Citations

PurposeFatigue is one of the most common symptoms experienced by patients with cancer. This trial was developed to evaluate the efficacy of long-acting methylphenidate for improving cancer-related fatigue and to assess its toxicities.Patients and MethodsAdults with cancer were randomly assigned in a double-blinded manner to receive methylphenidate (target dose, 54 mg/d) or placebo for 4 weeks. The Brief Fatigue Inventory was the primary outcome measure, while secondary outcome measures included a Symptom Experience Diary (SED), the Short Form-36 (SF-36) Vitality Subscale, a linear analog self-assessment, the Pittsburgh Sleep Quality Index, and the Subject Global Impression of Change.ResultsIn total, 148 patients were enrolled. Using an area under the serum concentration-time curve analysis, there was no evidence that methylphenidate, as compared with placebo, improved the primary end point of cancer-related fatigue in this patient population (P = .35). Comparisons of secondary end points, including clinically significant changes in quality-of-life variables and cancer-related fatigue change from baseline, were similarly negative. However, a subset analysis suggested that patients with more severe fatigue and/or with more advanced disease did have some fatigue improvement with methylphenidate (eg, in patients with stage III or IV disease, the mean improvement in usual fatigue was 19.7 with methylphenidate v 2.1 with placebo; P = .02). There was a significant difference in self-reported toxicities (SED), with increased levels of nervousness and appetite loss in the methylphenidate arm.ConclusionThis clinical trial was unable to support the primary prestudy hypothesis that the chosen long-acting methylphenidate product would decrease cancer-related fatigue.

Background— Mechanisms promoting the transition from hypertensive heart disease to heart failure with preserved ejection fraction are poorly understood. When inappropriate for salt status, mineralocorticoid (deoxycorticosterone acetate) excess causes hypertrophy, fibrosis, and diastolic dysfunction. Because cardiac mineralocorticoid receptors are protected from mineralocorticoid binding by the absence of 11-β hydroxysteroid dehydrogenase, salt-mineralocorticoid–induced inflammation is postulated to cause oxidative stress and to mediate cardiac effects. Although previous studies have focused on salt/nephrectomy in accelerating mineralocorticoid-induced cardiac effects, we hypothesized that hypertensive heart disease is associated with oxidative stress and sensitizes the heart to mineralocorticoid, accelerating hypertrophy, fibrosis, and diastolic dysfunction. Methods and Results— Cardiac structure and function, oxidative stress, and mineralocorticoid receptor–dependent gene transcription were measured in sham-operated and transverse aortic constriction (studied 2 weeks later) mice without and with deoxycorticosterone acetate administration, all in the setting of normal-salt diet. Compared with sham mice, sham plus deoxycorticosterone acetate mice had mild hypertrophy without fibrosis or diastolic dysfunction. Transverse aortic constriction mice displayed compensated hypertensive heart disease with hypertrophy, increased oxidative stress (osteopontin and NOX4 gene expression), and normal systolic function, filling pressures, and diastolic stiffness. Compared with transverse aortic constriction mice, transverse aortic constriction plus deoxycorticosterone acetate mice had similar left ventricular systolic pressure and fractional shortening but more hypertrophy, fibrosis, and diastolic dysfunction with increased lung weights, consistent with heart failure with preserved ejection fraction. There was progressive activation of markers of oxidative stress across the groups but no evidence of classic mineralocorticoid receptor–dependent gene transcription. Conclusions— Pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess, which promotes the transition to heart failure with preserved ejection fraction independently of classic mineralocorticoid receptor–dependent gene transcription.

External qigong as a pharmacotherapy adjunct was investigated in 50 subjects with chronic pain (pain lasting > 3 months with pain score of ≥ 3 on 0–10 numeric analog scale) who presented to a qigong healing center. Participants were randomized to receive either external qigong treatment (EQT) or equivalent attention time (EAT) in weekly 30-min sessions for four consecutive weeks. Outcomes were assessed before and after sessions. The primary outcome measure was intensity of pain by a 10-cm visual analog scale used to rate all pain severity measurements. At 8-week follow-up, participants were contacted by telephone and mailed a questionnaire. Most had experienced pain for > 5 years (66%); the rest, for > 3 to 5 years (8%), 1 to 3 years (10%), or < 1 year but > 3 months (10%). The most frequent concomitant diagnoses were multifactorial (26%), osteoarthritis (18%), and low back pain (12%). Most patients were also receiving other treatments (74%); none previously had EQT. Participants were randomly assigned to EQT ( n = 26) or EAT ( n = 24). These groups had no significant differences at baseline except for prior awareness of qigong (EQT 31% vs. EAT 63%; p = 0.025). Compared to the EAT group, EQT participants had a significant decrease in pain intensity in the 2nd ( p = 0.003), 3rd ( p < 0.001), and 4th weeks of treatment ( p = 0.003). At week 8, these differences in overall decreased pain intensity persisted but were not statistically significant.

Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.

Reactive oxygen species (ROS) and cellular oxidative stress are involved in many physiological and pathophysiological processes, including cellular and organismal aging, migration, proliferation, senescence or death of normal and cancer cells, and stress resistance of stem cells. The forkhead homeobox type O (FOXO) transcription factors FOXO1, FOXO3a, and FOXO4 are critical mediators of the cellular responses to oxidative stress and have been implicated in many of the above ROS-regulated processes. In cancer cells they converge oxidative stress signaling to cell cycle arrest and cell death or promote a motile phenotype. Dependent on their posttranslational modifications FOXOs can also actively regulate the detoxification of cells from ROS and promote stress resistance. Thus, FOXO transcription factors are of vital importance in processes regulating tumor survival or progression, stem cell maintenance, age-related pathological processes, and lifespan extension. Antioxid. Redox Signal. 14, 593–605.

OBJECTIVE The accumulation of old and damaged proteins likely contributes to complications of diabetes, but currently no methodology is available to measure the relative age of a specific protein alongside assessment of posttranslational modifications (PTM). To accomplish our goal of studying the impact of insulin deficiency and hyperglycemia in type 1 diabetes upon accumulation of old damaged isoforms of plasma apolipoprotein A-1 (ApoA-1), we sought to develop a novel methodology, which is reported here and can also be applied to other specific proteins. RESEARCH DESIGN AND METHODS To label newly synthesized proteins, [ring-13C6]phenylalanine was intravenously infused for 8 h in type 1 diabetic participants (n = 7) during both insulin treatment and 8 h of insulin deprivation and in nondiabetic participants (n = 7). ApoA-1 isoforms were purified by two-dimensional gel electrophoresis (2DGE) and assessment of protein identity, PTM, and [ring-13C6]phenylalanine isotopic enrichment (IE) was performed by tandem mass spectrometry. RESULTS Five isoforms of plasma ApoA-1 were identified by 2DGE including ApoA-1 precursor (pro-ApoA-1) that contained the relatively highest IE, whereas the older forms contained higher degrees of damage (carbonylation, deamidation) and far less IE. In type 1 diabetes, the relative ratio of IE of [ring-13C6]phenylalanine in an older isoform versus pro-ApoA-1 was higher during insulin deprivation, indicating that de novo synthesized pro-ApoA-1 more rapidly accumulated damage, converting to mature ApoA-1. CONCLUSIONS We developed a mass spectrometry–based methodology to identify the relative age of protein isoforms. The results demonstrated accelerated oxidative damage to plasma ApoA-1, thus offering a potential mechanism underlying the impact of poor glycemic control in type 1 diabetic patients that affects a patient's risk for vascular disease.

Salvage of failed total wrist arthroplasty by arthrodesis may be difficult because of bone loss and poor quality of bone and soft tissues. We examined the outcomes of wrist arthrodesis for failed total wrist arthroplasty in a retrospective study of 21 wrists in 17 patients. Clinical data, radiographs, patient-reported outcomes and DASH questionnaires were used. Thirteen women and four men had undergone total wrist arthroplasty at an average age of 55 years. The mode of failure was aseptic loosening in 13 wrists. The average time from the index arthroplasty to wrist arthrodesis was 7.6 years. Autograft and/or allograft bone graft was used in all of the wrists. Arthrodesis was achieved in 11 wrists and ten had a nonunion. Six arthrodeses underwent eight revisions for nonunion, with two achieving union. The mean DASH score was 29 in wrists that fused and 36 in those that did not fuse. Pain scores averaged 2.1 in the wrists that fused and 3.3 in the nonunion group. Most patients had clinical improvement.