Manifestations of diabeters mellitus on mouse preimplantation developement: effect of elevated concentration of metabolic intemediated

The metabolic derangements of pregnancies complicated by diabetesmellitus, specifically hyperglycaemia and hyper-ketonaemia,are known to be teratogenic during the period of organogenesisin animals. We have shown previously that poorly controled diabetesmellitus impairs in-vivo and in-vitro mouse preimplantationembryo growth, and that culturing embryos in elevated glucoseconcentrations only partially recreated this developmental dealy.To extend this observation we examined the effect on mouse preimplantationembryo growth of elevated concentrations of other metabolicintermediates, which may be deranged in diabetes mellitys, namelylipids, lactate, glycerol, amino acids, and ketones. Two-cellembryos from ovulation-induced B₆C₃F₁ mice were cultured for72 h in the presence of added lipids (250 mg/dl), lactate (5mM), glycerol (160 µM) or mixed amino acids (8.5% travosol,7 mM) and showed no significant difference in growth over 72h verus their control groups. However, growth of preimplantationembryos in acetoacetate (10 mM) or in the racemic micture ofDL--hydroxybutyrate (16 and 32mM) revealed marked retardationversus controls when assessed either by distribution of developmentalstages over time (24, 48, 72 h, P <0.001) or by the differencein the average rank of sums indicating a delay in maturation(P<0.0001). We conclude that elevated ketone concentrationsadversely affect preimplantation embryo development. These findingsextend previous studies which correlate uncontrolled diabetesmellitus as well as hyperglycaemia with abnormal organogenesis,and demonstrate tht exposure to metabolic derangements may alsohinder reproductive performane at even earlier stages in gestation.     

Soft-tissue sarcomas

Sarcomas of the soft tissues are challenging lesions for the surgical oncologist. Careful planning must be done at all stages of diagnosis and treatment, because every sarcoma is unique with respect to histologic type, size, and location. Pretreatment discussions in a multidisciplinary format are useful to ensure appropriate and effective management of these tumors.     

Live imaging reveals the link between decreased glucose uptake in ovarian cumulus cells and impaired oocyte quality in female diabetic mice

Maternal diabetes has been demonstrated to adversely affect preimplantation embryo development and pregnancy outcomes. Emerging data suggest that these effects are associated with compromised oocyte quality. However, direct evidence of a pathway by which maternal diabetes exerts its effects on the oocyte is still lacking. Cumulus cells are metabolically coupled to oocytes, and bidirectional communication between them is essential for the development and functions of both compartments. The primary focus of this work was to evaluate the connection between glucose uptake in cumulus cells and oocyte quality in diabetic mice. This experiment has been difficult, because cumulus cells need to be separated from oocytes and labeled with isotope in the process of measuring glucose uptake. Here, we report a method for live imaging glucose transport in single cumulus-oocyte complexes using a fluorescent glucose analog (6-(N-(7-nitrobenz-2-oxa-1,3-diazol- 4-yl)amino)-6-deoxyglucose). By tracking the ATP content and spindle/chromosome status in individual oocytes surrounded by cumulus cells with differing glucose uptake activity, we reveal that compromised oocyte quality in diabetic mice is linked to decreased glucose uptake in cumulus cells.     

High insulin-like growth factor 1 (IGF-1) and insulin concentrations trigger apoptosis in the mouse blastocyst via down-regulation of the IGF-1 receptor

Women with polycystic ovary syndrome have significantly higher rates of pregnancy loss, as well as elevated insulin and IGF-1 levels. In this study, preimplantation embryos exposed to high concentrations of IGF-1 or insulin undergo extensive apoptosis of the ICM nuclei. Lack of BAX expression, the caspase inhibitor, zVAD, or the ceramide synthase inhibitor, fumonisin B1, prevents this event, suggesting involvement of programmed cell death effector pathways. In other systems, the IGF-1 concentration regulates IGF-1R expression and thus high concentrations lead to down-regulation of the receptor. Here, data show a decrease in IGF-1 receptor protein expression, both by confocal immunofluorescent microscopy and by Western analysis upon exposure to 130 nM IGF-1. Insulin-stimulated glucose uptake, an event regulated via the IGF-1 receptor, is decreased upon exposure to excess IGF-1, suggesting decreased function of the receptor. The data also show that, by blocking receptor signal transduction or by decreasing receptor expression, the apoptotic event can be recreated, thus strongly suggesting that the mechanism of high IGF-1 induced apoptosis is decreased downstream IGF-1 receptor signaling. This embryotoxic insult by high IGF-1 levels may be responsible for the high incidence of pregnancy loss seen in women with polycystic ovary syndrome.     

