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PubMed2001

Behavior of fascicles and tendinous structures of human gastrocnemius during vertical jumping.

Behavior of fascicles and tendinous structures of human gastrocnemius medialis (MG) was determined by use of ultrasonography in vivo during jumping. Eight male subjects jumped vertically without countermovement (squat jump, SQJ). Simultaneously, kinematics, kinetics, and electromyography from lower leg muscles were recorded during SQJ. During phase I (-350 to -100 ms before toe-off), muscle-tendon complex (MTC) length was almost constant. Fascicles, however, shortened by 26%, and tendinous structures were stretched by 6%, storing elastic energy of 4.9 J during phase I. During phase II (-100 ms to toe-off), although fascicles generated force quasi-isometrically, MTC shortened rapidly by 5.3%, releasing prestored elastic energy with a higher peak positive power than that of fascicles. Also, the compliance of tendinous structures in vivo was somewhat higher than that of external tendon used in the simulation studies. The results demonstrate that the compliance of tendinous structures, together with no yielding of muscle fibers, allows MTC to effectively generate relatively large power at a high joint angular velocity region during the last part of push-off.

Adult↗
PubMed2006

Gastrocnemius muscle fascicle behavior during stair negotiation in humans.

The aim of the present study was to establish the behavior of human medial gastrocnemius (GM) muscle fascicles during stair negotiation. Ten healthy male subjects performed normal stair ascent and descent at their own comfortable speed on a standard-dimension four-step staircase with embedded force platforms in each step. Kinematic, kinetic, and electromyographic data of the lower limbs were collected. Real-time ultrasound scanning was used to determine GM muscle fascicle length changes. Musculotendon complex (MTC) length changes were estimated from ankle and knee joint kinematics. The GM muscle was mainly active during the push-off phase in stair ascent, and the muscle fascicles contracted nearly isometrically. The GM muscle was mainly active during the touch-down phase of stair descent where the MTC was lengthened; however, the GM muscle fascicles shortened by approximately 7 mm. These findings show that the behavior and function of GM muscle fascicles in stair negotiation is different from that expected on the basis of length changes of the MTC as derived from joint kinematics.

Adult↗
PubMed2004

Muscle activation and blood flow do not explain the muscle length-dependent variation in quadriceps isometric endurance.

We investigated the role of central activation in muscle length-dependent endurance. Central activation ratio (CAR) and rectified surface electromyogram (EMG) were studied during fatigue of isometric contractions of the knee extensors at 30 and 90 degrees knee angles (full extension = 0 degree). Subjects (n = 8) were tested on a custom-built ergometer. Maximal voluntary isometric knee extension with supramaximal superimposed burst stimulation (three 100-mus pulses; 300 Hz) was performed to assess CAR and maximal torque capacity (MTC). Surface EMG signals were obtained from vastus lateralis and rectus femoris muscles. At each angle, intermittent (15 s on 6 s off) isometric exercise at 50% MTC with superimposed stimulation was performed to exhaustion. During the fatigue task, a sphygmomanometer cuff around the upper thigh ensured full occlusion (400 mmHg) of the blood supply to the knee extensors. At least 2 days separated fatigue tests. MTC was not different between knee angles (30 degrees : 229.6 +/- 39.3 N.m vs. 90 degrees: 215.7 +/- 13.2 N.m). Endurance times, however, were significantly longer (P < 0.05) at 30 vs. 90 degrees (87.8 +/- 18.7 vs. 54.9 +/- 12.1 s, respectively) despite the CAR not differing between angles at torque failure (30 degrees: 0.95 +/- 0.05 vs. 90 degrees: 0.96 +/- 0.03) and full occlusion of blood supply to the knee extensors. Furthermore, rectified surface EMG values of the vastus lateralis (normalized to prefatigue maximum) were also similar at torque failure (30 degrees : 56.5 +/- 12.5% vs. 90 degrees : 58.3 +/- 15.2%), whereas rectus femoris EMG activity was lower at 30 degrees (44.3 +/- 12.4%) vs. 90 degrees (69.5 +/- 25.3%). We conclude that differences in endurance at different knee angles do not find their origin in differences in central activation and blood flow but may be a consequence of muscle length-related differences in metabolic cost.

Adult↗
PubMed2005

Medullary thyroid carcinoma arises in the absence of prolactin signaling.

