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Evidence from animal studies suggests that the n-6 LCPUFA arachidonic acid promotes adipose tissue deposition, whereas the n-3 LCPUFAs eicosapentaenoic acid and docosahexaenoic acid seem to exert an opposite effect

Overall, no effect of supplementation was found on BMI in preschool (<5 years) and school-aged (6–12 years) children

increased adiposity, once established in childhood, tends to track into adulthood

Many studies have shown that even children <2 years with a high BMI are at increased risk of developing obesity later in life

The acquisition of fat cells early in life appears to be an irreversible process

Evidence from cell culture and animal studies suggests that early exposure to n-3 LCPUFAs has the potential to limit adipose tissue deposition mainly by attenuating the production of the arachidonic acid metabolite prostacyclin, which has been shown to enhance adipogenesis

In conclusion, there is currently no evidence to support that maternal n-3 LCPUFA supplementation during pregnancy and/or lactation exerts a favourable programming effect on adiposity status in childhood

our systematic review highlights that most of the trials reviewed were prone to methodological limitations

An alcohol-induced rise in estrogens as a consequence of alcohol catabolism in the liver has been reported

The only study that looked at the association between alcohol and wine consumption in healthy women did not report a clear association

smoking has been reported to increase induction of the 2-hydroxylation metabolic pathway (24). However, the few epidemiological studies conducted on healthy women showed no difference in estrogen metabolites with smoking status (22) or smoking dose (20), in line with our findings.

Family history of a first-degree family member with breast cancer confers a 2- to 4-fold risk of developing breast cancer

16% of breast cancers are due to unidentified hereditary factors

Estrogen metabolism occurs through enzymes whose activity is determined by the presence of specific genetic polymorphisms, thus can be defined as unique to each individual.

the metabolism is also influenced by a number of environmental factors, which change over a lifetime

significantly lower 2:16 OHE ratio in women who have known breast cancer risk factors compared with healthy women

There was an additional significant association specifically with BMI and alcohol use, which also supports the evidence that these factors affect estrogen metabolism

Profiling estrogen metabolites may identify women who are more likely to develop breast cancer within a population of women with known risk factors

In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels

testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus

Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue

testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-α and IL-1β) and lipids (total cholesterol) and increased IL-10 in hypogonadal men

Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement

available data clearly show a relationship between obesity, low testosterone levels and ED

Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome

Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED

The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise

Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus

Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men

epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels

It is noteworthy that among the many mechanisms that may mediate associations between microbiota and human health [21]–[22], pro-inflammatory and immune cell activation in colon mucosa are of great importance in relation to malignancy

B. fragilis has been shown to induce mucosal regulatory T-cell responses in the intestine involving TH17 cell recruitment in experimental models

the elevations of Bacteroides in the stool and/or IL17 immunoreactive cells in the normal mucosa appear to be promising sensitive markers

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

saturation model

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

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.

Bioavailable and free testosterone are known to correlate better than total testosterone with clinical sequelae of androgenization such as bone mineral density and muscle strength

peak levels seen in the morning following sleep, which can be maintained into the seventh decade

Samples should always be taken in the morning before 11 am

The reliable measurement of serum free testosterone requires equilibrium dialysis. This is not appropriate for clinical use as it is very time consuming and therefore expensive.

With increasing age, a greater number of men have total testosterone levels just below the normal range or in the low-normal range. In these patients total testosterone can be an unreliable indicator of hypogonadal status.

It is advised that at least two serum testosterone measurements, taken before 11 am on different mornings, are necessary to confirm the diagnosis.

Patients with serum total testosterone consistently below 8 nmol/l invariably demonstrate the clinical syndrome of hypogonadism and are likely to benefit from treatment. Patients with serum total testosterone in the range 8–12 nmol/l often have symptoms attributable to hypogonadism and it may be decided to offer either a clinical trial of testosterone treatment or to make further efforts to define serum bioavailable or free testosterone and then reconsider treatment. Patients with serum total testosterone persistently above 12 nmol/l do not have hypogonadism and symptoms are likely to be due to other disease states or ageing per se so testosterone treatment is not indicated.

Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.

