Surgical treatment of thyrotoxicosis in children and adolescents

Forty-one children and adolescents had thyroidectomies for Grave's disease during an 8 yr period. Twenty patients became euthyroid within a short period after treatment with antithyroid drugs and had operations with minimal disruption of their lives. Antithyroid drugs were administered to 20 patients for a longer period of time as a primary form of treatment for Grave's disease. Complications resulting from drug toxicity, poor cooperation by patients, and persistent goiters were indications for thyroidectomies in this group. Permanent remissions, after prolonged antithyroid drug therapy, are rare in children. Because the treatment is associated with significant morbidity, this form of therapy is unacceptable in most cases. Iodine-131 was given to 30 children or adolescents for Grave's disease during the same time period. Iodine-131 is primarily indicated for patients who are resistant or allergic to antithyroid drugs, who have serious systemic diseases, or who have had previous thyroid operations. Hypothyroidism is an inevitable result of effective 131I treatment of Grave's disease in children. Serious consequences from 131I therapy were not observed during the short period of follow-up. Subtotal thyroidectomy continues to be the preferred primary treatment for most patients with Grave's disease in childhood. Total thyroidectomy may be indicated for patients in the first decade of life. Hypothyroidism, which is easily managed in this age group, is the price paid for the prevention of recurrent Grave's disease. Early detection and treatment of hypothyroidism can be achieved only by a careful follow-up of all patients treated by less than total thyroidectomy for Grave's disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22804/1/0000361.pd

Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates

(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primate

Head-to-head comparison of (R)-[C-11]verapamil and [F-18]MC225 in non-human primates, tracers for measuring P-glycoprotein function

PURPOSE: P-glycoprotein (P-gp) function is altered in several brain disorders; thus, it is of interest to monitor the P-gp function in vivo using PET. (R)-[11C]verapamil is considered the gold standard tracer to measure the P-gp function; however, it presents some drawbacks that limit its use. New P-gp tracers have been developed with improved properties, such as [18F]MC225. This study compares the characteristics of (R)-[11C]verapamil and [18F]MC225 in the same subjects.METHODS: Three non-human primates underwent 4 PET scans: 2 with (R)-[11C]verapamil and 2 with [18F]MC225, at baseline and after P-gp inhibition. The 30-min PET data were analyzed using 1-Tissue Compartment Model (1-TCM) and metabolite-corrected plasma as input function. Tracer kinetic parameters at baseline and after inhibition were compared. Regional differences and simplified methods to quantify the P-gp function were also assessed.RESULTS: At baseline, [18F]MC225 VT values were higher, and k2 values were lower than those of (R)-[11C]verapamil, whereas K1 values were not significantly different. After inhibition, VT values of the 2 tracers were similar; however, (R)-[11C]verapamil K1 and k2 values were higher than those of [18F]MC225. Significant regional differences between tracers were found at baseline, which disappeared after inhibition. The positive slope of the SUV-TAC was positively correlated to the K1 and VT of both tracers.CONCLUSION: [18F]MC225 and (R)-[11C]verapamil show comparable sensitivity to measure the P-gp function in non-human primates. Moreover, this study highlights the 30-min VT as the best parameter to measure decreases in the P-gp function with both tracers. [18F]MC225 may become the first radiofluorinated tracer able to measure decreases and increases in the P-gp function due to its higher baseline VT.</p