Prolactin, a pituitary hormone, exerts pleiotropic effects in various cells. These effects are mediated by a membrane receptor highly expressed in many tissues. To analyze prolactin effects on the thyroid gland, we first identified prolactin receptor (PRLR) mRNAs by in situ hybridization. To further evaluate the physiologic relevance of PRLR actions in the thyroid in vivo, we used PRLR knockout mice. Whereas the histologic structure of thyroid of PRLR-null mice was not disturbed, we show that T4 levels are lower in null animals (13.63 +/- 2.98 versus 10.78 +/- 2.25 pmol/L in null mice), confirming that prolactin participates in the control of thyroid metabolism. To further investigate thyroid effects in mice, we measured body temperature and thyroid-stimulating hormone in young and adult male and/or female PRLR-null mice and their normal siblings. Surprisingly, in null animals, we saw medullary thyroid carcinoma (MTC) arising from parafollicular C cells producing calcitonin. The incidence of these carcinomas attained 41% in PRLR-null mice, whereas this malignant tumor occurs sporadically or as a component of the familial cancer syndrome in humans. This finding suggests that PRLR-null mice could represent a valuable animal model for MTC, which could be compared with existing MTC models. These observations suggest a possible link between the appearance of this carcinoma and the absence of prolactin signaling.

Animals↗
PubMed2005

ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma.

Patients with hereditary medullary thyroid carcinoma (MTC) associated with multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC (FMTC) have mutations in the RET proto-oncogene. Approximately 40 percent of patients with papillary thyroid carcinoma (PTC) typically have either intrachromosomal or extrachromosomal rearrangements that join the promoter and NH(2)-terminal domains of unrelated genes to the COOH-terminal fragment of RET. The RET point mutations associated with MEN2A, MEN2B, or FMTC, or the chromosomal breakpoints and translocations associated with PTC, typically activate the RET receptor tyrosine kinase (RTK). RET kinase inhibitors are likely to be beneficial for patients with hereditary MTC, where currently there is no effective chemotherapy or radiation therapy. Recently, the low molecular weight tyrosine kinase inhibitor ZD6474 was found to block the enzymatic activity of RET-derived oncoproteins in cultured cell lines. We have developed a Drosophila model for MEN2A and MEN2B diseases by targeting oncogenic forms of RET to the developing Drosophila eye. Here we show that, when fed orally, ZD6474 suppressed RET-mediated phenotypes within the context of this in vivo model. Importantly, ZD6474 showed high efficacy and very low toxicity. This compound failed to significantly suppress an activated form of another RTK, the Drosophila epidermal growth factor receptor, nor did it suppress the activity of downstream components of the RET/Ras pathway. Our results support the view that targeting chemical kinase inhibitors such as ZD6474 to tissues with oncogenic forms of RET is a useful treatment strategy for RET-dependent carcinomas.

Animals↗
PubMed1989

Genetic screening of endocrine tumour syndromes with DNA probes: the example of medullary thyroid carcinoma.

Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal-dominant syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid hyperplasia. Recent reports have assigned the locus of MEN2A to the pericentromeric region of chromosome 10. Through the 'Groupe d'Etude des Tumeurs à Calcitonine', we have evaluated the ability to predict the carrier state using DNA probes. Our results suggest that the restriction fragment length polymorphism method can be used to identify individuals at risk within MEN2A families. They may then be followed by conventional endocrine methods for the onset of neoplastic changes, limiting the risk of subsequent metastatic disease. The method also permits the exclusion of further screening for family members at very low risk. Extension of the screening program can now be anticipated for other inherited forms of MTC, such as familial MTC without pheochromocytoma or other endocrinological tumor syndromes such as MEN1 for which the locus has also recently been mapped.

Carcinoma↗
PubMed1997

Genetic testing in presymptomatic diagnosis of multiple endocrine neoplasia.

Multiple endocrine neoplasias (MEN) are familial diseases characterized by endocrine neoplasms and transmitted in an autosomal dominant manner. In MEN type 1, the major lesions affect parathyroid glands, pancreatic islet cells and anterior pituitary. The MEN-1 gene has been mapped to chromosome 11q13 and a set of DNA-polymorphic markers localized close to this region provides a useful tool for presymptomatic diagnosis in MEN-1 families. MEN type 2 refers to the inherited forms of medullary thyroid carcinoma (MTC) associated or not with pheochromocytoma and hyperparathyroidism. In MEN-2, germinal mutations of the C-RET proto-oncogene which is localized on chromosome 10q11 have been found in the three clinical and allelic forms of the syndrome respectively, MEN-2 type A, B and familial isolated MTC. Mutations of C-RET are found in more than 90% of MEN-2 patients and genetic screening leads to accurate risk evaluation in families and consequently a preventive treatment of MTC and adrenal neoplasms. Recent discoveries on MEN syndromes and related familial endocrine disorders have a major clinical impact and allow a better understanding of the physiological pathways involved in familial as well as in sporadic endocrine tumor pathogenesis.

