in RYGB-treated rats have shown that the Roux limb displays hyperplasia and hypertrophy. Here, we report that the Roux limb of RYGB-treated rats exhibits reprogramming of intestinal glucose metabolism to meet its increased bioenergetic demands; glucose transporter-1 is up-regulated, basolateral glucose uptake is enhanced, aerobic glycolysis is augmented, and glucose is directed toward metabolic pathways that support tissue growth. We show that reprogramming of intestinal glucose metabolism is triggered by the exposure of the Roux limb to undigested nutrients. We demonstrate by positron emission tomography-computed tomography scanning and biodistribution analysis using 2-deoxy-2-[18F]fluoro-D-glucose that reprogramming of intestinal glucose metabolism renders the intestine a major tissue for glucose disposal, contributing to the improvement in glycemic control after RYGB.

Probing the mechanisms of the metabolic effects of weight loss surgery in humans using a novel mouse model system.

BACKGROUND: Gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is the most effective treatment for severe obesity. RYGB is associated with a remarkable decrease in the rate of death from obesity-related complications, such as diabetes mellitus, coronary artery disease, and cancer. Dissecting the mechanisms of RYGB effects could augment our understanding about the pathogenesis of obesity and its complications. OBJECTIVES AND METHODS: In this study, we describe in detail a mouse model of RYGB that closely reproduces the surgical steps of the human procedure. RESULTS: We show that RYGB in mice has the same effects as in human patients, proving the high translational validity of this model system. We present an intraoperative video to facilitate the widespread use of this complex and difficult method. CONCLUSIONS: The study of the mechanisms of RYGB using this model system can greatly facilitate our understanding about the effects of RYGB in human patients. The reverse engineering of the physiological mechanisms of RYGB could lead to discovery of new, effective, and less invasive treatments.

Genetic evidence links the ASTRA protein chaperone component Tti2 to the SAGA transcription factor Tra1.

Tra1 is a 3744-residue component of the Saccharomyces cerevisiae SAGA, NuA4, and ASTRA complexes. Tra1 contains essential C-terminal PI3K and FATC domains, but unlike other PIKK (phosphoinositide three-kinase-related kinase) family members, lacks kinase activity. To analyze functions of the FATC domain, we selected for suppressors of tra1-F3744A, an allele that results in slow growth under numerous conditions of stress. Two alleles of TTI2, tti2-F328S and tti2-I336F, acted in a partially dominant fashion to suppress the growth-related phenotypes associated with tra1-F3744A as well as its resulting defects in transcription. tti2-F328S suppressed an additional FATC domain mutation (tra1-L3733A), but not a mutation in the PI3K domain or deletions of SAGA or NuA4 components. We find eGFP-tagged Tti2 distributed throughout the cell. Tti2 is a component of the ASTRA complex, and in mammalian cells associates with molecular chaperones in complex with Tti1 and Tel2. Consistent with this finding, Tra1 levels are reduced in a strain with a temperature-sensitive allele of tel2. Further agreeing with a possible role for Tti2 in the folding or stabilization of Tra1, tra1-F3744A was mislocalized to the cytoplasm, particularly under conditions of stress. Since an intragenic mutation of tra1-R3590I also suppressed F3744A, we propose that Tti2 is required for the folding/stability of the C-terminal FATC and PI3K domains of Tra1 into their functionally active form.

Loss of nonsense mediated decay suppresses mutations in Saccharomyces cerevisiae TRA1.

