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The rate of water loss can be quantified through measurement of sweat rate

Pre- and postexercise body weight measurements are the most common means to estimate overall water loss but are condition specific

It appears that 1% to 2% body weight loss is well tolerated by the exercising athlete

Dehydration, defined as greater than 2% loss of body weight, can negatively affect performance

In highly trained endurance athletes, plasma volume and sodium serum concentration were preserved despite a 5% body weight loss

In Ironman triathletes, dehydration to 5% body weight loss did not correlate with occurrence of medical complications

hydration should begin hours prior to exercise, especially if known deficits are present, and fluids should be consumed at a slow, steady rate, with 5 to 7 mL/kg taken 4 hours prior to exercise

Sodium concentration did not produce significant changes in the rate of absorption but was primarily dependent on carbohydrate concentration

Replacing 150% of body weight loss over 60 minutes has been tolerated without complications

IV treatment of severe dehydration (>7% body weight loss), exertional heat illness, nausea, emesis, or diarrhea, and in those who cannot ingest oral fluids for other reasons, is clinically indicated

A recent survey of the National Football League teams revealed that 75% (24 of 32) of the teams utilized IV infusion of fluids for prehydration in at least some otherwise healthy individuals

In the National Football League, an average of 1.5 L of normal saline was administered approximately 2.5 hours prior to competition

after 2 hours of exercise, the rectal temperature was 0.6° higher in the group not receiving IV infusion. Also, stroke volume and cardiac output were 11% to 16% lower in the control group versus the IV infusion group.

Recent evidence suggests the etiology of EAMC is related to muscle fatigue and neuronal excitability

no correlation between hydration status or electrolyte concentrations with EAMC

there may be a subset of muscle cramping that is associated with a loss of both body fluid and sodium

Glycerol is the primary agent for oral hyperhydration

elevation of plasma volume by 200 to 300 mL via dextran infusion resulted in 15% increase in stroke volume, 4% increase in VO2 max, and an increase in the exercise time to fatigue

Neither the tonicity nor mode of hydration resulted in improved speed of rehydration, greater fluid retention, or improved performance

There are beneficial anecdotal reports of EAMC treatment in elite and professional-level athletes with IV hydration during the course of an event

Plasma volume was better restored during rehydration with IV fluids at preexercise and 5 minutes of exercise. At 15 minutes, there was no difference between IV and oral rehydration

More rapid restoration of plasma volume was accomplished in the IV treatment group with no advantages over oral rehydration in physiological strain, heat tolerance, ratings of perceived effort, or thermal sensations

No difference was found in exercise time to exhaustion. IV and oral rehydration methods were equally effective. Heart rates were statistically higher in the oral rehydration group through 75 minutes of exercise, and there were higher increases in norepinephrine plasma concentrations

No significant differences between the groups were found for time to recovery, number of days with pain, number of days with stiffness, sleep disturbance, fatigue, rectal temperature, and loss of appetite

The current data suggest that IV rehydration is faster than oral

There may be physiological benefits of decreased heart rate and norepinephrine in athletes rehydrated via IV route

Postexercise blood 1 hour and 24 hours showed no differences in circulating myoglobin or creatine kinase

The use of IV fluid may be beneficial for a subset of fluid sensitive athletes

this should be reserved for high-level athletes with strong histories of symptoms in well-monitored settings.

Volume expanders may also be beneficial for some athletes

The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal components through pattern-recognition receptors

TLRs are PRRs that recognize microbe-associated molecular patterns

TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain homologous to the IL1 receptor intracellular domain

The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6, which are also elevated in obese and insulin-resistant patients

Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.

Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption

LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease.

In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression.

In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.

the gut microbiota has been recently proposed to be an environmental factor involved in the control of body weight and energy homeostasis by modulating plasma LPS levels

dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a bacterially related factor might be responsible for high-fat diet-induced obesity.

This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in Bifidobacterium and Eubacterium spp.

n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations

it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).

this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A

these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of LPS-mediated nutritional changes.

This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can beneficially affect the host's weight and adiposity.

endotoxemia was independently associated with energy intake but not fat intake in a multivariate analysis

in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.

