Targeting patients' microbiota with probiotics and natural fibers in adults and children with constipation.

OBJECTIVE: Functional constipation (FC) is a common condition in which the gut microbiota composition plays a fundamental role. The increasing knowledge on the role of gut microbes in the regulation of gut motility and stool consistency has allowed reconsidering, with a new scientific-based approach, the possibility to target the composition of intestinal bacterial populations for FC treatment. In this review, we evaluate recent attempts that used prebiotics, natural fibers or probiotics to treat FC, with a deep microbiome-based focus. MATERIALS AND METHODS: This is a literature review of articles published in Medline, Web of Science, and the Cochrane Library. Studies on FC in adults and children were identified using the following terms: constipation AND probiotics OR prebiotics OR synbiotics PR fibers OR microbiome OR microbiota. Selected animal studies were also considered if showing mechanistic observations. RESULTS: FC is associated with alteration in microbiome composition. Motility and fecal consistency are affected with different efficacy by the type of fiber, prebiotic or probiotic strain used in patients. CONCLUSIONS: Selected bacterial strains, mainly belonging to the Bifidobacterium genus, and some poorly or non-fermented natural fibers, such as Psyllium, may significantly improve FC and may represent the basis for an effective supplementation.

Probiotics, prebiotics and synbiotics for weight loss and metabolic syndrome in the microbiome era.

OBJECTIVE: Excessive body fat and the associated dysmetabolic consequences affect both developed and emerging countries. An altered gut microbiota composition is an important environmental cause of these conditions. Clinical trials targeting gut microbiome composition or functions with pro or prebiotics to promote a healthier profile are considered a promising tool for excessive body weight treatment and prevention of dysmetabolic complications. MATERIALS AND METHODS: We searched PubMed and Cochrane Library using combinations of probiotics/prebiotics and synbiotics with obesity/weight loss/metabolic syndrome as the search terms. Clinical studies and significant pre-clinical results showing molecular mechanisms supporting clinical results were also discussed. RESULTS: Several studies in humans and in animal models have elucidated biological mechanisms supporting the observed clinical efficacy of selected probiotic and prebiotic compounds for weight management. Efficacy appears to be species or strain-specific. Fibers such as inulin or galactomannan promote independent and synergistic beneficial effects. CONCLUSIONS: Diet supplementation with synbiotics prepared using selected strains (such as Lactobacillus gasseri strains) showed to exert weight-reduction and anti-inflammatory activity in large independent studies. Their administration, together with galactomannan and/or inulin fibers, may increase weight management effects due to synergistic effect on short chain fatty acid production and microbiota 're-configuration'.

Therapeutic Strategies and Clinical Outcome in Papillary Thyroid Microcarcinoma: A Multicenter Observational Study.

PURPOSE: Papillary thyroid microcarcinoma (MPTC) has an excellent prognosis. We aimed to evaluate the evolution of therapeutic strategies over time and the clinical outcome of MPTC. METHODS: In this retrospective multicenter observational study in a northwest Italian region, patients with intrathyroidal, unifocal tumor ≤1 cm in size, incidentally found at histology or preoperative cytology diagnosis, were included. Exclusion criteria were a previous head-and-neck irradiation and/or node metastases. RESULTS: From 1985 to 2012, 437 patients had an MPTC diagnosis, which was incidental in 85% and preoperative in 15%. Patients with a preoperative diagnosis were younger at the time of diagnosis (47.6 ± 12.7 years, p < 0.01) and had a larger tumor (7.0 ± 2.5 mm, p < 0.0001) than patients with an incidental diagnosis (age 52 ± 13.5 years, size 4.4 ± 2.8 mm), but there were no differences in clinical outcome between both groups. We observed a significant (p < 0.001) reduction in radioiodine remnant ablation during the years. TSH levels were: <0.1 mIU/l in 27.5%, 0.1-0.5 mlU/l in 33.7%, 0.5-2.5 mlU/l in 32.6%, 2.5-4.2 mlU/l in 3.9%, and >4.2 mlU/l in 2.3% of patients. Six patients (1.37%) had nodal recurrence; 5 of them were cured after therapy. MPTC-linked mortality was null. CONCLUSIONS: We confirmed the favorable clinical outcome of MPTC. Despite the reduction in radioiodine ablation, overtreatment of MPTC is still observed.

HIV DNA loads, plasma residual viraemia and risk of virological rebound in heavily treated, virologically suppressed HIV-infected patients.

