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Purpose We herein aimed to review the new insights into the impact of impaired thyroid function on male and female fertility, spacing from spontaneous pregnancy to ART, with the objective of providing an updated narrative revision of the literature. Methods This narrative review was performed for all available prospective, retrospective and review articles, published up to 2021 in PubMed. Data were extracted from the text and from the tables of the manuscript. Results Thyroid dysfunction is frequently associated with female infertility, whereas its link with male infertility is debated. Female wise, impaired function is detrimental to obstetric and fetal outcomes both in spontaneous pregnancies and in those achieved thanks to assisted reproduction technologies (ART). Furthermore, the reference range of TSH in natural pregnancy and ART procedures has recently become a matter of debate following recent reports in this field. On the other hand, the impact of thyroid function on the male reproductive system is less clear, although a possible role is suggested via modulation of Sertoli and Leydig cells function and spermatogenesis. Conclusion Thyroid function should be carefully monitored in both male and female, in couples seeking spontaneous pregnancy as well as ART, as treatment is generally immediate and likely to improve chances of success.

Several studies have shown a strong correlation between the different types of diets and gut microbiota composition on glycemia and weight loss. In this direction, low-carbohydrate and ketogenic diets have gained popularity, despite studies published so far leading to controversial results on subjects with diabetes. In this narrative review, firstly, we aimed to analyze the role of very-low-calorie ketogenic diets (VLCKDs) in type 2 diabetes (T2DM) and obesity management. Secondly, in this context, we focused attention on gut microbiota as a function of VLCKD, particularly in T2DM and obesity treatment. Finally, we reported all this evidence to underline the importance of gut microbiota to exalt new nutritional strategies for "tailor-made" management, treatment, and rehabilitation in subjects with T2DM and obesity, even with diabetic complications. In conclusion, this narrative review outlined the beneficial impact of VLCKD on gut microbiota even in subjects with T2DM and obesity, and, despite inner VLCKD short-duration feature allowing no sound-enough provisions for long-term outcomes, witnessed in favor of the short-term safety of VLCKD in those patients.Level of evidence Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Purpose Women with type 1 diabetes mellitus (T1D), especially those with suboptimal glucose control, have 3–4 greater chances of having babies with birth defects compared to healthy women. We aimed to evaluate glucose control and insulin regimen modifications during the pregnancy of women with T1D, comparing the offspring’s weight and the mother’s weight change and diet with those of non-diabetic, normal-weight pregnant women. Methods Women with T1D and age-matched healthy women controls (CTR) were consecutively enrolled among pregnant women with normal weight visiting our center. All patients underwent physical examination and diabetes and nutritional counseling, and completed lifestyle and food intake questionnaires. Results A total of 44 women with T1D and 34 healthy controls were enrolled. Women with T1D increased their insulin regimen during pregnancy, going from baseline 0.9 ± 0.3 IU/kg to 1.1 ± 0.4 IU/kg (p = 0.009), with a concomitant significant reduction in HbA1c (p = 0.009). Over 50% of T1D women were on a diet compared to p p = 0.044) and gave birth to babies with higher mean birth weight (p = 0.043), likely due to the daily increase in insulin regimen. Conclusion A balance between achieving metabolic control and avoiding weight gain is crucial in the management of pregnant women with T1D, who should be encouraged to further improve lifestyle and eating habits with the aim of limiting upward insulin titration adjustments to a minimum.

Erectile dysfunction is recognized as one of the complications of diabetes mellitus. To date, a wide gap of knowledge is present on the efficacy of pharmacological treatments of diabetes mellitus on erectile function, acting not only through metabolic control. Similarly, the effects of different diet regimens on erectile dysfunction are still debated.We aimed to explore the effects of diet and antihyperglycemic drugs, considering both old and novel therapeutic approaches, on erectile function.We performed a systematic review, following the PRISMA guidelines. The research was conducted on studies reporting erectile dysfunction assessment in subjects with diabetes and the relationship with diet and antihyperglycemic drugs.The Mediterranean diet was effective in most studies for the protection of erectile function. Furthermore, antihyperglycemic drugs seem to show an overall protective role on erectile function.Although encouraging results are present for all classes of antihyperglycemic drugs, several studies are needed in humans, mainly on acarbose, pioglitazone, dipeptidyl-peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors.

Purpose The aim of this study was to evaluate in a population of patients with erectile dysfunction (ED): (a) the prevalence of a previously unknown endocrine/glycemic disorders; (b) the correlation between ED severity and endocrine/glycemic disorders. Methods 1332 patients referred for ED from 2013 to 2020 were included. The ED diagnosis was made using the International-Erectile-Function-Index-5 questionnaire. ED severity was considered according to presence/absence of spontaneous erections, maintenance/achievement deficiency. All patients were subjected to search for sociodemographic and clinical characteristics: age, ethnicity, marital status, previous use of PDE5i, previous prostatectomy, diabetes mellitus (DM), prediabetes, endocrine dysfunctions. Results The mean ± SD age was 54.3 ± 13.7 years. The 19.1% (255/1332) of patients were already in treatment for prediabetes/diabetes or endocrine dysfunctions. Among the remaining 1077, the prevalence of previously unknown endocrine and glycemic disorders was 30% (323/1077). Among them, 190/323 subjects (58.8%) were affected by hypogonadism, with high estradiol level observed in 8/190 (4.2%). The prevalence of new glycemic alterations was 17.3% (56/323) [specifically, 32/56 (57.1%) DM, and 24/56 (42.9%) prediabetes]. A thyroid dysfunction was observed in 40/323 subjects (12.3%) and hyperprolactinemia in 37/323 (11.5%). Patients with new diagnosis of DM showed more severe form of ED compared to the total group {difficulty in the achievement of erection: 46/56 [82.2%, vs 265/1332 (19.9%), p p Conclusion ED is an early marker of endocrine/glycemic disorder, and a previously unknown dysfunction was found in more than a quarter of patients. A newly diagnosed DM is associated with ED severity, especially in elderly man and in presence of hypertension.

Purpose To evaluate the association among andrological diseases at the first outpatient visit and the medications taken by patients for other comorbidities, as well as the differential impact between specific medication and relative comorbidities. Methods This is a single-center retrospective study based on subjects who referred to the Andrology Unit with a well-defined andrological diagnosis. Results A total of 3752 subjects were studied (mean age ± DS 46.2 ± 16.5 years). A total of 19 categories of andrological diseases and 110 type of medications for other comorbidities were identified. ED was the most frequent andrological pathology at the first andrological examination (28.7%), followed by infertility (12.4%). The couple of variables that were statistically significant in the univariate association analysis (p Conclusion ED is significantly associated with antihypertensive, antihyperglycemic, lipid-lowering, psychotropic drugs’ intake. Anyway, ED appears to be more related to the diseases than to the specific therapies. The definitive cause/effect relationship should be established based on future prospective studies.