T2DM patients have mean values of LPS that are 76% higher than healthy controls

LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both peripheral and hepatic

LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells

Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression of alcoholic and nonalcoholic fatty liver disease

The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted in bile

All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features

LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism

When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed, with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions such as obesity and metabolic syndrome

It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis

On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines like TNFα

high-fat diet mice presented with ME, which positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and F4/80 (a specific marker of mature macrophages) mRNAs

prebiotic administration reduces intestinal permeability to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls

Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative stress, and macrophage infiltration markers

This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat diet situation

high-fat feeding is associated with adipose tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between ME, proinflammatory status, oxidative stress, and, lately, increased CV risk

LPS has been shown to promote atherosclerosis

markers of systemic inflammation such as circulating bacterial endotoxin were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk

As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory state.

in eugonadal men, studies have demonstrated that the prostate can increase in volume by approximately 12%

There seems to be little doubt that the treatment with testosterone of a young hypogonadal male leads to significant growth of the prostate

Behre et al. [22] demonstrated increased prostate volume and prostate-specific antigen (PSA) levels in hypogonadal men

Most studies, however, have shown no effect of exogenous androgens on PSA or prostate volume for older hypogonadal males

They argue that the prostate is relatively insensitive to changes in androgen concentration at normal levels or in mild hypogonadism because the AR is saturated by androgens and therefore maximal androgen-AR binding is achieved. Conversely, the prostate is very sensitive to changes in androgen levels when testosterone is low

saturation model

visceral obesity (one of the most significant components of metabolic syndrome) is associated with prostate volume and influences prostate growth during TRT.

This hypothesis of inflammation induced LUTS is also argued to be a mechanism for improvement of LUTS with PDE5I

The concept, therefore, that treatment with TRT of hypogonadal males with metabolic syndrome might lead to improvement/stabilization of their LUTS, appears to be confirmed in recent work by Francomano et al.

There was also an improvement in components of the patient's metabolic syndrome (such as BMI, waist circumference, hemoglobin A1c [HbA1c], insulin sensitivity, and lipid profile) as well as inflammatory markers and C-reactive protein.

They concluded that TRT was safe in this group of men, and hypothesize that TRT mitigates the pro-inflammatory factors associated with metabolic syndrome.

Stretching, the primary treatment for acute EAMC

National Athletic Trainers’ Association recommends that athletes prone to muscle cramping add 0.3 to 0.7 g/L of salt to their drinks to stave off muscle cramps

Others have recommended adding higher amounts of sodium (about 3.0 to 6.0 g/L) to sports drinks based on the frequency of EAMC

intravenous infusion of fluids removes this delay, and it has been used to aid athletes who develop acute EAMC

maintaining hydration and adequate electrolyte levels is a good prevention strategy for individuals susceptible to EAMC

Fluid volumes of 1.8 L per hour have been well tolerated by tennis athletes who are susceptible to EAMC

Monitoring an athlete’s body weight is an easy method of ensuring adequate fluid replacement and individualizes each athlete’s fluid needs

the National Athletic Trainers’ Association and the American College of Sports Medicine recommend a volume of fluid that allows for less than a 2% body weight reduction

Endurance training may also serve as an effective means of preventing EAMC by expanding plasma volume and the extracellular fluid compartment15 and delaying neuromuscular fatigue

In terms of the histological proliferation biomarker Ki-67, we have shown a good correlation with FLT-PET pre-chemotherapy. The best predictive marker of response in terms of pCR was baseline Ki-67

Our study has shown that baseline Ki-67 and FLT SUVmax is well correlated in keeping with FLT-PETs status as a proliferation biomarker, although Ki-67 had a better predictive ability in terms of pathological outcome

none of the men stopped testosterone supplementation due to prostate cancer recurrence, and none demonstrated cancer progression

PSA level did transiently rise in one patient; however, none exceeded a PSA of 1.5 ng ml−1 to raise concern for biochemical recurrence

after 19 months on TRT, 10 hypogonadal patients with a history of undergoing a radical retropubic prostatectomy for prostate cancer had no PSA recurrence and had statistically significant improvements in serum total testosterone and hypogonadal symptoms

Similarly, Kaufman and Graydon14 examined case records of seven hypogonadal men who had undergone curative RP with symptoms of hypogonadism and low serum testosterone levels treated with testosterone replacement. No biochemical or clinical evidence of cancer recurrence was noted

In a much larger case series, Khera et al.15 reviewed the records of 57 men who received TRT following RP. After an average of 36 months following RP, testosterone replacement was initiated and followed for an average of 13 months. Mean testosterone values rose significantly and once again, there was no increase in PSA values and, therefore, no diagnosed biochemical recurrence

Four of the patients in the treatment group were found to have cancer recurrence, compared with eight in the control group

All biochemical recurrences were seen in individuals with high-risk disease

Our data show that ascorbic acid selectively killed cancer but not normal cells, using concentrations that could only be achieved by i.v. administration

Ascorbate-mediated cell death was due to protein-dependent extracellular H2O2 generation, via ascorbate radical formation from ascorbate as the electron donor. Like glucose, when ascorbate is infused i.v., the resulting pharmacologic concentrations should distribute rapidly in the extracellular water space (42). We showed that such pharmacologic ascorbate concentrations in media, as a surrogate for extracellular fluid, generated ascorbate radical and H2O2. In contrast, the same pharmacologic ascorbate concentrations in whole blood generated little detectable ascorbate radical and no detectable H2O2. These findings can be accounted for by efficient and redundant H2O2 catabolic pathways in whole blood (e.g., catalase and glutathione peroxidase) relative to those in media or extracellular fluid

ascorbic acid administered i.v. in pharmacologic concentrations may serve as a pro-drug for H2O2 delivery to the extracellular milieu

H2O2 generated in blood is normally removed by catalase and glutathione peroxidase within red blood cells, with internal glutathione providing reducing equivalents

The electron source for glutathione is NADPH from the pentose shunt, via glucose-6-phosphate dehydrogenase. If activity of this enzyme is diminished, the predicted outcome is impaired H2O2 removal causing intravascular hemolysis, the observed clinical finding.

