Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene.

Baller-Gerold syndrome (BGS) is a rare autosomal recessive condition with radial aplasia/hypoplasia and craniosynostosis (OMIM 218600). Of >20 cases reported so far, a few appear atypical and have been reassigned to other nosologic entities, including Fanconi anaemia, Roberts SC phocomelia, and Pfeiffer syndromes after demonstration of corresponding cytogenetic or molecular abnormalities. Clinical overlap between BGS, Rothmund-Thomson syndrome (RTS), and RAPADILINO syndrome is noticeable. Because patients with RAPADILINO syndrome and a subset of patients with RTS have RECQL4 mutations, we reassessed two previously reported BGS families and found causal mutations in RECQL4 in both. In the first family, four affected offspring had craniosynostosis and radial defect and one of them developed poikiloderma. In this family, compound heterozygosity for a R1021W missense mutation and a g.2886delT frameshift mutation of exon 9 was found. In the second family, the affected male had craniosynostosis, radial ray defect, poikiloderma, and short stature. He had a homozygous splice site mutation (IVS17-2A>C). In both families, the affected offspring had craniosynostosis, radial defects, and growth retardation, and two developed poikiloderma. Our results confirm that BGS in a subgroup of patients is due to RECQL4 mutations and could be integrated into a clinical spectrum that encompasses RTS and RAPADILINO syndrome.

Antiproliferative effects of isopentenylated coumarins isolated from Phellolophium madagascariense Baker.

From the leaves of Phellolophium madagascariense Baker (Apiaceae), an endemic herb to Madagascar, three known coumarins (osthol, murraol and meranzin hydrate) have been isolated and identified. This is the first report of these compounds in this species. The structural elucidations were based on the analysis of physical and spectroscopic data. The anticancer activity of the three isolated compounds and of a synthetic sample of osthol was evaluated on L1210 mouse leukemia and on human prostatic cancer hormonosensitive LNCaP and hormonoindependent PC3 and DU145 cell lines.

Screening of some New Caledonian and Vanuatu medicinal plants for antimycobacterial activity.

Twenty plants, belonging to sixteen families, used in traditional New Caledonian and Vanuatu medicine for treatment of symptoms potentially related to tuberculosis (cough, fever or inflammation) were screened for antimycobacterial activity. We also screened an original endemic plant, Amborella trichopoda, only member of the monogeneric family Amborellaceae and considered the most primitive living angiosperm. In total, 55 extracts were evaluated for inhibitory activity against Mycobacterium bovis BCG strain at a concentration of 100 microg/ml. Methanolic and dichloromethane extracts of Amborella trichopoda, Codiaeum peltatum, Myristica fatua, and essential oils Myoporum crassifolium showed an activity at this concentration. Methanolic extract of Amborella trichopoda fruits presented a significant activity with a minimal inhibitory concentration included between 1 and 2.5 microg/ml. In the same conditions, this activity was comparable with those of the reference drugs pyrazynamide and ethambutol, at 20 and 2.5 microg/ml, respectively.

Screening of New Caledonian and Vanuatu medicinal plants for antiprotozoal activity.

Sixty-seven extracts of 30 medicinal plants traditionally used in New Caledonia or Vanuatu by healers to treat inflammation, fever and in cicatrizing remedies were evaluated in vitro for their antiprotozoal activity against Leishmania donovani, Leishmania amazonensis and Trypanosoma cruzi. Among the selected plants, Pagiantha cerifera was the most active against both Leishmania species; four extracts were active against promastigotes of Leishmania donovani at EC(50) values inferior to 5 microg/ml. Garcinia pedicillata extract had an EC(50) value of 12.5 microg/ml against intracellular amastigotes of Leishmania amazonensis. Alone Amborella trichopoda reduced by more of 80% the trypomastigotes of Trypanosoma cruzi in the blood.

Genetic causes of hydrops fetalis.

A series of 1790 fetal and neonatal autopsies performed between 1976 and 1988 were retrospectively investigated for the presence of hydrops. Thirty (5.5%) and 35 (2.8%) cases of hydrops were found in the groups of fetal and neonatal autopsies, respectively. Genetic causes accounted for 35%. A careful search for previously reported genetic causes of fetal hydrops indicated 64 different etiologies. Twenty-one of them were not mentioned in the previous reviews: these include 9 skeletal dysplasias, 5 inborn errors of metabolism, 3 autosomal recessive, 3 autosomal dominant conditions, and 1 chromosomal abnormality.

Oral-facial-digital syndrome type I in a newborn male.