Background: The aim of this study was to evaluate the prevalence of DM among patients with ED and the impact of glycometabolic compensation and antihyperglycemic treatment on ED severity. Methods: In total, 1332 patients with ED were enrolled. The diagnosis was performed through the International-Index-of-Erectile-Function questionnaire. ED severity was considered according to presence/absence of spontaneous erections, maintenance/achievement deficiency and response to PDE5-i. DM patients were clustered according to antihyperglycemic treatment: “metformin”/“insulin”/“old antihyperglycemic drugs”/“new antihyperglycemic drugs”. Results: The prevalence of DM patients was 15.8% (Group A, patients with ED and DM). Among these, the prevalence of spontaneous erections (21.0%) was lower than in the remaining patients (Group B, patients with ED without DM) (32.0%, p < 0.001). The prevalence of poor response to PDE5-i was lower in Group B (10.0%) than in Group A (35.0%, p < 0.001). Patients with good response to PDE5-i therapy showed lower HbA1c values than patients with poor/no response (6.6 ± 1.1% vs. 7.7 ± 1.9%, p = 0.02). The prevalence of absent response to PDE5-i was higher in patients treated with old antidiabetic drugs than in the population treated with new drugs (p = 0.03). Conclusion: The severity of ED and lower response to PDE5-i were higher in DM patients. A better glycometabolic profile, as well as new antihyperglycemic drugs, seem to have a positive effect on ED.

The best nutritional strategy to fight the rise in obesity remains a debated issue. The Mediterranean diet (MD) and the Very Low-Calorie Ketogenic diet (VLCKD) are effective at helping people lose body weight (BW) and fat mass (FM) while preserving fat-free mass (FFM). This study aimed to evaluate the time these two diets took to reach a loss of 5% of the initial BW and how body composition was affected. We randomized 268 subjects with obesity or overweight in two arms, MD and VLCKD, for a maximum of 3 months or until they reached 5% BW loss. This result was achieved after one month of VLCKD and 3 months of MD. Both diets were effective in terms of BW (p < 0.0001) and FM loss (p < 0.0001), but the MD reached a higher reduction in both waist circumference (p = 0.0010) and FM (p = 0.0006) and a greater increase in total body water (p = 0.0017) and FFM (p = 0.0373) than VLCKD. The population was also stratified according to gender, age, and BMI. These two nutritional protocols are both effective in improving anthropometrical parameters and body composition, but they take different time spans to reach the goal. Therefore, professionals should evaluate which is the most suitable according to each patient’s health status.

Cyclic GMP–phosphodiesterase type 5 (PDE5) inhibition has been shown to counteract maladaptive cardiac changes triggered by diabetes in some but not all studies. We performed a single-center, 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828) to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy. A total of 122 men and women (45 to 80 years) with long-duration (>3 years) and well-controlled type 2 diabetes mellitus (T2DM; HbA1c < 86 mmol/mol) were selected according to echocardiographic signs of cardiac remodeling. Patients were randomly assigned (1:1) to placebo or oral tadalafil (20 mg, once daily). The primary outcome was to evaluate sex differences in cardiac torsion change. Secondary outcomes were changes in cardiovascular, metabolic, immune, and renal function. At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion (−3.40°, −5.96; −0.84, P = 0.011) and fiber shortening (−1.19%, −2.24; −0.14, P = 0.027) in men but not women. The primary outcome could not be explained by differences in cGMP concentrations or tadalafil pharmacodynamics. In both sexes, tadalafil improved hsa-miR-199-5p expression, biomarkers of cardiovascular remodeling, albuminuria, renal artery resistive index, and circulating Klotho concentrations. Immune cell profiling revealed an improvement in low-grade chronic inflammation: Classic CD14 ++ CD16 − monocytes reduced, and Tie2 + monocytes increased. Nine patients (14.5%) had minor adverse reactions after tadalafil administration. Continuous PDE5 inhibition could offer a strategy to target cardiorenal complications of T2DM, with sex- and tissue-specific responses. Further studies are needed to confirm Klotho and hsa-miR-199-5p as markers for T2DM complications.

Background: Coronavirus (COVID-19) disease portends a poor prognosis in patients with type 1 diabetes (T1D) . As a consequence, the booster dose of Covid-vaccination should be prioritized in these patients. Nonetheless, concerns exist about vaccine-induced dysglycemia. Objectives: Aim of this study was to assess the short-term effects of booster dose of Covid-vaccination on glycaemic control assessed by flash glucose monitoring (FGM) in people with T1D. Methods: In this observational cross-sectional study we investigated changes in daily insulin requirement (IR) and glycaemic control between 7 days before and 7 days after the third dose of vaccination with BioNTech Pfizer among 30 individuals with T1D on multiple daily insulin injections wearing a flash glucose monitoring (FGM) device. The following parameters of glycaemic variability were analysed: mean glucose, time in range (TIR) , time above range (TAR) , time below range (TBR) and coefficient of variation (CV) . Results: No significant differences were found for mean glycemia, TIR, TAR and TBR over the course of the vaccination from 7 days prior to receiving the third-dose vaccination until 7 days after. Nonetheless, CV and IR were significantly higher (CV, p-value = 0.001; IR, p-value = 0.05) in the week after the vaccination compared to the week earlier. The median value of CV was 35.5% [33-37] before and 36.9% [34-39] after the booster dose, whereas the median value of IR changed from 0.55 UI/Kg/day to 0.61 UI/Kg/day. Conclusions: Our study suggests that the booster dose of Covid-vaccination impact on glycaemic variability and insulin requirement in people with T1D, probably due to the pro-inflammatory cytokines and immune responses. While this observation should be investigated in larger studies, potential glycaemic aberrations in response to Covid-immunization should be considered by health care professionals and glucose monitoring intensified within the days around the vaccination. Disclosure S.Pieralice: None. L.Monte: None. G.Defeudis: None. G.Tabacco: None. N.Napoli: Advisory Panel; Novo Nordisk, Consultant; Lilly Diabetes. P.Pozzilli: Advisory Panel; Dompé, Consultant; Abbott, Speaker’s Bureau; Dompé, Lilly Diabetes, Medtronic, Sanofi.

