Distribution of vesicular glutamate transporter-2 messenger ribonucleic Acid and protein in the septum-hypothalamus of the rat

The excitatory neurotransmitter glutamate is involved in the control of most, perhaps all, neuroendocrine systems, yet the sites of glutamatergic neurons and their processes are unknown. Here, we used in situ hybridization and immunohistochemistry for the neuron-specific vesicular glutamate transporter-2 (VGLUT2) to identify the neurons in female rats that synthesize the neurotransmitter glutamate as well as their projections throughout the septum-hypothalamus. The results show that glutamatergic neurons are present in the septum-diagonal band complex and throughout the hypothalamus. The preoptic area and ventromedial and dorsomedial nuclei are particularly rich in glutamatergic neurons, followed by the supraoptic, paraventricular, and arcuate nuclei, whereas the suprachiasmatic nucleus does not express detectable amounts of VGLUT2 mRNA. Immunoreactive neurites are seen in very high densities in all regions analyzed, particularly in the preoptic region, followed by the ventromedial, dorsomedial, and arcuate nuclei as well as the external layer of the median eminence, whereas the mammillary complex does not exhibit VGLUT2 immunoreactivity. Many VGLUT2 immunoreactive fibers also contained synaptophysin, suggesting that the transporter is indeed localized to presynaptic terminals. Together, the results identify glutamatergic cell bodies throughout the septum-hypothalamus in region-specific patterns and show that glutamatergic nerve terminals are present in very large numbers such that most neurons in these brain regions can receive glutamatergic input. We examined the GnRH system as an example of a typical neuroendocrine system and could show that the GnRH perikarya are closely apposed by many VGLUT2-immunoreactive boutons, some of which also contained synaptophysin. The presence of VGLUT2 mRNA-containing cells in specific nuclei of the hypothalamus indicates that many neuroendocrine neurons coexpress glutamate as neurotransmitter, in addition to neuropeptides. These systems include the oxytocin, vasopressin, or CRH neurons as well as many others in the periventricular and mediobasal hypothalamus. The presence of VGLUT2 mRNA in steroid-sensitive regions of the hypothalamus, such as the anteroventral periventricular, paraventricular, or ventromedial nuclei indicates that gonadal and adrenal steroid can directly alter the functions of these glutamatergic neurons.     

Heavy chain diseases

Heavy chain diseases (HCDs) are rare B-cell lymphoplasma-cell proliferative disorders characterized by production of truncated monoclonal immunoglobulin heavy chains without associated light chains. HCDs involving the three main immunoglobulin classes have been described; alpha-HCD is the most common and has the most uniform presentation, gamma- and mu-HCDs have variable clinical presentations and histopathologic features. HCDs can be thought of as variant types of non-Hodgkin lymphoma: alpha-HCD presents as an extranodal marginal-zone lymphoma of mucosa-associated lymph-node tissue, gamma-HCD as lymphoplasmacytoid non-Hodgkin lymphoma, and mu-HCD as small lymphocytic non-Hodgkin lymphoma or chronic lymphocytic leukemia. Diagnosis of HCD requires documentation of a deleted immunoglobulin heavy chain without a bound light chain in the serum or urine. Prognosis is variable, and no standardized effective treatment programs are available except for alpha-HCD, which in its early stage may respond to antibiotics.     

Hepatic iron overload in blacks and whites: a comparative autopsy study

OBJECTIVE: Genetic susceptibility to iron loading is an important factor in the development of iron overload in Africans. This suggests that persons of African descent may be at risk to develop iron overload with its attendant complications, but relatively little is known about hepatic iron overload among blacks. The aim of this study was to compare the prevalence, histological features, and clinical correlates of hepatic iron overload in a group of autopsied black and white veterans. METHODS: Hepatic iron concentrations (HIC) were determined on liver tissue from autopsies performed at the John Cochran Veterans Affairs Medical Center during the period 1993 to 1996. Clinical information was obtained from autopsy protocols. Sections from livers in which the HIC exceeded the upper limit of normal were examined histologically. RESULTS: Of 256 specimens, 99 were from blacks (39%), whereas 157 were from whites (61%). Thirty-one blacks (31%) had an elevated HIC versus 44 whites (28%) (ns). In the majority of these cases (18 blacks, 30 whites), the HIC was less than twice the upper limit of normal. Nine of 15 subjects with an HIC greater than twice the upper limit of normal and no evident cause of secondary iron overload were black. CONCLUSIONS: The prevalence of mild-to-moderate hepatic iron overload was similar in this group of black and white veterans. Because of the inherent limitations of autopsy studies, prospective assessment of iron stores in healthy blacks is needed to determine more accurately the prevalence and clinical significance of iron overload in this population.     

IgD multiple myeloma: a cure at 21 years

A 52-year-old man with a plasmacytoma of the body of T-10 in February 1965 returned 6 months later with multiple myeloma characterized by bone pain, osteolytic lesions, and IgD lambda monoclonal protein in the serum, 6.1 g of Bence Jones protein in the urine, and 21% plasma cells in the bone marrow. The M-protein and bone pain disappeared within 6 weeks after therapy with melphalan and prednisone was started. Therapy was discontinued in December 1974. Immunoelectrophoreses and immunofixations of the serum and urine over the years revealed no monoclonal protein. A mediastinal tumor developed, and the patient died of respiratory insufficiency on October 23, 1986. Autopsy revealed a large bronchogenic carcinoma of the right lung extending to the mediastinum, trachea, and esophagus. There was no evidence of multiple myeloma. This patient had responded rapidly to chemotherapy and had no recurrence of myeloma during a 21-year follow-up.     

Control of systemic capillary leak syndrome with aminophylline and terbutaline.

