Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All‐trans‐retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT. We hypothesized that in human AT, family 1A aldehyde dehydrogenase (ALDH1A) enzymes contribute to atRA biosynthesis in a depot‐specific manner. To test this hypothesis, parallel samples of subcutaneous and omental AT from participants (n = 15) were collected during elective abdominal surgeries to quantify atRA biosynthesis and key atRA synthesizing enzymes. ALDH1A1 was the most abundant ALDH1A isoform in both AT depots with expression approximately twofold higher in omental than subcutaneous AT. ALDH1A2 was detected only in omental AT. Formation velocity of atRA was approximately threefold higher (p = 0.0001) in omental AT (9.8 [7.6, 11.2]) pmol/min/mg) than subcutaneous AT (3.2 [2.1, 4.0] pmol/min/mg) and correlated with ALDH1A2 expression in omental AT (β‐coefficient = 3.07, p = 0.0007) and with ALDH1A1 expression in subcutaneous AT (β‐coefficient = 0.13, p = 0.003). Despite a positive correlation between body mass index (BMI) and omental ALDH1A1 protein expression (Spearman r = 0.65, p = 0.01), BMI did not correlate with atRA formation. Our findings suggest that ALDH1A2 is the primary mediator of atRA formation in omental AT, whereas ALDH1A1 is the principal atRA‐synthesizing enzyme in subcutaneous AT. These data highlight AT depot as a critical variable for defining the roles of retinoids in human AT biology.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Rodent data suggest that dysregulated production of all‐trans‐retinoic acid (atRA), the primary bioactive metabolite of vitamin A, may contribute to body weight gain and its complications. However, the key enzymes responsible for atRA biosynthesis in human adipose tissue have not been identified, nor has the relationship between body weight and adipose tissue atRA biosynthesis been evaluated in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study sought to identify the key enzymes involved in atRA biosynthesis in human omental and subcutaneous adipose tissue. This study also quantified atRA formation velocity and explored the potential relationship between body mass index (BMI) and atRA biosynthesis in both adipose tissue depots.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study establishes that among the aldehyde dehydrogenase (ALDH) isoforms, ALDH1A1 and ALDH1A2 both contribute to atRA biosynthesis in human omental adipose tissue, whereas only ALDH1A1 contributes to atRA biosynthesis in subcutaneous adipose tissue. Both ALDH1A1 expression and atRA formation velocity are substantially higher in omental than subcutaneous adipose tissue. Omental ALDH1A1 protein expression exhibits a positive correlation with BMI, but atRA formation velocity in both omental and subcutaneous adipose tissue shows no correlation with BMI. Thus, these findings highlight discrepancies between human and rodent adipose tissue biology and, moreover, reveal depot‐specific regulation of vitamin A metabolism in human adipose tissue.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This line of research ultimately is intended to define the roles of vitamin A metabolites in the regulation of tissue remodeling and energy partitioning in human adipose tissue. This knowledge could contribute to the delineation of mechanisms underlying progressive obesity and its complications.     

Recurrent Metastatic Chordoma to the Liver: A Case Report and Review of the Literature

Chordoma is a rare malignant neoplasm derived from notochordal tissue that primarily affects the axial skeleton. Almost 40% of patients have non-cranial chordoma metastases. The most common metastatic sites are the lungs, bones, lymph nodes, and subcutaneous tissue. We present a 52-year female with a history of sacral chordoma presenting with abdominal fullness, early satiety, and a palpable abdominal mass. Abdominal magnetic resonance imaging (MRI) revealed an isolated, highly vascularized, and multilobed liver mass in the left lateral segment. The mass was surgically removed using a clean surgical margin. A histological examination and immunohistochemical staining were consistent with a metastatic chordoma. Two years later, follow-up imaging studies showed a 6.5 × 4.0 × 2.0 cm right liver lesion with multiple lungs, chest wall, pleural, and diaphragmatic lesions. Microscopic- and immunohistochemical staining revealed a recurrent metastatic chordoma. Herein, we present a unique case of metastatic recurrent chordoma in the liver with the involvement of other sites. To the best of our knowledge, no other case of recurrent liver metastasis has been reported.     