MEN I pancreas: A histological and immunohistochemical study

The spectrum and extent of islet cell histopathological findings in patients with multiple endocrine neoplasia, type I (MEN I) syndrome has never been clearly defined. Although some patients have discreet tumors causing clinically evident syndromes, others may have no symptoms until metastatic islet cell carcinoma is apparent. Whether diffuse islet cell disease occurs in all patients with grossly apparent tumors is not known. This study is an attempt to define both the functional and anatomical extent of islet cell disease and its relationship with the clinical course of patients with MEN I syndrome. The resected specimens of pancreas from 14 patients with MEN I syndrome were evaluated for hyperplasia, nesidioblastosis, multiple tumors, and evidence of malignancy. In 12 cases, specimens consisted of distal pancreas and, in 2 cases, the entire pancreas was available. Multiple sections were taken from each specimen. Immunoperoxidase staining was done for gastrin, pancreatic polypeptide, glucagon, serotonin, VIP, somatostatin, and neuron-specific enolase in sections of 24 tumors from 10 patients. Five of the 10 patients with Zollinger-Ellison syndrome underwent total gastrectomy and 3 others underwent only pancreatic procedures to control their acid hypersecretion. The following is concluded. All MEN I patients with pancreatic neoplasms have diffuse islet cell involvement consisting of nesidioblastosis, micro- and macronodular hyperplasia. Some tumors produce multiple hormones and these patients are at risk to develop new tumors, but complete excision of grossly apparent tumors may result in long-term control of the endocrinopathy present. This is particularly true for patients with insulinoma and hypoglycemia. Selected patients with gastrinoma may also be considered for excision of their islet cell tumor(s) without concomitant gastrectomy, especially if transhepatic venous sampling demonstrates a single site of excess gastrin production. However, if transhepatic venous sampling demonstrates diffuse sources of hypergastrinemia, a local pancreatic procedure will invariably be unsuccessful. Total pancreatectomy in MEN I patients with disease localized to the pancreas is the only curative surgical procedure but is rarely indicated. L'histopathologie des cellules insulaires pancréatiques des malades qui présentent un syndrome MEN I n'a jamais été parfaitement définie. Si certains parmi eux sont porteurs de petites tumeurs qui se manifestent par des syndromes cliniques patents, d'autres n'accusent aucun symptôme avant que des métastases néoplasiques ne se manifestent. En particulier, on ne sait pas si les altérations des cellules insulaires sont diffuses quand les malades présentent des tumeurs évidentes. Cette étude a pour but de définir à la fois l'importance anatomique et l'importance fonctionnelle de la maladie insulaire par rapport à son expression clinique chez les sujets concernés par ce syndrome. Pour ce faire, des spécimens provenant de 14 malades atteints du syndrome MEN I ont été étudiés eu égard à l'hyperplasie, à la nésidioblastose, à la multiplicité des îlots tumoraux, à la malignité. Dans 12 cas, les spécimens répondaient au pancréas distal, dans 2 cas à la totalité du pancréas. De multiples coupes furent pratiquées au niveau de chaque pièce soumise à l'examen. L'imprégnation à l'immunoperoxidase concerna les coupes de 24 tumeurs provenant de 10 patients. Cinq des 10 malades qui présentaient un syndrome de Zollinger-Ellison avaient subi une gastrectomie totale et 3 une intervention pancréatique pour contrôler leur hypersécrétion acide. Les conclusions tirées de cette étude furent les suivantes: tous les malades accusant un syndrome MEN I et porteurs d'un néopolasme pancréatique présentaient des lésions insulaires diffuses répondant à une nésidioblastose, à une hyperplasie micronodulaire et macronodulaire. Quelques tumeurs produisaient de multiples hormones: gastrine, polypeptide pancréatique, glucagon, sérotonine, V.I.P., somatostatine, testées par la méthode. Il résulte de ces constatations que les risques de récidive tumorale après exérèse complète des tumeurs évidentes ne sont pas à écarter, encore que l'exérèse permette de contrôler longtemps l'endocrinopathie. Ceci est particulièrement vrai pour les insulinomes hypoglycémiants. En ce qui concerne les gastrinomes, leur exérèse peut être suffisante, en particulier lorsque les prélèvements veineux étagés montrent qu'ils sont uniques; la gastrectomie concomitante est alors inutile. En revanche, lorsque la gastrine est trouvée en excès au niveau de multiples échantillons veineux, l'exérèse tumorale est insuffisante et la pancréatectomie totale représente l'intervention indispensable; en fait, son indication est rare. La variedad del espectro de la histopatología de las células insulares en pacientes con sindrome de neoplasias endocrinas múltiples tipo I (NEM I) todavía no ha sido claramente definido. Aún cuando algunos pacientes poseen tumores discretos que causan síndromes clínicamente evidentes, otros pueden no exhibir sintomatología alguna hasta cuando se hace evidente un carcinoma metastásico de células insulares. No se sabe si hay enfermedad difusa de las células insulares en todo paciente con tumores macroscópicamente aparentes, ni además se conoce con qué frecuencia se desarrollan nuevos tumores en pacientes con síndrome NEM I después de resección local o de pancreatectomía parcial para tumores primarios de células insulares. El presente estudio intenta definir la extensión funcional y anatómica de la enfermedad de las células insulares y su relación con la evolución clínica en pacientes con el síndrome NEM I.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41313/1/268_2005_Article_BF01654938.pd