Gastrointestinal manifestations of multiple endocrine neoplasia type 2

OBJECTIVE: To determine the clinical features, natural history, and role of surgery for gastrointestinal manifestations of the multiple endocrine neoplasia type 2 (MEN 2) syndromes. SUMMARY BACKGROUND DATA: The MEN 2 syndromes are characterized by medullary thyroid carcinoma and other endocrinopathies. In addition, some patients with MEN 2A develop Hirschsprung's disease (HD), and all patients with MEN 2B have intestinal neuromas and megacolon that can cause significant gastrointestinal problems. METHODS: From 83 families with MEN 2A, eight patients with HD were identified (MEN 2A-HD). These and all patients with MEN 2B followed at the authors' institution (n = 53) were sent questionnaires to describe the onset and type of gastrointestinal symptoms and treatment they had before the diagnosis of MEN 2. Records of all patients responding were reviewed, including radiographic imaging, histology, surgical records, and genetic testing. RESULTS: Thirty-six of the 61 patients (59%) responded (MEN 2A = 8, MEN 2B = 28) to the questionnaires. All patients with MEN 2A-HD were operated on for HD 2 to 63 years before being diagnosed with MEN 2. All patients responding were underweight as infants and had symptoms of abdominal pain, distention, and constipation. Eighty-eight percent had hematochezia, 63% had emesis, and 33% had intermittent diarrhea before surgery. All patients with MEN 2A-HD had rectal biopsies with a diverting colostomy as the initial surgical procedure. This was followed by a colostomy takedown and pull-through procedure at a later interval. Ninety-three percent of patients with MEN 2B had gastrointestinal symptoms 1 to 24 years before the diagnosis of MEN 2. Symptoms included flatulence (86%), abdominal distention or being underweight as a child (64%), abdominal pain (54%), constipation or diarrhea (43%), difficulty swallowing (39%), and vomiting (14%). Seventy-one percent of patients with MEN-2B with gastrointestinal symptoms had radiographic imaging, 32% were admitted to the hospital, and 29% underwent surgery. CONCLUSIONS: Patients with MEN 2A-HD had a typical HD presentation and always required surgery. Patients with MEN 2B have significant gastrointestinal symptoms, but less than a third had surgical intervention. Understanding the clinical course and differences in these patients will improve clinical management.     

Multiple endocrine neoplasias

Multiple endocrine neoplasia type 1 (MEN 1), and the multiple endocrine neoplasia type 2 syndromes (MEN 2A, MEN 2B, and familial non-MEN medullary thyroid carcinoma [FMTC]) encompass a wide range of endocrine problems, but arise from only two genes: the MEN 1 tumor suppressor gene and the RET proto-oncogene. MEN 1 is characterized by parathyroid hyperplasia, pancreaticoduodenal neuroendocrine tumors (PNTs), and pituitary adenomas. Surgery is the principal treatment modality for hyperparathyroidism and PNTs, but questions still remain concerning the timing and extent of surgery for PNTs. The MEN 2 syndromes are characterized by complete penetrance of medullary thyroid cancer. The MEN 2 syndromes differ in their variable expression of hyperparathyroidism, pheochromocytomas, and other clinical features. Genetic testing for mutations in the RET gene has revolutionized treatment by enabling thyroidectomies before significant disease occurs.     

Endocrine pancreatic tumors.

Neuroendocrine tumors of the pancreas are rare neoplasms that may arise sporadically or in association with a hereditary endocrine neoplasia syndrome. Effective management requires directed biochemical testing, careful choice of preoperative imaging tests, and complete pancreatic exploration by an experienced endocrine surgeon utilizing intraoperative ultrasound. Pancreatic endocrine tumors arising in the familial setting present unique diagnostic and therapeutic dilemmas.     