With advancing age there is also a reduction in androgen receptor concentration in some target tissues and this may contribute to the clinical syndrome of LOH

Metabolic clearance declines with age

Gonadotrophin levels rise during aging (Feldman et al 2002) and testicular secretory responses to recombinant human chorionic gonadotrophin (hCG) are reduced

There are changes in the lutenising hormone (LH) production which consist of decreased LH pulse frequency and amplitude, (Veldhuis et al 1992; Pincus et al 1997) although pituitary production of LH in response to pharmacological stimulation with exogenous GnRH analogues is preserved

the decreases in testosterone levels with aging seem to reflect changes at all levels of the hypothalamic-pituitary-testicular axis

Studies of similar meshes that are used in hernia repair have demonstrated that all polypropylene meshes induce a prolonged inflammatory response at the site of implantation

the long-term presence of activated inflammatory cells, such as macrophages at the mesh tissue interface, can impact negatively the ability of the mesh to function as intended.

All M1 proinflammatory and M2 proremodeling cytokines and chemokines were increased in mesh explants as compared with nonmesh tissue (Table 3Table 3), which indicated a robust, active, and ongoing host response to polypropylene long after implantation

Comparison of the ratio of the M2 proremodeling cytokines (IL-10+IL-4) with the M1 proinflammatory cytokines (TNF-α+IL-12p70) revealed a decrease in mesh explants as compared with controls (P = .003), which indicated a shift towards a proinflammatory profile.

Mesh explants contained a higher number of total cells/×200 field when compared with controls (682.46 ± 142.61 cells vs 441.63 ± 126.13 cells; P < .001) and a lower ratio of M2:M1 macrophages (0.260 ± 0.161 cells vs 1.772 ± 1.919; P = .001), which supported an ongoing proinflammatory response.

the host response was proportional to the amount of material in contact with the host

A persistent foreign body response was observed in mesh-tissue complexes that were excised from women who required surgical excision of mesh months to years after mesh implantation

The host response was characterized by a predominance of macrophages with an increase in both proinflammatory and proremodeling cytokines/chemokines along with increased tissue degradation, as evidenced by increased MMP-2 and -9

Mesh-tissue complexes removed for mesh exposure had increased pro–MMP-9 that indicated a proinflammatory and tissue destruction–type response

The presence of macrophages, elevated cytokines, chemokines, and MMPs in tissue-mesh complexes that were excised from patients with exposure or pain suggests that polypropylene mesh elicits an ongoing host inflammatory response

In the presence of a permanent foreign body, the implant is surrounded with a fibrotic capsule because it cannot be degraded

For hernia meshes, if the fibers are too close (<1 mm), the fibrotic response to neighboring fibers overlaps, or “bridges,” and results in “bridging fibrosis” or encapsulation of the mesh

Gynemesh PS has a highly unstable geometry when loaded that resulted in pore collapse and increasing stiffness of the product

mesh shrinkage (50-70%) has been described to occur after transvaginal insertion of prolapse meshes

uncoupling of mitochondrial oxidative phosphorylation is believed to be its anti-helminthic mechanism of action

we hypothesized that niclosamides antagonistic effects on OTICs could, in part, be due to its disruption of metabolism

Our results showed that genes participating in protein complexes of oxidative phosphorylation were downregulated

niclosamide treatment resulted in a more than 20% increase in reactive oxygen species (ROS) in cultured OTICs

niclosamide, which has proved to be safe and effective for the past 2 decades against numerous parasites, inhibited OTIC growth both in vitro and in vivo

niclosamide represses metabolic enzymes responsible for bioenergetics, biosynthesis, and redox regulation specifically in OTICs, presumably leading to mitochondrial intrinsic apoptosis pathways, loss of tumor stemness, and growth inhibition

Niclosamide is believed to inhibit mitochondrial oxidative phosphorylation

Niclosamide was reported to inactivate NF-κB, causing mitochondrial damage and the generation of ROS, leading to apoptosis of leukemic stem cells

niclosamide were identified in a screen for mTOR-signaling inhibitors

mTOR was reported to maintain stemness properties of HSCs by inhibiting mitochondrial biogenesis and ROS levels (39), implying that mTOR inhibitors (such as niclosamide) may interfere with mitochondria and various metabolic pathways in TICs via disruption of antioxidant responses

We observed Wnt hyperactivity in OTICs, in agreement with previous hypotheses of Wnt inhibitor effectiveness as an ovarian cancer therapy

niclosamide has now been independently identified in screens for Wnt inhibitors

downregulation of the Wnt/β-catenin target oncogenes survivin and c-Myc

ovarian carcinogenesis, the cell-to-cell signaling pathway Notch (8), were also suppressed by niclosamide (data not shown). These results agree with another recent niclosamide study in leukemia (49), and it has been widely hypothesized that disruption of Notch signaling may represent a highly effective therapy for ovarian and other solid tumors, via its essentiality to maintaining TIC stemness