Utilizing an Animal Model to Identify Brain Neurodegeneration-Related Biomarkers in Aging.

Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAMe), a methyl donor in methylation. Over-expressed SAMe may cause neurogenic capacity reduction and memory impairment. GNMT knockout mice (GNMT-KO) was applied as an experimental model to evaluate its effect on neurons. In this study, proteins from brain tissues were studied using proteomic approaches, Haemotoxylin and Eosin staining, immunohistochemistry, Western blotting, and ingenuity pathway analysis. The expression of Receptor-interacting protein 1(RIPK1) and Caspase 3 were up-regulated and activity-dependent neuroprotective protein (ADNP) was down-regulated in GNMT-KO mice regardless of the age. Besides, proteins related to neuropathology, such as excitatory amino acid transporter 2, calcium/calmodulin-dependent protein kinase type II subunit alpha, and Cu-Zn superoxide dismutase were found only in the group of aged wild-type mice; 4-aminobutyrate amino transferase, limbic system-associated membrane protein, sodium- and chloride-dependent GABA transporter 3 and ProSAAS were found only in the group of young GNMT-KO mice and are related to function of neurons; serum albumin and Rho GDP dissociation inhibitor 1 were found only in the group of aged GNMT-KO mice and are connected to neurodegenerative disorders. With proteomic analyses, a pathway involving Gonadotropin-releasing hormone (GnRH) signal was found to be associated with aging. The GnRH pathway could provide additional information on the mechanism of aging and non-aging related neurodegeneration, and these protein markers may be served in developing future therapeutic treatments to ameliorate aging and prevent diseases.

Does Routine Triple-Time-Point FDG PET/CT Imaging Improve the Detection of Liver Metastases?

Prior reports have demonstrated the improved ability of delayed fluorine-18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging (dual-time-point imaging) in detecting more patients with liver metastases. To evaluate whether routine triple-time-point FDG PET/CT imaging improves the detection of liver metastasis not visualized on initial imaging. To our knowledge, no triple-time-point imaging has been reported. This retrospective study included total 310 patients with various malignancies who underwent PET/CT scans. Triple-time-point imaging including the liver was obtained. The comparison between negative and positive liver lesions on delayed imaging for patients with initial negative imaging were analyzed. Of the 310 patients, 286 did not exhibit liver lesions on initial imaging, but six of the 286 patients exhibited lesions on delayed imaging. No additional liver lesions were detected on further delayed imaging in the 286 patients. The other 24 patients with liver lesions identified on initial imaging still showed lesions on delayed and further delayed imaging. The analysis showed a significant difference in the percentage of colorectal cancer (66.7%) and liver lesions before the PET scan (50.0%) compared with unchanged results (22.1% and 3.9%, respectively). Routine triple-time-point imaging did not improve the detection of liver metastases; however, it may be recommended in patients with colorectal cancer and liver lesions before the PET scan.

Follicular Thyroid Cancer With Nose-Tip Metastasis and 131I Uptake.

We present a 56-year-old woman with metastatic follicular thyroid cancer at the nose tip with I uptake that is clinically rare, mimicking physiological uptake in the nose, a common finding seen after routine I therapeutic imaging. The lesion revealed a metastatic follicular thyroid cancer with I uptake and response to I therapy. Surgical removal, however, was not performed due to cosmetic and functional considerations. Active surveillance is warranted owing to its relative aggressiveness in nature.

Pigmented villous nodular synovitis mimicking metastases on 18F-FDG PET/CT in a patient with rectal mucosal melanoma: a case report.

BACKGROUND: Mucosal melanomas are rare and have a high potential for metastasizing. Surgical resection is the treatment of choice for single distant metastases. Malignant melanoma usually shows the highest uptake of fluorine-18 fluorodeoxyglucose (18F-FDG). 18F- FDG positron emission tomography /computed tomography (PET/CT) is usually used for melanoma staging. An extensive literature review revealed only 4 published case reports and an original paper involving 8 cases (12 cases in total) of patients with skin melanomas in whom pigmented villous nodular synovitis (PVNS) mimicked metastatic melanoma, however, none of the melanomas reported were of rectal mucosal origin. CASE PRESENTATION: A 60-year-old woman presented with recent diagnosis of rectal mucosal melanoma, two additional 18F-FDG-avid lesions in the left ankle and left foot were detected on 18F-FDG PET/CT. Metastases were initially suspected; however, the final diagnosis was PVNS. CONCLUSIONS: This is the first report of PVNS mimicking metastases on 18F-FDG PET/CT in a patient with rectal mucosal melanoma. Although high 18F-FDG-avid lesions in patients with rectal mucosal melanoma are highly suspected to be metastasis and warrant an meticulous examination, the present case is a reminder that in such patients, not all lesions with high 18F-FDG uptake, especially those near a joint, are metastases and that more extensive resection is unnecessary.

