Concomitant sarcopenia and undernutrition: Impact on clinical outcomes in patients undergoing hemodialysis.

BACKGROUND: Sarcopenia and undernutrition are crucial in the cycle of frailty in patients requiring hemodialysis therapy, and their deleterious clinical consequences are well documented. However, little attention has been directed towards examining their combined impact on clinical outcomes. OBJECTIVE: This study aimed to elucidate the effects of concomitant sarcopenia and undernutrition on clinical outcomes in patients undergoing hemodialysis. METHODS: This prospective cohort study recruited outpatients undergoing hemodialysis from four facilities. Sarcopenia was diagnosed according to the criteria of the Asian Working Group for Sarcopenia, 2019. Undernutrition was determined using the Geriatric Nutritional Risk Index, with a score of <92 classified as undernutrition. Patients were classified into four groups according to the presence or absence of sarcopenia and undernutrition. Cox proportional hazards analysis was used to assess the independent association between concomitant sarcopenia and undernutrition, all-cause mortality, and cardiovascular (CV) events after adjusting for baseline characteristics. RESULTS: We included 450 patients in this analysis. Of the 450 patients, 69 (15.3%) had concomitant sarcopenia and undernutrition. The mean follow-up period was 1067 days, and there were 61 deaths and 60 CV events. The cumulative survival rate was significantly lower in the sarcopenia with undernutrition group (P = 0.011). The overlap of sarcopenia and undernutrition was significantly associated with a risk of mortality (hazard ratio 2.10; 95% confidence interval 1.05-4.21; P = 0.037). However, no association was observed between the co-occurrence of sarcopenia and undernutrition and the risk of CV events. CONCLUSIONS: Concomitant sarcopenia and undernutrition were significantly associated with an increased mortality risk among patients undergoing hemodialysis. This finding reaffirms the importance of managing sarcopenia and undernutrition in patients undergoing hemodialysis in daily clinical practice.

Simplified discriminant parameters for sarcopenia among patients undergoing haemodialysis.

BACKGROUND: Patients with end-stage renal disease (ESRD) are at an increased risk of developing sarcopenia, which can lead to various adverse health outcomes. Although the diagnosis of sarcopenia is essential for clinical management, it is not feasible in routine clinical practice for populations undergoing haemodialysis because it is time-consuming and resources are limited. Serum creatinine levels in patients with ESRD have been gaining attention as a screening parameter for sarcopenia because serum creatinine is a routinely measured byproduct of skeletal muscle metabolism. This study aimed to evaluate the discriminative ability of the creatinine-derived index for sarcopenia in patients undergoing haemodialysis. METHODS: We diagnosed sarcopenia according to the Asian Working Group for Sarcopenia (AWGS) 2 criteria in 356 clinically stable outpatients with ESRD enrolled from three dialysis facilities. We adopted the modified creatinine index as a simplified discriminant parameter for sarcopenia in addition to the calf circumference, SARC-F score, and combination of both (i.e. SARC-CalF score), which are recommended by the AWGS. Receiver operating characteristic analysis and logistic regression analysis were conducted to evaluate the discriminative ability of the modified creatinine index for sarcopenia. RESULTS: Of the study participants, 142 (39.9%) were diagnosed with sarcopenia. The areas under the curve of the modified creatinine index against sarcopenia in the male and female participants were 0.77 (95% confidence interval [CI]: 0.71 to 0.83) and 0.77 (95% CI: 0.69 to 0.85), respectively. All simplified discriminant parameters were significantly associated with sarcopenia, even after adjusting for patient characteristics and centre. In the comparison of the odds ratios for sarcopenia for 1-standard deviation change in the simplified discriminant parameters, the odds ratio of the modified creatinine index was 1.92 (95% CI: 1.15 to 3.19), which was lower than that of the calf circumference (odds ratio: 6.58, 95% CI: 3.32 to 13.0) and similar to that of the SARC-F (odds ratio: 1.57, 95% CI: 1.14 to 2.16) and SARC-CalF scores (odds ratio: 2.36, 95% CI: 1.60 to 3.47). CONCLUSIONS: This study revealed a strong association between the creatinine-derived index and sarcopenia in patients undergoing haemodialysis. The modified creatinine index was equal or superior to those of SARC-F and SARC-CalF score in discriminability for sarcopenia. However, the ability of the calf circumference to discriminate sarcopenia is extremely high, and further study is needed to determine whether it can be used to detect deterioration of muscle mass and function over time.

