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Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated.Report the results of the first years (2017-2019) of the Mexican FH registry.There are 60 investigators, representing 28 federal states, participating in the registry. The variables included are in accordance with the European Atherosclerosis Society (EAS) FH recommendations.To date, 709 patients have been registered, only 336 patients with complete data fields are presented. The mean age is 50 (36-62) years and the average time since diagnosis is 4 (IQR: 2-16) years. Genetic testing is recorded in 26.9%. Tendon xanthomas are present in 43.2%. The prevalence of type 2 diabetes is 11.3% and that of premature CAD is 9.8%. Index cases, male gender, hypertension and smoking were associated with premature CAD. The median lipoprotein (a) level is 30.5 (IQR 10.8-80.7) mg/dl. Statins and co-administration with ezetimibe were recorded in 88.1% and 35.7% respectively. A combined treatment target (50% reduction in LDL-C and an LDL-C100 mg/dl) was achieved by 13.7%. Associated factors were index case (OR 3.6, 95%CI 1.69-8.73, P = .002), combination therapy (OR 2.4, 95%CI 1.23-4.90, P = .011), type 2 diabetes (OR 2.8, 95%CI 1.03-7.59, P = .036) and age (OR 1.023, 95%CI 1.01-1.05, P = .033).The results confirm late diagnosis, a lower than expected prevalence and risk of ASCVD, a higher than expected prevalence of type 2 diabetes and undertreatment, with relatively few patients reaching goals. Recommendations include, the use of combination lipid lowering therapy, control of comorbid conditions and more frequent genetic testing in the future.

Resumen: Las alteraciones en el sentido del olfato (disosmia, anosmia, hiposmia) son frecuentes en los pacientes con enfermedad renal crónica; sin embargo, hasta el momento actual las causas, consecuencias y tratamiento de estas alteraciones han sido poco abordadas. Los pacientes con enfermedad renal crónica sin tratamiento de diálisis muestran disminución en la percepción olfativa y existe controversia sobre si estas alteraciones se corrigen con la diálisis. El grado de percepción olfativa es similar cuando se compara la población en diálisis peritoneal y en hemodiálisis. El trasplante renal corrige estos déficits olfativos. Una de las probables consecuencias de esta afección es el impacto en el estado nutricional del paciente. Abstract: Alterations in the sense of smell (dysosmia, anosmia, hyposmia) are frequently experienced by patients with chronic kidney disease. However, currently, the aetiology and consequences are poorly understood, with no effective treatments available to address such impairment. In general, the capacity of olfactory perception is affected in patients with chronic kidney disease (even in those who have not undergone dialysis therapy), and whether these alterations improve after dialysis is disputed. Patients in peritoneal dialysis and haemodialysis have the same olfactory perception defects. Kidney transplantation improves olfactory perception, and one important consequence of such impairment is the potential impact on the patient's nutritional status. Palabras clave: Sistema olfatorio, Disosmia, Enfermedad renal crónica, Hemodiálisis, Desnutrición, Receptores olfativos, Keywords: Olfactory system, Dysosmia, Chronic kidney disease, Haemodialysis, Malnutrition, Olfactory receptors

Background Vitamin D (VD) has been classically associated with calcium homeostasis and bone mineral density since it has a key role on mineralization and resorption. Immunomodulatory effects have been attributable to VD; low concentrations of VD have been associated with elevation of inflammatory markers. Inflammatory autoimmune diseases, such as multiple sclerosis (MS), a chronic neurodegenerative suffering, whose etiology is still unknown, is directly related to an increase in pro-inflammatory cytokines such as interleukin 17 and interleukin 1β who play an important role in this physiopathology. Nowadays, even though additional studies have linked MS's clinical signs with low VD concentration, there is scarce information of this association in people from regions with sufficient sun exposure. The aim of this study was to evaluate serum VD and cytokine concentrations, and bone density, in Mexican people with MS. Methods Vitamin D (25OHD), interleukin 1β, interleukin 6 and interleukin 17 concentrations of twenty-five volunteers with MS were determined by enzyme-linked immunosorbent assay. Bone mineral density and body composition assessment was performed by dual energy X-Ray absorptiometry. Results A mean concentration of 17.3 ± 4.6 ng/ml of 25OHD was obtained, in a range of 5.15 to 25.71 ng/ml; when international advisory bodies thresholds were applied 76% of the participants exhibited some degree of VD inadequacy. Pro-inflammatory markers were detectable among the participants: interleukin 1β in 100%, interleukin 6 in 64%, whereas interleukin 17 was found in 24% of the volunteers. Bone mineral density below the expected for the age was found in 8% of the participants, with lumbar spine as the most affected anatomic region. Non-significant correlations were found between VD and bone mineral density (Z-score) or pro-inflammatory markers. Conclusion Although non-significant correlations were found between VD and bone mineral density or cytokines, it is important to highlight that an important percentage of our participants exhibited some degree of VD inadequacy, an unknown fact for them, since these are not included in routine clinical evaluations. The low concentrations of VD among this sample regardless of annual UVB sun exposure may suggest the involvement of endogenous and not environmental factors. Further works are needed in order to deepen the physiological causes and effects of VD deficiency in people with MS.

