Acromegaly in Carney complex.

PURPOSE: Carney complex (CNC) is a rare autosomal dominant syndrome, characterized by mucocutaneous pigmentation, cardiac, cutaneous myxomas and endocrine overactivity. It is generally caused by inactivating mutations in the PRKAR1A (protein kinase cAMP-dependent type I regulatory subunit alpha) gene. Acromegaly is an infrequent manifestation of CNC, reportedly diagnosed in 10% of patients. METHODS: We here report the case of a patient who was concomitantly diagnosed with Carney complex, due to a new mutation in PRKAR1A ((NM_002734.3:c.80_83del, p.(Ile27Lysfs*101 in exon 2), and acromegaly. In parallel, we conducted an extensive review of published case reports of acromegaly in the setting of CNC. RESULTS: The 43-year-old patient was diagnosed with an acromegaly due to a GH-secreting pituitary microadenoma resistant to somatostatin analogs. He underwent transsphenoidal surgery in our tertiary referral center, which found a pure GH-secreting adenoma. In the literature, we identified 57 cases (24 men, 33 women) of acromegaly in CNC patients. The median age at diagnosis was 28.8 ± 12 year and there were 6 cases of gigantism. Acromegaly revealed CNC in only 4 patients. 24 patients had a microadenoma and two carried pituitary hyperplasia and/or multiple adenomas, suggesting that CNC may result in a higher proportion of microadenoma as compared to non-CNC acromegaly. CONCLUSIONS: Although it rarely reveals CNC, acromegaly is diagnosed at a younger age in this setting, with a higher proportion of microadenomas.

Antiproliferative and antibiofilm potentials of endolichenic fungi associated with the lichen Nephroma laevigatum.

AIMS: The objective of this study was to explore the diversity of endolichenic fungi from Nephroma laevigatum and to investigate their antiproliferative and antibiofilm potential. METHODS AND RESULTS: Forty-six isolates were obtained and identified by DNA barcoding. They belonged to genera Nemania, Daldinia, Peziza and Coniochaeta. Six strains belonging to the most represented species were selected and tested for their antiproliferative and antibiofilm activities. Extracts were analysed by reversed-phase HPLC. Activities against fungal and bacterial biofilm were evaluated using tetrazolium salt (XTT) assay and crystal violet assay respectively. Antiproliferative responses of extracts were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induction by two extracts was observed in two cell lines (HT-29 and PC-3) via morphological changes, pro-apoptotic and anti-apoptotic proteins analysis (Western blotting) and DNA fragmentation. Four extracts displayed activities against Candida albicans biofilm with IC50 values ranging from 25 to 200 µg ml-1 . All extracts were inactive against Staphylococcus aureus and Pseudomonas aeruginosa biofilms. The most active isolates against human colorectal (HT-29 and HCT116) and prostate (PC-3 and DU145) cancer cell lines were Nemania serpens (NL08) and Nemania aenea var. aureolatum (NL38) with IC50 values ranging from 13 to 39 µg ml-1 . These extracts induced an apoptotic process through activation of caspases 8 and 3, poly(ADP-ribose) polymerase cleavage and DNA fragmentation. CONCLUSIONS: Selected crude fungal extracts have antiproliferative and antibiofilm activities. Data suggest that this antipoliferative effect is due to apoptosis process. This is the first report showing the effects of endolichenic fungi from N. laevigatum. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the therapeutic potential of endolichenic fungi metabolites as sources for drug discovery programmes.

Effects of selective REM sleep deprivation on prefrontal gamma activity and executive functions.

Given that the dorsolateral prefrontal cortex is involved in executive functions and is deactivated and decoupled from posterior associative regions during REM sleep, that Gamma temporal coupling involved in information processing is enhanced during REM sleep, and that adult humans spend about 90 min of every 24h in REM sleep, it might be expected that REM sleep deprivation would modify Gamma temporal coupling and have a deteriorating effect on executive functions. We analyzed EEG Gamma activity and temporal coupling during implementation of a rule-guided task before and after REM sleep deprivation and its effect on verbal fluency, flexible thinking and selective attention. After two nights in the laboratory for adaptation, on the third night subjects (n=18) were randomly assigned to either selective REM sleep deprivation effectuated by awakening them at each REM sleep onset or, the same number of NREM sleep awakenings as a control for unspecific effects of sleep interruptions. Implementation of abstract rules to guide behavior required greater activation and synchronization of Gamma activity in the frontopolar regions after REM sleep reduction from 20.6% at baseline to just 3.93% of total sleep time. However, contrary to our hypothesis, both groups showed an overall improvement in executive task performance and no effect on their capacity to sustain selective attention. These results suggest that after one night of selective REM sleep deprivation executive functions can be compensated by increasing frontal activation and they still require the participation of supervisory control by frontopolar regions.