Background. The purpose of this study was to evaluate the effect of diet and antihyperglycemic drugs on erectile dysfunction (ED) in a setting of subjects affected by diabetes mellitus (DM) or preDM. Methods. This is a prospective observational study on 163 consecutive subjects with preDM or DM. All patients have undergone a medical evaluation (age, Body Mass Index (BMI), family history of DM, duration of DM, smoking, physical activity, dyslipidemia, cardiovascular comorbidities, and testosterone and HbA1c levels) and the International Index of Erectile Function (IIEF)-5 questionnaire. Results. Overall, the mean age was 62.8 ± 9.3 years, and the mean BMI was 28.4 ± 4.6 kg/m2. The IIEF-5 score mean value was 14.4 ± 6.2 (range 4–25). Among all confounders investigated for their association with the IIEF-5 score, only age and the duration of DM among diabetic patients showed a significant trend. The IIEF-5 score was higher in patients using GLP-1a compared to insulin (16.7 ± 4.7 vs. 12.9 ± 6.2; p = 0.02). This association was confirmed after adjustment for age and duration of DM (p = 0.01). All other treatments were similar (14.9 ± 6.2, 14.8 ± 9.2, 15.3 ± 5.4, and 13.6 ± 6.8 for metformin, sulfonylureas (SU), dipeptidyl-peptidase-4 inhibitors (DPP-4i), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) treatment, respectively). Conclusions. This prospective observational study increases attention and focus on the effect of antihyperglycemic drugs and diet on ED, above all about the role of new classes, showing a significant higher IIEF-5 mean value in patients using GLP-1a compared to patients on insulin treatment.

We herein aimed to review the new insights into the impact of impaired thyroid function on male and female fertility, spacing from spontaneous pregnancy to ART, with the objective of providing an updated narrative revision of the literature.This narrative review was performed for all available prospective, retrospective and review articles, published up to 2021 in PubMed. Data were extracted from the text and from the tables of the manuscript.Thyroid dysfunction is frequently associated with female infertility, whereas its link with male infertility is debated. Female wise, impaired function is detrimental to obstetric and fetal outcomes both in spontaneous pregnancies and in those achieved thanks to assisted reproduction technologies (ART). Furthermore, the reference range of TSH in natural pregnancy and ART procedures has recently become a matter of debate following recent reports in this field. On the other hand, the impact of thyroid function on the male reproductive system is less clear, although a possible role is suggested via modulation of Sertoli and Leydig cells function and spermatogenesis.Thyroid function should be carefully monitored in both male and female, in couples seeking spontaneous pregnancy as well as ART, as treatment is generally immediate and likely to improve chances of success.

Additional file 1. Supplementary tables and figure

Celiac disease is a rising disorder and is becoming frequently diagnosed in recent years. To date, the only available treatment is the gluten-free diet (GFD). The role of gluten on components of metabolic syndrome and on related inflammatory response is still unclear due to controversial results. In recent years, scientific focus on this topic has been growing up, in particular regarding the role of the GFD on glycometabolic parameters and diabetes. In addition, studies on the remaining components showed discordant results, which was likely due to heterogeneous and large celiac disease populations and to the lack of prospective studies. Furthermore, knowledge about the role of the GFD on inflammatory cytokines and the relationship among vitamin D and celiac disease, metabolic syndrome (MS) and GFD is needed. In this narrative review, we provided evidence regarding the role of the GFD on glycometabolic parameters, cholesterol, triglycerides, waist circumference, blood pressure and inflammatory cascade, also evaluating the role of vitamin D, trying to summarize whether this nutritional pattern may be a value-added for subjects with dysmetabolic conditions. Finally, due to the limited findings and very low-certainty evidence, predominantly based on observational studies, the real effects of a GFD on different components of MS, however, are unclear; nevertheless, an improvement in HDL levels has been reported, although data on glycemic levels are discordant.

In the last decades, MRI was proven a useful tool for the diagnosis and characterization of Prostate Cancer (PCa). In the literature, many studies focused on characterizing PCa aggressiveness, but a few have distinguished between low-aggressive (Gleason Grade Group (GG)=2) and high-aggressive (GG=3) PCas based on biparametric MRI (bpMRI). In this study, 108 PCas were collected from two different centers and were divided into training, testing, and validation set. From Apparent Diffusion Coefficient (ADC) map and T2-Weighted Image (T2WI), we extracted texture features, both 3D and 2D, and we implemented three different methods of Feature Selection (FS): Minimum Redundance Maximum Relevance (MRMR), Affinity Propagation (AP), and Genetic Algorithm (GA). From the resulting subsets of predictors, we trained Support Vector Machine (SVM), Decision Tree, and Ensemble Learning classifiers on the training set, and we evaluated their prediction ability on the testing set. Then, for each FS method, we chose the best classifier, based on both training and testing performances, and we further assessed their generalization capability on the validation set. Between the three best models, a Decision Tree was trained using only two features extracted from the ADC map and selected by MRMR, achieving, on the validation set, an Area Under the ROC (AUC) equal to 81%, with sensitivity and specificity of 77% and 93%, respectively.Clinical Relevance- Our best model demonstrated to be able to distinguish low-aggressive from high-aggressive PCas with high accuracy. Potentially, this approach could help clinician to noninvasively distinguish between PCas that might need active treatment and those that could potentially benefit from active surveillance, avoiding biopsy-related complications.

Background: This is a proof of concept, as a pilot study, with the aim to evaluate continuous glucose monitoring metrics (CGM) in subjects with type 2 diabetes (T2DM), treated with nutritional therapy and metformin, before and after testosterone replacement therapy (TRT). Methods: In this longitudinal observational study, subjects affected by T2DM and starting TRT for documented ED and hypogonadism were enrolled. All subjects mounted a CGM system during the v0 visit, one week before the beginning of the TRT (week−1), during v2, four weeks after the start of TRT (week 4), and v4 (week 12). CGM was worn for about 144 h after each visit. Results: A total of seven patients, referring to our clinic for erectile dysfunction (ED), were studied (aged 63.3 ± 2.3 years). Mean (± standard deviation) total testosterone level was 2.3 ± 0.6 ng/mL at baseline. After TRT, total testosterone level was 4.6 ± 3.04 ng/mL at week 4 and 3.93 ± 4.67 ng/mL at week 12. No significant differences were observed in TIR, TAR, TBR, estimated HbA1c, AUC below, and AUC above limit during the intervention period. Conclusions: This is the first study evaluating the effects of TRT on daily glucose excursions in subjects with T2DM and hypogonadism. Though we did not find any significant difference in key CGM metrics during the 12 weeks of TRT, this study confirms the glycometabolic safety of the TRT even on the most novel standardized glycemic targets.

Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM.

The aim of this study was to evaluate: 1) the prevalence of male infertility due to ejaculatory dysfunction (premature ejaculation-PE, intravaginal ejaculatory dysfunction-IVEjD, anejaculation-AE, and retrograde ejaculation-RE); and 2) the hormonal profile and semen characteristics of such subjects.N.3280 subjects who were referred to our andrology unit for infertility were studied. Exclusion criteria: the presence of known causes of male infertility and erectile dysfunction. In all subjects were performed: medical history and andrological physical examination; hormonal profile; semen analysis or centrifugation/resuspension of post-orgasmic urine; IIEF-5 questionnaire for the diagnosis of ED; PEDT questionnaire for the diagnosis of EP.the prevalence of ejaculatory dysfunctions in infertile males was 1.8% (59/3280). The causes were: a) absence of ejaculation in 37/3280 subjects (1.1%); among them, 23/3280 (0.7%) subjects showed a condition of RE and 14/3280 (0.4%) of AE; b) PE in 16/3280 subjects (0.5%); and c) IVEjD in 6/3280 subjects (0.2%). Hormonal values and seminal parameters (when semen analysis was possible) were within the normal ranges in all the cases. In subjects with RE, sperm recovery was possible in 69.9% (16/23) subjects after centrifugation and resuspension of post-orgasmic urine.The prevalence of male infertility due to ejaculatory dysfunctions is overall just under 2%. The main cause is retrograde ejaculation; psychogenic origins could also have an important role. It is important to identify the cause of ejaculatory dysfunction in order to decide upon correct management (PE treatment, centrifugation and resuspension of post-orgasmic urine, penile vibratory stimulation, and psychological counselling).

Liver metastases (mts) from colorectal cancer (CRC) can have different responses to chemotherapy in the same patient. The aim of this study is to develop and validate a machine learning algorithm to predict response of individual liver mts. 22 radiomic features (RF) were computed on pretreatment portal CT scans following a manual segmentation of mts. RFs were extracted from 7x7 Region of Interests (ROIs) that moved across the image by step of 2 pixels. Liver mts were classified as non-responder (R-) if their largest diameter increased more than 3 mm after 3 months of treatment and responder (R+), otherwise. Features selection (FS) was performed by a genetic algorithm and classification by a Support Vector Machine (SVM) classifier. Sensitivity, specificity, negative (NPV) and positive (PPV) predictive values were evaluated for all lesions in the training and validation sets, separately. On the training set, we obtained sensitivity of 86%, specificity of 67%, PPV of 89% and NPV of 61%, while, on the validation set, we reached a sensitivity of 73%, specificity of 47%, PPV of 64% and NPV of 57%. Specificity was biased by the low number of R- lesions on the validation set. The promising results obtained in the validation dataset should be extended to a larger cohort of patient to further validate our method.Clinical Relevance— to personalize treatment of patients with metastastic colorectal cancer, based on the likelihood of response to chemotherapy of each liver metastasis.

We aimed at evaluating residual β-cell function in insulin-treated patients with type 2 diabetes (T2D) while determining for the first time the difference in C-peptide level between patients on basal–bolus compared to those on the basal insulin scheme, considered as an early stage of insulin treatment, together with assessing its correlation with the presence of complications. A total of 93 candidates with T2D were enrolled in this cross-sectional study and were categorized into two groups based on the insulin regimen: Basal–Bolus (BB) if on both basal and rapid acting insulin, and Basal (B) if on basal insulin only, without rapid acting injections. HbA1c, fasting C-peptide concentration and other metabolic parameters were recorded, as well as the patient medical history. The average fasting C-peptide was 1.81 ± 0.15 ng/mL, and its levels showed a significant inverse correlation with the duration of diabetes (r = -0.24, p = 0.03). Despite similar disease duration and metabolic control, BB participants displayed lower fasting C-peptide (p

Background: The efficacy of increasing dietary fiber intake (DFI) to ameliorate glycemic control in patients with type 2 diabetes (T2D) is still controversial. In this randomized open-label comparator-controlled study we tested the effect of high-fiber diet and fiber supplement on glycemic control in patients with T2D on metformin monotherapy. Methods: Seventy-eight T2D overweight patients on metformin monotherapy were randomized 1:2:1 to 12 weeks intensive nutrition program to follow high-fiber diet (HFD), dietary fiber supplementation (FS) or standard diet recommendations (SDR). Dietary recommendations were reinforced in all groups every 4 weeks by study dieticians. Biochemistry, anthropometric measures, food frequency questionnaires to asses DFI were collected at baseline and after 12 weeks. Results: At baseline groups did not differ in terms of mean age, BMI, metformin intake, HbA1c, fiber and calorie intake (p>0.05 for all). After three months, DFI significantly increase in both HDF and FS group but not in SDR group (HFD: 19.8 ± 6.1 g vs. 24.3 ± 6.8 g, p= 0.0001; FS: 17.5 ± 5.9 g vs. 27.0 ± 6.2 g p< 0.0001; SDR: 22.8 ± 9.1 g vs. 21.2 ± 6.4 g, p= 0.32). HbA1c significantly improved in all groups (HFD: 7.1 ± 0.5 % vs. 6.6 ± 0.6 %, p< 0.0001; FS: 7.1 ± 0.5 % vs. 6.8 ± 0.5 % p< 0.001; SDR: 7.2 ± 0.4 % vs. 6.7 ± 0.5 g, p< 0.001). All HFD, FS and SDR intervention reduced mean body weight by 2.1 ± 2.6 Kg (p< 0.0001), 1.0 ± 1.8 Kg (p< 0.05) and 1.1 ± 2.1 Kg (p< 0.05), respectively. Changes in HbA1c and body weight did not differ among groups. A significant correlation between calorie intake and the reduction of HbA1c levels was seen across groups (r= 0.307 p Conclusions: Intensive nutrition education programs with monthly meetings similarly reduced HbA1c in all groups. Furthermore, our study suggested that rather than fiber intake, caloric restriction followed by moderate weight loss is the main driver for glycemic improvement in overweight patients with T2D. Disclosure F. Tramontana: None. E. Maddaloni: Consultant; Self; Merck KGaA. Speaker’s Bureau; Self; Abbott, AstraZeneca, Pikdare. S. Greci: None. G. Defeudis: None. R. Strollo: None. P. Pozzilli: Advisory Panel; Self; Abbott, AstraZeneca, Eli Lilly and Company. Research Support; Self; Medtronic, Sanofi. N. Napoli: None.

