Evaluation of Dynamic Effects of Depressive Symptoms on Physical Function in Knee Osteoarthritis.

OBJECTIVE: To assess how changes in depressive symptoms influence physical function over time among those with radiographic knee osteoarthritis (OA). METHODS: Participants from the Osteoarthritis Initiative with radiographic knee OA (n = 2,212) and complete data were identified at baseline. Depressive symptoms were assessed as a time-varying score at baseline and the first three annual follow-up visits using the Center for Epidemiological Studies Depression Scale (CES-D) Scale. Physical function was measured at the first four follow-up visits using 20-meter gait speed meters per second. The following two marginal structural models were fit: one assessing the main effect of depressive symptoms on gait speed and another assessing time-specific associations. RESULTS: Time-adjusted results indicated that higher CES-D scores were significantly associated with slower gait speed (-0.0048; 95% confidence interval -0.0082 to -0.0014), and time-specific associations of CES-D were largest during the first follow-up interval (-0.0082; 95% confidence interval -0.0128 to -0.0035). During subsequent follow-up time points, the influence of depressive symptoms on gait speed diminished. CONCLUSION: The negative effect of depressive symptoms on physical function may decrease over time as knee OA progresses.

Time-varying treatment effect modification of oral analgesic effectiveness by depressive symptoms in knee osteoarthritis: an application of structural nested mean models in a prospective cohort.

BACKGROUND: Depressive symptoms are common in knee osteoarthritis (OA), exacerbate knee pain severity and may influence outcomes of oral analgesic treatments. The aim was to assess whether oral analgesic effectiveness in knee OA varies by fluctuations in depressive symptoms. METHODS: The sample included Osteoarthritis Initiative (OAI) participants not treated with oral analgesics at enrolment (n = 1477), with radiographic disease at the first follow-up visit (defined as the index date). Oral analgesic treatment and depressive symptoms, assessed with the Center for Epidemiological Studies Depression [(CES-D) score ≥16] Scale, were measured over three annual visits. Knee pain severity was measured at visits adjacent to treatment and modifier using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale (rescaled range = 0-100). Structural nested mean models (SNMMs) estimated causal mean differences in knee pain severity comparing treatment versus no treatment. RESULTS: The average causal effects of treated versus not treated for observations without depressive symptoms showed negligible differences in knee pain severity. However, causal mean differences in knee pain severity comparing treatment versus no treatment among observations with depressive symptoms increased over time from -0.10 [95% confidence interval (CI): -9.94, 9.74] to -16.67 (95% CI: -26.33, -7.01). Accordingly, the difference in average causal effects regarding oral analgesic treatment for knee pain severity between person-time with and without depressive symptoms was largest (-16.53; 95% CI: -26.75, -6.31) at the last time point. Cumulative treatment for 2 or 3 years did not yield larger causal mean differences. CONCLUSIONS: Knee OA patients with persistent depressive symptoms and chronic pain may derive more analgesic treatment benefit than those without depressive symptoms and less pain.

Duloxetine plus exercise for knee osteoarthritis and depression: A feasibility study.

Objective: To assess the feasibility of a 24-week, center-based, aerobic exercise program plus duloxetine to treat symptomatic knee osteoarthritis (OA) and major depression. Design: Patients with symptomatic knee OA and major depression were recruited between August 2021 and November 2022 from the University of Maryland and VA Maryland Health Care Systems and Baltimore metropolitan area using medical records and advertisements. The intervention included 1) supervised treadmill walking 3 times weekly and 2) duloxetine starting at 30 â€‹mg each day and titrating up to the optimal dosage of 60 â€‹mg daily. Data collection occurred at baseline and 12- and 24-weeks follow-up. Feasibility was evaluated from recruitment rates, reasons for drop out, and treatment adherence. Clinical measures included the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Hamilton Depression Rating Scale (HAM-D). Results: Among 377 interested participants, 9 patients were enrolled, and 1 completed treatment. The most common reason reported for not prescreening was time commitment (n â€‹= â€‹39), many patients did not satisfy depression screening criteria (n â€‹= â€‹45), and most enrolled participants were not experiencing a major depressive episode (n â€‹= â€‹6). The single treated participant was 100 â€‹% adherent to duloxetine and depression severity decreased (HAM-D â€‹= â€‹25 to 1), but compliance to supervised exercise was only 26 â€‹%, and knee pain severity changed little (KOOS â€‹= â€‹41.7 to 44.4). Conclusions: This intervention had low feasibility. Time commitment to supervised exercise sessions reduced accessibility, and depression defined by diagnostic criteria precluded knee OA patients with depressive symptoms not a meeting case-level diagnosis from receiving treatment. Clinical trial registration number: NCT04111627.

