Dietary chromium tripicolinate supplementation reduces glucose concentrations and improves glucose tolerance in normal-weight cats.

The effect of dietary chromium supplementation on glucose and insulin metabolism in healthy, non-obese cats was evaluated. Thirty-two cats were randomly divided into four groups and fed experimental diets consisting of a standard diet with 0 ppb (control), 150 ppb, 300 ppb, or 600 ppb added chromium as chromium tripicolinate. Intravenous glucose tolerance, insulin tolerance and insulin sensitivity tests with minimal model analysis were performed before and after 6 weeks of feeding the test diets. During the glucose tolerance test, glucose concentrations, area under the glucose concentration-time curve, and glucose half-life (300 ppb only), were significantly lower after the trial in cats supplemented with 300 ppb and 600 ppb chromium, compared with values before the trial. Fasting glucose concentrations measured on a different day in the biochemistry profile were also significantly lower after supplementation with 600 ppb chromium. There were no significant differences in insulin concentrations or indices in either the glucose or insulin tolerance tests following chromium supplementation, nor were there any differences between groups before or after the dietary trial.Importantly, this study has shown a small but significant, dose-dependent improvement in glucose tolerance in healthy, non-obese cats supplemented with dietary chromium. Further long-term studies are warranted to determine if the addition of chromium to feline diets is advantageous. Cats most likely to benefit are those with glucose intolerance and insulin resistance from lack of exercise, obesity and old age. Healthy cats at risk of glucose intolerance and diabetes from underlying low insulin sensitivity or genetic factors may also benefit from long-term chromium supplementation.

Mixed conventional and desmoplastic infantile ganglioglioma: an autopsied case with 6-year follow-up.

We describe a case of desmoplastic infantile ganglioglioma (DIG) arising in the ventral diencephalon of a 3-1/2-month-old boy. On biopsy, the tumor featured a desmoplastic, S-100 protein and GFAP immunoreactive stromal element, as well as a variable spectrum of ganglion cells. Electron microscopy demonstrated astrocytes, and morphologically fibroblasts, as well as neurons containing 120-nm dense core granules. In addition, tubular structures composed of tightly apposed cells with features of astrocytes and of Schwann-like cells were also noted. Devoid of fibroblasts, the tubular structures were surrounded by a single basal lamina. At autopsy 6 years later, the multinodular, cystic mass had replaced the diencephalon, extended into both temporal lobes as well as the optic nerves, and showed marked leptomeningeal involvement. Microscopically, superficial portions of the tumor consisted of typical DIG, whereas deep, nondesmoplastic portions exhibited pattern variation ranging from pilocytic astrocytoma to ganglioglioma and gangliocytoma. There was also a minor element of small, 'primitive-appearing' neuroepithelial cells. Dysplastic ganglion cells variously reactive for neurofilament protein and synaptophysin were present throughout the tumor. Our study not only confirms DIG as a variant of ganglioglioma, one capable of slow growth, infiltration, and fatal progression but suggests that its differentiating potential includes elements of both the central and peripheral nervous systems. If so, their derivation may be from multipotential cells of the neural plate.

Perceived health status in African American and Caucasian men 40 to 70 years old.

There is limited data on the relationship between perceived health status and the demographic variables of education and income in African American men. A sample of 2,001 men (72% African Americans and 28% Caucasians) who were participating in prostate cancer screening was studied to identify predictors of men's health status. Data on the concepts of self-rated health status, age, race, education, income, living arrangements, and marital status were collected. Findings indicated that men who were more likely to report excellent health status were older Caucasians, had more than a high school education, an annual income over 25,021 dollars, were living with others, and were married. Men more likely to report fair health status were older African Americans, unmarried, had less than a high school education, had an annual income less than 9,600 dollars, were living alone, and were unmarried. Implications for targeting at-risk men are presented.

Myosin heavy chain isoform and ubiquitin protease mRNA expression after passive leg cycling in persons with spinal cord injury.