Background: Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes (T2DM) patients. Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition was shown to counteract maladaptive cardiac changes triggered by diabetes in some studies. Our aim was to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy (DCM). Methods: We performed a 20-week, double-blind, randomized, placebo-controlled trial. Men and women (45–80 years) with controlled T2DM and echocardiographic (ECG) signs of cardiac remodeling were randomly assigned (1:1) to placebo or tadalafil 20 mg once daily. The primary outcome was analyzing the sex-difference in cardiac torsion change, from baseline to 20 weeks. Secondary outcomes included changes in cardiovascular, metabolic, immune and renal function. Efficacy analyses included all patients who received at least one dose of treatment. Findings: Between May 2014 and July 2018, we screened 220 diabetic subjects; 122 met the inclusion criteria and were randomized to tadalafil (n=61) or placebo (n=61). At 20 weeks, the sex-by-treatment interaction documented an improvement in cardiac torsion [-3·40°(-5·96;-0·84, p =0·011)], paralleled by a consensual increase in fiber shortening, in men but not women. Biomarkers of cardiovascular remodeling , titin and hsa-miR-199-5p, improved accordingly. In both sexes, tadalafil reduced TGF-beta and improved albuminuria, renal artery’s resistive index, Klotho , and symmetric-di-methyl-arginine markers . Five months of 20 mg daily tadalafil in patients with DCM was proven safe. The most common adverse reactions were myalgia (9[14·5%]), gastric reflux (6[9·7%]), headache (4[6·4%]) and flushing (2[3·8%]); one SAE occurred in the placebo arm. Interpretation: Continuous PDE5 inhibition could represent a new treatment strategy to target cardiac and renal complications of T2DM, with a different tissue-specific response in men and women. Klotho and hsa-miR-199-5p appear as novel players linking renal disease to DCM progression. Trial Registration: NCT01803828. Funding Statement: Italian Ministry of University and Research, SIR RBSI141LY2. Declaration of Interests: Prof. Isidori reports personal fees from Takeda; non-financial support from Takeda and Ipsen; and grants from Shire and Pfizer outside the submitted work; Prof. Pozzilli reports research contracts and consulting from Eli Lilly, Sanofi, Merck, Merck Sharpt Dohme, Astra Zeneca, Medtronic, Abbott; Dr. Defeudis reports grants from Ibsa, personal fees from Abbott, grants from Novo Nordisk, grants from Kyowa Kirin , personal fees from Roche, outside the submitted work; Prof. Badagliacca reports personal fees from Bayer, personal fees from MSD, personal fees from Dompe, personal fees from GSK, personal fees from Ferrer, personal fees from United Therapeutics, personal fees from Galenica, personal fees from Janssen, outside the submitted work; all others have nothing to disclose. Ethics Approval Statement: The study was performed in the Policlinico Umberto I in Rome (Italy) and approved by the local ethical review board (3083/14), published on public registries (NCT01803828, EUDRACT 2014-000077-39), and conducted under the Declaration of Helsinki and good clinical practice.

Diabetes and osteoporosis are rapidly growing diseases. The link between the high fracture incidence in diabetes as compared with the non-diabetic state has recently been recognized. While this review cannot cover every aspect of diabetic osteodystrophy, it attempts to incorporate current information from the First International Symposium on Diabetes and Bone presentations in Rome in 2014. Diabetes and osteoporosis are fast-growing diseases in the western world and are becoming a major problem in the emerging economic nations. Aging of populations worldwide will be responsible for an increased risk in the incidence of osteoporosis and diabetes. Furthermore, the economic burden due to complications of these diseases is enormous and will continue to increase unless public awareness of these diseases, the curbing of obesity, and cost-effective measures are instituted. The link between diabetes and fractures being more common in diabetics than non-diabetics has been widely recognized. At the same time, many questions remain regarding the underlying mechanisms for greater bone fragility in diabetic patients and the best approach to risk assessment and treatment to prevent fractures. Although it cannot cover every aspect of diabetic osteodystrophy, this review will attempt to incorporate current information particularly from the First International Symposium on Diabetes and Bone presentations in Rome in November 2014.

Normal sleep is characterized by increased glycogen stores and reduced glucose turnover by metabolically active tissues, thus it is a state of decreased metabolism. It has been reported that reduced sleep quality is associated with increased insulin-resistance and disrupted metabolism. However, the relationship between energy expenditure during sleep (EEDS) and insulin-resistance (homeostasis model assessment, HOMA-IR) has not been clarified. The aim of this study was to investigate the role of EEDS in the association between sleep quality and insulin resistance. A total of 226 individuals [women 72.1%; mean (DS) age 50.46 (±13.1) years; BMI 33.4 (±8.41) Kg / m2] undergoing the oral glucose tolerance test (OGTT) were also asked to wear a metabolic holter (Armband) for 3-days, to assess their daily energy expenditure. The Armband is capable of measuring energy expenditure every minute, but also the duration and quality of sleep. The EEDS corrected for weight (EEDS/WEIGHT) was lower in patients with insulin resistance, HOMA-IR above 2.5 (p Disclosure D. Tuccinardi: None. E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; European Foundation for the Study of Diabetes. I. Capasso: None. L. Rampa: None. A. Soare: None. D. Maggi: None. G. Defeudis: None. S. Kyanvash: None. A. Maurizi: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp.. S. Manfrini: None.

The purpose of this study is to evaluate the effectiveness of the educational tool, Conversation Maps™ (CM), combined with a weight loss program, in improving metabolic control of as well as knowledge about diabetes, in a population with type 2 diabetes (T2DM) with mildly impaired glycemic control. This is a longitudinal observational study in which 66 subjects, aged 67.8 ± 7.93, were included either in the educational program with CM, once weekly for 4 weeks (T4), combined with a weight loss regime (group A, n = 32), or in standard care with a weight loss regime (group B, n = 34), both followed for 3 months (T3M) after T4. At T4, both groups A and B had significantly lost weight and reduced waist circumference. However, group B did not lose weight or reduce waist circumference at T3M compared to T4. At T3M, only group A significantly lowered glycated hemoglobin (A1c) from baseline. At T3M, only group A had a significant increase in knowledge on diabetes therapy and foot care. CM may also play a significant role in T2DM characterized by mildly impaired glycemic control. Moreover, a systematic use of CM could be suggested for management of diabetes together with lifestyle changes and a weight loss diet.