Enhanced synchronization of gamma activity between frontal lobes during REM sleep as a function of REM sleep deprivation in man.

UNLABELLED: Studies have shown that synchrony or temporal coupling of gamma activity is involved in processing and integrating information in the brain. Comparing rapid eye movement (REM) sleep to waking and non-REM (NREM) sleep, interhemispheric temporal coupling is higher, but lower between the frontal and posterior association areas of the same hemisphere. However, the homeostatic response of REM sleep temporal coupling after selective REM sleep deprivation (REMD) has not been studied. This study proposed exploring the effect of one night of selective REMD on the temporal coupling of cortical gamma activity during recovery REM sleep. Two groups of healthy subjects were subjected to either REMD by awakening them at each REM sleep onset, or to NREM sleep interruptions. Subjects slept four consecutive nights in the laboratory: first for adaptation, second as baseline, third for sleep manipulation, and fourth for recovery. Interhemispheric and intrahemispheric EEG correlations were analyzed during tonic REM (no eye movements) for the first three REM sleep episodes during baseline sleep, and recovery sleep after one night of selective REMD. Temporal coupling between frontal lobes showed a significant homeostatic rebound that increased during recovery REM sleep relative to baseline and controls. Results showed a rebound in temporal coupling between the two frontal lobes after REM sleep deprivation, indicating that the enhanced gamma temporal coupling that occurs normally during REM sleep has functional consequences. CONCLUSION: results suggest that synchronized activity during REM sleep may play an important role in integrating and reprocessing information.

Participation rates of Ashkenazi Jews in a colon cancer community-based screening/prevention study.

In a recent colon cancer risk study, genetic assessment and colonoscopy were offered to virtually all of the adult Ashkenazi Jews in an urban community. The present study was designed to examine factors influencing participation and response in the initial study and to suggest strategies for improving participation in future health promotion programs. The study comprised a random sample of three groups of individuals who had been targeted for participation in the previous study: those who had (a) agreed to participate (n = 234); (b) declined participation (n = 179); and (c) failed to respond to a mailed recruitment package (n = 128). All participants completed a brief telephone survey. Key multivariate predictors of both response and participation were individuals' perceptions of the drawbacks of participating in colon cancer screening research and the degree of decisional conflict they experienced. Response was further predicted by the influence of spouses, family history of colon cancer, past knowledge of genetic testing for colon cancer, and education level. Participation was predicted by awareness that the study was supported by the Ashkenazi Jewish community, past experience with genetic testing, individuals' perceptions of the benefits of participating, and whether or not they had children. The degree to which individuals understand the purpose and nature of genetic screening research, along with their levels of decisional conflict and other psychosocial factors, may influence the likelihood of their participation in such research. Results of this study suggest a number of possible strategies for improving participation and response rates in disease prevention and detection studies.

APC I1307K increases risk of transition from polyp to colorectal carcinoma in Ashkenazi Jews.

BACKGROUND & AIMS: The I1307K allele of the APC gene has been shown to confer a modestly elevated risk of colorectal cancer in the Ashkenazi Jewish population (relative risk, 1.5-1.7). However, it is unclear whether the alteration predisposes to adenomas and whether the genetic information can be used in clinical practice. To further address the pathogenic significance of I1307K, we offered both a genetic test and a screening program to individuals considered to be at increased risk for colorectal cancer. We compared the prevalence of polyps and their characteristics between carriers and noncarriers. METHODS: Invitations to participate in a DNA and colonoscopy screening program were mailed, together with a family questionnaire, to 3540 households forming the Jewish Community in Ottawa. The I1307K variant was analyzed in 242 eligible respondents who were selected because they had a personal or family history of colon cancer. Nearly 80% of these respondents (n = 189; age range, 32-83 years) consented to undergo a single colonoscopic examination. RESULTS: The overall carrier frequency of I1307K in the study group was 10.3%. A higher proportion of heterozygous gene carriers was found in the subgroup of colon cancer survivors (27%) than among asymptomatic individuals (8%, P < 0.02). A total of 59 polyps were identified in 44 subjects. Histologically confirmed adenomatous polyps were diagnosed in 11.8% of carriers and 12.8% of noncarriers (P > 0.5). No significant differences in polyp size, multiplicity, location, degree of villosity, or age-dependent prevalence were found between the 2 groups of participants. CONCLUSIONS: The high frequency of I1307K colorectal cancer patients found in the Ashkenazi Jewish community of Ottawa and the equivalent proportion of carriers and noncarriers who developed adenomatous polyps suggest that in this community, I1307K is associated with a significant predisposition to carcinoma but not adenoma.