Tc-99m imaging in thyroidectomized differentiated thyroid cancer patients immediately before I-131 treatment.

PURPOSE: The aim of this study was to evaluate the clinical role of technetium-99m pertechnetate (Tc-99m) imaging in thyroidectomized differentiated thyroid cancer patients immediately before radioiodine-131 (I-131) treatment (Tx). PATIENT AND METHODS: Eighty-six consecutive post-total-thyroidectomy patients (15 men, 71 women; mean age: 46.8 years) with pathologically diagnosed differentiated thyroid cancer were retrospectively studied. Tc-99m imaging immediately before I-131 Tx using both patient-based and lesion-based measurements were analyzed and were further compared with those of post-Tx I-131 whole-body scans. RESULTS: For patients with unequivocally positive Tc-99m uptake, the sensitivity was 77% (patient-based) and 59% (site-based). The positive predictive value (PPV) was 100% for both patient-based and site-based measurements. If equivocal Tc-99m uptake was counted as positive, the sensitivity was 83 and 67%, and the PPV was 100 and 99% for patient-based and site-based measurements, respectively. CONCLUSION: (a) To increase sensitivity yet maintaining high PPV, equivocal Tc-99m uptake should be considered a positive finding. (b) The nearly 100% PPV of Tc-99m imaging immediately before I-131 Tx for remnant detection suggests that Tc-99m imaging not only serves as an alternative to low-dose I-131 scanning in the low-risk post-thyroidectomy patients but also provides a clue for the subsequent I-131 therapeutic dosage and even for the outcome prediction.

Time sensitivity factor of single pulmonary nodule: a new cancer characteristic metabolic parameter by (18) F-FDG PET.

OBJECTIVE: To calculate the time sensitivity factor (S) for discriminating the solitary pulmonary nodule (SPN) by FDG PET at different time points. METHODS: The multiple time-point FDG PET images from 41 patients for evaluating SPN seen on chest X-ray or CT were prospectively analyzed to calculate and evaluate S against the gold standard of tissue histology (n = 38) or long term clinicoradiographic follow-up (n = 3). The maximal standardized uptake values (SUV) at the 3 hourly time points were measured. The S was calculated using S = d{ln⁡(SUV)}/d{ln⁡(t)} at 3 different time intervals. ROC analysis of the S parameters was performed to evaluate the optimal cut-off value and their accuracy in classifying the SPN. RESULTS: The SUV in malignant SPN was higher than the corresponding value in benign lesions at all 3 hourly time points (P < 0.003). The S parameters using 3 different time intervals all significantly separated the two groups (P < 0.0005) with an optimal cut-off point near the theoretical value of zero with a high sensitivity of 100% and specificity of 86%. CONCLUSION. The S can be calculated for SPNs using multiple time-point FDG PET, providing a tumor characteristic metabolic parameter with high discrimination power using a simple positive value representing malignancy.

Parotid-sparing intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma: preserved parotid function after IMRT on quantitative salivary scintigraphy, and comparison with historical data after conventional radiotherapy.

PURPOSE: To evaluate the parotid function after parotid-sparing intensity-modulated radiotherapy (IMRT) in patients with nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: From March 2003 to May 2004, 16 patients with nonmetastatic NPC underwent parotid-sparing IMRT. Eight of these patients had Stage III or IV NPC based on the 1997 American Joint Committee on Cancer staging system. The post-IMRT parotid function was evaluated by quantitative salivary scintigraphy and represented by the maximal excretion ratio (MER) of the parotid gland after sialogogue stimulation. The parotid function of 16 NPC patients who were previously treated with conventional radiotherapy was reviewed as the historical control. RESULTS: In the parotid-sparing IMRT group, all 16 patients were alive and without cancer at the end of follow-up period (median, 24.2 months). The mean parotid MER was 53.5% before radiotherapy, 10.7% at 1 month post-IMRT, and 23.3% at 9 months post-IMRT. In the conventional radiotherapy group, the mean parotid MER was 0.6% at 6 to 12 months postradiotherapy. The difference was statistically significant (23.3% vs. 0.6%, p<0.001, Mann-Whitney test). In the IMRT group, the mean parotid doses ranged from 33.2 Gy to 58.8 Gy (average, 43.9 Gy). The correlation between the mean parotid dose and the percentage decrease of parotid MER at 9 months post-IMRT (dMER) was statically significant (p=0.008, Pearson correlation). CONCLUSIONS: Although the mean parotid doses are relatively high, the significant preservation of parotid function is achieved with IMRT for NPC patients. The significant correlation between mean parotid dose and parotid dMER demonstrates the dose-function relationship of the parotid gland.

Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone.

Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.

Sleep disturbances before and after parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: The prevalence of insomnia in patients with symptomatic secondary hyperparathyroidism and the improvements of sleep disturbances after parathyroidectomy have not been previously reported. METHODS: Thirty-one patients who had undergone successful total parathyroidectomy and autotransplantation for symptomatic secondary hyperparathyroidism were enrolled in the study. The symptoms of skin itching, bone pain, and general weakness were recorded. Preoperatively, serum levels of calcium, phosphorus, alkaline phosphatase (Alk-ptase), intact parathyroid hormone (iPTH), am melatonin (noon), and pm melatonin (midnight) were measured in association with a simple yes/no questionnaire of 5 items about sleep disturbances as described previously. The severity of insomnia was the sum of positive items of sleeping disturbances. The sleep hours per night and the habit of taking sleeping pills were also recorded. One week after surgery, serum levels of calcium, phosphorus, Alk-ptase, iPTH, am melatonin, and pm melatonin were measured again. Three months after surgery, symptoms of skin itching, bone pain, and general weakness were recorded, and serum levels of calcium, phosphorus, Alk-ptase and iPTH were measured in association with a yes/no questionnaire of sleep disturbances. The severity of insomnia, sleep hours per night, and the habit of taking sleeping pills were recorded again. RESULTS: One week after parathyroidectomy, serum levels of calcium, phosphorus, and iPTH decreased significantly; serum levels of Alk-ptase and am melatonin increased significantly; serum levels of pm melatonin did not change significantly. Three months after parathyroidectomy, symptoms of skin itching, bone pain, and general weakness decreased significantly; serum levels of calcium, phosphorus, Alk-ptase, and iPTH decreased significantly; sleeping disturbances and severity of insomnia improved significantly in association with longer sleep hours per night. A significant reduction of the habit of taking sleeping pills was also noted. Preoperatively, the severity of insomnia was correlated with skin itching, general weakness, and levels of iPTH. Postoperatively, the severity of insomnia was correlated with skin itching, general weakness, and bone pain. CONCLUSIONS: Preoperatively, a high prevalence of sleep disturbances (97%) was found in patients with symptomatic secondary hyperparathyroidism. We conclude that nocturnal melatonin levels do not change after parathyroidectomy; the improvements in sleep disturbance and the decreases in severity of insomnia are found 3 months after surgery in association with longer sleep hours per night. Decreases of symptoms such as skin itching, bone pain, and general weakness may be the reasons for the improvement in sleep and the decrease in insomnia.

Influence of 131I diagnostic dose on subsequent ablation in patients with differentiated thyroid carcinoma: discrepancy between the presence of visually apparent stunning and the impairment of successful ablation.

BACKGROUND: In the management of patients with differentiated thyroid carcinoma, direct comparison of the presence of scintigraphic stunning after a diagnostic dose of 131I with subsequent successful ablation has not been evaluated. METHODS: This study included 245 patients who received a dose of 2775-3700 MBq of 131I for thyroid remnant ablation. In all patients, the thyroid-stimulating hormone (TSH) level before ablation was more than 30 microlU x ml. One hundred and twenty-six patients (Group A) were given a 185 MBq diagnostic scan (Dscan) 4-11 days before 131I ablation, and 119 patients (Group B) received 131I ablation directly after thyroidectomy. Scintigraphic stunning was considered to be present on any post-ablation scan that revealed either fewer foci or obviously less prominent uptake compared with the earlier corresponding Dscan. Successful ablation was defined as no visible uptake in the neck region or anywhere else on a follow-up Dscan 6-12 months later. RESULTS: Our results revealed that only 13 of the 126 patients (10.3%) in Group A had visually apparent thyroid stunning. Successful ablation was obtained in 56 of 126 cases (44.4%) in Group A, compared with 86 of 119 cases (72.2%) in Group B (P<0.001). In Group A, the success rate of ablation in patients with stunning (5/13) was not statistically different from that in those without (51/113) (odds ratio, 0.76; 95% CI, 0.23-2.47). Multiple logistic regression analysis revealed that the independent determinants of successful ablation were the use of Dscan before ablation (odds ratio, 0.23; 95% CI, 0.10-0.56) and the ablation dose of 131I (odds ratio, 1.05; 95% CI, 1.00-1.10). CONCLUSIONS: Visually apparent stunning is infrequent and may not be sufficiently sensitive to detect the influence of a 185 MBq Dscan on subsequent ablation outcome. For patients with differentiated thyroid carcinoma, we recommend that ablation should be performed directly after thyroidectomy.

Spermatogenesis after parathyroidectomy in patients with symptomatic secondary hyperparathyroidism.