Only recently has it been understood that the discordant clinical findings can be explained by previously unrecognized fundamental pharmacokinetics properties of ascorbate

Intracellular transport of ascorbate is tightly controlled in relation to extracellular concentration

Intravenous ascorbate infusion is expected to drastically change extracellular but not intracellular concentrations

For i.v. ascorbate to be clinically useful in killing cancer cells, pharmacologic but not physiologic extracellular concentrations should be effective, independent of intracellular ascorbate concentrations.

It is unknown why ascorbate, via H2O2, killed some cancer cells but not normal cells.

There was no correlation with ascorbate-induced cell death and glutathione, catalase activity, or glutathione peroxidase activity.

H2O2, as the product of pharmacologic ascorbate concentrations, has potential therapeutic uses in addition to cancer treatment, especially in infections

Neutrophils generate H2O2 from superoxide,

i.v. ascorbate is effective in some viral infections

H2O2 is toxic to hepatitis C

Use of ascorbate as an H2O2-delivery system against sensitive pathogens, viral or bacterial, has substantial clinical implications that deserve rapid exploration.

Recent pharmacokinetics studies in men and women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose

As much as a 70-fold difference in plasma concentrations is expected between oral and i.v. administration,

Complementary and alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm

Human Burkitt's lymphoma cells

We first investigated whether ascorbate in pharmacologic concentrations selectively affected the survival of cancer cells by studying nine cancer cell lines

Clinical pharmacokinetics analyses show that pharmacologic concentrations of plasma ascorbate, from 0.3 to 15 mM, are achievable only from i.v. administration

plasma ascorbate concentrations from maximum possible oral doses cannot exceed 0.22 mM because of limited intestinal absorption

For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM, a concentration easily achievable from i.v. infusion

All tested normal cells were insensitive to 20 mM ascorbate.

Lymphoma cells were selected because of their sensitivity to ascorbate

As ascorbate concentration increased, the pattern of death changed from apoptosis to pyknosis/necrosis, a pattern suggestive of H2O2-mediated cell death

Apoptosis occurred by 6 h after exposure, and cell death by pyknosis was ≈90% at 14 h after exposure

In contrast to lymphoma cells, there was little or no killing of normal lymphocytes and monocytes by ascorbate

Ascorbate is transported into cells as such by sodium-dependent transporters, whereas dehydroascorbic acid is transported into cells by glucose transporters and then immediately reduced internally to ascorbate

Whether or not intracellular ascorbate was preloaded, extracellular ascorbate induced the same amount and type of death.

extracellular ascorbate in pharmacologic concentrations mediates death of lymphoma cells by apoptosis and pyknosis/necrosis, independently of intracellular ascorbate.

H2O2 as the effector species mediating pharmacologic ascorbate-induced cell death

Superoxide dismutase was not protective

Because these data implicated H2O2 in cell killing, we added H2O2 to lymphoma cells and studied death patterns using nuclear staining (19, 28). The death patterns found with exogenous H2O2 exposure were similar to those found with ascorbate

For both ascorbate and H2O2, death changed from apoptosis to pyknosis/necrosis as concentrations increased

Sensitivity to direct exposure to H2O2 was greater in lymphoma cells compared with normal lymphocytes and normal monocytes

There was no association between the EC50 for ascorbate-mediated cell death and intracellular glutathione concentrations, catalase activity, or glutathione peroxidase activity

H2O2 generation was dependent on time, ascorbate concentration, and the presence of trace amounts of serum in media

ascorbate radical is a surrogate marker for H2O2 formation.

whatever H2O2 is generated should be removed by glutathione peroxidase and catalase within red blood cells, because H2O2 is membrane permeable

The data are consistent with the hypothesis that ascorbate in pharmacologic concentrations is a pro-drug for H2O2 generation in the extracellular milieu but not in blood.