Adult-onset hypogonadism is a syndrome often underdiagnosed, undertreated, or incompletely explored. There are various reasons for this: firstly, undefined age range of men in whom testosterone levels should be investigated and then no definitive serum cutoff point for the diagnosis of hypogonadism; and finally, variable and non-specific signs and symptoms; men and physicians do not pay adequate attention to sexual health. All these factors make the diagnostic criteria for hypogonadism controversial. The evaluation of the clinical features and causes of this syndrome, its link with age, the role of testosterone and other hormone levels, and the presence of any comorbidities are all useful factors in the investigation of this population. The purpose of this manuscript, after an accurate analysis of current literature, is to facilitate the diagnosis of hypogonadism in men through the use of the CATCH acronym and a checklist to offer a practical diagnostic tool for daily clinical practice. A narrative review of the relevant literature regarding the diagnosis of late-onset hypogonadism or adult-onset hypogonadism was performed. PubMed database was used to retrieve articles published on this topic. A useful new acronym CATCH (Clinical features [symptoms] and Causes, Age, Testosterone level, Comorbidities, and Hormones) and a practical checklist to facilitate the evaluation of hypogonadism in aging men were used. The evaluation of the clinical features and causes of hypogonadism, the link with age, the role of Testosterone and other hormones, and the evaluation of comorbidities are important in investigating adult-onset hypogonadism. The CATCH checklist could be helpful for clinicians for an early diagnosis of both hypogonadism and associated comorbidities. We suggest the use of this acronym to advocate the investigation of declining testosterone in aging men.

Type 2 diabetes mellitus is one of the fastest growing diseases; the number of people affected by diabetes will soon reach 552 million worldwide, with associated increases in complications and healthcare expenditure. Lifestyle and medical nutrition therapy are considered the keystones of type 2 diabetes prevention and treatment, but there is no definite consensus on how to treat this disease with these therapies. The American Diabetes Association has made several recommendations regarding the medical nutrition therapy of diabetes; these emphasize the importance of minimizing macrovascular and microvascular complications in people with diabetes. Four types of diets were reviewed for their effects on diabetes: the Mediterranean diet, a low-carbohydrate/high-protein diet, a vegan diet and a vegetarian diet. Each of the four types of diet has been shown to improve metabolic conditions, but the degree of improvement varies from patient to patient. Therefore, it is necessary to evaluate a patient's pathophysiological characteristics in order to determine the diet that will achieve metabolic improvement in each individual. Many dietary regimens are available for patients with type 2 diabetes to choose from, according to personal taste and cultural tradition. It is important to provide a tailor-made diet wherever possible in order to maximize the efficacy of the diet on reducing diabetes symptoms and to encourage patient adherence. Additional randomized studies, both short term (to analyse physiological responses) and long term, could help reduce the multitude of diets currently recommended and focus on a shorter list of useful regimens.

Introduction Colorectal cancer (CRC), the 2nd cause of cancer death worldwide, is an indolent disease with 50% of patients eventually developing liver metastases (mCRC). Repeated cycles of different chemotherapies, combined with surgery in oligo-metastatic cases, are the therapeutic standard in mCRC. However, this strategy is resolutive in less than 15% of cases. Differentiating non- and short-term responders from potentially “cured” patients will spare patients needless toxicity and allow alternative treatments earlier, with conceivable cost and life savings. In this study we aimed to use CT texture analysis (CTTA) to identify specific imaging biomarkers of hepatic metastases, able to predict patient’s response to therapy and overall survival. Methods We exploited the imaging data-set of the HERACLES trial (NCT03225937): 23 patients with amplified Human Epidermal growth factor Receptor 2 (HER2) mCRC were included in the study. All had received anti HER2 treatment, and underwent CT examination every 8 weeks, until disease progression. CT scans were semi-automatically segmented to extract for each patient all liver metastases. Texture analysis was performed on each segmented area, computing for each lesion 34 quantitative parameters. Both mono-parametric and multi-parametric analysis were assessed to identify features most correlated to therapy response. We also performed a correlative survival (OS) analysis, considering subjects with good survival those with OS > 9 months. Results In 23 patients we found 124 metastases, 55 of which were classified as responding and 69 as non-responding. Nine parameters reached statistical significance in the mono-parametric analysis (best AUC=0.67, p=0.001), while in the multivariate regression ten parameters were used in the model, achieving and AUC equal to 0.82, with sensitivity of 82% and specificity 72%. For OS analysis, 12 patients were “good” and 11 “poor” survivors. In the mono-parametric analysis “cluster prominence” and “sum entropy” predicted OS with AUC equal to 0.78 and 0.83, respectively. The regression model with two variables (“cluster prominence” and “dissimilarity”) reached a sensitivity of 83% and a specificity of 82%. Conclusions Our study demonstrated CTTA as a potential biomarker to predict response of hepatic metastases to chemotherapy treatment, possibly saving patients predicted as non-responder from toxicity. Moreover, CTTA could give indications on patients OS, without the need for additional tests. Acknowledgments This study was funded by the Italian Association for Cancer Research (AIRC), ref. 21091. Citation Format: Simone Mazzetti, Valentina Giannini, Lorenzo Vassallo, Arianna Defeudis, Angelo Vanzulli, Rita Golfieri, Silvia Marsoni, Daniele Regge. CT texture analysis to predict response to target therapy of hepatic metastases from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1412.

e15086 Background: Metastatic Colorectal cancer (mCRC) is the 2nd cause of cancer death worldwide. Repeated cycles of therapies, combined with surgery in oligo-metastatic cases, are the therapeutic standard in mCRC. However, this strategy is seldom resolutive. Different lesions in in the same patient could have different responses to systemic therapy. Recently, CT texture analysis (CTTA) had been shown to potentially provide with prognostic and predictive markers, overcoming the limitations of biopsy sampling in defining tumor heterogeneity. The aim of this study is to use CT texture analysis (CTTA) to identify imaging biomarkers of HER2+ mCRC able to predict lesion response to therapy. Methods: The dataset is composed of 39 extended RAS wild type patients with amplified HER2 mCRC enrolled in the HERACLES trial (NCT03225937) that received either a lapatinib+trastuzumab treatment (n = 23) or a pertuzumab+ trastuzumab-emtansine treatment (n = 16). All patients underwent CT examination every 8 weeks, until disease progression. All mCRC on baseline CT were semi-automatically segmented and quantitative features extracted: size, mean, percentiles, 28 texture features. A logistic regression model was created using: (i) the whole dataset of mCRC as training and test set and (ii) 100 randomly generated training sets (with 70% of responder (R+) mCRC and an equal number of non-responder (R-) mCRC), and 100 test sets including the remaining mCRC. A mCRC was classified as R+ if size decreased (-10%) or was stable (±10%); as R- if size increased (+10%), during subsequent CT scans. Results: A total of 199 metastases were included (75R+ and 124R-). The training set was composed of 53R+ and 53R- mCRC and the test set of 22R+ and 71R- mCRC. Using the whole dataset, the model reached an AUC = 0.82 (sensitivity = 84%, specificity = 70%), while it reached a mean AUC of 0.70 (sensitivity = 68%, specificity = 67%) within the 100 repetitions. Conclusions: CTTA might help in stratifying different behaviors of mCRC, opening the way for lesion-specific therapies, with conceivable cost and life savings. Further extended analysis is needed to better characterize and validate predictive value of these biomarkers.

