Thyroglobulin gene mutations producing defective intracellular transport of thyroglobulin are associated with increased thyroidal type 2 iodothyronine deiodinase activity

CONTEXT: Most patients with defective synthesis and/or secretion of thyroglobulin (Tg) present relatively high serum free T3 (FT3) concentrations with disproportionately low free T4 (FT4) resulting in a high FT3/FT4 ratio. The mechanism of this change in FT3/FT4 ratio remains unknown. OBJECTIVE: We hypothesize that increased type 2 iodothyronine deiodinase (D2) activity in the thyroid gland may explain the higher FT3/FT4 ratio that is frequently observed in patients with abnormal Tg synthesis. DESIGN: We recently identified a compound heterozygous patient (patient A) with a Tg G2356R mutation and one previously described (C1245R) that is known to cause a defect in intracellular transport of Tg. In the current study, after determining the abnormality caused by G2356R, we measured D2 activity as well as its mRNA level in the thyroid gland. We also measured the thyroidal D2 activity in three patients with Tg transport defect and in normal thyroid tissue. RESULTS: Morphological and biochemical analysis of the thyroid gland from patient A, complemented by a pulse-chase experiment, revealed that G2356R produces a defect in intracellular Tg transport. D2 activity but not type 1 deiodinase in thyroid glands of patients with abnormal Tg transport was significantly higher than in normal thyroid glands, whereas D2 mRNA level in patient A was comparable with that in normal thyroid glands. Furthermore, there was a positive correlation between D2 activity and FT3/FT4 ratios. CONCLUSION: Increased thyroidal D2 activity in the thyroid gland is responsible for the higher FT3/FT4 ratios in patients with defective intracellular Tg transport.     

A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism

Constitutively activating germline mutations of the thyrotropin receptor (TSHR) gene have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. We describe here a Japanese kindred with two affected individuals who showed overt hyperthyroidism and mild goiter in the absence of TSHR antibodies. A novel heterozygous germline point mutation, identified in both individuals, resulted in an amino acid substitution of aspartic acid for tyrosine at codon 617 (Asp617Tyr) in the third intracellular loop of the TSHR. Screening of 7 additional family members led to the identification of the same mutation in 4 relatives: 1 had undergone thyroidectomy due to hyperthyroidism but 3 were asymptomatic with subclinical hyperthyroidism. In vitro functional studies of the Asp617Tyr TSHR demonstrated a constitutive activation of the cyclic adenosine monophosphate pathway, but not of the inositol phosphate cascade, with data similar to those of Asp619Gly, the first constitutively activating mutant TSHR identified. Treatment with inorganic iodine for 7 months successfully relieved all symptoms of hyperthyroidism in both patients.     

Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: Final results of a randomized multi-institutional trial

Purpose  Although the outcome of surgery for locally advanced pancreatic cancer remains poor, it is improving, with 5-year survival up to about 10% in Japan. The preliminary results of our multi-institutional randomized controlled trial revealed better survival after surgery than after radiochemotherapy. We report the final results of this study after 5 years of follow-up. Methods  Patients with preoperative findings of pancreatic cancer invading the pancreatic capsule without involvement of the superior mesenteric or common hepatic arteries, or distant metastasis, were included in this randomized controlled trial, with their consent. If the laparotomy findings were consistent with these criteria, the patient was randomized to a surgery group or a radiochemotherapy group (5-fluorouracil 200 mg/m²/day and 5040 Gy radiotherapy). We compared the mean survival time, 3-and 5-year survival rates, and hazard ratio. Results  The surgery and radiochemotherapy groups comprised 20 and 22 patients, respectively. Patients were followed up for 5 years or longer, or until an event occurred to preclude this. The surgery group had significantly better survival than the radiochemotherapy group (P < 0.03). Surgery increased the survival time and 3-year survival rate by an average of 11.8 months and 20%, respectively, and it halved the instantaneous mortality (hazard) rate. Conclusion  Locally invasive pancreatic cancer without distant metastases or major arterial invasion is treated most effectively by surgical resection.     

Desensitization of guinea-pig taenia caeci smooth muscle induced by a low concentration of carbachol