OBJECTIVE: To determine the effects of passive leg cycling exercise on myosin heavy chain (MHC) isoform and ubiquitin (UBI) protease mRNA expression in patients with spinal cord injury (SCI). STUDY DESIGN: Case series. INTERVENTION: Eight SCI subjects (5 men, 3 women) participated in a 12-week exercise program involving the Psycle ergometer. Training occurred 2 days a week at 75% of each subject's maximum heart rate. Anthropometric measures (body weight, thigh girth, and body mass index) and muscle biopsy specimens were obtained before and after training. Analyses were performed to determine the mRNA expression of types I, IIa, and IIx MHC, as well as UBI, a UBI-conjugating enzyme (E2), and 20S proteasome (20S). RESULTS: Despite small increases, paired t tests (p < .05) to assess changes from pretraining to posttraining failed to locate significant differences for the three anthropometric measures. For mRNA expression, there were significant increases in expression of MHC types IIa and IIx and significant decreases in expression for UBI, E2, and 20S. CONCLUSION: Exercise using passive leg cycling increases the expression of fast MHC isoforms while concomitantly decreasing proteolytic activity associated with muscle degradation, thus helping to possibly ameliorate muscle atrophy in patients with SCI.

Pleuropulmonary blastoma: a clinicopathologic study of 50 cases.

BACKGROUND: Pleuropulmonary blastoma (PPB) is a unique dysontogenetic neoplasm of childhood that appears as a pulmonary and/or pleural-based mass and is characterized histologically by a primitive, variably mixed blastematous and sarcomatous appearance. METHODS: Histologic material from all cases was reviewed and the tumors subclassified as type I (purely cystic), type II (cystic and solid), or type III (purely solid). Data regarding presenting symptoms, family history, operative findings, pathologic subtypes, therapeutic interventions, and outcome were correlated with survival by standard statistical methods. RESULTS: The series was comprised of 24 males and 26 females. Respiratory difficulty with or without fever was the most common clinical symptom reported. Cyst formation in the affected lung was identified radiographically in 19 children (38%) at or before the definitive pathologic diagnosis. The ages at presentation of the 7 type I, 24 type II, and 19 type III PPBs were significantly different: 10, 34, and 44 months, respectively (P < 0.001). Local recurrence developed in 1 of 7 type I PPBs (14%) and in 18 of 43 type II and III PPBs (46%); distant metastasis occurred in 13 patients, chiefly to the brain/spinal cord or bone, and was observed only in those with type II or type III PPB. Patients with pleural or mediastinal involvement fared significantly worse than those without such involvement. Five-year survival was 83% for type I and 42% for types II and III. Survival differences on the basis of pathologic subtype did not reach statistical significance. CONCLUSIONS: PPB is an aggressive, intrathoracic neoplasm of early childhood with an unfavorable outcome. Although survival differences among patients with different histologic subtypes of disease did not reach statistical significance, the apparently better outcome for patients with purely cystic type I tumors may be borne out in a large series. These observations support the premise that type I and III PPB are bridged morphologically by type II PPB with its combined cystic and solid features. The PPB should be regarded as the pulmonary dysontogenetic analogue to Wilms' tumor in the kidney, neuroblastoma in the adrenal gland, and hepatoblastoma in the liver. Molecular genetic investigations, especially in constitutional PPB, should be revealing. In view of the poor outcomes for patients with types II and III, new and aggressive therapies must be developed.

Cystic renal lymphangiectasia: a distinctive clinicopathologic entity in the pediatric age group.

This report describes the features of unilateral cystic renal lymphangiectasia in a 2-year-old child who presented with hypertension, massive ascites, a left flank mass, and no evidence of familial renal cystic disease. The child became normotensive and is now asymptomatic more than 3 years after surgery. The clinical presentation and diffuse pathologic involvement are similar to findings for the few pediatric patients with cystic lymphangiectasia described in the literature and appear distinct from the more localized form of the disease seen in adults.

Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency.

A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive bearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23-11.4 (z = 2.723 at theta = 0.0). A candidate gene approach using the Norrie disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation of neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular disease may provide valuable insight into the potential role of this gene in cellular processes.

In vitro import of the Rieske iron-sulfur protein by trypanosome mitochondria.

Most of the proteins present in the mitochondrion are imported to that location from the cytosol. While this process has been studied extensively in fungal and mammalian systems, little work has been done in other eukaryotic organisms. We are particularly interested in the Trypanosoma brucei system because this organism developmentally regulates mitochondrial function during its life cycle and because one of the imported proteins lacks a conventional targeting sequence. We report here the development of an in vitro import system using crude trypanosome mitochondria and a nuclear encoded, mitochondrial protein. Import of the Rieske iron-sulfur protein subunit of the cytochrome c reductase complex requires a membrane potential, ATP, and a protein component on the mitochondrial surface. The precursor protein is sequentially processed to the mature form in two steps by peptidases that require divalent metal ions for activity. As in other eukaryotic systems, the first processing event occurs inside the inner membrane and is probably catalyzed by a matrix-processing protease. Surprisingly, the second processing activity is located outside the inner membrane. Both processing steps require ATP but are independent of a membrane potential. We suggest that the trypanosome iron-sulfur protein is imported along a "conservative sorting pathway" but that the assembly mechanism of the reductase complex may be unique to trypanosomes.