Purpose High circulating levels of the hormone prolactin (PRL) protect against experimental diabetic retinopathy (DR) due to the retinal accumulation of vasoinhibin, a PRL fragment that inhibits blood vessel permeability and growth. A phase 2 clinical trial is investigating a new therapy for DR based on elevating serum PRL levels with levosulpiride, a prokinetic dopamine D2 receptor blocker. Here, we tested whether levosulpiride-induced hyperprolactinemia elevates PRL and vasoinhibin in the vitreous of volunteer patients with proliferative DR (PDR) undergoing elective pars plana vitrectomy. Methods Patients were randomized to receive placebo (lactose pill, orally TID; n = 19) or levosulpiride (25 mg orally TID; n = 18) for the 7 days before vitrectomy. Vitreous samples from untreated non-diabetic (n = 10) and PDR (n = 17) patients were also studied. Results Levosulpiride elevated the systemic (101 ± 13 [SEM] vs. 9.2 ± 1.3 ng/mL, P < 0.0001) and vitreous (3.2 ± 0.4 vs. 1.5 ± 0.2 ng/mL, P < 0.0001) levels of PRL, and both levels were directly correlated (r = 0.58, P < 0.0002). The vitreous from non-diabetic patients or from PDR patients treated with levosulpiride, but not from placebo-treated PDR patients, inhibited the basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-induced proliferation of endothelial cells in culture. Vasoinhibin-neutralizing antibodies reduced the vitreous antiangiogenic effect. Matrix metalloproteases (MMPs) in the vitreous cleaved PRL to vasoinhibin, and their activity was higher in non-diabetic than in PDR patients. Conclusions Levosulpiride increases the levels of PRL in the vitreous of PDR patients and promotes its MMP-mediated conversion to vasoinhibin, which can inhibit angiogenesis in DR. Translational Relevance These findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.

Chronic kidney disease (CKD) is an important global health problem that affects 8-15% of the population according to epidemiological studies done in different countries. Essential to prevention is the knowledge of the environmental factors associated with this disease, and heavy metals such as lead and cadmium are clearly associated with kidney injury and CKD progression. Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression. Global efforts to reduce arsenic exposure remain important and research is also needed to determine whether specific therapies are beneficial in susceptible populations.

The prolactin/vasoinhibin axis defines an endocrine system, in which prolactin (PRL) and vasoinhibins regulate blood vessel growth and function, the secretion of other hormones, inflammatory and immune processes, coagulation, and behavior. The core element of the PRL/vasoinhibin axis is the generation of vasoinhibins, which consists in the proteolytic cleavage of their precursor molecule PRL. Vasoinhibins can interact with multiple different partners to mediate their effects in various tissues and anatomical compartments, indicating their pleiotropic nature. Based on accumulating knowledge about the PRL/vasoinhibin axis, two clinical trials were initiated, in which vasoinhibin levels are the target of therapeutic interventions. One trial investigates the effect of levosulpiride, a selective dopamine D2-receptor antagonist, on retinal alterations in patients with diabetic macular edema and retinopathy. The rationale of this trial is that the levosulpiride-induced hyperprolactinemia resulting in increased retinal vasoinhibins could lead to beneficiary outcomes in terms of a vasoinhibin-mediated antagonization of diabetes-induced retinal alterations. Another trial investigated the effect of bromocriptine, a dopamine D2-receptor agonist, for the treatment of peripartum cardiomyopathy. The rationale of treatment with bromocriptine is the inhibition of vasoinhibin generation by substrate depletion to prevent detrimental effects on the myocardial microvascularization. The trial demonstrated that bromocriptine treatment was associated with a high rate of left ventricular recovery and low morbidity and mortality. Therapeutic interventions into the PRL/vasoinhibin axis bear the risk of side effects in the areas of blood coagulation, blood pressure, and alterations of the mental state.

Acute Kidney Injury (AKI) is a common complication in patients with cancer and even though there are many causes of renal failure in this population the classical classification of prerenal, renal, and postrenal is useful as a diagnostic guide. Important risk factors for AKI are dehydration, use of nephrotoxic drugs, preexisting renal impairment and large tumor burden. The development of AKI is associated with poor prognosis but early recognition and treatment initiation are associated with better outcomes in this population.