The effects of amino acid/protein supplementation in patients undergoing hemodialysis: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND & AIMS: We evaluated the efficacy of the intervention consisting of amino acid/protein supplementation on muscle mass, muscle strength and physical function in patients on hemodialysis. METHODS: This systematic review and meta-analysis identified potential studies through a systematic search of 4 electronic databases and references from eligible studies from database inception to August 2020. We included only randomized controlled trials reporting the efficacy of amino acid/protein supplementation on muscle mass, muscle strength and physical function in patients on hemodialysis. RESULTS: Of 6529 unique citation records, 4 studies including 243 participants were selected for inclusion in the meta-analysis. Although there were no significant differences in muscle mass and muscle strength between the intervention and control groups, amino acid/protein supplementation was shown to significantly improve physical function (shuttle walk, MD 32.7, 95% CI 21.7 to 43.7, P < 0.001; gait speed, MD 0.07, 95% CI 0.01 to 0.13, P = 0.02; timed up and go, MD -0.42, 95% CI -0.68 to -0.15, P = 0.002) in patients on hemodialysis. CONCLUSIONS: We confirmed the positive effect of amino acid/protein supplementation on physical function in people undergoing hemodialysis. However, there is still insufficient evidence, and more rigorously designed randomized controlled trials with high quality are needed.

Synthesis and SAR of 2-phenyl-1-sulfonylaminocyclopropane carboxylates as ADAMTS-5 (Aggrecanase-2) inhibitors.

A series of 1-sulfonylaminocyclopropanecarboxylates was synthesized as ADAMTS-5 (Aggrecanase-2) inhibitors. After an intensive investigation of the central cyclopropane core including its absolute stereochemistry and substituents, we found compound 22 with an Agg-2 IC50=7.4 nM, the most potent ADAMTS-5 inhibitor reported so far.

Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity.

SCD1 is a rate-limiting enzyme in the conversion of saturated fatty acids to monounsaturated fatty acids. SCD1 inhibitors have potential effects on obesity, diabetes, acne, and cancer, but the adverse effects associated with SCD1 inhibition in the skin and eyelids are impediments to clinical development. To avoid mechanism-based adverse effects, we explored the compounds that selectively inhibit SCD1 in the liver in an ex vivo assay. Starting from a systemically active lead compound, we focused on the physicochemical properties tPSA and cLogP to minimize exposure in the off-target tissues. This effort led to the discovery of thiazole-4-acetic acid analog 48 as a potent and liver-selective SCD1 inhibitor. Compound 48 exhibited significant effects in rodent models of diabetes, hepatic steatosis, and obesity, with sufficient safety margins in a rat toxicology study with repeated dosing.

Cetylpyridinium chloride at sublethal levels increases the susceptibility of rat thymic lymphocytes to oxidative stress.

Cetylpyridinium chloride (CPC) is an antimicrobial agent used in many personal care products, with subsequent release into the environment. Since CPC is found at low concentrations in river and municipal wastewater, its influence on wildlife is of concern. Therefore, in this study, we used flow cytometry to examine the effects of sublethal concentrations of CPC on rat thymic lymphocytes in order to characterize the cellular actions of CPC at low concentrations in the presence and absence of H2O2-induced oxidative stress. CPC treatment increased the population of living cells with phosphatidylserine exposed on the outer surface of their plasma membranes (a marker of early stage apoptosis), elevated intracellular Zn2+ levels, and decreased the cellular content of nonprotein thiols. CPC also potentiated the cytotoxicity of H2O2. Our results suggest that, even at environmentally relevant sublethal concentrations, CPC exerts cytotoxic effects under oxidative stress conditions by increasing intracellular Zn2+ concentration and decreasing the cellular content of nonprotein thiols. These findings indicate that, under some in vitro conditions, CPC is bioactive at environmentally relevant concentrations. Therefore, CPC release from personal care products into the environment may need to be regulated to avoid its adverse effects on wildlife.

