Acute and chronic hypothyroidism are associated with similar left ventricular diastolic dysfunction relative to the euthyroid state: results of doppler echocardiographic comparisons.

BACKGROUND: How the duration of hypothyroidism affects left ventricular diastolic function is not well-characterized. AIM: We sought to compare left ventricular diastolic function in acutely vs chronically hypothyroid patients vs euthyroid controls, and within individuals while on vs off T4. SUBJECTS AND METHODS: We prospectively performed such comparisons measuring pulsed-wave and color M-mode Doppler echocardiographic variables: early or late mitral peak velocities (E wave or A wave, respectively), E wave/A wave ratio, E wave deceleration time, isovolumic relaxation time (IVRT), mitral flow propagation velocity (Vp), E wave/Vp ratio. Subjects comprised the acute HYPO group, 10 patients undergoing T4 withdrawal ≥ 6 months post-primary treatment for differentiated thyroid cancer (DTC); the chronic HYPO group, 23 treatment-naïve Hashimoto thyroiditis patients; and 21 healthy euthyroid controls. Subjects were adults aged ≤ 60 yr, predominantly female, with sinus rhythm; exclusion criteria were cardiovascular or thyroid disorder besides DTC (Hashimoto thyroiditis) in acute (chronic) HYPO patients or medication (besides thyroid hormone) affecting cardiac or thyroid function. RESULTS: Mean IVRT was significantly delayed and mean Vp, significantly slowed in both HYPO groups vs controls (p<0.0005), but did not differ between HYPO groups. These variables also were significantly impaired (p<0.05) within individuals when off vs on T4 (no.=8 acute, 10 chronic HYPO patients). Both HYPO groups had elevated mean E wave/Vp ratios vs controls, but the elevation reached significance (p<0.05) only in the larger chronic HYPO group. CONCLUSIONS: Left ventricular diastolic dysfunction is largely similar in acutely or chronically hypothyroid patients off T4 vs healthy controls or the same patients on T4.

Resistencia a Hormonas Tiroideas (RHT): Descripción de una nueva mutación / Resistance to Thyroid Hormones (RTH): Description of a new mutation

Introducción: La resistencia a hormonas tiroideas (RHT) es un desorden genético de transmisión dominante poco frecuente, caracterizado por una respuesta reducida de los tejidos blanco a las hormonas tiroideas. RHT está ligada al gen del receptor beta de hormona tiroidea (TRβ). El síndrome se identifica por niveles persistentemente elevados de T4 y T3 totales y libres en presencia de TSH no suprimida. Materiales y Métodos: Paciente femenina de 62 años de edad con antecedente de hemitiroidectomía a los 22 años por bocio. Clínicamente, la mujer se encontraba eutiroidea y hemodinámicamente estable. En los exámenes complementarios se constató la presencia de nódulo tiroideo, con estudio citológico benigno y en el laboratorio hormonas tiroideas totales y libres elevadas con TSH no suprimida. La impresión diagnóstica fue RHT, siendo el principal diagnóstico diferencial el tirotropinoma. Se realizó perfil tiroideo completo en el caso índice y en dos familiares de primer grado. Se dosaron gonadotropinas y prolactina, y se realizó RMN de hipófisis en el caso índice. Se estudiaron mutaciones del gen TRβ en ADN genómico en la paciente y en uno de sus familiares. Resultados: Avalando la impresión diagnóstica, tanto el caso índice como los dos familiares mostraron un perfil tiroideo compatible con RHT. El estudio genético identificó una nueva mutación en el exón 10: c.1339C>A que resulta en una sustitución p.P447T. La misma fue observada tanto en el caso índice como en el familiar estudiado. Conclusión: La historia de esta paciente con RHT, al igual que otros casos descriptos en la bibliografía, remarcan la importancia de un diagnóstico adecuado y temprano de esta patología poco frecuente para evitar conductas terapéuticas iatrogénicas y con consecuencias relevantes en la vida de estos pacientes. Paralelamente, se describe una nueva mutación genética en esta familia.

Introduction: Resistance to thyroid hormones (RTH) is an unusual autosomal dominant inherited disorder characterized by a reduced target organ responsiveness to thyroid hormones. RTH is linked to the gene encoding the thyroid receptor β (TR β). This syndrome is characterized by persistent high levels of total and free T4 and T3 while TSH is not inhibited. Materials and Methods: 62 years old female who underwent a partial thyroidectomy because of goiter forty years ago. Clinically, she seemed to be an euthyroid patient and her hemodynamic status was normal. The exams revealed the existence of a benign thyroid nodule, high levels of total and free thyroid hormones and normal values of TSH. Our diagnostic impression was RTH, though differential diagnosis with thyrotropin secreting pituitary adenoma was mandatory. Complete assays of thyroid hormones were performed in the patient and in two first degree relatives. Basal LH, FSH and prolactin were assayed in the patient; and a magnetic resonance imaging of her pituitary gland was obtained. Finally we performed genetic testing in patient's DNA and a relative's DNA to demonstrate gene defect. Results: According to our diagnostic impression, not only the patient's laboratory was compatible with RTH, but so was the laboratory of the two relatives. DNA mutation analisys demonstrated a new mutation in exon 10: c.1339C>A responsible for the substitution p.P447T. This mutation was found in DNA of the patient and DNA of her relative. Conclusion: This patient with RTH, as well as other reported cases, reminds us about the importance of a certain and early diagnosis of this rare disorder in order to avoid iatrogenic treatments. A new mutation is described in this family.

A simple method for field measurements of leg stiffness in hopping.