We report on a newborn male, born at term with clinical manifestations of oral-facial-digital (OFD) syndrome type I. This syndrome is generally assumed to be inherited in an X-linked dominant fashion with lethality in males. Therefore, liveborn males are exceptional. This liveborn male also had Dandy-Walker malformation and polycystic kidneys. From a general point of view, distinction between the 8 types of OFD syndromes described so far appears subtle and considerable overlap exists between them. In this regard, it should be noted that polycystic kidneys different from adult polycystic kidney disease both macroscopically and microscopically are a frequent manifestation of OFD I.

Antitumoral effects of squamocin on parental and multidrug resistant MCF7 (human breast adenocarcinoma) cell lines.

The antiproliferative effects of squamocin, one of the easiest annonaceous acetogenins to obtain, were studied in the parental (MCF7-S) and the multidrug resistant (MCF7-R) human breast adenocarcinoma cell lines. Squamocin inhibited proliferation of both cell lines identically, by blocking the cell cycle in the G1-phase. This inhibition was reversible in the long term. Squamocin decreased the ATP pool in both MCF7 cell lines, but did not seem to induce apoptosis. Cytotoxic activity of adriamycin was not restored in MCF7-R Pgp expressing cells by squamocin addition.

In vitro antileishmanial activity of acetogenins from Annonaceae.

Twelve acetogenins from Annonaceae were evaluated in vitro for their antileishmanial activities in order to search for new lead-compounds having antileishmanial properties. The compounds were comparatively evaluated by the 50% inhibitory concentrations (IC50) determination on promastigote forms of wild-type and four drug-resistant lines of Leishmania donovani. In addition, after testing the toxicity on mouse peritoneal macrophages, the compounds were evaluated on amastigote infected macrophages and a therapeutic index was calculated. The IC50 of the acetogenins against promastigote forms of L. donovani was in a range 4.7-47.3 microM. The most active compound was Rolliniastatin 1 (IC50 at 4.7 microM). On the intramacrophage amastigote in vitro model, only seven compounds exhibited measurable antileishmanial activity with IC50 values in a range 2.5-29.7 microM. Rollinistatin 1 was the most interesting compound with IC50 of 2.5 microM and it appears as the most promising one on the basis of therapeutic index (18.08). Isoannonacin, which is active against intramacrophagic amastigotes (IC50 of 6.2 microM) with a therapeutic index of 2.05, exhibited a strong action on drug-resistant strains (IC50 from 5.1 to 9.8 microM). Acetogenins are a new chemical series with interesting in vitro antileishmanial activity and further studies will be focused on the understanding of this selectivity in regard to the membrane and mitochondrial action using specific probes.

Prenatal diagnosis of trisomy 6 mosaicism.

We report on a fetus with multiple congenital anomalies detected at the prenatal ultrasound examination and a trisomy 6 mosaicism in the amniocytes. The pregnancy was interrupted in the 18th gestational week and the autopsy revealed malformations including cleft right hand, arthrogryposis and hypoplasia of the 4th digit of the left hand, syndactylies and overlapping toes, facial dysmorphism with hypertelorism and low-set ears, ventricular septum defect (VSD), intestinal malrotation and scoliosis. Trisomy 6 mosaicism was detected in cultured amniocytes (13.3%), confirmed in umbilical cord fibroblasts (40%) and by fluorescence in situ hybridization on other fetal tissues. Trisomy 6 mosaicism is a very rare finding with only eight cases previously reported to our best knowledge.

Thiol regulation of the production of TNF-alpha, IL-6 and IL-8 by human alveolar macrophages.

Reactive oxygen intermediates exert signalling functions and modulate gene transcription, particularly for pro-inflammatory cytokines. Since exogenous as well as endogenous thiols could be potent inhibitors of the production of cytokines, the effects of N-acetylcysteine (NAC), glutathione (GSH) and modulated GSH synthesis on the production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8 by human alveolar macrophages (AMs) was evaluated, as well as the potential role of intracellular GSH depletion on the effect of exogenous thiols. AMs were stimulated with lipopolysaccharide (LPS) and cytokine production was measured by evaluating messenger ribonucleic acid (mRNA) expression and protein secretion. Depletion of intracellular GSH by treatment with buthionine sulphoximine (BSO) reached 45.2% after 3 h and was nearly complete at 24 h. Whereas a 24-h preincubation of AMs with BSO significantly increased LPS-induced secretion of TNF-alpha and IL-8, a 3-h preincubation only enhanced LPS-stimulated production of IL-8 (p<0.05). Treatment with NAC and GSH did not significantly increase intracellular content of GSH even after a 48-h incubation. Addition of GSH and NAC significantly reduced the secretion of TNF-alpha (mean+/-SEM 21.2+/-5 and 44.7+/-4.4% inhibition, respectively) as well as LPS-induced IL-6 and IL-8 (p<0.05). Similarly, NAC inhibited the production of TNF-alpha, IL-6 and IL-8 in GSH-depleted AMs obtained by BSO pretreatment. In conclusion, N-acetylcysteine and glutathione inhibit the production of tumour necrosis factor-alpha, interleukin-8 and interleukin-6 by alveolar macrophages by a mechanism independent of glutathione metabolism. However, total depletion of glutathione within alveolar macrophages significantly increases tumour necrosis factor-alpha and interleukin-8 synthesis whereas it does not modulate interleukin-6 secretion.