Pleuropulmonary blastoma: a marker for familial disease.

OBJECTIVE: To catalog and evaluate patterns of disease in families of children with pleuropulmonary blastoma (PPB). METHODS: Data have been collected since 1988 on 45 children with PPB and their families. All pathologic materials were centrally reviewed. Preliminary molecular genetic analyses were performed when possible. RESULTS: In 12 of 45 patients, an association was found between PPB and other dysplasias, neoplasias, or malignancies in the patients with or in their young relatives. The diseases found to be associated with PPB include other cases of PPB, pulmonary cysts, cystic nephromas, sarcomas, medulloblastomas, thyroid dysplasias and neoplasias, malignant germ cell tumors, Hodgkin disease, leukemia, and Langerhans cell histiocytosis. Abnormalities of the p53 tumor suppressor gene, Wilms tumor suppressor gene (WT1), and the putative second genetic locus for Wilms tumor (WT2) were not found in preliminary investigations. CONCLUSIONS: The occurrence of PPB appears to herald a constitutional and heritable predisposition to dysplastic or neoplastic disease in approximately 25% of cases. All patients with PPB and their families should be investigated carefully. Further research of this new family cancer syndrome may provide insight into the genetic basis of these diseases.

Monosomy 7 and activating RAS mutations accompany malignant transformation in patients with congenital neutropenia.

Individuals with severe forms of congenital neutropenia suffer from recurrent infections. The therapeutic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to increase the neutrophil count is associated with fewer infections and an improved quality of life. However, the long-term effects of this new therapy are largely unknown. In particular, it is unclear if myeloid leukemia, a known complication of some forms of congenital neutropenia, will occur with increased frequency among patients who receive long-term treatment with hematopoietic growth factors. We report 13 patients with congenital disorders of myelopoiesis who developed leukemic transformation with either myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) and 1 who acquired a clonal cytogenetic abnormality without evidence of MDS or AML while receiving rhG-CSF. The bone marrows of 10 patients showed monosomy 7 and 5 had activating RAS mutations. These abnormalities were not detected in pretreatment bone marrows and cessation of rhG-CSF was not associated with either clinical improvement or cytogenetic remission. We conclude that patients with severe forms of congenital neutropenia are at relatively high risk of developing MDS and AML. The occurrence of monosomy 7 and RAS mutations in these cases suggests that the myeloid progenitors of some patients are genetically predisposed to malignant transformation. The relationship between therapeutic rhG-CSF and leukemogenesis in patients with severe chronic neutropenia is unclear.

The trypanosomatid Rieske iron-sulfur proteins have a cleaved presequence that may direct mitochondrial import.

We have cloned the gene that encodes subunit 4 of the T. brucei cytochrome-c reductase complex and a fragment of the C. fasciculata subunit 4 cDNA and have shown that subunit 4 is the Rieske iron-sulfur protein. The cleaved presequences of the trypanosomatid iron-sulfur proteins resemble conventional mitochondrial targeting presequences but are smaller than other eukaryotic iron-sulfur protein signal peptides.

Primary mediastinal hemangiopericytoma with fatal outcome in a child.

Hemangiopericytoma occurs infrequently in children, and mediastinal sites are exceedingly rare. We report a case of mediastinal hemangiopericytoma in a 4-year-old child, which resulted in the patient's death due to large size, anatomic location, and associated perioperative bleeding. The pathologic diagnosis was established on the basis of light microscopic, immunohistochemical, and electron microscopic features. The presentation and clinical course of this case contrast with those of congenital or infantile hemangiopericytoma, which generally has a favorable outcome. Hemangiopericytoma should be considered in the differential diagnosis of large mediastinal masses in children.

Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases.

