Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity.

Peripheral inflammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. Inflammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin gene-related peptide (CGRP). In the present study, mice deficient in the calcitonin/alpha CGRP gene (CGRP(-/-)) displayed normal responses to noxious stimuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint inflammation in two tests that assess central sensitization, through testing at sites remote from the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP(-/-) mice showed no signs of secondary hyperalgesia after development of knee joint inflammation, while the expected significant decrease in the PWL was observed in the CGRP(+/+) mice as control. The CGRP(-/-) mice also had a prolonged rather than a shortened response latency in the hot-plate test 4 h after knee joint injection of k/c. Immunohistological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(-/-) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral inflammatory events including the development of nociceptive behaviors.

Multiple endocrine neoplasias.

The multiple endocrine neoplasia syndromes form a distinct group of genetic tumor syndromes. They include multiple endocrine neoplasia types 1 and 2, von Hippel Lindau syndrome, neurofibromatosis, and Carney complex. Research over the past decade has identified a molecular basis for each of these syndromes. This knowledge has revolutionized not only the clinical management but also has illuminated the field of human cancer research by the identification of new and important genes critical for regulation of cell growth, differentiation, and death. This review focuses on the structure, physiologic function, and molecular abnormalities of the genes involved in these syndromes.

Calcium-induced activation of a mutant G-protein-coupled receptor causes in vitro transformation of NIH/3T3 cells.

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that is widely expressed, has tissue-specific functions, and regulates cell growth. Activating mutations of this receptor cause autosomal dominant hypocalcemia, a syndrome characterized by hypocalcemia and hypercalciuria. The identification of a family with an activating mutation of the CaR (Thr151Met) in which hypocalcemia cosegregates with several unusual neoplasms led us to examine the transforming effects of this mutant receptor. Transfection of NIH/3T3 cells with the mutant but not the normal receptor supported colony formation in soft agar at subphysiologic calcium concentrations. The mutant CaR causes a calcium-dependent activation of the extracellular signal-regulated protein kinase (ERK) 1/2 and Jun-N-terminal kinase/stress-activated (JNK/ SAPK) pathways, but not P38 MAP kinase. These findings contribute to a growing body of information suggesting that this receptor plays a role in the regulation of cellular proliferation, and that aberrant activation of the mutant receptor in this family may play a role in the unusual neoplastic manifestations.

The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia.

BACKGROUND: Tumor hypoglycemia can be recurrent and severe enough to interfere with definitive antineoplastic treatment. Therefore, rapid commencement of effective therapy is essential. This is best accomplished by identifying which of the hypoglycemic processes is involved, as treatments differ. Some patients present with hypoglycemia and liver metastases; among them, only a few develop hypoglycemia as a result of a failure of hepatic glucose production. Most develop hypoglycemia as a result of an insulin-mediated process--either the secretion of insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II by an extrapancreatic tumor. Administration of glucagon can rapidly make the two groups distinguishable, thus allowing institution of therapy and prompt symptomatic control of hypoglycemia. METHODS: The charts of seven patients with tumor hypoglycemia and liver metastases who had a glucagon stimulation test (serial glucose measurements after a 1 mg infusion of glucagon) as part of the workup for hypoglycemia were retrospectively reviewed. Those patients whose test revealed a rise in serum glucose of >30 mg/ dL were subsequently treated as outpatients, with a continuous glucagon infusion delivered by a portable pump. RESULTS: Three patients had an insulinoma and four had non-islet cell tumor hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal sarcoma, and hemangiopericytoma, respectively. All of the patients had liver metastases. Evaluation of these patients included a glucagon stimulation test (1 mg intravenous push), which quickly provided information about the mechanism of tumor hypoglycemia and the direction towards therapy. All patients with insulinoma responded to glucagon with a rise in blood serum glucose levels, indicating adequate glycogen stores. The four patients with NICTH had mixed responses: in two patients, the response suggested that hypoglycemia was due to an insulin-like tumor product; glucose levels did not rise in the other two cases, indicating that hypoglycemia was due to poor hepatic glycogen reserve/liver failure. In all cases, a glycemic response to glucagon predicted good response to long term treatment with glucagon (0.06-0.3 mg/hour, via intravenous infusion pump). CONCLUSIONS: The glucagon stimulation test is a simple and fast approach that serves to clarify the etiology of hypoglycemia (diagnostic use) and guide effective long term strategies for its control (therapeutic use) in patients with neoplastic diseases and liver metastases.