Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: high incidence of endocrine and growth problems.

Due to the poor prognosis of high-risk (HR) neuroblastoma (NBL), scant data exist on late effects after treatment. Recently, protocols utilizing intense multimodal treatment have resulted in improved long-term survival. The objective of this study was to determine the prevalence of late effects in survivors of HR NBL. A retrospective review of clinical data for serial patients completing treatment between September 1994 and October 2007 and surviving for at least 1 year was performed. Therapy included aggressive chemotherapy, surgery, radiation and single or tandem SCT. Oncology follow-up was standard; clinical criteria were utilized for referrals to endocrinology and other services. Fifty-one eligible patients were identified. Median follow-up was 6.1 years (range 1.0-15.2). Height was significantly impacted (ΔZ-score -1.91 in those treated with TBI and -0.77 in those without). Pre-diabetes or diabetes, hypothyroidism and ovarian insufficiency were observed in 50, 59 and 75% of at-risk survivors, respectively. Hearing loss and dental issues were common. Nine patients had relapse of NBL; seven died of progressive disease. As there is a high prevalence of late effects in long-term survivors of HR NBL, close monitoring and further studies after treatment are indicated, and in particular after more modern, non-TBI regimens.

Memory deficits among children with craniopharyngiomas.

OBJECTIVE: To describe neuropsychological functioning (with a specific focus on cognition and memory) after surgical treatment of craniopharyngiomas. METHODS: Sixteen patients who were between 6 and 15 years of age at the time of surgery comprised the sample. Each child had been treated for a craniopharyngioma with surgery only, on Dana-Farber Cancer Institute Protocol 92-077. RESULTS: The overall level of cognitive functioning was well within the average range, with both language and visuospatial functioning being generally intact; however, specific memory problems, in both the language and visuospatial domains, were evident. CONCLUSION: Although general cognitive functioning was intact after the surgical treatment of craniopharyngiomas, difficulties in the retrieval of learned information were observed. Neuropsychological assessments, with a focus on memory recall, should be a component of the medical management plan for each child.

cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes.

Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). Since cAMP response element-binding protein (CREB)-binding protein (CBP) integrates a number of cell signaling pathways, we investigated whether CBP is important for TRH stimulation of the TSH subunit genes. Cotransfection of E1A in GH(3) cells completely blocked TRH stimulation of the TSH subunit genes, suggesting that CBP is a key factor for TRH signaling in the pituitary. CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-beta promoter, and amino acids 1-450 of CBP were sufficient for the TRH effect. In contrast, on the human alpha-GSU promoter, CREB and P-Lim mediated TRH signaling. Intriguingly, CREB was phosphorylated upon TRH stimulation, leading to CBP recruitment to the alpha-GSU promoter. CBP also interacted with P-Lim in a TRH-dependent manner, suggesting that P-Lim is an important factor for non-cAMP response element-mediated TRH stimulation of this promoter. Distinct domains of CBP were required for TRH signaling by CREB and P-Lim on the alpha-GSU promoter, amino acids 450-700 and 1-450, respectively. Thus, the amino terminus of CBP plays a critical role in TRH signaling in the anterior pituitary via both Pit-1-dependent and -independent pathways, yielding differential regulation of pituitary gene products.

Genetic regulation of the embryology of the pituitary gland and somatotrophs.

Extrinsic and intrinsic signaling gradients determine expression patterns of pituitary-specific factors in the developing anterior pituitary gland. The temporal and spatial relations of these developmental factors are required for the determination of each of the pituitary cell lineages. Rpx is required for early differentiation of the anterior pituitary. The determination of the somatotroph cell line is dependent on the transcription factors Lhx3, Prop-1, and Pit-1. Pit-1 also plays a role in the activation and regulation of the somatotroph gene product, GH. Additional factors such as CREB and the GHRH receptor, may be involved in somatotroph determination, while Zn-15 and Pitx2 may be involved in GH gene activation.

Adenocarcinoma arising in interposed colon: report of a case.

A rare occurrence of primary adenocarcinoma arising in an interposed colon nearly seven years after the surgery is described. Remarkably, there were no symptoms from a large mass in the transposed bowel. Diagnosis was made fortuitously while searching for the cause of the patient's iron-deficiency anemia. The rationale for careful preoperative screening of the colonic segment intended for transplant to exclude pre-existing pathology is reemphasized. The various methods of evaluating the postoperative colon graft and their advantages and limitations are discussed.