Inflammatory myofibroblastic tumor (IMT) or inflammatory pseudotumor is a spindle cell proliferation of disputed nosology, with a distinctive fibroinflammatory and even pseudosarcomatous appearance. Although the lung is the best known and most common site, inflammatory myofibroblastic tumor occurs in diverse extrapulmonary locations. We report our experience with 84 cases occurring in the soft tissues and viscera of 48 female patients and 36 male patients between the ages of 3 months and 46 years (mean, 9.7 years; median, 9 years). A mass, fever, weight loss, pain, and site-specific symptoms were the presenting complaints. Laboratory abnormalities included anemia, thrombocytosis, polyclonal hypergammaglobulinemia, and elevated erythrocyte sedimentation rate. Sites of involvement included abdomen, retroperitoneum, or pelvis (61 cases); head and neck, including upper respiratory tract (12 cases); trunk (8 cases); and extremities (3 cases). The lesions ranged in size from 1 to 17 cm (mean, 6.4; median, 6.0). Excision was performed in 69 cases. Eight had biopsy only. Five patients received chemotherapy or radiation in addition to undergoing biopsy or resection as initial treatment. Sixteen patients had multinodular masses involving one region. Clinical follow-up in 53 cases revealed that 44 patients were alive with no evidence of disease, four were alive with IMT, and five were dead. Thirteen patients had one or more recurrences at intervals of 1-24 months (mean, 6 months; median, 10 months). No distant metastases were documented. The five patients who died had complications either due to the location of the lesion (heart, peritoneum, retroperitoneum, or mesentery) or related to treatment (lymphoproliferative disorder following hepatic transplantation; sepsis following wound infection). The abdominal masses were the largest. All tumors were firm and white with infiltrative borders and focal myxoid change. Three basic histologic patterns were recognized: (a) myxoid, vascular, and inflammatory areas resembling nodular fasciitis; (b) compact spindle cells with intermingled inflammatory cells (lymphocytes, plasma cells, and eosinophils) resembling fibrous histiocytoma; and (c) dense plate-like collagen resembling a desmoid or scar. Immunohistochemistry demonstrated positivity for vimentin, muscle-specific actin, smooth muscle actin, and cytokeratin consistent with myofibroblasts. Based on this series, inflammatory myofibroblastic tumor is a benign, nonmetastasizing proliferation of myofibroblasts with a potential for recurrence and persistent local growth, similar in some respects to the fibromatoses.

Use of intracavitary cisplatin for the treatment of childhood solid tumors in the chest or abdominal cavity.

PURPOSE: Intracavitary (IC) delivery of cisplatin (CDDP) has been used in the treatment of a variety of adult malignancies based on the favorable pharmacokinetics obtained locally. Since IC CDDP has not been reported in children, we studied its use in a group of pediatric patients with regard to safety, toxicity, pharmacokinetics, and responses. PATIENTS AND METHODS: Eleven patients with an age range of 8 months to 21 years with diagnoses of rhabdomyosarcoma (n = 5), pleuropulmonary blastoma (n = 2), osteosarcoma (n = 2), Ewing's sarcoma (n = 1), and malignant rhabdoid tumor of the kidney (n = 1) were studied. Eight patients received intrapleural (IPL) CDDP and three received intraperitoneal (IP) CDDP, either at diagnosis (n = 3) or relapse (n = 8), for malignant pleural effusion (n = 3), malignant ascites (n = 2), pleural-based tumor (n = 4), pulmonary metastases (n = 1), or abdominal tumor spillage (n = 1). RESULTS: IC CDDP was well tolerated by pediatric patients. Two patients experienced a transient increase in serum creatinine levels (> two times baseline) and two patients experienced severe neutropenia (absolute neutrophil count < 500/microL). Pharmacokinectic measurements showed a 40-fold advantage for the pleural cavity versus serum after IPL CDDP and serum levels comparable to those achieved with systemic administration of CDDP. Four of five patients who received IC CDDP for malignant ascites or pleural effusion had at least a temporary response. Only three of 11 patients studied had local recurrences following IC CDDP. There are currently four survivors in the study group, including two long-term survivors at greater than 8 years since IPL CDDP treatment. CONCLUSION: The safety, toxicity, and pharmacokinetics of IC CDDP in pediatric patients are similar to that reported in adult patients. The low incidence of local recurrence following IC CDDP in this group of largely relapsed patients suggests that further study of IC CDDP for pediatric patients is warranted.

Excessive spinal cord toxicity from intensive central nervous system-directed therapies.

BACKGROUND: Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty-three cases of myelopathy that occurred in patients who received intensive CNS-directed therapy were evaluated to identify the determinants of this severe CNS toxicity. METHODS: Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS-directed therapies, including intrathecal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations. RESULTS: Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara-C before toxicity occurred; other received intrathecal ara-C and varying combinations of intrathecal MTX, HD ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were ventilator-dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. CONCLUSION: Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara-C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara-C and systemic HD ara-C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara-C does not protect against myelopathy. Multiple, frequently spaced courses of CNS-directed therapies must be avoided, especially in patients who have received prior CNS radiation.