Chromosomes, Human, Pair 10↗
PubMed1997

Multiple endocrine neoplasia type 2: management of patients and subjects at risk. French Study Group on Calcitonin-Secreting Tumors (GETC).

Multiple endocrine neoplasia type 2 (MEN-2) is an inherited multiglandular disease with age-related penetrance and variable expression. The prognosis of MEN-2 is linked to the carcinological evolution of medullary thyroid cancer (MTC), which depends mainly on the stage of discovery, and to the incidents related to pheochromocytomas. The emphasizes the need for early diagnosis and management of MEN-2. Since 1993, mutations evidenced on the protooncogene RET have allowed subjects at risk to be identified, thus leading to a three-step management of these patients. (1) For all the potentially affected members of a MEN-2 family, screening by molecular genetics of the ret gene enables one to identify the subjects at risk who bear the mutation. When no mutation is observed, a linkage analysis study may be proposed. (2) In the subjects at risk, early screening for the various types of endocrine lesions may then start in childhood and be performed using specific biological markers of MTC, pheochromocytoma and primary hyperparathyroidism, and particularly, basal and pentagastrin-stimulated calcitonin measurement, which is known to be the most sensitive marker for the monitoring of MTC. (3) This step of biological investigations enables the earliest possible treatment of any endocrine lesion detected before it is expressed clinically, thus improving the prognosis of MEN-2. When genetic screening cannot be performed, only annual clinical and biological monitoring remain available in all members of a family affected with MEN-2.

Drosophila Proteins↗
PubMed1991

Functional characteristics of the peritoneal membrane in long-term continuous ambulatory peritoneal dialysis.

Peritoneal transport characteristics of 20 long-term (LT) patients with a mean duration on continuous ambulatory peritoneal dialysis (CAPD) of 60 months were compared with those of 20 matched patients who recently started (RS) CAPD (mean 39 days, range 11-63). Mass transfer area coefficients (MTC) of creatinine, glucose and inulin were higher in the LT group than in the RS group (12.1 versus 9.2 ml/min, p less than 0.01; 9.9 versus 8.3 ml/min, p less than 0.05; 4.1 versus 3.5 ml/min, p less than 0.05). The MTC of alpha 2-macroglobulin were lower in the LT group (13 versus 25 microliters/min; p less than 0.01). The size selectivity of the membrane for the transport of macromolecules, determined as protein MTC ratios, showed a more restricted passage for macromolecules in the LT group. Net fluid removal using glucose 3.86% was lower in the LT patients (487 versus 826 ml/4 h; p less than 0.001). The results indicate the development of a larger effective peritoneal surface area combined with a less permeable peritoneal membrane after many years of CAPD.

Adult↗
PubMed1981

Multiple endocrine neoplasia, type IIb. Report of a case.

Multiple endocrine neoplasia, type IIb, is a rare syndrome characterized by mucosal neuromas, medullary thyroid carcinoma (MTC), pheochromocytoma and somatic abnormalities. A case of a 10-year-old girl with multiple mucosal neuromas and bilateral MTC is reported. The presumptive diagnosis of MTC was made on the basis of abnormal basal values of calcitonin and increased calcitonin secretion after pentagastrin injection. The manifestations of the syndrome are summarized, and the importance of repeated evaluation of thyroidal C-cell and adrenal medullary function in patients with the characteristic aspect of the syndrome is emphasized.

Adrenal Gland Neoplasms↗
PubMed2004

Different predictions by the minimum variance and minimum torque-change models on the skewness of movement velocity profiles.

We investigated the differences between two well-known optimization principles for understanding movement planning: the minimum variance (MV) model of Harris and Wolpert (1998) and the minimum torque change (MTC) model of Uno, Kawato, and Suzuki (1989). Both models accurately describe the properties of human reaching movements in ordinary situations (e.g., nearly straight paths and bell-shaped velocity profiles). However, we found that the two models can make very different predictions when external forces are applied or when the movement duration is increased. We considered a second-order linear system for the motor plant that has been used previously to simulate eye movements and single-joint arm movements and were able to derive analytical solutions based on the MV and MTC assumptions. With the linear plant, the MTC model predicts that the movement velocity profile should always be symmetrical, independent of the external forces and movement duration. In contrast, the MV model strongly depends on the movement duration and the system's degree of stability; the latter in turn depends on the total forces. The MV model thus predicts a skewed velocity profile under many circumstances. For example, it predicts that the peak location should be skewed toward the end of the movement when the movement duration is increased in the absence of any elastic force. It also predicts that with appropriate viscous and elastic forces applied to increase system stability, the velocity profile should be skewed toward the beginning of the movement. The velocity profiles predicted by the MV model can even show oscillations when the plant becomes highly oscillatory. Our analytical and simulation results suggest specific experiments for testing the validity of the two models.

