Reduction of serum lipids by soy protein and soluble fiber is not associated with the ABCG5/G8, apolipoprotein E,and apolipoprotein A1 polymorphisms in a group of hyperlipidemic Mexican subjects

Several studies have evaluated the effect of soy protein or soluble fiber on serum cholesterol in hypercholesterolemic subjects, with different results. We hypothesized that this response is associated with the presence of polymorphisms in genes encoding proteins involved in lipoprotein metabolism or reverse cholesterol transport. Thus, the aims of the present work were to study the effectiveness of a dietary portfolio consisting of a combination of soy protein and soluble fiber integrated in a low saturated fat (LSF) diet on blood lipids in a Mexican group with hyperlipidemia and to determine the association between responsiveness to the diet and the frequency of apolipoprotein (Apo) E and ApoA1 and ABCG5/8 polymorphisms. Forty-three hyperlipidemic subjects (20 men and 23 women) were given an LSF diet for 1 month, followed by an LSF diet that included 25 g of soy protein and 15 g of soluble fiber daily for 2 months. After the 3-month dietary intervention, serum total cholesterol (TC) significantly decreased by 20.6%, and serum triglycerides (TGs) decreased by 40.4%. Fifty-one percent of the subjects had a reduction more than 20% in serum TC, and 77% of the subjects had a reduction more than 20% in serum TG (hyperresponders). Approximately 14% of the hypercholesterolemic subjects had the ABCG8 (52 G/C) polymorphism, 65% had the ABCG5 (1950 C/G and G/G) polymorphism, 53.5% had the ApoA1 (−75 G/A and A/A) polymorphism, and 23.3% had the ApoE (3/4) polymorphism. Independently of genotype, the combination of cholesterol-lowering foods in an LSF diet significantly reduced serum TC and TG in Mexican hypercholesterolemic subjects.     

Early changes in oxidative stress markers in a rat model of acute stress: effect of l-carnitine on the striatum

This work focuses on the effect of acute stress on different markers of oxidative stress and mitochondrial dysfunction in the rat striatum. In addition, the effect of a single dose of l-carnitine (l-CAR, 300 mg/kg, i.p.) was evaluated in these animals. Immobilization (restraint) stress was induced to rats for 24 hr. The levels of lipid peroxidation (LP) and mitochondrial function (MF), as well as the superoxide dismutase (SOD) activity and content and reduced glutathione (GSH) levels, were all measured in striatal samples of animals subjected to stress. Our results indicate that acute stress is able to increase the striatal LP and reduced the levels of MF, while significantly lowered the manganese superoxide dismutase (Mn-SOD) activity. No changes were observed in the total striatal content of SOD, nor in GSH levels, but serum corticosterone content was increased by stress. l-CAR exhibited partial protective effects on the immobilized group, reducing the striatal LP and recovering the striatal MF and Mn-SOD activity. Our results suggest that acute restraint stress brings an accurate model for early pro-oxidant responses that can be targeted by broad-spectrum antioxidants like l-CAR.     

Potential pharmacological interventions in polycystic kidney disease

Polycystic kidney diseases (autosomal dominant and autosomal recessive) are progressive renal tubular cystic diseases, which are characterised by cyst expansion and loss of normal kidney structure and function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common life- threatening, hereditary disease. ADPKD is more prevalent than Huntington's disease, haemophilia, sickle cell disease, cystic fibrosis, myotonic dystrophy and Down's syndrome combined. Early diagnosis and treatment of hypertension with inhibitors of the renin-angiotensin-aldosterone system (RAAS) and its potential protective effect on left ventricular hypertrophy has been one of the major therapeutic goals to decrease cardiac complications and contribute to improved prognosis of the disease. Advances in the understanding of the genetics, molecular biology and pathophysiology of the disease are likely to facilitate the improvement of treatments for these diseases. Developments in describing the role of intracellular calcium ([Ca(2+)](i)) and its correlation with cellular signalling systems, Ras/Raf/mitogen extracellular kinase (MEK)/extracellular signal-regulated protein kinase (ERK), and interaction of these pathways with cyclic adenosine monophosphate (cAMP) levels, provide new insights on treatment strategies. Blocking the vasopressin V(2) receptor, a major adenylyl cyclase agonist, demonstrated significant improvements in inhibiting cytogenesis in animal models. Because of activation of the mammalian target of rapamycin (mTOR) pathway, the use of sirolimus (rapamycin) an mTOR inhibitor, markedly reduced cyst formation and decreased polycystic kidney size in several animal models. Caspase inhibitors have been shown to decrease cytogenesis and renal failure in rats with cystic disease. Cystic fluid secretion results in cyst enlargement and somatostatin analogues have been shown to decrease renal cyst progression in patients with ADPKD. The safety and efficacy of these classes of drugs provide potential interventions for experimental and clinical trials.     