Development of a user-defined surgical database using a personal computer network.

Advances in personal computer technology have made powerful methods for the collection and analysis of patient information available to clinical users. This report details the development of a multi-user database distributed across a network of personal computers that facilitates operative scheduling, and collection and analysis of operative data. Clinicians from each surgical service in our medical center developed customized data entry programs that contribute information centrally through a telephone-line network to prepare the daily operative schedule. Subsequently, information from the operating rooms is added to the preoperative database to form an operative log, which is distributed to client services for further analysis and modification. This system has improved the efficiency and accuracy of operative scheduling and information management and shifted the burden of data collection away from the physician. Widespread availability of these data has contributed to the development of an effective quality improvement program and facilitated effective management of personnel and resources.

Antithymocyte globulin, cyclosporine, and prednisone for the treatment of severe aplastic anemia in children. A pilot study.

PURPOSE: The aim of the therapeutic trial was to try to optimize the treatment of severe and moderate aplastic anemia in children who lack a suitable bone marrow donor using the most successful available drugs, with the least amount of side effects. PATIENTS AND METHODS: A pilot study for the treatment of severe aplastic anemia in children was conducted by four institutions. The treatment protocol included antithymocyte globulin (ATG), prednisone, and cyclosporine A. Twelve patients were enrolled, and 11 were evaluable. All patients had severe aplastic anemia (SAA); three had hepatitis-induced severe aplastic anemia (HI-SAA). RESULTS: Of 11 evaluable patients, eight have responded with normalization of their blood counts. Two of the three patients with HI-SAA responded to the therapy. CONCLUSION: The results of our pilot study compare favorably with previous therapeutic trials. All the patients who responded achieved complete response, i.e., restoration of blood counts to within the normal range.

Autoimmune neutropenia of infancy and early childhood.

Forty-one children were identified with autoimmune neutropenia of infancy and early childhood (absolute neutrophil count [ANC] less than 500/microliters and demonstrable serum antineutrophil antibodies). There were 21 boys and 20 girls; the median age at diagnosis was 11 months (range 5-38 months). No life-threatening infections occurred. There was a gradual upward trend in ANC in all patients over many months, with 87% having an ANC > 1000/microliters by 24 months from diagnosis. Among various clinical and laboratory parameters analyzed statistically, only younger age at diagnosis was associated with earlier neutrophil recovery. There was no association between degree or duration of neutropenia and sex, race, antibody reactivity, or presence of serious illness at diagnosis.

Cook obstetrics and gynecology catheter multicenter chorionic villus sampling trial: comparison of birth defects with expected rates.

OBJECTIVE: The null hypothesis was that offspring of women undergoing first-trimester chorionic villus sampling do not experience a rate of birth defects exceeding background rates. STUDY DESIGN: Follow-up information regarding major malformations was prospectively sought on offspring of 4105 women undergoing first-trimester chorionic villus sampling from nine centers participating in a collaborative study with the Cook obstetrics and gynecology catheter. These data were compared with data from the Collaborative Perinatal Project and other registries. RESULTS: A total of 84 offspring with major malformations was identified (2.36%). Compared with background rates, there was no increase in the incidence of total malformations or specific malformations (including limb reduction defects) in the subjects. One institution experienced all three limb reduction defects in this series; the probability of this occurring by chance alone is < 1%. CONCLUSION: Chorionic villus sampling was not found to result in an increase in major birth defects or in specific categories of birth defects in this series.

Fatal brain stem necrosis after standard posterior fossa radiation and aggressive chemotherapy for metastatic medulloblastoma.

A 3-year-old girl received conventional-dose external beam posterior fossa irradiation (5400 cGy in 30 fractions over 40 days) for good-risk medulloblastoma. Soon thereafter, she experienced an extraneural (occipital scar, cervical lymph nodes) and central nervous system (CNS) recurrence. Intensive cisplatin and cyclophosphamide chemotherapy led to rapid disappearance of the extraneural disease. Methotrexate was administered via a ventricular reservoir. After 2 months of chemotherapy, CNS toxicity progressed rapidly from ataxia to paraplegia to quadriplegia to central respiratory failure. Radiographic scans and autopsy material revealed brain stem necrosis. This unusual toxicity raises concern about the safety of aggressive systemic chemotherapy and intrathecal therapy, when given after conventional radiotherapy.