1. In guinea-pig taenia caeci smooth muscle we have found that 10(-4) mol/L carbachol-induced desensitization to muscarinic agonists develops within 15-30 s, followed by transient resensitization at 1 min, whereas the desensitization to depolarizing high K(+) develops with maximal desensitization at 1 min followed by sustained resensitization up to 30 min. In both cases, Ca(2+)-dependent processes play a crucial role in determining the development of desensitization. 2. To elucidate whether these peculiar processes of desensitization/resensitization may be induced by a lower concentration of carbachol, we examined the development of desensitization induced by 10(-6) mol/L carbachol, because at this concentration carbachol is known to induce biphasic changes in intracellular Ca(2+) concentrations, with a smaller transient increase followed by a larger sustained increase than seen with 10(-4) mol/L carbachol. 3. Contractile responses to muscarinic agonists (carbachol or AHR-602) and high K(+) were desensitized by pretreatment with 10(-6) mol/L carbachol for 30 min in a manner dependent on the presence of extracellular Ca(2+). 4. The development of 10(-6) mol/L carbachol-induced desensitization to these muscarinic agonists in the presence of extracellular Ca(2+) showed three successive phases: fast desensitization within 30 s, followed by transient resensitization at 1 min and the subsequent development of desensitization up to 30 min. In contrast, desensitization to high K(+) did not develop up to 10 min and significant desensitization occurred at 30 min, with no apparent resensitization phase. 5. These results suggest that the characteristics of the Ca(2+)-dependent development of desensitization to muscarinic agonists, but not to high K(+), are well maintained in desensitization induced by a lower concentration of carbachol.     

Effects of postoperative continuous epidural analgesia after laparoscopy-assisted colectomy

BACKGROUND: This study was conducted to evaluate the effects of continuous epidural analgesia on the postoperative pain and the early recovery after laparoscopy-assisted colectomy (LAC). METHODS: A total of 50 patients undergoing elective LAC were investigated for postoperative pain score and other variables retrospectively. RESULTS: Thirty patients who had received epidural analgesia (E group) showed significantly lower pain scores for 2 and 24 hours after surgery, compared with twenty patients who had received analgesics intramuscularly or transrectally (C group). The patients in the E group needed significantly less supplemental analgesics than those in C group for 12 to 24 hours after the operation. The incidence of postoperative complications and the early recovery were not significantly different between the two groups. CONCLUSIONS: These results show that postoperative continuous epidural analgesia is effective for postoperative pain relief in patients after laparoscopy-assisted colectomy.     

Pulmonary edema due to venous air embolism during craniotomy: a case report

We present a 35-year-old healthy male patient who developed pulmonary edema (PE) probably due to venous air embolism during craniotomy in the semi-sitting position for arteriovenous malformation (AVM). Anesthesia was maintained with oxygen, nitrous oxide, propofol and fentanyl. During craniotomy, end-tidal carbon dioxide pressure decreased suddenly from 26 to 9 mmHg. Concurrently, a decrease in oxygen saturation from 99% to 91% occurred. There were no serious changes in blood pressure and heart rate. A "mill-wheel murmur" was confirmed. PE due to venous air embolism was suspected. The operation was discontinued and the patient was transferred to the intensive care unit. In the post-operative period, the patient developed PE and made a full recovery within a week. Four months later, the patient was scheduled again for surgical excision of AVM in the semi-sitting position in the same way as the first time. Anesthesia was maintained with oxygen, air, propofol and fentanyl. Transoesophageal echocardiography and pulmonary artery catheter were used. Saline was filled at the surgical site to prevent aspiration of air bubbles and surgical procedure was performed carefully without large vein injury and uneventfully. During neurosurgical intervention in the sitting position, special attention should be paid to entry of air bubbles into the venous system which may lead to PE.     

Breast cancer developing after chemotherapy for osteosarcoma: a case report.

A 24-year-old patient who developed breast cancer 16 years after chemotherapy for osteosarcoma is presented. She had no family history of cancer. She had also not had radiotherapy. She had been given chemotherapy consisting of VAOMT (vincristine 10.2 mg, cyclophosphamide 900 mg, mitomycin C 15.2 mg, chromomycin A3 25.8 mg) pre- and post-operatively in the treatment of her osteosarcoma. Careful long-term follow-up is required after treatment of malignant neoplasms because there is a possibility of developing a second malignancy.     

Interleukin-1 alpha enhances hepatotoxicity of tumor necrosis factor-alpha in galactosamine-sensitized mice.

The possible involvement of interleukin-1 alpha (IL-1 alpha) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. The injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1 alpha antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-alpha (TNF) antiserum significantly protected mice from liver injury. The use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-1 alpha could not substitute for LPS. However, recombinant murine IL-1 alpha enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-1 alpha acts synergistically with TNF in this hepatitis model.     

Right hepatic lobectomy with removal of tumor thrombus from the portal vein for hepatocellular carcinoma

Hepatocellular carcinoma with tumor thrombus in the portal trunk and collateral veins in the hepatoduodenal ligament is usually considered to be unresectable. To resect the tumor, it is necessary to handle the portal trunk and bile duct after the hepatic artery and liver parenchyma have been transected without dissection of the hepatoduodenal ligament. In this way, we were able to perform right lobectomy with removal of the tumor thrombus in the portal trunk, avoiding profuse bleeding due to transection of the collateral veins. Our procedure is associated with certain problems, one being whether the tumor thrombus can be separated from the endothelium of the portal vein, and another being related to the radical extent of this operation. The major issue is the radical nature of this procedure. It is presumed that the collateral veins can be extirpated to achieve a curative operation.