CREB-independent regulation by CBP is a novel mechanism of human growth hormone gene expression.

Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) gene expression in anterior pituitary somatotrophs by binding to the GHRH receptor, a G-protein-coupled transmembrane receptor, and by mediating a cAMP-mediated protein kinase A (PKA) signal-transduction pathway. Two nonclassical cAMP-response element motifs (CGTCA) are located at nucleotides -187/-183 (distal cAMP-response element; dCRE) and -99/-95 (proximal cAMP-response element; pCRE) of the human GH promoter and are required for cAMP responsiveness, along with the pituitary-specific transcription factor Pit-1 (official nomenclature, POU1F1). Although a role for cAMP-response element binding protein (CREB) in GH stimulation by PKA has been suggested, it is unclear how the effect may be mediated. CREB binding protein (CBP) is a nuclear cofactor named for its ability to bind CREB. However, CBP also binds other nuclear proteins. We determined that CBP interacts with Pit-1 and is a cofactor for Pit-1-dependent activation of the human GH promoter. This pathway appears to be independent of CREB, with CPB being the likely target of phosphorylation by PKA.

Defective retinoic acid regulation of the Pit-1 gene enhancer: a novel mechanism of combined pituitary hormone deficiency.

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. Pit-1 contains two protein domains, termed POU-specific and POU-homeo, which are both necessary for DNA binding and activation of the GH and PRL genes and regulation of the PRL, TSH-beta subunit (TSH-beta), and Pit-1 genes. Pit-1 is also necessary for retinoic acid induction of its own gene during development through a Pit-1-dependent enhancer. Combined pituitary hormone deficiency is caused by defective transactivation of target genes in the anterior pituitary. In the present report, we provide in vivo evidence that retinoic acid induction of the Pit-1 gene can be impaired by a Pit-1 gene mutation, suggesting a new molecular mechanism for combined pituitary hormone deficiency in man.

A novel mechanism for cyclic adenosine 3',5'-monophosphate regulation of gene expression by CREB-binding protein.

The pituitary-specific transcription factor, Pit-1, is necessary to mediate protein kinase A (PKA) regulation of the GH, PRL, and TSH-beta subunit genes in the pituitary. Since these target genes lack classical cAMP DNA response elements (CREs), the mechanism of this regulation was previously unknown. We show that CREB binding protein (CBP), through two cysteine-histidine rich domains (C/H1 and C/H3), specifically and constitutively interacts with Pit-1 in pituitary cells. Pit-1 and CBP synergistically activate the PRL gene after PKA stimulation in a mechanism requiring both an intact Pit-1 amino-terminal and DNA-binding domain. A CBP construct containing the C/H3 domain [amino acids (aa) 1678-2441], but not one lacking the C/H3 domain (aa 1891-2441), is sufficient to mediate this response. Neither construct augments PKA regulation of CRE-containing promoters. Fusion of either CBP fragment to the GAL4 DNA-binding domain transferred complete PKA regulation to a heterologous promoter. These findings provide a mechanism for CREB-independent regulation of gene expression by cAMP.

Familial growth hormone deficiency associated with MRI abnormalities.

Idiopathic growth hormone deficiency is, in most cases, a sporadic condition. In a number of these patients magnetic resonance imaging (MRI) demonstrates a small anterior pituitary, small or absent pituitary stalk, and ectopically located posterior pituitary. These findings have been attributed to a developmental defect, trauma, or ischemia at birth. We report on a case of familial isolated growth hormone deficiency with mother and son demonstrating the MRI findings described above. The son also had a Chiari type I malformation and medial deviation of the carotid arteries secondary to a narrow skull base. Testing failed to identify a mutation in either the Pit-1 gene or GH gene cluster. This case appears to be an autosomal dominant defect in early development, lending support to the hypothesis that dysgenesis, rather than birth trauma, may cause a small anterior pituitary and ectopic posterior pituitary.

The molecular basis of hypopituitarism.

