Cushing's Syndrome from an Ectopic Pituitary Adenoma with Peliosis: A Histological,Immunohistochemical, and Ultrastructural Study and Review of the Literature

Ectopic pituitary adenoma (EPA) is rare and, to the authors’ knowledge, its association with peliosis has not yet been described. The case of a 38-yr-old woman with clinical and biochemical evidence of Cushing’s syndrome is reported. Magnetic resonance imaging (MRI) disclosed a normal pituitary and a separate mass in the sphenoid sinus. The surgically remove’s hyaline change in the corticotrophs, indicating exposure to glucocorticoid excess. By histology, the mass in the sphenoid sinus was a congested, chromophobic, partly basophilic, periodic acid-Schiff (PAS)-positive pituitary adenoma composed of pleomorphic, adrenocorticotropic hormone (ACTH)-positive, corticotrophs. There was focal immunopositivity for MIB-1 and proliferating cell nuclear antigen (PCNA). Electron microscopy confirmed the diagnosis of corticotroph adenoma. A striking finding, consistent with the diagnosis of peliosis, was the presence of multiple large blood-filled spaces lacking an endothelial lining. The capillaries were dilated, but often appeared empty and the fenestrated endothelium exhibited discontinuities. The cause of peliosis is obscure. It may be that the venous outflow was impaired in this case leading to capillary dilation, congestion, hyperpermeability, rupture, and accumulation of blood in extravascular spaces.     

The signaling pathways induced by neutrophil-endothelial cell adhesion

Adhesion of neutrophils to vascular endothelial cells (ECs), mediated by the interaction of CD11/CD18 and intercellular adhesion molecule-1 (ICAM-1), is often required for neutrophil transmigration across endothelium during most inflammatory responses. Induction of intracellular signaling in neutrophils as a result of adhesion has been recognized for many years. Recent studies demonstrated that neutrophil-endothelial adhesion also activates ECs. Examples of neutrophil adherence-induced changes in ECs include increases in intracellular Ca(2+), production of reactive oxygen species, and actin cytoskeleton changes. These changes result, in part, from ligation of EC adhesion molecules. This review article focuses on the signaling events that occur in ECs during neutrophil adhesion and the role of EC adhesion molecules, particularly ICAM-1, in the initiation of these signaling events in ECs. The evidence to date describing the molecular basis of ICAM-1-induced signaling will be summarized. Finally, the potential physiological roles of these signaling events induced by EC adhesion molecules in mediating neutrophil migration will be addressed.     

Rapid DNA haplotyping using a multiplex heteroduplex approach: Application to duchenne muscular dystrophy carrier testing

A new strategy has been developed for rapid haplotype analysis based on an initial multiplex amplification of several polymorphic sites, followed by heteroduplex detection. Heteroduplexes formed between two different alleles are detected because they migrate differently than the corresponding homoduplexes in Hydrolink-MDE gel. This simple, rapid method does not depend on specific sequences such as restriction enzyme sites or CA boxes and does not require the use of isotope. This approach has been tested using commonly occurring polymorphisms spanning the dystrophin gene as a model. We describe the use of the method to assign the carrier status of females in Duchenne muscular dystrophy (DMD) pedigrees. The method may be used for other genetic diseases when mutations are unknown or there are few dinucleotide markers in the gene proximity, and for the identification of haplotype backgrounds of mutant alleles. © 1995 Wiley-Liss, Inc.     

Leucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemia

The present study was designed to assess the effects of dietary leucine supplementation on muscle protein synthesis and whole body protein kinetics in elderly individuals. Twenty healthy male subjects (70 ± 1 years) were studied before and after continuous ingestion of a complete balanced diet supplemented or not with leucine. A primed (3.6 μmol kg⁻¹) constant infusion (0.06 μmol kg⁻¹ min⁻¹) of l -[1-¹³C]phenylalanine was used to determine whole body phenylalanine kinetics as well as fractional synthesis rate (FSR) in the myofibrillar fraction of muscle proteins from vastus lateralis biopsies. Whole body protein kinetics were not affected by leucine supplementation. In contrast, muscle FSR, measured over the 5-h period of feeding, was significantly greater in the volunteers given the leucine-supplemented meals compared with the control group (0.083 ± 0.008 versus 0.053 ± 0.009% h⁻¹, respectively, P < 0.05). This effect was due only to increased leucine availability because only plasma free leucine concentration significantly differed between the control and leucine-supplemented groups. We conclude that leucine supplementation during feeding improves muscle protein synthesis in the elderly independently of an overall increase of other amino acids. Whether increasing leucine intake in old people may limit muscle protein loss during ageing remains to be determined.     

Activation of the CD3/T cell receptor (TcR) complex or of protein kinase C potentiate adenylyl cyclase stimulation in a tumoral T cell line: involvement of two distinct intracellular pathways.