Lethal femoral-facial syndrome: a case with unusual manifestations.

The femoral-facial syndrome is a very rare syndrome of uncertain inheritance comprising hypoplastic femora, microretrognathia, and a peculiar facies. We report an additional observation detected by ultrasound at 25 weeks and diagnosed at birth. In addition to the malformations usually described in this syndrome, there were heterotopias of the brain, partial agenesis of the corpus callosum, bilobed lungs, intestinal malrotation, and vertebral segmentation defects.

Squamocin and benzyl benzoate, acaricidal components of Uvaria pauci-ovulata bark extracts.

Annonaceae have been commonly described in traditional medicine as remedies against head lice and for their insecticidal properties. Acaricidal effects of Uvaria pauci-ovulata bark extracts were investigated on Dermatophagoides pteronyssinus, the European house dust mite, and compared with those of benzyl benzoate used as standard acaricidal compound. A dichloromethane extract was the most effective with an EC50 = 0.028 g/m2 after a 24 h period as compared with benzyl benzoate (EC50 = 0.06 g/m2). Bioassay-guided fractionation of this extract led to the isolation of benzyl benzoate and squamocin; this latter compound also had acaricidal properties (EC50 = 0.6 g/m2). Moreover, squamocin was shown to potentiate the activity of benzyl benzoate using the fractional effective concentration (FEC) method.

[A case of (benign) teratoma of the nasopharynx]. / A propos d'un cas de tératome (bénin) du cavum.

The authors relate a case of a benign tumor (teratoma) sitting in the nasopharynx of a 10-year-old boy. A short review of the literature is presented: speculations over the origins of these tumors, possible diagnosis, treatments... The authors insist on the necessity of realizing some investigations (X-rays, fibro-endoscopy) when regarding a posterior nasal obstruction.

Mental retardation with blepharo-naso-facial abnormalities and hand malformations: a new syndrome?

A syndrome involving facial abnormalities (telecanthus, epicanthus, broad flattened nose, large inverted W-shaped mouth and malformed ears), malformed extremities (camptodactyly, clinodactyly, interdigital webbing and joint hyperlaxity) and mental retardation is described in a girl at birth and at 11 years old. A comparison with Pashayan-Pruzansky syndrome, fetal alcohol syndrome, VATER association, Marden-Walker syndrome and Tel-Hashomer syndrome is discussed. We suggest this patient represents a new malformation syndrome or an extreme phenotypic variant of one of the above-mentioned syndromes.

A technique for continuously measuring filtration resistance at constant pressure.

A device for continuously measuring, at constant pressure, the filtration resistance of different liquid suspensions is described. It is made up of two main parts: flowmeter system and electronic circuit. The flowmeter consists of a capillary tube and a sensitive pressure transducer, and has a time response of 100 ms and a linearity of +/- 1% from 1 uls-1. The electronic part allows the calculation and recording of flow versus time and filtration resistance versus the volume which passes through the filter. Principle, technical characteristics of the system and examples of recording with several Red Blood Cell populations are reported.

Keratinocyte growth factor (KGF) decreases ICAM-1 and VCAM-1 cell expression on bronchial epithelial cells.