Diabetes mellitus (DM) is a widespread disease in our country. Urogenital infections, including urinary tract infections, vaginitis, balanitis, balanoposthitis, and male accessory gland infections, show a higher risk of occurrence in patients with DM that non-diabetic subjects. Both non-drug-related and drug-related mechanisms are involved in their pathogenesis. These conditions may impact on glucose control and islets function in DM and more likely develop into adverse complications. A throughout microbial characterization, including the drug-sensitivity test, is required for a proper management. To reduce the risk of recurrence, combined treatment, including antibiotic, anti-inflammatory, and fibrinolytic molecules, should be prescribed also to the sexual partner. The choice of the antidiabetic drug to prescribe should take into consideration the presence of urogenital infections. In conclusion, urogenital infections may more likely lead to complication in diabetic than non-diabetic patients, affect fertility and glucose control. Therefore, they need proper management.

To improve insulin sensitivity, insulin-sensitizing drugs such as metformin are commonly used in overweight and obese T1D patients. Similarly to metformin, D-chiro-inositol (DCI), as putative mediator of intracellular insulin action, can act as insulin sensitizer. The aim of this pilot study was to evaluate the hypothesis that DCI plus folic acid may improve glucose control reducing insulin resistance in overweight or obese T1D patients.A 24-week randomized control trial was carried out in 26 overweight or obese T1D patients, undergoing intensive insulin therapy. Patients were randomized to 1 g DCI plus 400 mcg folic acid once daily (treated group) or to 400 mcg folic acid only once daily (control group). The primary end point was to evaluate the efficacy of DCI on metabolic control as assessed by HbA1c. As secondary endpoints, BMI and insulin requirement (IR) were evaluated. Paired t test (two tailed) and analysis of variance were used to evaluate differences in HbA1c, BMI and IR at different time points.A significant reduction in HbA1c levels in treated group versus control group (7.5% ± 0.9 vs. 7.9% ± 1.7, respectively, p 0.05) was observed. However, no significant reduction in BMI and IR was observed [(BMI 25.7 ± 2.8 vs. 26.7 ± 1.0, respectively, p NS); (IR 0.52 ± 0.26 vs. 0.52 ± 0.19, respectively, p NS)].This trial demonstrated for the first time that DCI plus folic acid oral supplementation can improve metabolic control in overweight T1D patients. CLINICALTRIAL.NCT02730949.

Forty-two adult males - 10 with Klinefelter's syndrome (karyotype XXY), 17 with normal sex chromosome karyotype (XY) but with physical signs of hypogonadism, and 15 presumed to be normal both chromosomally and hormonally - completed tests of Verbal and Nonverbal ability. It was predicted: a) that the XXY group would perform more poorly than the other two groups on tests of Verbal ability, and b) that the XY, hypogonadal group would perform more poorly than the others on tests of Non-verbal ability. The first hypothesis was supported. However, in spite of measurable verbal deficits, the XXY men (whose parents were more highly educated than those of the other two groups) did not appear to be underachievers. Rather, they were, in general, as well educated, as likely to be employed, and of socioeconomic status equivalent to that of the other men in the study. These findings are discussed briefly in terms of implications for early childhood education and genetic counselling. The second hypothesis was not supported: this is attributed to presumed heterogeneity of etiology of hypogonadism in the XY, hypogonadal group.

Diabetes can be described as a syndrome of multiple closely related conditions induced by a chronic state of hyperglycaemia resulting from defective insulin secretion, insulin action or both. Chronic complications associated with diabetes (including neuropathy, vascular disease, nephropathy and retinopathy) are common, and of these, erectile dysfunction (ED) deserves special attention. ED and its correlation with cardiovascular disease require careful evaluation and appropriate treatment. PDE5 inhibitors (PDE5is) are an important tool for the treatment of ED, with new drugs coming onto the market since the late 90s. This review offers an overview of PDE5is and their use in treating ED in diabetes. We underline the differences between different types of PDE5i, focusing on available doses, duration of action, T ½, side effects and selectivity profiles in relation to patients with diabetes. We also discuss the link between diabetes and ED in presence of various associated cofactors (obesity, hypertension and its pharmacological treatments, atherosclerosis, hyperhomocysteinaemia, neuropathy, nephropathy, hypogonadism and depression). Finally a number of past and ongoing clinical trials on the use of PDE5is in patients with diabetes are presented to offer an overview of the appropriate treatment of ED in this condition.

This overview is focused on the stress-alleviating and vigilance-enhancing properties of Ginkgo biloba extract (EGb 761) that have been observed in animal models and in humans and that appear useful in explaining the therapeutic effects of the extract on non-cognitive brain functions that may be reflective of mood changes. With regard to its stress-alleviating activity, in rodents EGb 761 facilitates behavioral adaptation, decreases circulating levels of corticosterone, catecholamines, ACTH, and CRH, suppresses the expression of the mitochondrial peripheral benzodiazepine receptor of the adrenal cortex, increases the anxiolytic activity of diazepam, increases arousal by an action that may involve GABAA receptor antagonism, induces anxiolytic-like activity, prevents stress-induced desensitization of hippocampal 5-HT1A receptors, suppresses the down-regulation of hippocampal glucocorticoid receptors, and facilitates decision-making. In humans, EGb 761 has vigilance-enhancing effects that support its clinical use in treating disorders involving stress-induced brain dysfunction and those non-cognitive symptoms of dementia currently classified as “behavioral and psychological symptoms of dementia” (BPSD). Collectively, these findings indicate that EGb 761 is useful for treating symptoms that are now classified as components of BPSD. As drug combinations consisting of EGb 761 and a non-selective cholinesterase inhibitor, an antidepressant drug, or a neuroleptic could possibly be even more useful in treating BPSD, evaluation of such therapy is recommended. Drug Dev. Res. 62:1–25, 2004. © 2004 Wiley-Liss, Inc.