A monoclonal antibody (OKT3) directed against the T cell receptor (TcR)/CD3 molecular complex, as well as a protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate, PMA) were added to a culture of tumoral Jurkat T cells, in order to precise the sequence of intracellular signals leading to T cell activation. The experiments were performed in the presence or in absence of various stimulators of adenylate cyclase (AC) such as forskolin (FK), cholera toxin (CT) or prostaglandin E2 (PGE2). OKT3 increased inositol phosphate (IP) production; in parallel, it induced a slight accumulation of cAMP. The effect was markedly potentiated in presence of FK or CT, and to a lesser extent in the presence of PGE2. FK stimulated adenylate cyclase of Jurkat cell membranes, but the effect was not potentiated by OKT3, suggesting that potentiation of cAMP accumulation requires intact cells and is not mediated by direct receptor coupling. On the other hand, elevated cAMP accumulation induced a negative feedback on IP production. The effect of OKT3 on cAMP was mimicked by A23187, a Ca2+ ionophore, and abolished in the absence of extracellular Ca2+. PMA had the same effect as OKT3 on basal or FK- and CT-induced accumulation of cAMP. In contrast, it inhibited the PGE2 effect on the cyclic nucleotide. After desensitization of PKC by pretreatment with a high concentration of PMA, the phorbol ester was no longer effective. Under those conditions, facilitation by OKT3 of FK-induced accumulation of cAMP was preserved, whereas potentiation by the monoclonal antibody of the PGE2 stimulation of AC was even enhanced. The data indicate that cAMP accumulation indirectly elicited by phospholipase C activation is, at least partly, mediated by IP-dependent Ca2+ mobilization, while PKC is preferentially effective as an inhibitor of PGE2 stimulation.     

Novel missense mutations and a 288-bp exonic insertion in PAX9 in families with autosomal dominant hypodontia

We describe the molecular analysis of three families with hypodontia involving primarily molar teeth and report two novel mutational mechanisms. Linkage analysis of two large families revealed that the hypodontia was linked to the PAX9 locus. These two families revealed missense mutations consisting of a glutamic acid substitution for lysine and a proline substitution for leucine within the paired domain of PAX9. A pair of identical twins affected with hypodontia in a third family demonstrated a 288-bp insertion within exon 2 that resulted in a putative frameshift mutation and a premature stop codon. The insertion was associated with the loss of 7-bp from exon 2. A block of 256-bp of sequence within the insertion was completely identical to downstream sequence from the second intron of the PAX9 gene. These studies extend the spectrum of mutations in PAX9 associated with hypodontia to include heretofore undescribed categories, including missense mutations.     

A Nice development: The first joint meeting of the British and French Societies for Developmental Biology, 13-16th September, 2003, Nice, France.

Held this autumn on the beautiful Cote d'Azur, the first joint meeting of the BSDB and SFBD provided delegates with the perfect informal setting for discussion spanning a broad cross-section of Developmental Biology. Participants' interests were diverse, ranging from the implementation of genome-wide approaches aimed at identifying all the molecular components of cell proliferation, signalling, patterning, and morphogenesis, to those engaged in capturing mesmerising glimpses of the minute and intricate workings of the cell. The meeting considered a wide spectrum of model organisms, including the simple plant Arabidopsis, the invertebrates Dictyostelium, Caenorhabditis elegans, and Drosophila melanogaster, the ascidian Ciona intestinalis, and the vertebrates Xenopus, zebrafish, chick, and mouse. Such a diverse approach served to highlight both similarities and differences in the molecular mechanisms that govern embryonic development among different species. Here, we highlight a few aspects of the meeting that illustrate this point.     

Self-criticism and social phobia in the US national comorbidity survey

BACKGROUND: This study sought to extend findings from a preliminary clinical investigation [J. Affect. Disord. 57 (2000) 223] by examining relations between the personality dimension of self-criticism and diagnostic prevalence of social phobia in a large nationally representative sample. METHODS: Participants were from the national comorbidity survey Part II [n=5877; Arch. Gen. Psychiatry 51 (1994) 8]. Psychiatric diagnoses were made using a modified version of the composite international psychiatric interview. Personality dimensions and distress were assessed using brief self-report measures with strong psychometric properties. RESULTS: Self-criticism was elevated in NCS respondents with a diagnosis of social phobia, even in cases of only past history of social phobia (i.e. >1 year ago), compared to individuals with no psychiatric disorder. The highest levels of self-criticism were reported by people with the complex subtype of social phobia, both with and without comorbid major depression. These levels were significantly greater compared to those observed in another anxiety disorder (panic disorder), the pure speaking subtype of social phobia, and cases of major depression alone. In a regression analysis that controlled for current emotional distress, the broad personality trait of neuroticism, and lifetime histories of mood, anxiety, and substance use disorders, self-criticism remained significantly associated with lifetime prevalence of social phobia. LIMITATIONS: The cross-sectional design of the study does not permit causal inferences. CONCLUSIONS: Findings from this general population mental health survey demonstrated that self-criticism is robustly associated with social phobia. It may represent an important core psychological process in the complex subtype of this anxiety disorder.