Diagnostic sensitivity of three tumour markers in non-small cell lung cancer: a pilot study.

BACKGROUND: Three tumour markers (CEA, CYFRA 21.1 and CA125) were evaluated for diagnostic sensitivity in newly diagnosed, untreated non-small cell lung cancer. METHODS: In the 24 patients studied, the tumours were classified histologically as 15 squamous cell carcinomas and 9 adenocarcinomas. In 19 cases, the disease was confined to the lung (M0); 5 cases presented with metastatic disease at the time of diagnosis (M1). RESULTS: CA125 displayed the best overall sensitivity (62%) and also when only localised disease was evaluated (63%). CA125 was the most sensitive marker for adenocarcinomas (89%), with values differing significantly with histological type (p < 0.005). CYFRA 21.1 was most sensitive in squamous cell carcinomas (53%); this was the only marker which was elevated in all cases involving metastatic disease, and exhibited a significant correlation with stage (p<0.02). CEA presented the poorest overall sensitivity (42%). The overall sensitivity of the three-tumour marker association was 79% and the best combination of two markers was CYFRA 21.1 + CA125 (75%). CONCLUSIONS: This pilot study allows recommendation of the associated use of these two markers as first choice of diagnostic aid in non-small cell lung cancer. Further measurements, including specificity studies in benign lung diseases, should be performed to confirm these results.

Genetics of hereditary colon cancer: a model for prevention.

Accompanying the explosion of genetic information about cancer is the technology to allow a better understanding of carcinogenesis and tools that can be exploited in the diagnosis and management of cancers. The familial forms of colorectal cancer, including familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer offer the most tangible examples of potential improvements in mortality and morbidity incorporating molecular markers. This article reviews the current direct applications of molecular genetics in identifying the risk, prevention and management of colon cancer. The limitations and current controversies in the field are discussed, including research strategies being adopted to solve the remaining problems. Parallel strategies in familial breast cancer and ovarian cancer are being developed to bring the medical profession into the molecular age of cancer management.

[Use of a medium and long chain triglyceride mixture for parenteral nutrition in a university hospital: results of an internal audit]. / Utilisation d'un mélange de triglycérides à chaînes longues et chaînes moyennes pour la nutrition parentérale en hôpital universitaire. Résultats d'un audit interne.

OBJECTIVES: The aim of this study was to determine whether a medium and long chain triglyceride mixture for parenteral nutrition is used in accordance with indications and contraindications in hospital practice. METHODS: Patient data recorded in 30 consecutive patients included illness, nutritional status, laboratory findings before nutrition as well as indications and contraindications for parenteral nutrition. RESULTS: When expressed in g.kg-1.day-1 maximal recommended doses of the mixture were exceeded in 32% but there was no excess when expressed in g.kg-1.hr-1. Serious hepatic insufficiency was present in 11% of the patients, 38% had hypertriglyceridemia and one had serious coagulopathy. There were 3 contraindications for the mixture. CONCLUSION: Indications for using this emulsion were respected, but there were contraindications in 45% of the cases. These contraindications are however questionable as is the daily dosage. Because the mixture seems better for use in many cases of parenteral nutrition, it would appear best to discuss the prescription case by case.

Insulin-like growth factor binding protein 1 level in amniotic fluid: correlation with birth weight.

Insulin-like growth factor binding protein 1 is the predominant insulin-like growth factor binding protein in amniotic fluid. It is produced by the decidua and by fetal tissues, and it is thought to play an important role in fetal growth. We have measured this protein in 58 samples of amniotic fluid, from 13 to 19 gestational weeks, and found a highly significant negative correlation with fetal weight at birth. We conclude that the level of insulin-like growth factor binding protein 1 in amniotic fluid at midpregnancy is a good marker of fetal growth failure.