In this single-centre, retrospective study, we analyzed data of 194 patients receiving antiretroviral therapy with <50 human immunodeficiency virus (HIV) RNA copies/mL in plasma and 318 HIV RNA/DNA paired samples. By kinetic polymerase chain reaction (kPCR) molecular system analysis, 104 (54%) subjects had undetectable HIV RNA and 90 (46%) had residual viraemia. Median (interquartile range) HIV DNA load was 780 (380-1930) copies/10(6) peripheral blood lymphocytes (PBL), and HIV DNA loads were independently associated with residual viraemia (p 0.002). Virological rebound occurred in 29/194 (15%) patients over a median (interquartile range) follow-up of 17.5 (13.5-31.5) months. Residual viraemia (p 0.002), but not HIV DNA load, was independently associated with virological rebound.

Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption.

The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4-24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4(+) T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono-therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process.

A study of the efficacy of radioiodine therapy with individualized dosimetry in Graves' disease: need to retarget the radiation committed dose to the thyroid.

Although Iodine-131 (131I) therapy is fully validated for Graves' disease (GD), there is debate about radioiodine amount to be administered (prescribed activity), as well as the use of individualized dosimetry vs fixed 131I activity. The clinical outcome of 119 GD patients treated with 131I from 2003 to 2008 has been evaluated. The prescribed activity was calculated according to a dosimetric protocol taking into account several variables, including thyroid volume reduction during treatment. In addition, we performed a simulation according to other dosimetric protocols, by calculating the corresponding prescribed activities. The patients were followed up for at least 12 months after treatment. In the first period of observation (2003), a 120-200 Gray (Gy) radiation dose to the thyroid was prescribed, according to the guidelines published by the Italian Societies of Endocrinology, Nuclear Medicine and Medical Physics: hyperthyroidism cure with a single radioiodine administration was obtained in 53% of patients. This outcome raised up to 89% when a higher radiation dose to the target (200- 250 Gy) was prescribed, although the administered activities were still lower, as a rule, than the most commonly employed fixed activities (400-600 Mega-Becquerel--MBq). Our method showed a high level of individual dose optimisation, particularly when compared to simplified methods. In conclusion, the protocol adopted in this study ensures a satisfactory rate of hyperthyroidism cure, while administering quite low 131I activities, provided that an adequate committed radiation dose to the thyroid is prescribed. In this context, the dose indication given by the aforementioned guidelines should probably be revised.

Thyrotropin receptor autoantibody measurement following radiometabolic treatment of hyperthyroidism: comparison between different methods.

BACKGROUND: TSH receptor antibodies (TRAb) play a crucial role in the pathogenesis of Graves' disease (GD). The use of human recombinant TSH-receptor far improved the analytical performance of TRAb assays (2nd-generation assays). The 3rd-generation assay is based on the inhibition of binding of a human biotin-labeled monoclonal thyroid- stimulating antibody (M22) to TSH-receptor by the autoantibodies present in the serum. AIM: We aimed to assess the ability of the 2nd- and 3rd-generation assays to detect serum TRAb following radioiodine therapy for hyperthyroidism. METHODS: Sera from 47 hyperthyroid (25 autoimmune, 22 non-autoimmune) patients were tested using the two different assays before and at different time intervals after radioiodine therapy. The modifications of TRAb were evaluated, as well as the correlation between the two methods. RESULTS: The results obtained by the two methods proved to be closely correlated. A rise in TRAb was invariably observed in GD patients following radioiodine, with a median peak at 6 months, irrespective of their initial clinical status, presence of ophthalmopathy, smoking habits or other variables. Such a rise was nearly superimposable using both methods. No TRAb appearance was observed in patients with non-autoimmune hyperthyroidism. CONCLUSIONS: The use of methods of higher sensitivity with respect to that formerly used indicate that nearly all GD patients develop TRAb following radioiodine, and that this phenomenon is transient and not related to baseline conditions and clinical outcome/efficacy of treatment.

Safety and efficacy of administering 0.2 mg of recombinant human TSH for two consecutive days as an adjuvant to therapy with low radioiodine doses in elderly out-patients with large nontoxic multinodular goiter.