Pit-1 is a pituitary-specific transcription factor responsible for pituitary development and hormone expression in mammals. My laboratory and others have recently described several patients with combined pituitary hormone deficiency (CPHD) due to point mutations in the pit-1 gene. In addition to pit-1, other nuclear factors appear to be necessary for full expression of pituitary genes. A zinc finger transcription factor, Zn-15, is responsible with pit-1 for synergistic activation of the GH gene. The Pr1 gene is regulated synergistically by pit-1 and the estrogen receptor. Finally, the pit-1 gene itself is regulated by an enhancer element located > 10 kb upstream of the transcriptional start. This element contains several pit-1 DNA binding sites and retinoic acid response elements (RAREs). On one of these elements, pit-1 and RAR interact functionally to mediate a synergistic response to RA. Recent data from our laboratory suggests that RA induction of the pit-1 gene can be impaired by pit-1 gene mutations. Study of pit-1 mutations and their diverse pathophysiological mechanisms should increase our understanding of anterior pituitary gland development and gene regulation in normal and disease states.

Optic chiasm astrocytomas of childhood. 1. Long-term follow-up.

We reviewed 61 patients seen from 1975 to 1994 with a biopsy-confirmed optic chiasm astrocytoma or a characteristic clinical and imaging presentation. The mean age at diagnosis was 72 months, including 30 who were less than 5 years old. The mean tumor diameter at presentation was 31 mm among 54 tumors measured. Tumors involved the optic nerve in 41, hypothalamus in 38, optic tract in 15, and optic radiations in 2. Four patients, all with neurofibromatosis, received no treatment. Forty patients received conventional radiation therapy at a mean age of 89 months. Chemotherapy was given to 19 children and 7 of these were followed for greater than 1 year. Six of these 7 had progressive disease which required subsequent surgery and/or radiation therapy. Thirty-six patients underwent surgery. We restricted our analysis of outcome to those 38 patients followed for longer than 60 months. Development was normal in 13%, mildly disabled in 53%, severely disabled in 21% and dead in 13%. Children were severely disabled or dead in 47% if younger than 5 years at diagnosis, and 21% if older. There was no endocrine dysfunction in 18% and new endocrine failure was seen in 61%. More posterior tumors did not portend a poorer prognosis. Children less than 5 years old had a poorer prognosis. Neurofibromatosis did not have a marked effect on outcome. Intracranial hypertension was an indicator of a poor prognosis. No specific treatment modality was clearly superior in terms of long-term survival or improvement in quality of life.

Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin.

To date, nine different mutations in the Pit-1 gene resulting in CPHD have been described in mammals. Four of these mutations alter residues important for DNA binding or alter the predicted alpha helical nature of the Pit-1 protein (A158P, R172X, E250X, and W261C). The A158P mutation, however, has minimal effects on DNA binding. Four mutations lie outside alpha helical regions (P24L, R143Q, K216E, and R271W) and do not significantly alter DNA binding either experimentally or by prediction. One mutation is a large deletion of the Pit-1 gene locus in the Jackson dwarf mouse. Mutant Pit-1 proteins that do not interfere with binding cause CPHD through interference with target gene activation and regulation. The R271W mutant acts as a dominant inhibitor of transcription of the GH and Prl genes. The A158P mutant is incapable of activating transcription from the GH-I site and has low activation of transcription of the distal enhancer and proximal promoter sites of Prl and of 320 bp of the 5' GH promoter sequence. Some mutant proteins interfere with nuclear receptors. For example, the K216E mutant has defective retinoic acid signaling on the Pit-1 gene enhancer. There is phenotypic variability in the degree of CPHD and in pituitary size in patients with Pit-1 gene mutations. Since Pit-1 has different functions in the somatotroph, lactotroph, and thyrotroph, it is not surprising that point mutations in different regions of the gene interfere in different ways with Pit-1 function. A mutant Pit-1 may be able to carry out its developmental role, but may be aberrant in GH and Prl gene activation or Pit-1 autoregulation. Study of Pit-1 mutations and their diverse pathophysiologic mechanisms should increase the understanding of anterior pituitary gland development and gene regulation in normal and disease states.

A "hot spot" in the Pit-1 gene responsible for combined pituitary hormone deficiency: clinical and molecular correlates.