BACKGROUND: The changes in spermatogenesis after parathyroidectomy in patients with symptomatic secondary hyperparathyroidism have not been reported before. STUDY DESIGN: Nineteen men with symptomatic secondary hyperparathyrodism were enrolled in our study. Their ages ranged from 29 to 50 years and duration of dialysis from 72 to 168 months. Before operation, serum levels of calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and testosterone were checked routinely in association with semen analysis. Those data were checked again 3 months after successful operation. Finally, 15 patients had total parathyroidectomy with subcutaneous autotransplantation of 60 or 90 mg of tissue and complete postoperative data was available for 13 patients. The semen analysis included sperm density, volume of semen, motility index, percentage of active motility, and percentage of normal morphology. RESULTS: Ten patients had normal sperm density (> or =20 x 10(6)/mL), and nine patients had oligospermia (<20 x 10(6)/mL) (n = 4) or azoospermia (n = 5). The ages of patients, duration of dialysis, and weight of removed parathyroid glands were quite similar between the two groups. The serum levels of calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone, prolactin, luteinizing hormone, follicle-stimulating hormone, and testosterone were not significantly different between the group with normospermia and the group with oligospermia or azoospermia. Three months after total parathyroidectomy with autotransplantation, the serum levels of calcium, phosphorus, alkaline phosphatase, and intact parathyroid hormone were markedly decreased; the percentage of active motility and motility index were markedly improved; the serum levels of prolactin, luteinizing hormone, follicle-stimulating hormone, and testosterone had no significant changes; and the volume of semen, sperm density, and percentage of normal morphology had no significant improvements. One patient, who had oligospermia with primary infertility, had paternity 6 months after parathyroidectomy, though his oligospermia remained unchanged at that time. CONCLUSION: After parathyroidectomy, the sperm motility index and percentage of active motility can be improved. We speculate that increases in fertilization and paternity in uremic male patients can be expected after surgery.

Persistent and recurrent hyperparathyroidism after total parathyroidectomy with autotransplantation.

OBJECTIVE: To conduct a retrospective study of 15 patients with persistent (n = 4) and recurrent (n = 11) hyperparathyroidism. SUMMARY BACKGROUND DATA: Secondary hyperparathyroidism may persist or recur because of hyperfunction of the parathyroid remnant or transplanted parathyroid tissue. It is a great challenge to localize the parathyroid tissue either in the neck or at the arm before surgery. METHODS: From June 1994 to June 2000, 15 patients with recurrent and persistent secondary hyperparathyroidism were selected for surgery for the removal of parathyroid tissue. The indications for surgery included bone pain, hypercalcemia, general weakness, and skin itching. Their ages ranged from 23 to 66 years. The average period of persistent hyperparathyroidism after total parathyroidectomy with autotransplantation was 3.8 months; that of recurrent hyperparathyroidism was 53 months. Serum levels of calcium, phosphorus, parathyroid hormone (iPTH), and alkaline phosphatase were measured before surgery and 1 week after surgery. Before surgery, the parathyroid gradient in the blood draining the graft-bearing arm versus the contralateral arm was measured. A 99mTc-sestamibi (MIBI) scan was performed including the neck and the arm area, and a computed tomography (CT) scan of the neck was performed to confirm the localization. The neck and mediastinal exploration was done directly at the side of localization under general anesthesia to remove the parathyroid tissue that had been located with the MIBI scan or CT scan. An arm exploration was done under local anesthesia to remove all parathyroid tissues detected in the MIBI scan or palpable masses during surgery. If all glands were removed, 0.5 x 0.5 x 0.5 cm of tissue (60-100 mg) was maintained in situ or the same amount of tissue was reimplanted. RESULTS: The average ratio of iPTH in the graft-bearing arm to the contralateral arm in the 5 patients with parathyroid tissue in the neck was 1.17 +/- 0.16, and that in the 10 patients with parathyroid at the arm was 14.15 +/- 16.62. A significant difference was found between the two groups. MIBI scans showed parathyroid tissues in the neck in four of five patients and in seven of eight patients at the arm. Computed tomography showed the parathyroid tissues in the neck and mediastinum in five of five patients (100%). Five glands were removed from these five patients, three in the neck, one in the mediastinum, and one in the carotid sheath. In total, 20 glands and 2 half-glands were removed from 10 patients; among these, 14 glands were shown in the MIBI scan. All patients had improvements of symptoms and signs after surgery. Serum levels of calcium, phosphorus, and iPTH decreased rapidly after surgery, but alkaline phosphatase did not. CONCLUSIONS: With the results obtained from the ratio of iPTH of the graft-bearing arm to the contralateral arm, clinical palpation of the arm, MIBI scan, CT scan, careful surgical exploration, and adequate resection, recurrent and persistent secondary hyperparathyroidism can be successfully treated with surgery in the neck or at the arm.