David Hirsch

Identification of the Major Intestinal Fatty Acid Transport Protein

While intestinal transport systems for metabolites such as carbohydrates have been well characterized, the molecular mechanisms of fatty acid (FA) transport across the apical plasmalemma of enterocytes have remained largely unclear. Here, we show that FATP4, a member of a large family of FA transport proteins (FATPs), is expressed at high levels on the apical side of mature enterocytes in the small intestine. Further, overexpression of FATP4 in 293 cells facilitates uptake of long chain FAs with the same specificity as enterocytes, while reduction of FATP4 expression in primary enterocytes by antisense oligonucleotides inhibits FA uptake by 50%. This suggests that FATP4 is the principal fatty acid transporter in enterocytes and may constitute a novel target for antiobesity therapy.

Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle

Insulin resistance in skeletal muscle plays a major role in the development of type 2 diabetes and may be causally associated with increases in intramuscular fatty acid metabolites. Fatty acid transport protein 1 (FATP1) is an acyl-CoA synthetase highly expressed in skeletal muscle and modulates fatty acid uptake and metabolism by converting fatty acids into fatty acyl-CoA. To investigate the role of FATP1 in glucose homeostasis and in the pathogenesis of insulin resistance, we examined the effect of acute lipid infusion or chronic high-fat feeding on insulin action in FATP1 KO mice. Whole-body adiposity, adipose tissue expression of adiponectin, intramuscular fatty acid metabolites, and insulin sensitivity were not altered in FATP1 KO mice fed a regular chow diet. In contrast, FATP1 deletion protected the KO mice from fat-induced insulin resistance and intramuscular accumulation of fatty acyl-CoA without alteration in whole-body adiposity. These findings demonstrate an important role of intramuscular fatty acid metabolites in causing insulin resistance and suggest that FATP1 may be a novel therapeutic target for the treatment of insulin resistance and type 2 diabetes.

Insulin Causes Fatty Acid Transport Protein Translocation and Enhanced Fatty Acid Uptake in Adipocytes

Fatty acid uptake into 3T3 L1 adipocytes is predominantly transporter mediated. Here we show that, during 3T3 L1 adipocyte differentiation, expression of fatty acid transport proteins (FATPs) 1 and 4 is induced. Using subcellular membrane fractionation and immunofluorescence microscopy, we demonstrate that, in adipocytes, insulin induces plasma membrane translocation of FATPs from an intracellular perinuclear compartment to the plasma membrane. This translocation was observed within minutes of insulin treatment and was paralleled by an increase in long chain fatty acid (LCFA) uptake. In contrast, treatment with TNF-alpha inhibited basal and insulin-induced LCFA uptake and reduced FATP1 and -4 levels. Thus, hormonal regulation of FATP activity may play an important role in energy homeostasis and metabolic disorders such as type 2 diabetes.

Fatty acid transport proteins

Purpose of review Fatty acid transport proteins are a family of proteins involved in fatty acid uptake and activation. This review summarizes recent progress in elucidating the function of fatty acid transport proteins. Recent findings Recent experiments clearly establish FATP1 as a regulated fatty acid transporter in both adipose tissue and muscle with important roles in energy homeostasis, thermogenesis and insulin resistance. Knockout of FATP5 in mice show it to be a bifunctional protein required for both hepatic fatty acid uptake and bile acid reconjugation. The most striking phenotype of FATP4 deletion is a defect in skin homeostasis, which may be due to its very long chain acyl-coenzyme A synthetase activity. Fatty acid transport proteins are increasingly being recognized as multifunctional proteins that can mediate the uptake of fatty acids as well as catalyze the formation of coenzyme A derivatives using long-chain and very-long chain fatty acids, bile acids and bile acid precursors as substrates. Summary Modulation of fatty acid transport protein function can result in altered energy homeostasis and insulin sensitivity, defective skin homeostasis, and altered bile acid metabolism. Both fatty acid uptake and enzymatic activity of fatty acid transport proteins likely contribute to these phenotypes. Future studies are needed to better understand the molecular mechanism of fatty acid transport protein function and the physiological role of FATP2, FATP3, and FATP6.