Twenty-nine day study of stability for six different parenteral nutrition mixtures.

: BACKGROUND: The aim of the study was to assess the particle size stability of six parenteral nutrition regimens, fitted to various pathologies, and used by the University Hospital of Limoges. The mixtures contained glucose (30 or 50%), amino acids (Hyperamine(R)25), and either long-chain triglycerides (20% Intralipide(R)) or a combination of medium and long-chain triglycerides (20% Médialipide(R)). The regimens were not supplemented. RESULTS: The visual examinations, particle size analysis and physico-chemical tests, carried out during a long storage period, did not reveal any significant evolution of the lipid emulsions. All the tested formulae were stable for 28 days at 4 degrees C plus 24 h at room temperature. CONCLUSIONS: It was concluded that the choice of lipid emulsions depends, for these formulae, on the metabolic and clinical needs of the treated patients.

Genetic pre-disposition to colorectal cancer: Initiation of a prospective study in Eastern Ontario.

A pilot study which is part of both a larger provincial initiative and a network is in progress to address the question of genetic pre-disposition to non-polyposis colorectal cancer in eastern Ontario (population 1,200,000). It is modeled along a dual process of recruitment of at-risk individuals based on either prior documentation of family histories or a close relationship to patients who are hospitalized for colorectal cancer treatment. The molecular diagnostic and genetic counseling components of the project are in their initial phase of operation while follow-up strategies are being planned.

Three-dimensional shape reconstruction by phase-shifting shadow moire.

Shadow moiré shows contour lines of an object with respect to a master grating plane; they result from the interference between the lines of the master grid and their shadow projected by a point source of light. In best cases the sensitivity of this procedure is a few tenths of a millimeter. The introduction of a phase-shifting procedure gives a better resolution, but the problem in practice is how can we shift the phase of the interferogram into shadow moiré? A complete study is presented showing the influence of different parameters. It is shown that only one possibility is available. Some applications to threedimensional shape reconstructions are presented with an accuracy of 0.01 mm, showing that the potentiality of shadow moiré is greatly improved.

Allogeneic tumor-specific cytotoxic T lymphocytes.

We report the development of cytotoxic T lymphocytes specific for an allogeneic brain tumor in a rat model. DA strain cytotoxic T cell precursors stimulated by an allogeneic tumor (9L gliosarcoma) from the Fischer rat could generate a population of cytotoxic T lymphocytes that lysed the allogeneic 9L tumor but failed to lyse other targets, including Fischer concanavalin-A(ConA)-stimulated lymphoid blast targets. DA T cells depleted of reactivity to the Fischer haplotype (DA-F) retained reactivity to the 9L tumor, demonstrating that T cell precursors with specificity for normal Fischer alloantigens were not required for the generation of a response to the 9L Fischer tumor. The preferential lysis of the tumor target did not simply reflect a higher density of Fischer target antigens on the tumor than that found on normal Fischer ConA blast targets. First, the relative densities of class I antigen on the 9L tumor and normal Fischer ConA blasts were comparable. Second, cytotoxic T cells could not be generated from DA-F precursors when Fischer ConA blasts were used as stimulators. If DA-F T cells were simply responding to the higher density of Fischer antigen found on 9L tumor, it would have been expected that the ConA blasts expressing comparable levels of antigen to that found on the tumor would have generated cytotoxicity for both the 9L and ConA targets. We conclude that the cytotoxic T cells are specific for a determinant expressed only by the tumor. Such tumor-specific cytotoxic T cells could be useful in vivo for adoptive immunotherapy of brain tumors.

Cytotoxic T-cell precursors with low-level CD8 in the diabetes-prone Biobreeding rat: implications for generation of an autoimmune T-cell repertoire.

Lymphocytes from diabetes-prone Biobreeding rats consistently fail to generate T-cell-mediated cytotoxicity under conditions where cytotoxic T lymphocyte activity is readily demonstrated in normal rats. The failure is associated with generalized T-cell lymphopenia and marked reduction in the frequency of CD8+ cells. The few remaining CD8+ cells are widely held to be natural killer cells rather than class I major histocompatibility complex-restricted T lymphocytes. In this report we show that a detectable percentage of CD8+ lymphocytes express the T-cell receptor for antigen, thus identifying them as part of the T-cell lineage. The failure of these CD8+ T-cell-receptor-positive T cells to lyse target cells that are susceptible to T-cell mediated cytotoxicity is associated with markedly reduced expression of cell-surface CD8. Targets expressing higher than normal levels of class I major histocompatibility complex target antigen could be lysed, suggesting that reduction in CD8 has decreased T-cell activity for target antigen. We discuss the derivation of T cells that express low levels of CD8 and the role they could play in generating autoimmune diabetes.

