High risk pregnancies in hypopituitary women

BACKGROUND: Various short papers have suggested that pregnancies in women with hypopituitarism are high risk but no formal assessment of pregnancy outcome has yet been reported. METHODS: An audit was carried out concerning the outcome of 18 pregnancies in nine women who underwent ovulation induction in a single centre over 20 years. RESULTS: The live birth rate was 61%, miscarriage rate 28% and mid-trimester uterine death rate 11% with no survivors from four sets of twins. The Caesarian section rate was 100% and half of the live births were on or below the 10th centile for weight. One woman successfully breast-fed. CONCLUSIONS: Women with hypopituitarism have high-risk pregnancies, perhaps because of a uterine defect secondary to endocrine deficiency. Fertility treatment must strive for singleton pregnancies with application of particularly strict criteria to avoid twin pregnancies. Early elective Caesarian section is probably warranted in this group.     

Control of recombination within and between DNA plasmids of Saccharomyces cerevisiae

Summary [2 m⁺ and [2m°] yeast were transformed to stable leucine prototrophy with the hybrid yeast — E. coli plasmid, pJDB219. This plasmid contains the entire sequence of the endogenous 2 m yeast DNA plasmid in addition to the yeast nuclear LEU2 ⁺ gene and the Co1E1 derivative, pMB9. In the [2 m⁺] transformants, a new wholly yeast LEU2 ⁺ plasmid, pYX, was generated, probably by a recombination event between pJDB219 and 2 m DNA. The plamid, pYX, in the absence of 2 m DNA, was found to exist in equimolar amounts of two forms, A and B, which probably arise by intramolecular recombination across the inverted repeat sequences of the 2 m DNA portion of the plasmid. pJDB219 was found to require the presence of 2 m DNA to undergo this intramolecular recombination. The results suggest that 2, m DNA and pYX code for a gene product required in this recombination event which pJDB219 cannot produce.     

Partial trisomy 6p and partial monosomy 9p from a de novo translocation 46, XY, -9, + DER(9)T(6:9)(p211:p24)

This report describes an adult male with a partial trisomy 6p(p211-pter) and a partial monosomy 9p(9p24-pter) resulting from a de novo unbalanced translocation. This patient does not show the classical featured of the 9p partial monosomy syndrome, thus disputing the claim of Hoo et al. (1982) that 9p24 is the critical segment for the monosomy syndrome. Partial trisomy for 6p has only been previously reported in children. In addition to the chromosomal anomalies, the patient has autosomal recessive spinal muscular atrophy with a different age of onset than two affected sibs. Finally, he shows unusual audiologic and ophthalmologic signs nor previously reported as part of the 9p monosomy or 6p trisomy syndromes.     

Complex CGH alterations on chromosome arm 8p at candidate tumor suppressor gene loci in breast cancer cell lines

Loss of genetic material from chromosome arm 8p occurs frequently in human breast carcinomas, consistent with this region of the genome harboring one or more tumor suppressor genes (TSGs). We used the complementary techniques of microsatellite-based LOH, high-density FISH, and conventional CGH on 6 breast cancer cell lines (MCF7, SKBR3, T47D, MDA MB453, BT549, and BT474) to investigate the molecular cytogenetic changes occurring on chromosome 8 during tumorigenesis, with particular emphasis on 6 potential TSGs on 8p. We identified multiple alterations of chromosome 8, including partial or complete deletion of 8p or 8q, duplication of 8q, and isochromosome 8q. The detailed FISH analysis showed several complex rearrangements of 8p with differing breakpoints of varying proximity to the genes of interest. High rates of LOH were observed at markers adjacent to or within PCM1, DUSP4/MKP2, NKX3A, and DLC1, supporting their status as candidate TSGs. Due to the complex ploidy status of these cell lines, relative loss of 8p material detected by CGH did not always correlate with microsatellite-based LOH results. These results extend our understanding of the mechanisms accompanying the dysregulation of candidate tumor suppressor loci on chromosome arm 8p, and identify appropriate cellular systems for further investigation of their biological properties.     

Correct promoter control is needed for trafficking of the ring-infected erythrocyte surface antigen to the host cytosol in transfected malaria parasites

Following invasion of human erythrocytes, the malaria parasite, Plasmodium falciparum, exports proteins beyond the confines of its own plasma membrane to modify the properties of the host red cell membrane. These modifications are critical to the pathogenesis of malaria. Analysis of the P. falciparum genome sequence has identified a large number of molecules with putative atypical signal sequences. The signals remain poorly characterized; however, a number of molecules with these motifs localize to the host erythrocyte. To examine the role of these atypical signal sequences in the export of parasite proteins, we have generated transfected parasites expressing a chimeric protein comprising the N-terminal region of the P. falciparum ring-infected erythrocyte surface antigen (RESA) appended to green fluorescent protein (GFP). This N-terminal region contains a hydrophobic stretch of amino acids that is presumed to act as a noncanonical secretory signal sequence. Modulation of the timing of transgene expression demonstrates that trafficking of malaria proteins into the host erythrocyte is dependent on both the presence of an appropriate transport signal and the timing of expression. Transgene expression under the control of a trophozoite-specific promoter mistargets the chimeric molecule to the parasitophorous vacuole surrounding the parasite. However, expression of RESA-GFP in schizont stages, under the control of the RESA promoter, enables correct trafficking of a population of the chimeric protein to the host erythrocyte.     