BACKGROUND: Tra1 is an essential protein in Saccharomyces cerevisiae. It was first identified in the SAGA and NuA4 complexes, both with functions in multiple aspects of gene regulation and DNA repair, and recently found in the ASTRA complex. Tra1 belongs to the PIKK family of proteins with a C-terminal PI3K domain followed by a FATC domain. Previously we found that mutation of leucine to alanine at position 3733 in the FATC domain of Tra1 (tra1-L3733A) results in transcriptional changes and slow growth under conditions of stress. To further define the regulatory interactions of Tra1 we isolated extragenic suppressors of the tra1-L3733A allele. RESULTS: We screened for suppressors of the ethanol sensitivity caused by tra1-L3733A. Eleven extragenic recessive mutations, belonging to three complementation groups, were identified that partially suppressed a subset of the phenotypes caused by tra1-L3733A. Using whole genome sequencing we identified one of the mutations as an opal mutation at tryptophan 165 of UPF1/NAM7. Partial suppression of the transcriptional defect resulting from tra1-L3733A was observed at GAL10, but not at PHO5. Suppression was due to loss of nonsense mediated decay (NMD) since deletion of any one of the three NMD surveillance components (upf1/nam7, upf2/nmd2, or upf3) mediated the effect. Deletion of upf1 suppressed a second FATC domain mutation, tra1-F3744A, as well as a mutation to the PIK3 domain. In contrast, deletions of SAGA or NuA4 components were not suppressed. CONCLUSIONS: We have demonstrated a genetic interaction between TRA1 and genes of the NMD pathway. The suppression is specific for mutations in TRA1. Since NMD and Tra1 generally act reciprocally to control gene expression, and the FATC domain mutations do not directly affect NMD, we suggest that suppression occurs as the result of overlap and/or crosstalk in these two broad regulatory networks.

Resting energy expenditure and energetic cost of feeding are augmented after Roux-en-Y gastric bypass in obese mice.

Although the prevalence of obesity has increased dramatically throughout the world during the last 25 yr, its long-term control remains poor. Currently, only gastrointestinal weight loss surgery, especially Roux-en-Y gastric bypass (RYGB), is associated with substantial and sustained weight loss and resolution or significant improvement of diabetes mellitus and other metabolic obesity-induced complications. Clinical observations and recent studies have suggested that RYGB induces its effects by changing the physiology of weight regulation. Understanding the underlying mechanisms of these profound and sustainable effects could facilitate the development of novel and less invasive treatments against obesity and its complications. To study the physiological mechanisms of RYGB, we have developed a mouse RYGB model that replicates the human operation. The aims of this study were to develop a roadmap for assessing energy expenditure (EE) in animal models of weight loss surgery and to examine the effects of RYGB on EE. We first measured EE by indirect calorimetry in groups of animals that underwent RYGB or a sham operation. Calorimetry data were analyzed using three different methods: normalization by total body mass, allometric scaling, and analysis of covariance modeling. RYGB in mice induced a significant increase in EE that was independent of the method used. An energy balance analysis was then performed, which also confirmed that RYGB-treated animals have higher energy maintenance needs. Finally, we determined the EE components that account for the observed increase in EE, and we found that resting EE and postprandial thermogenesis are the major contributors to this increase.

Mutational analysis of the C-terminal FATC domain of Saccharomyces cerevisiae Tra1.

Tra1 is a component of the Saccharomyces cerevisiae SAGA and NuA4 complexes and a member of the PIKK family, which contain a C-terminal phosphatidylinositol 3-kinase-like (PI3K) domain followed by a 35-residue FATC domain. Single residue changes of L3733A and F3744A, within the FATC domain, resulted in transcriptional changes and phenotypes that were similar but not identical to those caused by mutations in the PI3K domain or deletions of other SAGA or NuA4 components. The distinct nature of the FATC mutations was also apparent from the additive effect of tra1-L3733A with SAGA, NuA4, and tra1 PI3K domain mutations. Tra1-L3733A associates with SAGA and NuA4 components and with the Gal4 activation domain, to the same extent as wild-type Tra1; however, steady-state levels of Tra1-L3733A were reduced. We suggest that decreased stability of Tra1-L3733A accounts for the phenotypes since intragenic suppressors of tra1-L3733A restored Tra1 levels, and reducing wild-type Tra1 led to comparable growth defects. Also supporting a key role for the FATC domain in the structure/function of Tra1, addition of a C-terminal glycine residue resulted in decreased association with Spt7 and Esa1, and loss of cellular viability. These findings demonstrate the regulatory potential of mechanisms targeting the FATC domains of PIKK proteins.