Recent studies conducted with various molecular, cellular and whole animal models have revealed that leaf extracts of Ginkgo biloba may have anticancer (chemopreventive) properties that are related to their antioxidant, anti-angiogenic and gene-regulatory actions. The antioxidant and associated anti-lipoperoxidative effects of Ginkgo extracts appear to involve both their flavonoid and terpenoid constituents. The anti-angiogenic activity of the extracts may involve their antioxidant activity and their ability to inhibit both inducible and endothelial forms of nitric oxide synthase. With regard to gene expression, a Ginkgo extract and one of its terpenoid constituents, ginkgolide B, inhibited the proliferation of a highly aggressive human breast cancer cell line and xenografts of this cell line in nude mice. cDNA microarray analyses have shown that exposure of human breast cancer cells to a Ginkgo extract altered the expression of genes that are involved in the regulation of cell proliferation, cell differentiation or apoptosis, and that exposure of human bladder cancer cells to a Ginkgo extract produced an adaptive transcriptional response that augments antioxidant status and inhibits DNA damage. In humans, Ginkgo extracts inhibit the formation of radiation-induced (chromosome-damaging) clastogenic factors and ultraviolet light-induced oxidative stress - effects that may also be associated with anticancer activity. Flavonoid and terpenoid constituents of Ginkgo extracts may act in a complementary manner to inhibit several carcinogenesis-related processes, and therefore the total extracts may be required for producing optimal effects.

Dr. Willmar Schwabe III, a German physician-pharmacist, introduced Ginkgo biloba leaf extracts into medical practice in 1965. The earliest publications concerning the therapeutic use of these extracts dealt with their actions on cerebral and peripheral disturbances of blood flow. These extracts led to the development of the extract named EGb 761® (definition see editorial). Clinical studies conducted during the past 25 years have revealed that EGb 761® is useful in treating a wide range of symptoms associated with both early cognitive decline and more severe types of senile dementia of primary degenerative, vascular and mixed origin, as well as peripheral arterial occlusive diseases and various neurosensory disturbances. Laboratory experiments conducted during the past two decades have revealed that several effects of EGb 761® - vasoregulatory, antioxidant, neuroprotective, and anti-stress effects, as well as effects on learning and memory and on gene-regulation - caused by various active constituents of the extract (or their metabolites) act in a complementary manner in producing health-related benefits.

Ginkgo biloba leaf extract (EGb 761), which contains many constituents, including flavonoid glycosides and terpenoids (ginkgolides, bilobalide), is used to treat cerebrovascular and peripheral vascular insufficiency, as well as cognitive impairment and other symptoms of dementia. Recent studies have indicated that these therapeutic effects of EGb 761 probably involve modification of the expression of many genes by actions involving several of its active constituents. As examples: EGb 761 and its ginkgolide B constituent inhibit the expression of the peripheral benzodiazepine receptor in the adrenal cortex and decrease circulating levels of corticosterone in the rat, effects that provide a mechanism for explaining the “antistress” action of the extract. Both the flavonoid and terpenoid constituents of EGb 761 decrease the expression of inducible nitric oxide synthase (iNOS), supporting an action of the extract of opposing the deleterious effects of excessive formation of NO. EGb 761 upregulates several genes that encode vital antioxidant enzymes, including heme oxygenase-1 and the regulatory and catalytic subunits of γ-glutamyl-cysteinyl synthetase. Dietary treatment of mice with EGb 761 upregulates the expression of genes encoding neuronal tyrosine/threonine phosphatase 1 and microtubule-associated tau in the cerebral cortex, findings that are of interest since these proteins are associated with the intracellular neurofibrillary tangles found in the brain in Alzheimer's disease. Bilobalide upregulates two mitochondrial-DNA-encoded genes, subunit III of cytochrome c oxidase and subunit ND1 of NADH dehydrogenase, indicating a fundamental mechanism that may underlie EGb 761-induced neuroprotection. Collectively, such results indicate that the therapeutic effects of EGb 761 on cognitive impairment (dementia) may involve its action of altering gene expression. Drug Dev. Res. 57:214–235, 2002. 2003 Wiley-Liss, Inc.

In vivo studies have indicated that systemically administered bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, can reduce cerebral edema produced by triethyltin, decrease cortical infarct volume in certain stroke models, and reduce cerebral ischemia. In vitro and ex vivo studies indicate that bilobalide has multiple mechanisms of action that may be associated with neuroprotection, including its preservation of mitochondrial ATP synthesis, its inhibition of apoptotic damage induced by staurosporine or by serum-free medium, its suppression of hypoxia-induced membrane deterioration in the brain, and its actions of increasing the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome c oxidase and the ND1 subunit of NADH dehydrogenase. As multiple modes of action may apply to bilobalide, it could be useful in developing therapy for disorders involving cerebral ischemia and neurodegeneration.

Although there is an evidence of correlation between irisin and osteoporotic fractures, previous studies have not elucidated the relationship between irisin and either lean or fat mass. The main aim of this study is to investigate the relationship between irisin and body composition in postmenopausal women with osteoporosis and the impact of irisin levels on fragility vertebral fractures.In this cross-sectional study, 36 overweight subjects affected by at least one vertebral osteoporotic fracture confirmed by an X-ray vertebral morphometry and 36 overweight nonosteoporotic subjects were enrolled. Serum irisin levels were measured using an irisin competitive ELISA. We evaluated lumbar spine and hip BMD and body composition using dual energy X-ray absorptiometry. To measure and monitor daily physical activity, each subject wore an armband for approximately 72 h.No significant correlations were found between irisin and BMD at any site and between irisin with either lean or fat mass. Serum levels of irisin were not correlated with the daily physical activity. Serum irisin levels were lower in subjects with previous osteoporotic fractures than in controls (P = 0·032), and the difference in irisin levels remained significant after adjustment for creatinine (P = 0·037), vitamin D (P = 0·046), lean mass (P = 0·02), lumbar BMD (P = 0·023) and femoral BMD (P = 0·032).Our data confirm an inverse correlation between irisin levels and vertebral fragility fractures, but no significant correlation was found with BMD or lean mass. Irisin may play a protective role on bone health independent of BMD but further studies are needed to clarify the relationship between irisin and bone metabolism.