Manuel Puig-Domingo

Role of melatonin in health and disease

Pineal function and its main hormonal product melatonin has often been ignored by many clinicians. In this review, the evidence pointing towards an undeniable role of melatonin in certain clinical instances will be presented and discussed. In the last 3 decades tremendous advances in the understanding of the biochemistry and physiology of the pineal gland have occurred. It is now evident that the pineal interacts with many endocrine as well as non-endocrine tissues to influence their metabolic activity. The most extensively studied pineal effect on the neuroendocrinereproductive axis is by no means the only or necessarily the most important role of this gland, which through its hormone, melatonin, is able to modulate many organs and functions.

IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in Genetic Susceptibility to Type 1 Diabetes (Insulin-dependent)

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.

Growth hormone treatment for sustained pain reduction and improvement in quality of life in severe fibromyalgia

Summary Growth hormone might be an effective complementary treatment for pain and fatigue management in fibromyalgia patients, particularly in a subset with low insulin‐like growth factor 1 values. ABSTRACT Functional defects in growth hormone (GH) secretion and its efficacy as a complementary treatment have been suggested for fibromyalgia. This study investigated the efficacy and safety of low‐dose GH as an add‐on therapy in patients with both severe FM and low insulin‐like growth factor 1 levels. A total of 120 patients were enrolled in a multicenter, placebo‐controlled study for 18 months. They were randomly assigned to receive either 0.006 mg/kg/day of GH subcutaneously (group A, n = 60) or placebo (group B, n = 60) for 6 months (blind phase). The placebo arm was switched to GH treatment from month 6 to month 12 (open phase), and a follow‐up period after GH discontinuation was performed until month 18. Standard treatment for fibromyalgia (selective serotonin re‐uptake inhibitors, opioids, and amitriptyline) was maintained throughout the study. Number and intensity of tender points, Fibromyalgia Impact Questionnaire (FIQ) with its subscales, and EuroQol 5 dimensions test (EQ5D) with visual analogue scale (VAS) were assessed at different time points. At the end of the study, 53% of group A patients obtained fewer than 11 positive tender points, vs 33% of group B patients (P < .05). 39.1% vs 22.4% reached more than 50% improvement in VAS (P < .05). Group A patients showed significantly improved FIQ scores (P = .01) compared with group B. Although GH discontinuation worsened all scores in both groups during follow‐up, impairment in pain perception was less pronounced in the GH‐treated group (P = .05). In this largest and longest placebo‐controlled trial performed in FM (NCT00933686), addition of GH to the standard treatment is effective in reducing pain, showing sustained action over time.

The role of ghrelin in the energy homeostasis of elderly people: A population-based study

Objective: Ghrelin is a hormone secreted mainly in the stomach which stimulates appetite and food intake. Endocrine factors are among the causes of anorexia in elderly people. The main objective of the present study was to examine the effect of age on ghrelin levels in non-institutionalized elderly people. Design and setting: Observational, cross-sectional, population-based study. Participants: A random sample of men aged 70 yr or older was taken from the municipal census. Measurements: All participants underwent a physical examination which measured weight and height, grip strength, functional capacity (according to the Barthel Index) and nutritional status (according to the short form of the Mini Nutritional Assessment). Blood was taken for basic biochemical analysis, determination of somatotropic, corticotropic, and gonadotropic hormones, and for measurement of ghrelin and cholecystokinin. Results: 152 men with a mean (SD) age of 76.7 (5.4) yr were recruited. Mean ghrelin levels were 1143 (401) pg/ml. A weak negative correlation was found between ghrelin levels and age (r=−0.16, p=0.057). Multiple linear regression analysis showed a significant and independent effect of age (β=−12.1, p=0.049), body mass index (BMI) (β=−22.0, p=0.021), and creatinine levels (β=407.7, p=0.002) on ghrelin. No correlations with age and BMI were found for cholecystokinin. Conclusions: There is a slight decrease in ghrelin levels with age in older men aged 70 yr or more, although the clinical relevance of this finding remains unclear.

Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes

Introduction The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow β-cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. Objective To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to β-cells in type 1 diabetes. Methods A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine-liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. Results We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine-free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. Conclusions We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases.

Relationship between ghrelin and the metabolic syndrome in the elderly: a longitudinal population-based study

Context  Ghrelin regulates energy homeostasis and may contribute to the development of the metabolic syndrome (MS) in the elderly.