Primary hyperparathyroidism in children, adolescents, and young adults

Primary hyperparathyroidism (HPT) is considered a rare disease in children and an uncommon one in adolescents and young adults. Until 1975, only 60 children under the age of 16 years had been reported with proven HPT. Most had symptoms of weakness, irritability, anorexia, and weight loss. Severe hypercalcemia (serum calcium>15 mg/ 100 ml) and radiologic evidence of bone changes were common findings, and suggested delayed diagnoses . This report is based on the clinical and laboratory findings in 53 young patients with proven primary HPT (range: 1–30 years of age) from 1971 to 1980, treated in one hospital. There were 29 male and 24 female patients, 26 of whom developed symptoms before age 18. Common symptoms included hematuria and renal colic (50%), renal calculi (50%), and hypertension with (6%) and without (3%) severe headaches. Although 64.2% of patients had adenomas, only 54% of patients under 18, and as many as 77.8% over 18, had them. The incidence of hyperplasia was markedly increased in the patients under 18 (38%) as compared to the patients over 18 (18.5%) or the group taken as a whole (30.2%). The following associated diseases were identified: MEA I syndrome (4); MEA II syndrome (4); von Recklinghausen's neurofibromatosis; papillary carcinoma of thyroid; craniopharyngioma; and multiple metaphyseal chondromatosis. One child had hereditary neonatal parathyroid hyperplasia . Primary hyperparathyroidism is more common than previously suspected in young people. Symptoms of renal stones, hypertension, persistent headaches, unexplained anorexia, and weight loss should prompt evaluation for primary HPT. If hyperplasia is found, the patient and family should be investigated for associated endocrinopathies . L'hyperparathyroïdie est considérée une maladie extraordinaire des infants et bien rare des adolescents et des jeunes adultes. Jusqu'à 1975, seulement 60 enfants qui avaient moins de 16 ans étaient rapportés avec l'hyperparathyroïdie verifiée. La majorité avaient les symptômes de faiblesse, irritabilité, anorexie et perdu des poids. L'hypercalcémie severe (calcémies > 15 mg/100 ml) et l'évidence radiologique d'abnormalitiés osseux sont les conclusions ordinaires, et cela donne l'idée que le diagnostic était tard.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41310/1/268_2005_Article_BF01655371.pd

Suppression of type 1 pilus assembly in uropathogenic Escherichia coli by chemical inhibition of subunit polymerization

OBJECTIVES: To identify and to characterize small-molecule inhibitors that target the subunit polymerization of the type 1 pilus assembly in uropathogenic Escherichia coli (UPEC). METHODS: Using an SDS-PAGE-based assay, in silico pre-filtered small-molecule compounds were screened for specific inhibitory activity against the critical subunit polymerization step of the chaperone-usher pathway during pilus biogenesis. The biological activity of one of the compounds was validated in assays monitoring UPEC type 1 pilus biogenesis, type 1 pilus-dependent biofilm formation and adherence to human bladder epithelial cells. The time dependence of the in vivo inhibitory activity and the overall effect of the compound on UPEC growth were determined. RESULTS: N-(4-chloro-phenyl)-2-{5-[4-(pyrrolidine-1-sulfonyl)-phenyl]-[1,3,4]oxadiazol-2-yl sulfanyl}-acetamide (AL1) inhibited in vitro pilus subunit polymerization. In bacterial cultures, AL1 disrupted UPEC type 1 pilus biogenesis and pilus-dependent biofilm formation, and resulted in the reduction of bacterial adherence to human bladder epithelial cells, without affecting bacterial cell growth. Bacterial exposure to the inhibitor led to an almost instantaneous loss of type 1 pili. CONCLUSIONS: We have identified and characterized a small molecule that interferes with the assembly of type 1 pili. The molecule targets the polymerization step during the subunit incorporation cycle of the chaperone-usher pathway. Our discovery provides new insight into the design and development of novel anti-virulence therapies targeting key virulence factors of bacterial pathogens

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

Background: Autism spectrum disorders (ASDs) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. Methodology/Principal Findings: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62 % similar overall (28 % identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. Conclusions/Significance: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-lik

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population