Medullary thyroid cancer: Medical management and follow-up

Opinion statement Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy that occurs in hereditary (25%) and sporadic (75%) clinical settings. MTC is present in all patients with the multiple endocrine neoplasia type 2 (MEN 2) syndromes. MTCs produce calcitonin, measurement of which indicates the presence of tumor in at-risk individuals and the effectiveness of therapy in treated patients. Surgery is the mainstay of therapy for primary and recurrent disease. Routine serial postoperative measurement of calcitonin levels should be done. Patients with elevated calcitonin levels should have imaging by computed tomography scan, magnetic resonance imaging, and/or fluorodeoxyglucose positron emission tomography to identify sites of recurrence and metastasis. The role of radiation therapy is not well defined. There is no effective systemic therapy for MTC at present. Activating mutations in a tyrosine kinase receptor gene are present in the majority of MTCs, and experience with tyrosine kinase inhibitors and other agents in the setting of clinical trials is critical for the identification of effective systemic treatment.     

Medullary thyroid carcinoma: Management of lymph node metastases

Opinion statement Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy of the thyroid C cells. Spread of MTC commonly occurs to cervical and mediastinal lymph nodes. MTC cells do not concentrate radioactive iodine, and are not sensitive to hormonal manipulation. Because of these features, the treatment of metastatic or recurrent MTC is different from the treatment of differentiated thyroid cancer. Surgery is the only effective therapy at present that can result in cure, or reduction in tumor burden, or effective palliation. Systematic surgical removal of at-risk or involved lymph node basins should be done in patients with palpable primary tumors and recurrence. A “berry-picking” approach is discouraged. Although data are limited, standard chemotherapy and radiation therapy have not been effective in the treatment of MTC. Newer targeted drug therapies are being examined in therapeutic clinical trials.     

Long-term functionality of cryopreserved parathyroid autografts: a 13-year prospective analysis

BACKGROUND: The functional results of cryopreserved heterotopic parathyroid autotransplantation (CHPA) are not well defined. The authors evaluated the outcomes of delayed CHPA for the treatment of surgically induced hypoparathyroidism. METHODS: Since November 1991, 448 parathyroid samples from 436 patients were cryopreserved at our institution. Of these, 29 patients underwent 34 CHPA procedures, with placement of 20 to 25 pieces of parathyroid tissue (approximately 50 to 75 mg) into the forearm. Outcomes were determined based on peripheral parathyroid hormone (PTH) levels and, where available, PTH gradients between grafted and nongrafted arms. Graft function results were defined as completely functional (patients with normal PTH and calcium levels off all calcium/vitamin D supplementation), partially functional (normal PTH levels and mild hypocalcemia on calcium supplementation), or nonfunctional (low PTH levels and dependent on calcium/vitamin D supplementation). RESULTS: Of the 29 patients with CHPA, prospective data were available for 26 patients undergoing 30 CHPA procedures (9 patients with MEN 1, 4 with MEN 2A, 1 with MEN 2B, and 12 with sporadic hyperparathyroidism). The mean follow-up interval was 2 years. Twelve of 26 patients (46%) had completely functional grafts, 6 patients (23%) had partially functional grafts, and the remaining 8 patients (31%) had nonfunctional grafts. No patient with CHPA had graft-dependent recurrent hyperparathyroidism. Of the 14 patients (15 autografts) with MEN, 7 patients (50%) had fully functional grafts, and 2 patients (14%) had partially functional grafts. The mean cryopreservation period was 7.9 months (range, 1 week to 22 months) for functional autografts and 15.3 months (range, 2 weeks to 106 months) for nonfunctional autografts (P < .01). CONCLUSIONS: Based on these data and those in previous studies, approximately 60% of delayed, cryopreserved parathyroid autografts are functional. In this study 40% autografts (46% of patients) achieved full competency off supplements. Some patients have evidence of graft function with normal PTH levels but are not normocalcemic. Results were similar for patients with MEN and nonhereditary hyperparathyroidism. The duration of cryopreservation was a significant indicator of graft failure, and no functional autograft was observed beyond 22 months of preservation. CHPA is a useful treatment modality for patients with postoperative hypocalcemia after thyroid or parathyroid surgery, who do not respond to immediate parathyroid autotransplantation.