Discontinuing Long-Term GH Replacement Therapy--A Randomized, Placebo-Controlled Crossover Trial in Adult GH Deficiency

Context: Adult GH deficiency (GHD) is associated with impaired quality of life (QoL) and increased cardiovascular risk. Continued long-term efficacy in terms of QoL and cardiovascular risk factors has been indicated in open surveillance studies. Objectives: The aim was to study the impact of discontinuation of long-term GH replacement on QoL, body composition, and metabolism. Design and Setting: We conducted a randomized, double-blind, placebo-controlled 4-month crossover trial in a referral center. Patients: Sixty adult hypopituitary patients with GHD and more than 3 yr of continuous GH replacement therapy (mean treatment duration, 10 yr) participated in the study. Intervention: Patients received GH or placebo. Main Outcome Measurements: We measured QoL using validated questionnaires; body composition using computer tomography, dual-energy x-ray absorptiometry, and bioelectrical impedance spectroscopy; and insulin sensitivity using the short insulin tolerance test. Results: Mean serum IGF-I decreased from 168 ± 52 to 98 ± 47 μg/liter during the placebo period (P < 0.001). Two QoL domains (emotional reactions and positive well-being) in the Nottingham Health Profile and Psychological General Well-Being questionnaires deteriorated during placebo, compared with GH treatment (P < 0.05). Waist circumference and sc and visceral fat mass increased, and extracellular water and muscle area decreased during the placebo period (all P < 0.05). C-reactive protein and total-, low-density lipoprotein-, and high-density lipoprotein-cholesterol increased, and insulin sensitivity improved during placebo, compared to GH treatment (P < 0.05). Conclusion: After more than 3 yr of GH replacement therapy, a 4-month period of placebo treatment caused self-perceived deterioration in QoL and increased abdominal fat accumulation. Moreover, markers of systemic inflammation and lipid status deteriorated, whereas insulin sensitivity improved. Long-term continuous GH replacement is needed to maintain therapeutic effects of GH on QoL and cardiovascular risk factors.     

Long-Term Cognitive Impairments and Attentional Deficits in Patients with Cushing's Disease and Cortisol-Producing Adrenal Adenoma in Remission

Context: Cognitive function is impaired in patients with active Cushing's syndrome (CS). Objective: The aim was to study cognitive function in patients with CS in long-term remission. Design: We conducted a cross-sectional, case-controlled, single center study. Patients: Fifty-five patients previously treated for Cushing's disease (n = 43) and cortisol-producing adrenal adenoma (n = 12) and 55 controls matched for age, gender, and educational level participated in the study. Methods: Working memory, attention, information-processing speed, verbal fluency, and reading speed were studied using standardized neuropsychological testing and alerting, orienting, and executive control using the Attentional Network Test. Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue and affective disorder. Results: Median (interquartile range) duration of remission was 13 (5-19) yr and the mean ± sd age at follow-up was 54 ± 14 yr. Compared to controls, patients had a higher score on the fatigue impact scale, indicating greater burdens of fatigue, and a higher score on the comprehensive psychopathological rating scale subscales for depression and anxiety. In a multivariate analysis, attention, spatial orienting, alerting, working memory, verbal fluency, and reading speed were all diminished in comparison to controls, independent of scores for affective disorder and fatigue. No overall difference in outcome was seen between patients in long-term remission for Cushing's disease and cortisol-producing adrenal adenoma. Conclusion: Patients with CS in remission have impaired cognitive function that cannot be explained by the coexistence of affective disorder or chronic fatigue. The pattern of cognitive and attentional deficits suggests a more global involvement of the brain function than has previously been suggested.     

Distribution of fixed beneficial mutations and the rate of adaptation in asexual populations

When large asexual populations adapt, competition between simultaneously segregating mutations slows the rate of adaptation and restricts the set of mutations that eventually fix. This phenomenon of interference arises from competition between mutations of different strengths as well as competition between mutations that arise on different fitness backgrounds. Previous work has explored each of these effects in isolation, but the way they combine to influence the dynamics of adaptation remains largely unknown. Here, we describe a theoretical model to treat both aspects of interference in large populations. We calculate the rate of adaptation and the distribution of fixed mutational effects accumulated by the population. We focus particular attention on the case when the effects of beneficial mutations are exponentially distributed, as well as on a more general class of exponential-like distributions. In both cases, we show that the rate of adaptation and the influence of genetic background on the fixation of new mutants is equivalent to an effective model with a single selection coefficient and rescaled mutation rate, and we explicitly calculate these effective parameters. We find that the effective selection coefficient exactly coincides with the most common fixed mutational effect. This equivalence leads to an intuitive picture of the relative importance of different types of interference effects, which can shift dramatically as a function of the population size, mutation rate, and the underlying distribution of fitness effects.     

Mathematical Modelling of Glucose‐Dependent Insulinotropic Polypeptide and Glucagon‐like Peptide‐1 following Ingestion of Glucose

The incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), play an important role in glucose homeostasis by potentiating glucose‐induced insulin secretion. Furthermore, GLP‐1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP‐1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP‐1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP‐1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP‐1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.     

Bauhinia forficata in the treatment of diabetes mellitus: a patent review

Introduction: Diabetes Mellitus has been considered an epidemic by the World Health Organization, with a high risk of morbidity and mortality. The treatment of this pathology consists in glycemic control, which can be done by oral hypoglycemic agents, insulin therapy, dietary guidance, regular physical activity, and psychosocial support. In addition, other adjuvant treatments are employed, such as phytotherapic, and one of the most used plants is Bauhinia forficata.

Areas covered: In the current review, patents using Bauhinia forficata for the Diabetes Mellitus treatment have been analyzed. There were 03 patents in WIPO, 01 in Espacenet, 01 in USPTO, and 02 in INPI.

Expert opinion: Patents on the adjuvant treatment of Diabetes Mellitus by Bauhinia forficata are discussed. Although there are some phytotherapy products containing this medicinal plant which has hypoglycemic effect here is still a need for the development of more products based on natural resources, for the treatment of this pathology, without side effects and with other benefits, to assist in the glycemia control in diabetic patients, and to improve their quality of life.     

Influence of reciprocating tachycardia on the development of atrial fibrillation in patients with preexcitation syndrome

BACKGROUND: We sought to evaluate the influence of atrio-ventricular reentrant tachycardia (AVRT) on atrial pressures during tachycardia and the presence of atrial fibrillation (AF) in patients with preexcitation syndrome. METHODS: The study population consisted of 88 patients (37 females, mean age 37.3 years) with left-sided accessory pathway and AVRT induced during electrophysiologic study. The AF-inducible group consisted of 32 patients with sustained episodes of AF provoked during electrophysiologic study, whereas the noninducible group comprised 56 patients without AF. RESULTS: We found significantly higher values of maximal and mean left (LAP) and right (RAP) atrial pressures in the AF group compared with noninducible group: LAP max 32.0 versus 20.8, LAP mean 21.6 versus 13.2, RAP max 15.2 versus 11.5, RAP mean 8.2 versus 6.2 respectively (P < 0.001). When analyzing the effect of AVRT on atrial pressures, we found a significant (P < 0.001) negative correlation between anterograde conduction times during tachycardia and LAP max and LAP mean in the whole population, but a significant positive correlation between retrograde conduction time and left atrial pressures. Similar effects of AVRT on the right atrial pressures were found. CONCLUSIONS: Atrial pressures during AVRT, which depend on the electrophysiological features of tachycardia, play an important role in the genesis of atrial fibrillation in patients with preexcitation syndrome.