Rates of and Risk Factors for Adverse Drug Events in Outpatient Parenteral Antimicrobial Therapy

Background To better monitor patients on outpatient parenteral antimicrobial therapy (OPAT), we need an improved understanding of risk factors for and timing of OPAT-associated adverse drug events (ADEs). Methods We analyzed a prospective cohort of patients on OPAT discharged from 2 academic medical centers. Patients underwent chart abstraction and a telephone survey. Multivariable analyses estimated adjusted incident rate ratios (aIRR) between clinical and demographic risk factors and clinician-determined clinically significant ADEs. Descriptive data were used to present patient-reported ADEs. Results Of 339 patients enrolled in the study, 18.0% experienced an ADE (N = 65), of which 49 were significant (14.5%, 2.24/1000 home-OPAT days). Patients with longer courses of therapy had lower rates of ADEs compared with patients treated for 0-13 days (14-27 days: aIRR, 0.44; 95% confidence interval [CI], 0.20-0.99; at least 28 days: aIRR, 0.11; 95% CI, 0.056-0.21). Risk factors for ADEs included female gender and receipt of daptomycin or vancomycin, while treatment for uncomplicated bacteremia and empiric treatment were associated with lower rates of ADEs. Conclusions OPAT-related ADEs were common and often occurred within 2 weeks of hospital discharge. Patients on OPAT should be monitored more closely for ADEs, including clinical assessment and laboratory monitoring, especially within the first weeks after hospital discharge and particularly among women and patients who receive vancomycin.

Screening for Dysplasia in Idiopathic Achalasia Using Lugol Staining

Background and aims: Patient with achalasia have a 10-50 fold increased risk to develop esophageal squamous cell carcinoma (ESCC). Early diagnosis of ESCC is essential, and detection of an earlier dysplastic stage is preferred. Endoscopic detection is however difficult and often delayed. Chromoendoscopy with Lugol dye increases detection rates dysplasia and ESCC to 91-100%. The aim of this study was therefore to evaluate a screening program using chromoendoscopy with Lugol to detect dysplasia in patients with idiopathic achalasia. Methods: A cohort of 138 patients with achalasia (86 males, mean age 50.4yr, range 20-87) underwent 3-annually upper endoscopy with Lugol dye staining. Suspected regions for dysplasia with white light endoscopy and unstained lesions after Lugol staining were biopsied. Patients with low grade intraepithelial neoplasia (LGIN) underwent yearly screening, while patients with high grade intraepithelial neoplasia or ESCC were treated endoscopically, surgically or by radiotherapy. Results: On a per patient basis, 2 of 138 patients (1.4%) developed ESCC in our cohort, leading to an incidence of 122/100.000 person-years. The hazard rate of esophageal cancer was 10 compared to the matched population. Dysplasia/ESCC was detected only after a median of 23.5 yrs (IQR 2229yr) after achalasia was diagnosed. On a per-endoscopy basis, 56 and 76 suspicious lesions were identified during white light endoscopies (n=273) and after Lugol staining respectively. Biopsies taken from these lesions were positive for dysplasia and ESCC in 13 and 2 cases respectively. Lugol staining detected significantly more histologically proven cases of LGIN (n=13, 100%) compared to white light endoscopy (n=8, 62%, p<0.01). Patients with LGIN underwent annual control endoscopies: no progression to high grade dysplasia or ESCC was observed during a period of 4.6 yrs of follow-up. LGIN was confirmed in 9 control endoscopies of 4 patients. Conclusions: Patients with long-term disease (>15-20yr) have an increased risk to develop dysplasia and carcinoma. In these patients, the use of a screening program may be indicated, preferably using Lugol chromoendoscopy to detect early lesions.