Gastric helicobacter infection induces a Th2 phenotype but does not elevate serum cholesterol in mice lacking inducible nitric oxide synthase

Persistent Helicobacter felis infection in (C57BL/6 x 129SvEv)F1 mice induces chronic gastritis. Expression of inducible nitric oxide synthase (iNOS) is upregulated in response to Helicobacter infection. In this study, 20 10-week-old iNOS-/- mice and 20 wild-type [(C57BL/6 x 129SvEv)F1] mice were infected with H. felis by oral gavage and were assessed histologically and serologically at 32 weeks postinfection. Equal numbers of uninfected controls were sham inoculated. The mice were scored for severity of gastric inflammation, hyperplasia, glandular atrophy, and mucous metaplasia in the corpus and for the level of helicobacter colonization. The immunoglobulin G1 (IgG1), IgG2a, and IgG2c antibody responses to H. felis were determined. As a secondary measure, serum cholesterol levels were assessed. iNOS-/- mice have a propensity for increased serum cholesterol, and although controversial, several human epidemiologic studies have demonstrated an association between Helicobacter infection and several risk factors for cardiovascular disease, including elevated serum cholesterol. Nevertheless, no differences in serum cholesterol levels were observed between the H. felis-infected and -uninfected iNOS-/- mice in this study. The uninfected animals had minimal to no gastric pathology. The gastric pathology scores for the infected animals were reduced significantly in the iNOS-deficient mice relative to those for the wild-type mice (all P <0.01). Helicobacter-infected iNOS-/- mice had chronic lymphoid infiltration and negligible to mild glandular atrophy and mucous metaplasia in the fundic mucosa, while H. felis-infected wild-type mice had severe atrophic and metaplastic mucosal changes. The atrophic gastritis in the infected wild-type mice, particularly the female mice, was also accompanied by greater granulocytic infiltration, antral hyperplasia, and diminished antral colonization, unlike that in the infected iNOS-/- mice. iNOS-/- mice developed significantly lower Th1-associated IgG2c antibody responses to H. felis (P <0.0003); the Th2-associated IgG1 responses were similar (P=0.09), suggesting a greater effect of the iNOS defect on Th1 responses. H. felis colonization was significantly greater in the iNOS-deficient mice. These findings are indicative of an impaired Th1 component of the H. felis-induced inflammatory response when the influence of iNOS is removed.     

Clinical correlates and symptom patterns of anxious depression among patients with major depressive disorder in STAR*D

BACKGROUND: Anxious depression, defined as Major Depressive Disorder (MDD) with high levels of anxiety symptoms, may represent a relatively common depressive subtype, with distinctive features. OBJECTIVE: The objective of this study was to determine the prevalence of anxious depression and to define its clinical correlates and symptom patterns. METHOD: Baseline clinical and sociodemographic data were collected on 1450 subjects participating in the STAR*D study. A baseline Hamilton Rating Scale for Depression (HAM-D) Anxiety/ Somatization factor score of > or =7 was considered indicative of anxious depression. The types and degree of concurrent psychiatric symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items endorsed by study participants for each diagnostic category. MDD symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology (IDS-C30). RESULTS: The prevalence of anxious depression in this population was 46 %. Patients with anxious MDD were significantly more likely to be older, unemployed, less educated, more severely depressed, and to have suicidal ideation before and after adjustment for severity of depression. As far as concurrent psychiatric symptoms are concerned, patients with anxious depression were significantly more likely to endorse symptoms related to generalized anxiety, obsessive compulsive, panic, post-traumatic stress, agoraphobia, hypochondriasis, and somatoform disorders before and after adjustment for severity of depression. Anxious-depression individuals were also significantly less likely to endorse IDS-C30 items concerning atypical features, and were significantly more likely to endorse items concerning melancholic/endogenous depression features. CONCLUSION: This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).     

CD40 ligand is a T cell growth factor

CD40 ligand (CD40L) is a 33-kDa type II membrane glycoprotein induced on T cells upon activation. CD40L has previously been shown to induce proliferation of resting B cells, immunoglobulin (Ig) secretion from B cells cultured with cytokines and cytokine secretion and tumoricidal activity from monocytes. In this report CD40L is shown to be stimulatory for human T cells, inducing CD25 (p55 IL-2R) and CD40L expression on resting peripheral blood T cells, enhanced expression of these molecules and CD69 on CD3-activated cells and secretion of interferon-y, tumor necrosis factor-a and interleukin (IL)-2 from T cells cultured in the presence of a sub-mitogenic concentration of phytohemagglutinin A (PHA). Furthermore, stimulation with CD40L induces proliferation of CD3- or PHA-activated T cells of blood, tonsillar or thymic origin. A similar proliferative response is observed with CD4^? and CD8⁺ T cells and this effect is largely IL-2 independent. A soluble construct of the extracellular domain of the CD40L has similar activity to that of membrane-expressed ligand in the induction of T cell surface antigens and proliferation. The results presented here taken together with the various activities ascribed for CD40L on B cells and monocytes demonstrate that CD40L has pleiotropic biological activity for cells of the hemopoietic lineage.