Grass-roots entrepreneurship complements traditional top-down innovation in lung and breast cancer.

The majority of biomedical research is funded by public, governmental, and philanthropic grants. These initiatives often shape the avenues and scope of research across disease areas. However, the prioritization of disease-specific funding is not always reflective of the health and social burden of each disease. We identify a prioritization disparity between lung and breast cancers, whereby lung cancer contributes to a substantially higher socioeconomic cost on society yet receives significantly less funding than breast cancer. Using search engine results and natural language processing (NLP) of Twitter tweets, we show that this disparity correlates with enhanced public awareness and positive sentiment for breast cancer. Interestingly, disease-specific venture activity does not correlate with funding or public opinion. We use outcomes from recent early-stage innovation events focused on lung cancer to highlight the complementary mechanism by which bottom-up "grass-roots" initiatives can identify and tackle under-prioritized conditions.

Risk factors for colorectal cancer in man induce aberrant crypt foci in rats: Preliminary findings.

Epidemiological studies have demonstrated clear associations between specific dietary and environmental risk factors and incidence of colorectal cancer, but the mechanisms responsible for these associations are not known. An animal model could facilitate such an understanding. Both genotoxic and nongenotoxic carcinogens induce aberrant crypt foci (ACF) in the colons of F344 rats. F344 rats were provided with diets that contained putative risk factors for CRC: low calcium and low vitamin D, high iron, high fructose, and decreased light (UV) exposure or a control diet for 14 wk. The rats were then assessed with biochemical measures and by topological examination for evidence of colon abnormalities. Circulating ionized calcium was decreased from 2.85 to 1.69 mmol/L, and ACF were increased from 0.7 to 13.6 lesions/colon (both P < 0.001). Rats exposed to the multiple environmental conditions associated with colon cancer, developed ACF similar to the heterogeneous or ill-defined ACF in the human colon. Heterogeneous ACF are the most frequently seen in humans and are also seen in rats shortly after exposure to the non-genotoxic colon carcinogen, dextransulfate sodium. The rodent model could be used to assess the pathways from diet and environment to colon cancer and to provide guidance for clinical studies.

Rescuing hepatocytes from iron-catalyzed oxidative stress using vitamins B1 and B6.

In the following rescue experiments, iron-mediated hepatocyte oxidative stress cytotoxicity was found to be prevented if vitamin B1 or B6 was added 1h after treatment with iron. The role of iron in catalyzing Fenton-mediated oxidative damage has been implicated in iron overload genetic diseases, carcinogenesis (colon cancer), Alzheimer's disease and complications associated with the metabolic syndrome through the generation of reactive oxygen species (ROS). The objectives of this study were to interpret the cytotoxic mechanisms and intracellular targets of oxidative stress using "accelerated cytotoxicity mechanism screening" techniques (ACMS) and to evaluate the rescue strategies of vitamins B1 and B6. Significant cytoprotection by antioxidants or ROS scavengers indicated that iron-mediated cytotoxicity could be attributed to reactive oxygen species. Of the B6 vitamers, pyridoxal was best at rescuing hepatocytes from iron-catalyzed lipid peroxidation (LPO), protein oxidation, and DNA damage, while pyridoxamine manifested greatest protection against ROS-mediated damage. Thiamin (B1) decreased LPO, mitochondrial and protein damage and DNA oxidation. Together, these results indicate that added B1 and B6 vitamins protect against the multiple targets of iron-catalyzed oxidative damage in hepatocytes. This study provides insight into the search for multi-targeted natural therapies to slow or retard the progression of diseases associated with Fenton-mediated oxidative damage.

Differences in glyoxal and methylglyoxal metabolism determine cellular susceptibility to protein carbonylation and cytotoxicity.