Preclinical diagnosis of testotoxicosis in a boy with an activating mutation of the luteinizing hormone receptor

BACKGROUND: Testotoxicosis is an autosomal dominant disorder usually recognized by progressive virilization, linear growth acceleration, skeletal maturation and pubertal testosterone levels in boys before 4 years of age. OBJECTIVE: To describe the clinical and hormonal follow-up of a male infant with testotoxicosis who was initially diagnosed by molecular analysis. PATIENT: A healthy asymptomatic 10 month-old boy was referred to the endocrinologist because his older brother had diagnosis of familial testotoxicosis due to the activating mutation Thr577Ile of the luteinizing hormone (LH) receptor. RESULTS: Automatic sequencing of exon 11 of the LH receptor gene revealed the same heterozygous Thr577Ile mutation in the asymptomatic boy. He had no signs of virilization or accelerated growth. His bone age was delayed. Serum LH and follicle stimulating hormone (FSH) concentrations were in the prepubertal range, testosterone levels were slightly elevated (31 ng/dl [1.07 nmol/l]). In the following 6 months, his testosterone levels progressively increased, achieving higher levels (146 ng/dl [5 nmol/l]) without testicular enlargement or pubic hair development. Despite the lack of virilization signs, an anti-androgen was started due to the increase in testosterone levels and growth velocity at the age of 1.3 years. CONCLUSION: We describe the preclinical diagnosis of testotoxicosis in a boy by DNA analysis. Very early diagnosis in affected families can result in prompt treatment, and reduce the deleterious consequences of premature puberty in boys with this rare monogenic disorder.     

Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology

Macrophage/neutrophil-specific IL-4 receptor alpha-deficient mice (LysM(Cre)IL-4Ralpha(-/flox)) were generated to understand the role of IL-4/IL-13 responsive myeloid cells during Type 2 immune responses. LysM(Cre)IL-4Ralpha(-/flox) mice developed protective immunity against Nippostrongylus brasiliensis accompanied by T(H)2 development and goblet cell hyperplasia. In contrast, LysM(Cre)IL-4Ralpha(-/flox) mice were extremely susceptible to Schistosoma mansoni infection with 100% mortality during acute infection. Mortality was not dependent on neutrophils and occurred in the presence of T(H)2/Type 2 responses, granuloma formation, and egg-induced fibrosis. Death was associated with increased T(H)1 cytokines, hepatic and intestinal histopathology, increased NOS-2 activity, impaired egg expulsion, and sepsis. IL-10 was not able to compensate for the absence of IL-4/IL-13-activated alternative macrophages. Together, this shows that alternative macrophages are essential during schistosomiasis for protection against organ injury through downregulation of egg-induced inflammation.     

46,XY disorders of sex development (DSD)

The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical.
Mutations in genes present in X, Y or autosomal chromosomes can cause abnormalities of testis determination or disorders of sex differentiation leading to 46,XY DSD. Detailed clinical phenotypes allow the identification of new factors that can alter the expression or function of mutated proteins helping to understand new undisclosed biochemical pathways. In this review we present an update on 46,XY DSD aetiology, diagnosis and treatment based on extensive review of the literature and our three decades of experience with these patients.     

Comparison between weight-based and IGF-I-based growth hormone (GH) dosing in the treatment of children with GH deficiency and influence of exon 3 deleted GH receptor variant

ObjectiveCompare the most frequently used weight-based GH dosing with an IGF-I level-based strategy in the treatment of children with severe GH deficiency. Additionally, analyse the influence of the GH receptor exon 3 polymorphism on IGF-I levels during GH therapy.DesignThirty children with GH deficiency on treatment with GH for 4.3 ± 3.2 yr in a single University Hospital were divided in group W (weight-based GH dosing) and group I (IGF-I-based dosing). In group I, GH doses were changed by 8.3 μg/kg d to maintain IGF-I levels between 0 and +2 SDS, whereas in group W the dose was fixed at 30 μg/kg d in prepubertal and 50 μg/kg d in pubertal patients. Growth velocity was measured after 1 yr, IGF-I and IGFBP3 levels quarterly. GH receptor exon 3 was genotyped by PCR.ResultsMost patients in Group I reached target IGF-I levels after 6 months with a GH dose ranging between 25 and 66 μg/kg d (mean ± SD, 38 ± 8). Each change of 8.3 μg/kg d of GH dose, resulted in change of 1.17 ± 0.6 SDS of IGF-I levels. Mean IGF-I levels were higher in Group I 0.8 ± 0.5 SDS than in Group W ?0.3 ± 1.9 SDS (p < 0.05), but growth velocities were similar, 6.8 ± 2.6 cm/yr and 6.9 ± 2.6 cm/yr (p = NS), respectively. Serum IGFBP3 levels were similar in both groups and were less useful to individualize GH therapy. Even treated with a similar mean GH dose, patients carrying at least one GH receptor d3-allele reached higher IGF-I levels (0.7 ± 1.2 SDS) than those homozygous for the full-length allele (?0.3 ± 1.2 SDS; p < 0.05), however, growth velocities were not different.ConclusionsBy adjusting the GH dose, it was feasible to maintain IGF-I in the desired range (0–+2 SDS). Patients carrying at least one GH receptor d3-allele reached higher circulating IGF-I levels than those homozygous for the full-length allele. A multiple regression analysis failed to demonstrate an independent influence of IGF-I levels on GV during the 12 months of observation.