AIM: The aim of this study was to evaluate the efficacy of recombinant human TSH (rhTSH) as an adjuvant to radioiodine therapy for nontoxic multinodular goiter (MNG) in elderly subjects. METHODS: Twelve elderly out-patients with large MNG (group 1) were studied. The effect of adjuvant rhTSH administration (0.2 mg i.m. on 2 consecutive days) before low-dose (131)I was compared with that of radioiodine alone in 8 out-patients matched for age and MNG volume (group 2). The follow-up period was similar in both groups. RESULTS: The number and severity of side-effects during the first month of treatment were similar in both groups. On final examination, the number of patients symptomatic for goiter was significantly lower in group 1 than in group 2 (P=0.03). In group 1, TSH levels peaked at 40.3+/-9.5 mU/L on day 3, from the baseline value of 0.5+/-0.1 mU/L (P<0.001). In group 2, baseline TSH was 0.4+/-0.1 mU/L. Although a marked increase in f-T3, f-T4 and Tg (P<0.001) was noted in both groups during the first 2 weeks of treatment, peak values were much higher in group 1 than in group 2. On final examination, a slightly significant increase (P=0.01) in TSH levels from the baseline was noted in both groups (group 1: 1.2+/-0.2 mU/L; group 2: 1.4+/-0.3 mU/L). The percentage of patients who did not need therapies to control TSH secretion at the last examination was higher in group 1 (83%) than in group 2 (38%). Only in group 1, a significant reduction was noted in mean anterior-posterior lobar width (31+/-1.7 mm) from the baseline value (24.5+/-1.7 mm, P=0.04). Thyroid volume was reduced from 78.1+/-11.7 mL to 49.4+/-13.4 mL (P=0.001) in group 1 and from 89.8+/-25.2 mL to 67.1+/-20.5 mL (P=0.04) in group 2. Six months after (131)I therapy, slight changes in thyroid length and tracheal lumen were noted in both groups. CONCLUSIONS: This long-term controlled study demonstrates that 0.2 mg of rhTSH on 2 consecutive days increases the efficacy of ambulatory (131)I dosages in treating nontoxic MNG in elderly subjects. Adequate drug preparation generally prevents side-effects due to short-term but marked thyrotoxicosis that is aggravated by rhTSH administration. An increase in thyroid volume reduction seems to be the most important effect of rhTSH administered before (131)I.

A case-controlled study on the quality of life in a cohort of patients with history of differentiated thyroid carcinoma.

Although quality of life (QoL) has become an important aspect of cancer rehabilitation, psychometric studies on thyroid cancer patients are rare. We performed a case-controlled study on QoL in patients with differentiated thyroid carcinoma (DTC). QoL was evaluated in 61 patients with a history of DTC diagnosed from < 1 to 23 yr earlier. An undetectable thyroglobulin (Tg) level after recombinant human TSH (rhTSH) testing was considered the best predictor of cure. QoL was evaluated by means of a general psychiatric interview, the self-rating Kellner Symptoms Questionnaire (KSQ) and the Hamilton Depression Scale (HDS). QoL was also evaluated in a control group of subjects on L-T4 therapy with a non-toxic multinodular goiter diagnosed from < 1 to 25 yr earlier. DTC and control subjects were similar in age, male-female distribution and concomitant psychiatric therapies. Per-week dosage of L-T4 was higher in DTC patients than in controls (p < 0.01). In neither group of subjects was there any correlation between current TSH levels or interval from diagnosis and KSQ or HDS scores. Only in DTC patients was there a positive correlation between age and KSQ (p < 0.05) or HDS (p < 0.01) scores. There was a significant difference in overall KSQ scores between DTC (33.4 +/- 2.1) and control (24.5 +/- 1.9; p < 0.01) subjects. The subscales of KSQ showed a significant inter-group difference. HDS scores were higher in DTC subjects (35.8 +/- 1.0) than in controls (30.0 +/- 1.1; p < 0.01). HDS score was significantly (p = 0.02) higher in female than in male DTC patients. In patients with papillary carcinoma there was a positive correlation between the MACIS (metastases, age, completeness, invasiveness, size) score and KSQ (p = 0.01) or HDS (p < 0.01) scores. After rhTSH testing, detectable Tg levels were found in 13% of DTC patients. In Tg-positive patients, KSQ and HDS scores were not different from those of Tg-negative patients. After an 8-14 month period, a significant decrease in the KSQ scale somatization (p = 0.02) was found in a sub-set of 31 DTC patients. In conclusion, even in the age of rhTSH testing, DTC patients suffer an impairment of their QoL, as noted when short-term L-T4 withdrawal was the gold standard. Longitudinal evaluation seems to indicate a slight improvement in QoL when safe rhTSH testing is extensively used in the management of the disease.

Potential indications for somatostatin analogues: immune system and limphoproliferative disorders.

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.