Substituting Resistance Spot Welding with Flexible Laser Spot Welding to Join Ultra-Thin Foil of Inconel 718 to Thick 410 Steel

This paper investigated various aspects of replacing existing micro-resistance spot welding (micro-RSW) with micro-laser spot welding for joining Inconel 718 thin foils to thick 410 steel stack-up to allow faster, non-contact joining together with flexibility in spot positioning and removal of tip dressing required for RSW electrodes. The joint quality was evaluated based on the mechanical strength, microstructural characteristics and joint strength at elevated temperature as these joints are often used for high-temperature applications. Experimental investigations were performed using micro-RSW and micro-laser spot welding to obtain the 90° peel and lap shear specimens, each comprising four spots. The obtained strength from laser joints was significantly higher than that of micro-RSW joints due to larger weld nugget formation and interface width. The process map for obtaining good quality welds was also identified, and about a 17% reduction in joint strength was obtained when welded specimens were subjected to elevated temperature (i.e., 500 °C) in comparison with room temperature. This reduction was compensated for using the flexibility of laser welding to add two extra spots. The overall performance of the micro-laser spot welds was found to be better than the micro-RSW considering joint strength, flexibility in placing the spots and time to produce the welds.     

Single-Incision Laparoscopic Cholecystectomy Versus Conventional Laparoscopic Cholecystectomy: Meta-analysis and Systematic Review of Randomized Controlled Trials

Background

The objective of this study was to analyze systematically the randomized, controlled trials that compared single-incision laparoscopic cholecystectomy (SILC) and conventional laparoscopic cholecystectomy (CLC).

Methods

The meta-analysis was conducted according to the Quality of Reporting of Meta-analysis (QUORUM) standards. The included studies were analyzed systematically using the statistical software package RevMan. The summated outcomes were expressed as the risk ratios (RR) for dichotomous variables and standardized mean differences (SMD) for continuous variables.

Results

Eleven randomized trials encompassing 858 patients were retrieved from the electronic databases. In the random effects model, postoperative pain, postoperative complications, length of hospital stay, cosmesis score, conversion rate, and time to return to normal activities were statistically comparable between the two cholecystectomy techniques. SILC was associated with a longer operating time [SMD 0.71; 95?% confidence interval (CI) 0.38, 1.05; z?=?4.18; p?<?0.0001) and an increased requirement for additional port insertion (RR 6.54; 95?% CI 2.19, 19.57; z?=?3.36; p?<?0008). However, there was significant heterogeneity among the trials.

Conclusions

SILC does not offer any advantage over CLC for treating benign gallbladder disorders. CLC may be used assiduously for this purpose.     

Impact of Sarcopenia on Outcomes Following Intra-arterial Therapy of Hepatic Malignancies

Background

Assessment of patient performance status is often subjective. Sarcopenia—measurement of muscle wasting—may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT).

Methods

Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors.

Results

Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm²/m²) was greater than women (413 mm²/m²). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR?=?1.84) and Child's score (HR?=?2.15) (all P?<?0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR?=?1.84; P?=?0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients.

Conclusions

Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.     

Acute and Chronic Respiratory Symptoms among Primary Care Patients Who Smoke Crack Cocaine

Among inner-city populations in Canada, the use of crack cocaine by inhalation is prevalent. Crack smoking is associated with acute respiratory symptoms and complications, but less is known about chronic respiratory problems related to crack smoking. There is also a gap in the literature addressing the management of respiratory disease in primary health care among people who smoke crack. The purpose of our study was to assess the prevalence of acute and chronic respiratory symptoms among patients who smoke crack and access primary care. We conducted a pilot study among 20 patients who currently smoke crack (used within the past 30 days) and who access the “drop-in clinic” at an inner-city primary health care center. Participants completed a 20- to 30-min interviewer-administered survey and provided consent for a chart review. We collected information on respiratory-related symptoms, diagnoses, tests, medications, and specialist visits. Data were analyzed using frequency tabulations in SPSS (version 19.0). In the survey, 95 % (19/20) of the participants reported having at least one respiratory symptom in the past week. Thirteen (13/19, 68.4 %) reported these symptoms as bothersome. Chart review indicated that 12/20 (60 %) had a diagnosis of either asthma or chronic obstructive pulmonary disease (COPD), and four participants (4/20, 20 %) had a diagnosis of both asthma and COPD. Majority of the participants had been prescribed an inhaled medication (survey 16/20, 80 %; chart 12/20, 60 %). We found that 100 % (20/20) of the participants currently smoked tobacco, and 16/20 (80 %) had smoked both tobacco and marijuana prior to smoking crack. Our study suggests that respiratory symptoms and diagnoses of asthma and COPD are prevalent among a group of patients attending an inner-city clinic in Toronto and who also smoke crack. The high prevalence of smoking tobacco and marijuana among our participants is a major confounder for attributing respiratory symptoms to crack smoking alone. This novel pilot study can inform future research evaluating the primary health care management of respiratory disease among crack smokers, with the aim of improving health and health care delivery.