PURPOSE: Patients with systemic capillary leak syndrome have a characteristic triad of hypotension, hemoconcentration, and monoclonal gammopathy. They have frequent and severe attacks of hemoconcentration and hypotension accompanied by marked plasma shifts. The exact role of this monoclonal protein is unknown, but it probably leads, in some way, to an increase in capillary permeability. Despite efforts to resuscitate the patients during an acute attack, the syndrome is often fatal. Some success has been obtained in preventing the attacks with the beta-adrenergic-stimulating agent terbutaline. The purpose of this study was to determine the effectiveness of aminophylline and terbutaline in the treatment of systemic capillary leak syndrome. METHODS: Over a decade, three patients with systemic capillary leak syndrome presented at our institution. All three patients were treated with terbutaline and aminophylline. Prednisone was used during the course of treatment in each of the three patients. RESULTS: In contrast to previous reports of partial or temporary control of episodes, all three patients are alive with almost complete resolution of their recurrent attacks and have been able to return to their normal lifestyles. CONCLUSION: The regimen of terbutaline and aminophylline effectively prevents the attacks of hypotension and hemoconcentration that occur in systemic capillary leak syndrome. The role of prednisone is not clear. Until more is known about the pathophysiology of the disorder, treatment must remain empiric and supportive.     

Acute leukemia and cytogenetic abnormalities complicating melphalan treatment of primary systemic amyloidosis

We followed up 153 patients with biopsy-proven primary systemic amyloidosis to determine their risk for acute nonlymphocytic leukemia or a dysmyelopoietic syndrome. In 10 patients cytogenetic abnormalities developed consistent with alkylator-induced damage to hematopoietic cells. In this group, the total melphalan dose ranged from 476 to 2450 mg (median, 1764 mg) administered over 21 to 92 months (median, 38 months). Eight of the 10 patients died as a direct result of pancytopenia, 1 died of progressive renal amyloid, and 1 remains alive with persistent complex cytogenetic abnormalities. Four patients had acute nonlymphocytic leukemia; 5 had a dysmyelopoietic syndrome; and 1 had a nondiagnostic bone marrow examination. Although only 6.5% of the entire group had leukemia or a dysmyelopoietic syndrome, the actuarial risk in patients surviving 3.5 years was 21%. Median survival from onset of dysmyelopoietic syndrome or acute leukemia was 8.1 months.     

Anaplastic plasma cell myeloma and immunoblastic lymphoma. Clinical, pathologic, and immunologic comparison

To test whether highly anaplastic myeloma and immunoblastic lymphoma are truly identical disease processes, simultaneous series were compared in respect to cytomorphologic features, immunoglobulin content or secretion, clinical and laboratory findings, and patient survival. Although the series partially overlapped in each studied feature, different trends served to distinguish them. Of the 14 patients with myeloma, all were dead at two years, whereas six of the 22 patients with lymphoma were disease-free at 35 to 78 months. Only 50 percent of patients with myeloma received intensive chemotherapy, whereas all 19 patients with stage III or IV lymphoma received such therapy. Myelomas secreted predominantly IgA heavy chain rather than IgG and lambda light chain rather than kappa. Lymphomas contained predominantly IgM rather than IgG and kappa rather than lambda. There were no IgM myelomas and no IgA lymphomas. The shorter survival of patients with the extremely anaplastic form of myeloma, as compared with patients who had immunoblastic lymphoma, may relate, in part, to prior therapy for previous lower grade myeloma; however, intrinsic differences in the nature of these two disease processes are reflected in their disparate immunologic characteristics.     

Monoclonal gammopathy of undetermined significance. Natural history in 241 cases

Two hundred forty-one patients with a monoclonal protein in the serum but initially no evidence of multiple myeloma, macroglobulinemia, amyloidosis or lymphoma were followed up for more than five years. At the conclusion of the studies the patients were classified as follows: Group 1, patients without significant increase in monoclonal protein, 57 per cent; group 2, patients with more than 50 per cent increase in monoclonal serum protein or development of monoclonal urine protein, 9 per cent; group 3, patients who died without five-year serum studies, 23 per cent; and group 4, patients in whom myeloma, macroglobulinemia or amyloidosis developed, 11 per cent. Initially, the hemoglobin level, size of serum monoclonal protein peak, number of plasma cells in the bone marrow and levels of normal immunoglobulins were not significantly different among the four groups. The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 64 months, of macroglobulinemia 103 months and of amyloidosis 92 months. A significant increase of the monoclonal protein or development of myeloma, macroglobulinemia or amyloidosis occurred in 18 per cent of the patients with monoclonal immunoglobulin G(IgG), in 28 per cent with immunoglobulin A (IgA) and in 25 per cent with immunoglobulin M (IgM). Retrospective analysis of age, sex, presence of organomegaly, hemoglobin level, size and type of serum monoclonal protein peak, presence of small amounts monoclonal light chain in the urine, serum albumin level, levels of uninvolved immunoglobulins, IgG subclass and level of plasma cells in the bone marrow did not show how to distinguish initially between stable benign disease and progressive disease. Therefore, periodic reexamination of patients with monoclonal gammopathy is essential.     

Familial myeloma. Report of eight families and a study of serum proteins in their relatives

During a 6 year period, eight instances of familial occurrence of myeloma involving siblings (16 cases of myeloma and 3 of probable benign monoclonal gammopathy) were encountered at the Mayo Clinic. No other monoclonal serum protein abnormalities were found in 70 relatives studied. In view of the infrequency of myeloma, the high familial occurrence of this disease suggests the possibility of genetic factors in its etiology. It is most important that a complete family history be obtained from patients with myeloma.