Chronic hyperglycemia in diabetic patients often leads to chronic side effects associated with protein glycation and the formation of reactive carbonyl species, such as methylglyoxal (MGO) and glyoxal (GO). We have shown that both MGO and GO carbonylated bovine serum albumin (BSA) in vitro to the same degree and stability. The carbonylated BSA formed initially could be a reversible Schiff base as the UV absorbance formed after the addition of 2,4-dinitrophenylhydrazine was decreased when sodium borohydride was added. MGO and GO also carbonylated hepatocyte protein rapidly with similar dose and time dependence. In contrast to BSA carbonylation, the amount of carbonylated proteins in hepatocytes decreased over time, much more rapidly for hepatocytes treated with MGO than with GO. This could be attributed to the rapid hepatocyte metabolism of MGO with glyoxalase I, the predominant detoxification enzyme for MGO. Protein carbonylation and the associated toxicity caused by GO and MGO were studied in the following hepatocyte models: (1) control hepatocytes, (2) glutathione (GSH)-depleted hepatocytes, (3) mitochondrial aldehyde dehydrogenase (ALDH2)-inhibited hepatocytes, (4) hepatocyte inflammation model, and (5) catalase-inhibited hepatocyte model. Carbonylation and cytotoxicity caused by MGO or GO was markedly increased in GSH-depleted hepatocytes as compared to control hepatocytes. Hepatocytes exposed to non-toxic concentrations of H(2)O(2) or hepatocytes treated with catalase inhibitors also showed a marked increase in GO-caused cytotoxicity and protein carbonylation, whereas there were only minor increases with MGO. The GO effect was attributed to potential radical formation and the inhibition effect of H(2)O(2) on aldehyde dehydrogenase, a major GO metabolising enzyme. GO-caused cytotoxicity and protein carbonylation were also increased with ALDH2-inhibited hepatocytes whereas such an increase was only observed with MGO in GSH-depleted hepatocytes.

Cytoprotective mechanisms of carbonyl scavenging drugs in isolated rat hepatocytes.

Diabetes is a disease among several others that has been linked with the accumulation of carbonylated proteins in tissues. Carbonylation is an irreversible, non-enzymatic modification of proteins by carbonyls. In Diabetes, dicarbonyls are thought to be generated by the autoxidation of reducing sugars which react with proteins and eventually lead to the formation of advanced glycation end-products (AGEs). Carbonyl scavenging drugs containing thiol or amine functional groups have been suggested to act therapeutically in preventing protein carbonylation by trapping the dicarbonyls glyoxal and methylglyoxal to form non-toxic adducts. This study seeks to determine the mechanism by which carbonyl scavenging drugs prevent glyoxal toxicity in a cell-free system as well as in isolated rat hepatocytes. In a cell free system, the glyoxal trapping ability of the drugs was measured by following glyoxal disappearance using Girard's Reagent T. For the thiol-containing drugs, the order of effectiveness for glyoxal trapping was penicillamine>cysteine>N-acetyl-cysteine, whereas for the amine-containing drugs, the order of effectiveness for glyoxal trapping was aminoguanidine>>pyridoxamine>metformin. Furthermore, aminoguanidine, penicillamine and cysteine at concentrations equimolar to glyoxal prevented protein carbonylation. Other scavenging drugs such as pyridoxamine, hydralazine or metformin did not prevent glyoxal-induced cytotoxicity by trapping glyoxal, but instead prevented cytotoxicity by acting as a mitochondrial vitamin, lipid antioxidant or reactive oxygen species scavenger, respectively.

Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents.