Activation of leucocytes during airway inflammatory reaction involves adhesion to bronchial epithelial cells (BEC), a process implicating specific interactions between glycoproteins with epithelial cell surface proteins, mainly intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). In this study, the effect of keratinocyte growth factor (KGF), a growth factor involved in pulmonary epithelium repair, was evaluated on adhesion molecule expression with BEAS-2B cells and BEC and granulocyte adherence to BEAS-2B. The modulation by KGF of membrane and mRNA expression of ICAM-1 and VCAM-1 was studied on confluent cells stimulated or not with tumour necrosis factor-alpha (TNF) (200 UI/ml) or TNF and interleukin (IL)-4 (50 UI/ml and 10 ng/ml). Levels of soluble-(s)ICAM-1 and sVCAM-1 were measured by ELISA. Although moderately, KGF significantly decreased membrane ICAM-1 expression in unstimulated BEAS-2B cells (24% inhibition at 100 ng/ml) or in TNF- or TNF + IL-4-stimulated cells (22.5 and 18.7% inhibition, respectively). Treatment with KGF tended to decrease VCAM-1 expression in TNF- and TNF + IL-4-stimulated BEAS-2B (P = n.s. and P < 0.05, 14 and 15% inhibition, respectively). In primary culture of BEC, adhesion molecule expression was also reduced. ICAM-1 and VCAM-1 mRNA expression were also inhibited by KGF. Levels of sICAM-1 and sVCAM-1 were not significantly increased in supernatants from KGF-treated cells (30% and 24% increase at 100 ng/ml, respectively) compared to controls. Moreover, KGF decreased by 31% the adherence of neutrophils to TNF-activated BEAS-2B. In conclusion, KGF decreases ICAM-1 and VCAM-1 expression and neutrophil adherence in BEC. These suggest its involvement in the resolution of the inflammatory reaction.

Cohibins C and D, two important metabolites in the biogenesis of acetogenins from Annona muricata and Annona nutans.

Two new annonaceous acetogenins, cohibins C (1a) and D (1b), have been isolated by extensive chromatography of a hexane extract of Annona muricata seeds and a cyclohexane extract of Annona nutans root bark. Their structures have been established on the basis of spectral evidence (NMR, MS) and confirmed by chemical transformation into a pair of monotetrahydrofuran (mono-THF) acetogenins. The role of these compounds in the biogenesis of mono-THF acetogenins is discussed.

Two unrelated children with partial trisomy 1q and monosomy 6p, presenting with the phenotype of the Larsen syndrome.

Two unrelated children presented with similar clinical features (facial dysmorphism and multiple joint dislocations) suggesting the diagnosis of Larsen syndrome. Both carried an inherited unbalanced translocation resulting in partial trisomy 1q and partial monosomy 6p. Analysis of skin collagen from one of the probands disclosed a decreased alpha 1/alpha 2 chain ratio of collagen type I, increased thermal stability and increased hydroxylation of proline and lysine. The present findings suggest that, as a result of the chromosome rearrangements, both patients have a mutation on a gene involved in collagen production, located either on chromosome 1q or, more probably, on 6p. It is furthermore suggested that other cases of Larsen syndrome are the result of a similar mutation.

Characterization of human colorectal mucosa, polyps, and cancers by means of computerized morphonuclear image analyses.

Fifty-eight Feulgen-stained imprint smears from freshly resected colorectal tissue were analyzed by means of a SAMBA 200 cell image processor to establish a quantitative grading of their evolution from normal to malignant mucosa on the basis of 15 morphonuclear parameters relative to morphometry (nuclear size), densitometry (DNA content), and texture (chromatin pattern). The colorectal samples belonged to six groups: normal mucosa from patients without (Group 1) or with (Group 2) colorectal cancer, adenomas (Group 3), and cancers corresponding to the three stages of the Dukes' classification (Groups 4 to 6). Results indicated that analysis of the morphonuclear parameters computed on 250 to 300 nuclei/cases objectively and quantitatively showed the adenoma-cancer sequence. This need for only a small number of nuclei to assess a highly efficient analysis created a preoperative investigative tool using cytologic smears during endoscopy. The authors also made preliminary data banks for objective and reproducible grading of unknown cases by comparisons (discriminant analyses) with their contents. This approach must be validated prospectively on a large series of cases to furnish a system for colorectal malignancy diagnosis.

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and early-onset liver cirrhosis in two siblings.

UNLABELLED: We present the clinical, pathological, biochemical, and molecular results on an infant girl with long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and data on her deceased elder brother for whom this condition was retrospectively diagnosed. Clinical signs were liver enlargement and elevated liver enzymes, failure to thrive, and neurological disease (coma, seizures) triggered by an infectious stress. In the second child hepatic failure and status epilepticus developed during the onset of a rotavirus gastroenteritis. A barbituric coma was induced, but hypotonia and lack of eye pursuit persisted after suppression of antiepileptic drugs. She ultimately died of heart failure. Unlike previously reported cases, both of these patients had early-onset cirrhosis, and severe neurological disease was observed in the second child. CONCLUSION: Liver cirrhosis and brain damage may be underestimated in cases of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency and may occur early in life.