A new method to measure the leg stiffness in hopping and bouncing, with simple technical equipment and under field conditions, is introduced and validated. The leg stiffness (K (N)) was calculated from only contact and flight times measured by a contact mat. It was compared to the reference stiffness (K (R)) obtained from force platform measurements. Eight subjects performed, first, submaximal hopping movements at different frequencies (1.8 to 4 Hz, by step 0.2 Hz) and, second, maximal hopping. In sub maximal hopping K (N) was significantly correlated with K (R) (r = 0.94; p < 0.001) and the difference between K (N) and K (R) ranged from -7.2 % to 6.9 % (at 1.8 and 3.6 Hz respectively) with a limit of agreement of -1.5 kN x m (-1). In maximal hopping K (N) was also related to K (R) (r = 0.98, p < 0.001) and the inter individual rank order was respected (R = 0.87). It was concluded that the new method could be applied to study extensively intra individual and inter individual variations of leg stiffness in respectively sub maximal and maximal hopping and thus to simplify further investigations in field conditions of the role of stiffness regulation in the optimization of human locomotion.

Cell cycle effects of gemcitabine.

Gemcitabine (2',2'-difluoro-2'-deoxycytidine, or dFdC) is a promising anticancer agent with demonstrated clinical activity in solid tumours currently undergoing clinical trials. Despite extensive studies on the biochemical mechanism of action, cell cycle perturbations induced by dFdC have not yet been thoroughly investigated, apart from the expected inhibition of DNA synthesis. The aim of our study was to clarify whether cell population kinetics is a vital factor in the cytotoxicity of dFdC in single or repeated treatments and in the dFdC-cisplatin combination. Ovarian cancer cells growing in vitro were treated with dFdC for 1 hr in a range of concentrations from 10 nM to 10 microM. Cell kinetics was investigated by DNA-bromodeoxyuridine flow cytometry, using different experimental protocols to measure either the time course of DNA-synthesis inhibition or the fate of cells in G(1), S or G(2)M at the time of dFdC treatment or 24 hr later. A modified sulforhodamine B test was used to assess the growth inhibition caused by dFdC given alone or with cisplatin. Although dFdC promptly inhibited DNA synthesis, cytotoxicity on proliferating cells was not specific for cells initially in the S phase. DNA synthesis was restored after a G(1) block of variable, dose-dependent length, but recycling cells were intercepted at the subsequent checkpoints, resulting in delays in the G(2)M and G(1) phases. The activity of repeated treatment with dFdC + dFdC or dFdC + cisplatin was highly dependent on the interval length between them. These results suggest that the kinetics of cell recycling from a first dFdC treatment strongly affects the outcome of a second treatment with either dFdC itself or cisplatin.

Force/velocity and power/velocity relationships in squat exercise.

The purpose of this study was to describe the force/velocity and power/velocity relationships obtained during squat exercise. The maximal force (F0) was extrapolated from the force/velocity relationship and compared to the isometric force directly measured with the aid of a force platform placed under the subject's feet. Fifteen international downhill skiers [mean (SD) age 22.4 (2.6) years, height 178 (6.34) cm and body mass 81.3 (7.70) kg] performed maximal dynamic and isometric squat exercises on a guided barbell. The dynamic squats were performed with masses ranging from 60 to 180 kg, which were placed on the shoulders. The force produced during the squat exercise was linearly related to the velocity in each subject (r2 = 0.83-0.98, P < 0.05-0.0001). The extrapolated F0 was 23% higher than the measured isometric force (P < 0.001), and the two measurements were not correlated. This may be attributed to the position of the subject, since the isometric force was obtained at a constant angle (90 degrees of knee flexion), whereas the dynamic forces were measured through a range of movements (from 90 degrees to 180 degrees). The power/velocity relationship was parabolic in shape for each subject (r2 = 0.94-0.99, P < 0.01-0.0001). However, the curve obtained exhibited only an ascending part. The highest power was produced against the lightest load (i.e., 60 kg). The maximal power (Wmax) and optimal velocity were never reached. The failure to observe the descending part of the power/velocity curve may be attributed to the upper limitation of the velocities studied. Nevertheless, the extrapolation of Wmax from the power/velocity equation showed that it would be reached for a load close to body mass, or even under unloaded conditions.

Leg stiffness and foot orientations during running.

This study was done to determine whether leg stiffness (Kleg) during running was related to rearfoot-to-forefoot angle in standing (RFAst) and running (RFArun). Footprints obtained from 32 subjects were used to calculate RFAst and RFArun, defined as positive when forefoot axis was abducted from rearfoot axis. A spring-mass model was used to calculate Kleg in running from ground reaction forces, measured by a force platform. The Kleg of runners (13.0 +/- 2.7 kN x m(-1)) was negatively correlated with RFAst (-8.4 degrees +/- 6.4 degrees) and RFArun (-0.4 degrees +/- 7.2 degrees). When runners were divided into opened foot (RFArun > 0; N = 19) and closed foot (RFArun < 0; N = 12) groups, the Kleg of opened foot runners was less than that of the closed runners. We suggest that foot structure is a factor responsible for the differences in leg stiffness observed in runners.

Foot orientation and lower limb kinematics during running.

The purpose of this study was to determine the possible mechanisms explaining the interindividual differences in foot orientations observed during running. Foot orientations, foot pressures, and ankle dorsiflexion and plantarflexion were simultaneously recorded on 12 male subjects running barefooted at 3.9 +/- 0.6 m.sec-1. The abduction of the forefoot was significantly related to the ankle dorsiflexion and plantarflexion velocities (P < 0.01 and P < 0.05, respectively). Because it was not possible, from pressure measurements, to determine differences in foot lever arm of runners, it is suggested that the interindividual variability of foot kinematics could not be explained by Bojsen-Møller's model, but could reflect differences in the lower limb stiffness control.