OBJECTIVE—We measured plasma markers of endothelial dysfunction, vascular inflammation, and pro-coagulation in obese Hispanic/Latino children and adolescents with normal glucose tolerance and determined their relationship to body composition and indexes of glucose and lipid metabolism. RESEARCH DESIGN AND METHODS—A total of 38 lean or obese Hispanic children and adolescents (10–18 years of age) were selected. The overweight group (n = 21) had a BMI >85th percentile for their age and sex, and the lean group (n = 17) had a BMI between the 25th and 50th percentiles. Studies included an oral glucose tolerance test, measurements of plasma glucose and lipids, several markers of endothelial function and inflammation, and determination of body composition by dual X-ray absorptiometry. RESULTS—The obese group had higher systolic blood pressure and plasma triglycerides and was more insulin resistant than the lean group. The obese group also had higher plasma soluble intercellular adhesion molecule (259.5 ± 60.0 vs. 223.2 ± 47.5 ng/ml, P = 0.047), tumor necrosis factor-α (2.57 ± 1.1 vs. 1.74 ± 0.6 pg/ml, P = 0.008), high-sensitivity C-reactive protein (2.0 vs. 0.13 mg/l, P < 0.0001), plasminogen-activated inhibitor-1 (47.0 ± 35.7 vs. 12.0 ± 5.2 ng/ml, P < 0.0001), tissue plasminogen activator (6.1 ± 1.9 vs. 4.1 ± 0.8 ng/ml, P = 0.001), and white blood cell count (6.9 vs. 5.3 × 103, P = 0.031) and lower levels of adiponectin (8.7 ± 3.3 vs. 12.6 ± 5.2 μg/ml, P = 0.022). No significant differences were observed for soluble vascular cell adhesion molecule or interleukin-6. CONCLUSIONS—Overweight Hispanic children and adolescents with normal glucose tolerance exhibit increased plasma markers of endothelial dysfunction and subclinical inflammation in association with obesity and insulin resistance. These abnormalities may predispose them to the development of type 2 diabetes and cardiovascular disease.

Objective: To identify the fasting plasma glucose (FPG) value with the best performance for detecting an abnormal response on the oral glucose tolerance test (OGTT) in patients at risk for having type 2 diabetes. Methods: All patients who underwent a 2-hour OGTT during an 18-month period were included in this study. Pretest and posttest odds, likelihood ratios, and receiver operating characteristic curves were used to identify the FPG value most strongly associated with an abnormal result on the OGTT (either diabetes or impaired glucose tolerance [IGT]). Results: Of the 1,371 patients who underwent an OGTT during the designated study period, 1,239 fulfilled the inclusion criteria. The prevalence of IGT was 25.34% (314 patients). Diabetes was diagnosed in 141 patients (11.38%). IGT was more commonly found in the FPG strata below 115 mg/dL; above this value, diabetes was more frequently diagnosed. In general, the percentage of cases of IGT increased progressively throughout the “normal” FPG range. The prevalence varied from 11.4% (in patients with FPG values

Background Familial defective apolipoprotein B100 (FDB) is one of the known causes of familial hypercholesterolemia (FH). Its frequency among subjects with FH varies among ethnic groups; information on FH is insufficient for populations from Latin America. We proposed to describe prevalence of FDB in a cohort of Mexican FH probands ( n = 30). Methods We searched for the known FDB mutations using polymerase chain reaction assays. In this set of patients, mean lipid values were representative of FH (cholesterol 351 mg/dL, LDL cholesterol 274 mg/dL, HDL cholesterol 51 mg/dL, and triglycerides 132 mg/dL). Results One subject with Arg3500Gln mutation was found: a 44-year-old male with a history of coronary heart disease (CHD) among paternal relatives. His lipid profile was cholesterol 370 mg/dL, LDL-cholesterol 300 mg/dL, HDL-cholesterol 32 mg/dL, and triglycerides 189 mg/dL. Tendinous xanthomata were detected. Three of four siblings, one of three sons, and one of nine nieces and nephews carried the mutation. The mutation was confirmed by automated sequencing. Tendinous xanthomata were absent in affected subjects younger than age 20 years; additionally, the subjects had borderline cholesterol levels. Conclusions Our data suggest that FDB explains the small number of FH cases in Mexico. Inclusion of molecular biology assays to the clinical laboratory makes it possible to diagnose affected individuals with borderline cholesterol levels or without tendinous xanthomata.