[Anomalies of enamel formation in subjects with maxillary clefts]. / Anomalies de formation de l'émail chez les sujets présentant des fentes maxillaires.

A structural and ultrastructural study of teeth located in the vicinity of maxillary cleft and teeth located outside the cleft region, was made in 12 cases, using correlated light microscopy, microradiography and SEM. All teeth directly involved in cleft process presented gross hypoplasia of the crown where the enamel surface was hypomineralized. Globular calcified masses of different radiodensity were seen on the hypomineralized enamel surface. The teeth located outside the cleft region presented less pronounced anomalies constituted by isolated or group microhypoplasia on hypomineralized enamel. The observation of enamel pearl was not pathognomonic of maxillary cleft.

Autoregulation of MeWo metastatic melanoma cell growth: characterization of intracellular (FGF, MGSA) and secreted (PDGF) growth factors.

MeWo melanoma cells (clone LC1) secrete a potent mitogenic activity susceptible to reinitiate DNA replication in quiescent rodent fibroblasts (CCL39, NRK-49F, NIH-3T3) but not in BHK-21 kidney cells. This activity appears to be closely related to platelet-derived growth factor (PDGF) based on 1) its cationic nature, heat and acid resistance, but sensitivity to reducing agents; 2) its apparent molecular weight (33 kDaltons) as estimated by Biogel filtration, once dissociated from binding proteins by mild acidic treatment; 3) its weak affinity for heparin; and 4) its ability to compete with 125I-PDGF for binding to human and rodent fibroblasts, and to be recognized by anti-PDGF antibodies. Although MeWo cells coexpress the PDGF-A and PDGF-B (c-sis) chain gene transcripts, the secreted product shows reactivity on CCL39 fibroblasts more compatible with the PDGF-BB than with the PDGF-AB isoform. MeWo cell lysates contain activities that bind moderately and strongly to heparin-Sepharose, being eluted with 1.0 and 2.0 M NaCl, respectively. The latter may correspond to basic fibroblast growth factor (basic FGF), consistent with the expression of basic FGF gene mRNAs. The former has not been fully characterized and is probably not the product of the acidic FGF gene. In addition, MeWo cells react positively with the FB2 AH7 antibody, thus indicating that they elaborate material similar to melanoma growth-stimulating activity (MGSA). MeWo cells proliferate in serum-free medium in a cell-density-dependent fashion, both in liquid and semisolid cultures. Their division is modestly enhanced by basic FGF and by human and porcine PDGF but not by the factors that they release. However, the absence of demonstrable 125I-PDGF binding sites on MeWo cells, in conjunction with their lack of sensitivity to suramin growth inhibition, suggests that the secreted PDGF does not act as an autocrine factor. Instead, the autonomous proliferation of MeWo melanoma cells may result from the concerted action of basic FGF and MGSA, which are mostly cell-associated.

Metastatic conversion of factor-dependent lung fibroblasts (CCL39) requires over-expression of oncogenes which induce high rate of autonomous replication.

Several classes of oncogenes were tested for their ability to confer cellular growth autonomy and the metastatic phenotype on CCL39 lung fibroblasts. v-sis as well as highly but not weakly expressed activated ras, v-fps and myc genes were susceptible to relieve CCL39 cells from their dependence on exogenous growth factors. However, based on growth rate estimations, ras and fps cells divided 2 to 3 times more rapidly than myc and sis cells in serum-free medium. All ras and fps cells produced pulmonary metastases in 60-100% of young nude mice, following subcutaneous or intravenous injection. Acquisition of factor-independent growth during in vivo passage was demonstrated in two instances. Animals developed either no or sporadic metastases after implantation of transfected cells expressing v-sis, normal Ha-ras, myc or no foreign oncogene. The results are consistent with the notion that the rate at which tumor cells can proliferate independently from growth factor stimulation is a good predictor of their metastatic potential. Oncogenes such as activated ras and fps appear more efficient than myc and sis to induce the metastatic conversion of preneoplastic CCL39 cells and to abrogate Go-arrest controls of division.