Carbonyls generated by autoxidation of carbohydrates or lipid peroxidation have been implicated in advanced glycation end product (AGE) formation in tissues adversely affected by diabetes complications. Tissue AGE and associated pathology have been decreased by vitamin B(1)/B(6) in trials involving diabetic animal models. To understand the molecular cytoprotective mechanisms involved, the effects of B(1)/B(6) vitamers against cytotoxicity induced by AGE/advanced lipid end product (ALE) carbonyl precursors (glyoxal/acrolein) have been compared to cytotoxicity induced by oxidative stress (hydroperoxide) or mitochondrial toxins (cyanide/copper). Thiamin was found to be best at preventing cell death induced by carbonyl stress and mitochondrial toxins but not oxidative stress cell death suggesting that thiamin pyrophosphate restored pyruvate and alpha-ketoglutarate dehydrogenases inhibited by mitochondrial toxicity. However, B(6) vitamers were most effective at preventing oxidative stress or lipid peroxidation cytotoxicity suggesting that pyridoxal or pyridoxal phosphate were antioxidants and/or Fe/Cu chelators. A therapeutic vitamin cocktail could provide maximal prevention against carbonyl stress toxicity associated with diabetic complications.

Hepatocyte susceptibility to glyoxal is dependent on cell thiamin content.

Glyoxal, a reactive dicarbonyl, is detoxified primarily by the glyoxalase system utilizing glutathione (GSH) and by the aldo-keto reductase enzymes which utilizes NAD[P]H as the co-factor. Thiamin (Vitamin B(1)) is an essential coenzyme for transketolase (TK) that is part of the pentose phosphate pathway which helps maintain cellular NADPH levels. NADPH plays an intracellular role in regenerating glutathione (GSH) from oxidized GSH (GSSG), thereby increasing the antioxidant defenses of the cell. In this study we have focused on the prevention of glyoxal toxicity by supplementation with thiamin (3mM). Thiamin was cytoprotective and restored NADPH levels, glyoxal detoxification and mitochondrial membrane potential. Hepatocyte reactive oxygen species (ROS) formation, lipid peroxidation and GSH oxidation were decreased. Furthermore, hepatocytes were made thiamin deficient with oxythiamin (3mM) as measured by the decreased hepatocyte TK activity. Under thiamin deficient conditions a non-toxic dose of glyoxal (2mM) became cytotoxic and glyoxal metabolism decreased; while ROS formation, lipid peroxidation and GSH oxidation was increased.

Mitochondrial involvement in genetically determined transition metal toxicity II. Copper toxicity.

Copper, like iron, is an essential transition metal ion in which its redox reactivity, whilst essential for the activity of mitochondrial enzymes, can also be a source of harmful reactive oxygen species if not chelated to biomolecules. Therefore, both metals are sequestered by protein chaperones and moved across membranes by protein transporters with the excess held in storage proteins for future use. In the case of copper, the storage proteins in the mitochondria are a distinct ceruloplasmin and metallothionein (MT). If the cell accumulates too much copper or copper is needed by other cells, then copper can be chaperoned to the trans-Golgi secretory compartment where it is transported into the Golgi by ATP-dependent pumps ATP7A/B. In liver, the copper is then incorporated into ceruloplasmin in vesicles that travel to the plasma membrane and release ceruloplasmin into the plasma. This paper reviews the genetic basis for diseases associated with copper deficit or excess, particularly those attributed to defective ATP7A/B transporters, with special emphasis on pathologies related to a loss of mitochondrial function.

Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways.

The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed.

Mitochondrial function and toxicity: role of the B vitamin family on mitochondrial energy metabolism.

The B vitamins are water-soluble vitamins required as coenzymes for enzymes essential for cell function. This review focuses on their essential role in maintaining mitochondrial function and on how mitochondria are compromised by a deficiency of any B vitamin. Thiamin (B1) is essential for the oxidative decarboxylation of the multienzyme branched-chain ketoacid dehydrogenase complexes of the citric acid cycle. Riboflavin (B2) is required for the flavoenzymes of the respiratory chain, while NADH is synthesized from niacin (B3) and is required to supply protons for oxidative phosphorylation. Pantothenic acid (B5) is required for coenzyme A formation and is also essential for alpha-ketoglutarate and pyruvate dehydrogenase complexes as well as fatty acid oxidation. Biotin (B7) is the coenzyme of decarboxylases required for gluconeogenesis and fatty acid oxidation. Pyridoxal (B6), folate and cobalamin (B12) properties are reviewed elsewhere in this issue. The experimental animal and clinical evidence that vitamin B therapy alleviates B deficiency symptoms and prevents mitochondrial toxicity is also reviewed. The effectiveness of B vitamins as antioxidants preventing oxidative stress toxicity is also reviewed.