[Sudden difficulty in ventilation due to massive subcutaneous emphysema during laparoscopic cholecystectomy].

A 56-year-old woman with cholecystolithiasis was scheduled for laparoscopic cholecystectomy. Anesthesia was induced with fentanyl and propofol IV, and the trachea was intubated using vecuronium IV. Anesthesia was maintained with 60% nitrous oxide and propofol intravenously, and vecuronium was used for muscle relaxation. Following induction of carbon dioxide pneumoperitoneum, PETCO2 slightly increased. During pneumoperitoneum PETCO2 as easily controlled by increasing minute volume of ventilation. Fifty minutes after the start of pneumoperitoneum, suddenly the peak airway pressure increased and PETCO2 reached 70 mmHg continuously. At this time, severe massive subcutaneous emphysema from the anterior thorax to the head and neck was noted, and the manual lung ventilation was very difficult. After discontinuation of pneumoperitoneum, PETCO2 gradually decreased with improvement of the neck subcutaneous emphysema. At the same time the lung ventilation improved. We speculate that major causes of difficulty in ventilation were the decreased compliance and the tracheal tube comppression, which were due to massive subcutaneous emphysema. Our findings show that we have to stop pneumoperitoneum immediately, when we find a sudden increase of the peak airway pressure or PETCO2 with subcutaneous emphysema during laparoscopic cholecystectomy.

Swallowing syncope: complex mechanisms of the reflex.

A 69-year-old woman was admitted to our hospital for the examination of syncope. When she ate solid food, she had dizziness or loss of consciousness. The ambulatory ECG suggested sino-atrial block during swallowing with a maximum sinus pause of 6 seconds. An electrophysiologic study revealed pre-existing sinus node dysfunction, which was exaggerated by the balloon inflation in the esophagus. Atropine counteracted the slowing of the basal sinus rate induced by esophageal pressure, but it did not block the effect on the maximum sinus node recovery time. This observation suggested that the syncope was mediated partly by a non-vagal mechanism.

A 40-year follow-up of whetstone cutters on silicosis.

The present study, consisted of two separate surveys, was initiated to clarify the development of clinical pictures of silicosis after termination of dust exposure. The first survey was a 40-year follow-up of radiographic pictures of the chest among 200 male whetstone cutters (Group I workers). The second survey was conducted in 75 male recipients (Group II workers) of disability compensation for silicosis due to whetstone dust exposure. The study on Group I workers made it clear that the proportion of those free of radiographic findings in the chest pictures decreased during a 40-year follow-up period from 84% in the 1st health examination in 1952-6 to 36% in the 3rd examination in 1995. The rate of progression of the disease from Category 1 to 3 (after ILO-guided classification) to higher categories in a 15-year period was as high as >50%. Longer service duration and higher category of chest radiography at the previous health examination were the influential factors in determining the rapid progression of silicosis. The latter observation was confirmed also through a similar analysis on Group II workers. Whetstone preparations contained SiO2 by about 50%. No industrial hygiene data were available for both groups of stone cutters, but the exposure of Group I workers was estimated to be about 1 mg/m3, or well in excess of the current occupational exposure limit.

Mortality due to silico-tuberculosis and lung cancer among 200 whetstone cutters.