Biomechanical Phenomena↗
PubMed2001

Is compartment pressure related to plasma colloid osmotic pressure, in patients during and after cardiac surgery?

Haemodilution is always considerable during cardiopulmonary bypass (CPB). If this extra fluid sits in the muscle compartments then a corresponding rise in the compartment pressure (CP) is to be expected. The aim of this study was to measure pressure changes in a body compartment with new equipment, the MTC (Microtransducer). Changes in plasma colloid osmotic pressure (COP) were also measured during and after CPB to find a connection, if any, between CP and plasma COP. Ten elective consecutive CPB patients were studied. A 3-French (3-F) catheter-size electronic MTC was inserted in an anterior tibial compartment before CPB. The CP was monitored for 48 h. Plasma COP was also measured before, during and after CPB. CP increased significantly during and after CPB in all patients (p=0.01). COP decreased significantly in all patients (p=0.005), but no correlation was found between changes in COP and CP values in this study. Most of the patients reached their highest CP just after weaning off bypass. The CP remained elevated for 48 h, even though it then tended to decrease again. None of the patients reached the starting value within 48 h. COP decreased rapidly after going on bypass, but returned towards its starting value approximately 6 h after bypass. It is concluded that CP increases considerably during and after CPB and stays increased for at least 2 days after CPB. COP decreases during CPB, but reaches normal values 6 h after the CPB. No correlation was found between changes in CP and COP The MTC is a safe and easy way to measure intracompartment pressure.

Aged↗
PubMedDate not supplied

FDG-PET in thyroid cancer.

The most widely used diagnostic nuclear medicine technique in well-differentiated thyroid cancer (DTC) is radioiodine scintigraphy, either diagnostic or post-therapeutic, together with serum thyroglobulin (Tg) measurement; this combination is usually able to determine the presence or absence of cancer. FDG-PET has shown less sensitivity in DTC that retains the ability to trap 131I. Several alternative procedures with single photon emitting radiopharmaceuticals have been evaluated including whole body scan with 201Tl, 99mTc-sestamibi or tetrofosmin scan, with different sensitivity and specificity. The main advantage of these tests is that their results are not influenced by the levels of TSH, therefore they do not require a hypothyroid state in the patient. Recently positron emission tomography (PET) with FDG has been demonstrated to be highly useful in thyroid cancer patients with a negative 131I whole body scan but measurable Tg. According to reports in the literature FDG-PET in the follow-up of operated patients has a sensitivity ranging from 70% to 90% in identifying the source of Tg. The demonstration of lesions can lead to a change in treatment including surgery or external radiation instead of radioiodine treatment. In Europe, medullary thyroid cancer (MTC) is currently visualized by 99mTc pentavalent dimercaptosuccinic acid (DMSA) and 99mTc-sestamibi or tetrofosmin. Metaiodobenzylguanidine (MIBG) radiolabeled with 123I or 131I is another reliable radiopharmaceutical for medullary tumors. (111)In-pentetreotide scan is positive in a high percentage of patients because MTC expresses somatostatin receptors. FDG-PET has an interesting role to play in calcitonin-positive patients, where PET has been shown to correctly identify lesions in cervical and mediastinal lymph nodes as well as at distant sites. Furthermore, calcitonin-guided PET has been found to be superior to CT and MRI in many patients. Recent reports indicated that 18F-DOPA scan in MTC seems to be more accurate than FDG-PET.

Carcinoma, Medullary↗
PubMedDate not supplied

RETMEN2A and RETMEN2B oncoproteins are targets of PP1 inhibitor.

Medullary thyroid carcinoma (MTC) responds very poorly to chemotherapy. Mutations in the RET gene are critical for MTC pathogenesis. RET therefore represents a rational target for the development of novel MTC therapies. The accumulation of evidence from laboratory studies strongly suggests that PP1 inhibitor is a cytostatic agent for cells expressing RET oncoproteins. PP1 functions as a potent and selective inhibitor of RET oncoprotein phosphorylation, promoting its proteasomal degradation.

Antineoplastic Agents↗
PubMedDate not supplied

The role of radionuclide therapy in medullary thyroid cancer.