Immunoreactive somatostatin diurnal rhythms in rat pineal, retina and harderian gland : effects of sex, season, continuous darkness and estrous cycle

Diurnal profiles of the content of immunoreactive somatostatin (IRS) in the male and female rat pineal, Harderian gland and retina have been studied. Supplementary experiments have been performed to elucidate a possible effect of infradian cycles, namely estrous and seasonal cycles, and continuous dark on IRS concentration. Results demonstrate that the IRS content in the rat pineal gland, Harderian gland and retina is submitted to diurnal variations, but not under all studied conditions. A sexual dimorphism exists between male and female animals: male rats showed higher IRS content in pineal (103.8±4.7 vs 32.3±1.8pg IRS/gland), but lower in retina (1,362.1±82.7 vs 2,176±102.2± pg IRS/mg of protein) and Harderian gland (10.3±0.8 vs 30.6±3.5 pg IRS/mg of protein). Additionally, seasonal differences appeared: in male and female animals pineal IRS content was lower in spring than in November. This decrease also appeared in female retina IRS concentration. Estrous cycle did not seem to change IRS content in the three studied tissues. Finally, pineal IRS rhythm persisted after continuous dark for a week. These results demonstrate, in the rat, sexual differences in the IRS content of the various tissues studied and suggest a physiological role for somatostatin, possibly related to seasonal adaptation.

Muscle strength in the Mataró aging study participants and its relationship to successful aging

Background and aims: Successful aging is a worldwide aim, but its related factors and instruments of measurement are currently hotly debated. To investigate the relationship between muscle strength and functional capacity, and its association with successful aging. Methods: A population-based cross-sectional study was performed in Mataró (Spain). Included in the study were 313 subjects (153 men, 160 women) aged 70 years and over. Physical and cognitive functions were assessed, as well as muscle strength, nutritional status, lifestyle factors, and associated morbidities. Results: A state of successful aging (SA), defined as optimal functional and cognitive capacities with absence of cancer, stroke, cardiovascular or pulmonary chronic diseases, was found in 20% of women and 32% of men. SA was associated with higher muscle strength in comparison with the non-SA condition. Muscle strength measurements were higher in men, and decreased with age, poor balance, decreased functional capacity, and impaired cognitive status. It was also associated with higher academic level, regular exercise, and nutritional status in both genders. Multivariate analysis showed that independent variables related to SA were: hand grip, arthrosis, deafness and unipodal balance test, but not age or gender. Conclusions: Muscle strength is positively associated with the successful aging condition, and may be one of its functional links, reflecting the integrated health status of old men and women. The systematic inclusion of the measurement of muscle strength may be helpful in clinical evaluation of the elderly.

Estudio comparativo de las series históricas de carcinoma diferenciado de tiroides en dos centros hospitalarios de tercer nivel españoles en relación a series norteamericanas

BACKGROUND AND OBJECTIVE There is little national literature on descriptive series of patients with differentiated thyroid carcinoma (DTC) and long-term monitoring in Spain. The aim of our study was to describe the DTC series in two tertiary hospitals [Hospital Clínic de Barcelona (HC) and Hospital Germans Trias i Pujol (HGTiP)] and compare these series with those described in the National Cancer Data Base (NCDB) and the Mayo Clinic, the leading international series by number of patients and length of follow-up. MATERIAL AND METHODS We performed a retrospective review of the medical records of patients diagnosed with DTC in two tertiary hospitals in the Barcelona area. The results were compared with those published by the NCDB and the Mayo Clinic. RESULTS We reviewed 480 medical records of patients with DTC diagnosed between 1973 and 2006, with a mean follow-up of 16±8 years. No significant differences were observed in clinical characteristics, risk factors or the most frequent form of presentation between the joint HC/HGTiP group and the NCDB series. The most commonly used diagnostic methods were ultrasound and cytology in all series and the main type of surgery was total or nearly total thyroidectomy, with no differences between groups. Postoperative I-131 was administered more often in the HC/HGTiP series (83.9%) than in the NCDB series (55.1%) and in the Mayo Clinic (46%). In the HC/HGTiP group tumor recurrence was 9.3% and mortality 1.8%. CONCLUSIONS The HC and HGTiP series were comparable and the various diagnostic and therapeutic techniques used were similar. This study highlights historical trends in the use of imaging techniques, as well as differences with large American series in some procedures (such as laryngoscopy) and the use of radioiodine therapy.

Expression of somatostatin in rat pineal cells in culture

Abstract: The expression of somatostatin mRNA was investigated in rat pineal cells after 1 week in culture, using reverse transcription of mRNA into cDNA and the polymerase chain reaction. The positive expression in cultured pineal cells demonstrates the capacity of this gland to synthesize somatostatin in denervated cells. Thus, apart from the neural origin of pineal somatostatin, which has been described in detail in the bovine species, a parenchymal source is demonstrated.