The objective of the present study was to examine if the mortality due to tuberculosis and cancer in the lungs was elevated in a cohort of 200 male whetstone cutters. 1955-1995 death certificate-based mortality data on the cohort were available, and the data were reviewed in the present study for mortality due to the two diseases to calculate standardized mortality ratios (SMR) in reference to the health statistics of Kyoto prefecture, where the cohort lived. Among the 200 cohort members, 99 men deceased during the observation period, the deaths including 10 cases of lung tuberculosis (of which 9 cases had silicosis together), 20 cases of all malignancies, and 6 cases of lung cancer (5 cases with silicosis). There was a significant elevation in the mortality due to lung tuberculosis (SMR = 3.47) although SMR for all causes was not elevated (1.10). There was no significant change in SMR for all malignancies (0.78), whereas SMR for lung cancer (1.24) tended to be elevated although insignificantly. Lung tuberculosis was a significant complication of silicosis in 1955-1995. Possible elevation in lung cancer SMR among this cohort needs further studies.

Discovery of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates: novel and highly selective aggrecanase inhibitors.

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.

Neurally mediated syncope manifesting during atrial fibrillation: a case report.

A 64-year-old male was admitted to hospital because of repeated episodes of syncope and palpitation. Ambulatory monitoring revealed paroxysmal atrial fibrillation (AF) as the cause of palpitation; he did not have structural heart disease. The induction of AF by rapid pacing (50 Hz for 1 s) in an upright position provoked syncope with a vasodepressor response. Atropine sulfate blocked the induction of syncope. The possible etiology was neurally mediated syncope that manifested only during AF, which suggests that the abnormal vagal activity during AF in this case exaggerated the vasodepessor response while upright.

Glycoglycerolipid from the membranes of Acholeplasma laidlawii binds to human immunodeficiency virus-1 (HIV-1) and accelerates its entry into cells.

We have reported previously that glycoglycerolipids derived from the membranes of Acholeplasma laidlawii, 3- O-[2'- O-(alpha-D-glucopyranosyl)-6'- O-acyl-alpha-glucopyranosyl]-1,2-di- O-acyl- sn-glycerols (GAGDGs) bind to human cell lines. In addition, the GAGDGs were found to augment HIV-1 infection in human cell lines. Here we show that GAGDG binds to HIV-1 and facilitates the entry of HIV-1 into cells. The binding ability of GAGDG to HIV-1 was blocked by anti-GAGDG serum. Binding assay with synthetic GAGDGs and related compounds showed that the presence of branching form of acyl chains at the C14 or C16 position, glucose, and the acyl chain binding to the glucose were critical for efficient binding. GAGDG efficiently augmented the entry of HIV-1 into cells in a single-cycle replication assay. These results indicate that GAGDG of A. laidlawii membranes participates in the facilitation of HIV-1 infection.

Binding of glycoglycerolipid derived from membranes of Acholeplasma laidlawii PG8 and synthetic analogues to lymphoid cells.

A component that binds to human lymphoid cells was isolated from the membranes of Acholeplasma laidlawii PG8. The component was extracted using the Bligh-Dyer method and purified using a silica-gel column and TLC. The active component was identified as 3-O:-[2'-O-(alpha-D-glucopyranosyl)- 6'-O-acyl-alpha-D-glucopyranosyl]-1,2-di-O- acyl-sn-glycerol (GAGDG) using (1)H- and (13)C-NMR and GC-MS. The compositions of the major saturated fatty acids were nC (14) (17.8%), isoC(14) (10.7%) and nC (16) (34.9%) as determined by GC-MS. The amounts of unsaturated species were less than 10% of those of the corresponding saturated acids. GAGDGs which have three tetradecanoyl groups were synthesized. These synthetic GAGDGs, as well as GAGDGs derived from A. laidlawii membranes, had a high binding affinity for MOLT-4 and HUT-78 (human T cell lines), Raji (a B cell line), HL-60 (a monoblastoid cell line) and primary cultured human T cells. The binding affinities of GAGDGs with an isoC(14) acyl group was higher than those with nC(14) and nC(16) acyl groups. The binding to lymphoid cells reveals a novel biological activity of GAGDGs.