In medullary thyroid carcinoma (MTC) the detection of occult metastases is difficult and the prognosis of widespread disease is poor. In recent years several radiopharmaceuticals have become available for the diagnosis of this tumor. None of these tracers, however, has satisfactory diagnostic sensitivity and specificity. Furthermore, only few radiopharmaceutical compounds proved to have clinical value in therapeutic applications. Radionuclide therapy utilizes unsealed radioactive sources in order to deliver selective irradiation to the target organs or cancer lesions. This approach is only clinically indicated when there is a scintigraphic evidence of sufficient tumor uptake and a favorable biodistribution. When these conditions are present, radionuclide therapy can be adopted in MTC patients. Due to the low incidence of this tumor, the poor sensitivity of the available radiopharmaceuticals and their limited indications, the clinical experience in radionuclide therapy of MTC is still limited and there is general agreement among experts that it has only a palliative role. Here we briefly report the main experiences in radionuclide therapy in the past and in recent years. In addition, we summarize the results obtained with 131I-MIBG therapy at the Istituto Nazionale Tumori of Milan, as well as the most important ongoing preclinical and phase I/II trials.

3-Iodobenzylguanidine↗
PubMedDate not supplied

Medullary carcinoma of the thyroid.

Medullary thyroid cancer (MTC) is a distinct C-cell tumor of the thyroid. We review the oncogenesis and management of both sporadic tumors and those tumors arising as part of specific inherited syndromes. The RET proto-oncogene plays a role in the development of inherited forms of MTC and has become important in the clinical management of patients and their families. The recognition of the high rate of regional nodal involvement has led to lymphadenectomy being strongly considered for patients undergoing thyroidectomy for MTC.

Carcinoma, Medullary↗
PubMed1992

Expression of the first calcitonin/CGRP gene in spontaneous and transplanted rat medullary thyroid carcinoma: a comparison of dot-blot analysis, in situ hybridization, and immunohistochemistry.

Calcitonin (CT) and calcitonin gene-related peptide (CGRP) are encoded by a single gene, the CALC-I gene. They are expressed in the thyroid and in the nervous system by alternative splicing of the pre-messenger RNA derived from the CALC-I gene. In medullary thyroid carcinoma (MTC), a malignancy derived from the calcitonin-producing C-cells in the thyroid, production of calcitonin and CGRP is a common feature. We investigated the CT and CGRP production of four spontaneous MTCs transplanted three to four times and 14 MTC lines transplanted for several years in WAG/Rij rats, a strain with hereditary MTC. The expression of CT and CGRP in the spontaneous and in the transplanted tumors was studied by means of RNA in situ hybridization (RISH), dot-blot analysis, and immunohistochemistry. A down-regulation of CT production in transplanted compared with spontaneous tumors was observed, but an inverse relation between CT and CGRP mRNA content in both spontaneous and transplanted tumors was not observed. In this study, RISH proved to be as sensitive as dot-blot analysis to detect gene expression in tissue samples. The different approaches of analyzing the gene expression in tissue samples (the cellular localization of gene expression by ISH vs the analysis of an extract of a total tissue sample with dot-blot analysis) showed that each technique is equal in value and that they are complementary to each other.

Animals↗
PubMed1993

Specific immunostaining for CCP II, a novel calcitonin carboxyl terminal peptide encoded by the calcitonin/CGRP gene.

Alternative splicing of the primary transcript of the CALC I gene in thyroid C-cells results predominantly in calcitonin (CT) mRNA (exons 1-4), whereas CGRP mRNA (exons 1, 2, 3, 5, and 6) is mainly produced in neuronal cells. The CT mRNA encodes for a protein precursor containing an amino terminal peptide, CT, and a carboxyl terminal peptide (CCP I). CGRP precursor is composed of the same amino terminal peptide and CGRP. Recently we reported the presence of a third mature transcript of the CALC I gene in human medullary thyroid carcinoma (MTC) tissues. This transcript encodes for a precursor containing the amino terminal peptide CT and a novel carboxyl terminal peptide, CCP II. This finding was further confirmed in the TT-cell line derived from a human MTC. We produced monoclonal antibodies against CCP II and developed a rapid and specific immunofluorescence method for this peptide. We demonstrated CCP II-specific immunoreactivity in TT-cells and in MTC tissues. CCP II labeling was relatively homogeneous in contrast to CT and CGRP, which presented striking heterogeneity for intensity of labeling. Therefore, CCP II mRNA is translated in tumor cells in an apparently constitutive way.

Alternative Splicing↗