The occurrence of one predicted complication, oxalate kidney stones, is controversial

In patients with glucose-6-phosphate dehydrogenase deficiency, i.v. ascorbate is contraindicated because it causes intravascular hemolysis

ascorbate at pharmacologic concentrations in blood is a pro-drug for H2O2 delivery to tissues.

ascorbate, an electron-donor in such reactions, ironically initiates pro-oxidant chemistry and H2O2 formation

data here showed that ascorbate initiated H2O2 formation extracellularly, but H2O2 targets could be either intracellular or extracellular, because H2O2 is membrane permeant

More than 100 patients have been described, presumably without glucose-6-phosphate dehydrogenase deficiency, who received 10 g or more of i.v. ascorbate with no reported adverse effects other than tumor lysis

the ketogenic diet may inhibit cancer progression in part by indirect dietary energy restriction

KD with HBO2T. Combining these therapies nearly doubled survival time in mice with metastatic cancer,

low carbohydrate or ketogenic diets promote weight loss in overweight individuals, they are also known to spare muscle wasting during conditions of energy restriction and starvation

dietary-induced therapeutic ketosis in a cancer patient would prevent muscle wasting similarly as it does with athletes undergoing intense exercise

when given as an adjuvant treatment to advanced cancer patients, the KD improves quality of life and enhances the efficacy of chemotherapy treatment in the clinic

The average age of FQ-induced tendinopathy is 64 years, with a male-to-female ratio of 2:1, and a 27-percent incidence of bilateral involvement

Although more than 95 percent of cases of tendinitis/rupture secondary to FQ involve the Achilles tendon, other reported sites of tendon involvement include the quadriceps, peroneus brevis, and rotator cuff

FQs demonstrate a 3.8-fold greater risk for development of Achilles tendinitis/rupture

a large population-based case control analysis, patients treated with FQs exhibited a substantially increased risk of developing tendon disorders overall (1.7-fold), tendon rupture (1.3-fold), and ATR (4.1-fold)

patients taking FQs with concurrent exposure to corticosteroids were found to experience a compounding effect on the risk of tendon rupture, specifically a 46-fold greater predisposition

Some authors have recommended that patients with a history of Achilles tendinitis and advanced age should not be prescribed FQ antibiotics

Approximately 50 percent of patients will recover within 30 days, with 25 percent of patients having symptoms persistent for longer than two months

The mean latency period between the start of FQ treatment and occurrence of tendinopathy has been reported to be a few hours to months, with a median onset of 6 days

The exact pathophysiology of FQ-induced tendinopathy remains elusive

it is possible that FQs have a direct cytotoxic effect on enzymes found in mammalian musculoskeletal tissue

It has been theorized that FQs disproportionately affect human tendons that have a limited capacity for repair, such as in older patients or structural compromise (i.e., pre-existing tendinopathy or trauma)

histopathological findings are similar to those observed in overuse conditions in athletes

Treatment with a FQ should be discontinued and physical therapy initiated

treatment should include rest and decreasing the physical load on the tendon.

Approximately 85 percent of patients present in less than one month

Because rupture can occur even late in the course of treatment or after discontinuation of FQ use, patients receiving a FQ should be counseled to seek medical attention immediately if symptoms, such as redness, pain, swelling, and stiffness, develop

FQs should be used cautiously in patients with risk factors associated with tendinitis, such as advanced age, history of tendon rupture, corticosteroid use, and/or acute or chronic renal dysfunction

A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication22, indicating that plant miRNAs may be useful for treating human diseases.

We found that plant miR159 could be detected in human sera and its levels were inversely correlated with BC incidence and progression.

We further identified TCF7 as a mammalian target for miR159 and showed the anti-proliferative function of miR159 in BC cells using in vitro and in vivo models, demonstrating for the first time that a plant miRNA is able to influence BC cell growth.

certain dietary miRNAs from plants and other species may serve as highly affordable and powerful means of treatment with minimal inconvenience to patients.

miR159 which (using a synthetic mimic) targets TCF7 to inhibit the proliferation of cells whose growth is dependent on TCF7 such as the BC cells MDA-MB-231

our study using a BC model clearly indicates the anti-tumor effect of orally administered synthetic miR159 in its naturally existing form with the plant-specific 2'-O-methylation, suggesting the feasibility of using synthetic forms of plant miRNAs as dietary supplements in the treatment of human cancers, including those outside of the GI track

Essential hypertension, associated with endothelial dysfunction because of an impaired nitric oxide/l-arginine pathway and impaired vasodilation can be restored by vitamin C

marked increase in BP response when IVB12 is administered

The mean BP increased significantly up to 12–16 mmHg systolic and diastolic independent of the dosage of vitamin B12

The production of norepinephrine, which can stimulate angiotensin-II production, which in turn influences BP, has been suggested as a possible mechanism for the increase in BP with IVB12

excess norephinephrine levels stimulate the sympathetic nervous system, leading to increased cortisol production, which has also been linked to increases in BP

Animal studies have found higher serum levels of norepinephrine (noradrenaline) in the adrenal medulla of rats receiving methylcobalamin (methyl-vitamin B12)