Pit-1 is a member of the POU family of transcription factors regulating mammalian development. Pit-1 is thought to be the major cell-specific activator of both the somatotrophs and lactotrophs in the anterior pituitary. When bound to DNA, Pit-1 activates GH and PRL gene expression. Pit-1 is also important for hormonal regulation of the PRL and TSH-beta genes by TRH and cAMP. We studied two unrelated patients with GH, PRL, and TSH deficiencies. Both patients have the same point mutation in the POU homeodomain of the Pit-1 gene (R271W). Patient 1 was studied as an adult and had combined deficiencies of GH, PRL, and TSH. Patient 2, who was studied in infancy, also had GH and PRL deficiencies, but had low thyroid hormone levels with a measurable basal level of TSH and a delayed response of TSH to TRH. Consequently, the current description of Pit-1 gene mutations leading to complete GH, PRL, and TSH deficiencies needs to be expanded to GH and PRL deficiencies associated with a compromise of the thyrotroph's ability to synthesize TSH.

The nature of crime : Is cheating necessary for cooperation?

The classical social theorist Emile Durkheim proposed the counterintuitive thesis that crime is beneficial for society because it provokes punishment, which enhances social solidarity. His logic, however, is blemished by a reified view of society that leads to group-selectionist thinking and a teleological account of the causes of crime. Reconceptualization of the relationship between crime and punishment in terms of evolutionary game theory, however, suggests that crime (cheating) may confer benefits on cooperating individuals by promoting stability in their patterns of cooperation.

Prostaglandin infusion therapy for intermittent digital ischemia in a patient with mixed connective tissue disease. Case report and review of the literature.

Intermittent digital ischemia is frequently resistant to therapy despite various treatment modalities. Recent studies have reported the successful treatment of intermittent digital ischemia with prostaglandin infusion therapy. We present a severe case of intermittent digital ischemia associated with mixed connective tissue disease, responsive to prostaglandin E1 infusion therapy.

Folliculitis decalvans--response to rifampin.

Folliculitis decalvans is a rare follicular inflammatory disease of the scalp. It is characterized by initial perifollicular inflammatory changes followed by peripheral extension and eventual circumscribed patches of cicatricial alopecia. The disease is known for its resistance to treatment, resulting in an unfavorable prognosis. The cause of the disease is unknown, although a bacterial etiology is postulated. We report a classic case that was temporized with various antibiotics and only subsequently resolved after ten weeks of therapy with rifampin. The patient has remained free of disease for more than one year. We present a brief review of the cicatricial alopecias and discuss rifampin therapy for this condition.

Scleromyxedema: therapeutic response to isotretinoin in three patients.

Scleromyxedema is a rare type of papular mucinosis that exhibits a generalized lichenoid pattern. A wide variety of clinical manifestations can occur in patients with this disease. Cutaneous involvement is characteristic, but neurologic, cardiovascular, renal, neoplastic, and other systemic manifestations have been described. A monoclonal gammopathy may be present. Many treatment modalities have been used in the past for scleromyxedema. None, however, have shown consistently favorable results. This report concerns the cases of three patients with scleromyxedema who were treated with isotretinoin.

Hemodynamics and intrathoracic pressure transmission during controlled mechanical ventilation and positive end-expiratory pressure in normal and low compliant lungs.

PEEP can significantly reduce cardiac output. This reduction in cardiac output is frequently attributed to transmission of airway pressure to intrathoracic vascular structures. We designed an acute lung injury (ALI) model in swine (n = 7) characterized by low lung thorax compliance (CLT) and compared the fractional transmission of airway pressure to pleura (PPL) and pericardium (PPC) and hemodynamics to normal animals (n = 5) during controlled mechanical ventilation (CMV) and PEEP. Fractional transmission of PEEP to PPL and PPC was reduced significantly from 62 +/- 8% and 54 +/- 19 (SD)% to 34 +/- 7% and 36 +/- 9% in normal and ALI animals, respectively. End-inspiration tracheal pressure was significantly higher in the low compliant group; thus, cardiac output was equally depressed in both groups despite reduction in fractional airway pressure transmission in ALI animals, possibly because absolute inspiratory PPL and PPC were similar due to increased pressure required to inflate injured lungs. The results of this investigation do not support the presumption that low CLT blunts hemodynamic consequences of CMV and PEEP.