Iodothyronine deiodinases, a ubiquitous family of selenoenzymes, are key tissue-specific regulators of intracellular thyroid hormone availability and signaling. This chapter reviews current information supporting the notion that the altered expression and/or activity of deiodinases contribute to the pathophysiology of diverse clinical disorders. Experimental and clinical evidence establishes an association of polymorphisms in deiodinase genes with mood, affective and cognitive functioning, as well as type 2 diabetes mellitus and lipid metabolism. Similarly, an imbalance in the activating and inactivating deiodinase pathways may promote cell proliferation and/or invasiveness of different types of neoplasms. Although a clear-cut picture has not yet been achieved, emerging data support the notion that the deiodinase-dependent thyroid hormone transcriptional footprint has a profound functional impact in health and disease.

Background Hispanics have a high rate of diabetes that exposes them to an increased risk of cardiovascular disease. We hypothesized that many of the pathophysiological mechanisms that cause atherosclerotic disease may be present in young Hispanics who do not have clinical diabetes but are at increased risk of developing it. Methods We studied 36 young Hispanic adults without diabetes (ages 18–40). Seventeen participants were at increased risk of developing type 2 diabetes given by overweight and a family history of diabetes on one or both parents (at risk group). Nineteen participants with normal body-mass index and no parental history of diabetes constituted the control group. We measured and compared plasma markers of endothelial dysfunction, disturbed coagulation and fibrinolysis, subclinical inflammation and adipose tissue dysfunction in the at risk and control groups. Results Participants at risk of diabetes were more insulin-resistant according to different indicators, and had significantly higher levels of soluble intercellular adhesion molecule-1 (sICAM-1), tissue plasminogen activator (tPA), inhibitor of plasminogen activator-1 (PAi-1), high sensitivity C-reactive protein and free fatty acids, signaling the presence of multiple proatherogenic alterations despite the absence of overt diabetes. Levels of the prothrombotic molecule PAi-1 were most elevated in participants who were not only at risk of diabetes by the study definition, but also abdominally obese. Conclusions Young adult Hispanics at risk of type 2 diabetes but without overt disease already bear considerably high levels of markers reflecting processes that lead to the development of atherosclerotic cardiovascular disease.

Iodide is a trace element and a key component of thyroid hormones (TH). The availability of this halogen is the rate-limiting step for TH synthesis; therefore, thyroidal iodide uptake and recycling during TH synthesis are of major importance in maintaining an adequate supply. In the rat, the thyroid gland co-expresses a distinctive pair of intrathyroidal deiodinating enzymes: the thyroid iodotyrosine dehalogenase (tDh) and the iodothyronine deiodinase type 1 (ID1). In the present work, we studied the activity of these two dehalogenases in conditions of hypo- and hyperthyroidism as well as during acute and chronic iodide administration in both intact and hypophysectomized (HPX) rats. In order to confirm our observations, we also measured the mRNA levels for both dehalogenases and for the sodium/iodide symporter, the protein responsible for thyroidal iodide uptake. Our results show that triiodothyronine differentially regulates tDh and ID1 enzymatic activities, and that both acute and chronic iodide administration significantly decreases rat tDh and ID1 activities and mRNA levels. Conversely, both enzymatic activities increase when intrathyroidal iodide is pharmacologically depleted in TSH-replaced HPX rats. These results show a regulatory effect by iodide on the intrathyroidal dehalogenating enzymes and suggest that they contribute to the iodide-induced autoregulatory processes involved in the Wolff-Chaikoff effect.

Background Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations of the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apoB) genes, respectively. A third locus on chromosome 1p34.1–p32 was recently linked to FH and the responsible gene has been identified [protein convertase subtilisin/kexin type 9 (PCSK9)]. Methods We assessed the contribution of the LDLR, apoB, and PCSK9 genes as cause of FH in Mexico. Forty six unrelated probands, as well as 68 affected and 60 healthy relatives, were included. Results All index cases were diagnosed as having heterozygous autosomal dominant FH. Seventeen of the 46 index cases had LDLR gene mutations, four of which were novel (Fs92ter108, C268R, Q718X, and Fs736ter743); and only one patient had an apoB mutation (R3500Q). We sequenced the PCSK9 gene in the remainder of the 28 probands with no identified LDLR or APOB gene defects; however, no PCSK9 mutations were found, including one large kindred with positive linkage to the 1p34.1–32 locus (multipoint LOD score of 3.3) and two small pedigrees. Linkage was excluded from these three loci in at least four kindreds suggesting that other yet uncharacterized genes are involved. Conclusions Our results underline substantial genetic heterogeneity for FH in the Mexican population.