Environmental Exposures and the Risk of Central Venous Catheter Complications and Readmissions in Home Infusion Therapy Patients

BACKGROUND Patients are frequently discharged with central venous catheters (CVCs) for home infusion therapy. OBJECTIVE To study a prospective cohort of patients receiving home infusion therapy to identify environmental and other risk factors for complications. DESIGN Prospective cohort study between March and December 2015. SETTING Home infusion therapy after discharge from academic medical centers. PARTICIPANTS Of 368 eligible patients discharged from 2 academic hospitals to home with peripherally inserted central catheters and tunneled CVCs, 222 consented. Patients remained in the study until 30 days after CVC removal. METHODS Patients underwent chart abstraction and monthly telephone surveys while the CVC was in place, focusing on complications and environmental exposures. Multivariable analyses estimated adjusted odds ratios and adjusted incident rate ratios between clinical, demographic, and environmental risk factors and 30-day readmissions or CVC complications. RESULTS Of 222 patients, total parenteral nutrition was associated with increased 30-day readmissions (adjusted odds ratio, 4.80 [95% CI, 1.51-15.21) and CVC complications (adjusted odds ratio, 2.41 [95% CI, 1.09-5.33]). Exposure to soil through gardening or yard work was associated with a decreased likelihood of readmissions (adjusted odds ratio, 0.09 [95% CI, 0.01-0.74]). Other environmental exposures were not associated with CVC complications. CONCLUSIONS complications and readmissions were common and associated with the use of total parenteral nutrition. Common environmental exposures (well water, cooking with raw meat, or pets) did not increase the rate of CVC complications, whereas soil exposures were associated with decreased readmissions. Interventions to decrease home CVC complications should focus on total parenteral nutrition patients. Infect Control Hosp Epidemiol 2016;1-8.

Placing Venous Catheters in the Home: Pilot Data from the Mobile VAD Program

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Scintigraphic Analysis of the Dynamics of the Acid Pocket During Different Mechanisms of Gastroesophageal Reflux

AIM: During transient lower esophageal sphincter relaxations (TLESRs) the position of the gastric acid pocket mainly determines the acidity of the refluxate. However, to what extent the position or dynamics of the acid pocket determines acidity of the refluxate during other mechanisms of reflux (straining, low lower esophageal sphincter pressure (LESp) or during swallows) remains unclear. METHODS: Twenty patients with gastroesophageal reflux disease (GERD) were invited to undergo combined high resolution manometry (HRM) and pHimpedance recording after a standardized meal (550kcal) in the upright position. The acid pocket was visualized using scintigraphy after i.v. injection of 350MBq 99mTc-pertechnetate. The position of the pocket was classified as supradiaphramatic, extending into the hiatal opening (infradiaphragmatic) or subdiaphragmatic using radionuclide markers on the HRM catheter. The underlying reflux mechanism was determined using HRM, according to predefined criteria (v Herwaarden, Gastroenterology 2000, 1439-46). RESULTS: A total of 494 reflux episodes were detected, of which 244 (49%) were acidic. The underlying mechanism of reflux was a TLESR in 328 (66%), low LESp in 21 (4.3%), straining in 126 (26%), swallow-associated in 14 (2.9%) and unknown in 5 (1.0%) events respectively. Acidic reflux occurred with a supradiaphragmatic localisation of the acid pocket in 117 of 129 (91%) events, in 103 of 169 (62%) events with an infradiaphragmatic localisation and in 19 of 175 (11%) events with a subdiaphragmatic localisation. When straining was the underlying mechanism, the refluxate was more often acidic than during a TLESR (n=100 (80%) vs n= 130 (40%) respectively P<0.0001, Chi square). There was no difference in acidity between reflux events during low LESp or events associated to swallows compared to TLESRs. Scintigraphic imaging clearly illustrated that straining pushes the acid pocket upwards into the esophagus regardless of its initial position. CONCLUSION: Our data confirm that a supradiaphragmatic position of the acid pocket is an important factor determining the risk for acidic reflux, also during mechanisms of reflux different from TLESRs. Scinitgraphic imaging of the pocket demonstrates that the acid pocket is pushed into the esophagus during straining regardless of its position, further illustrating that the pocket is indeed the reservoir of acidic refluxate.