Matthew-Wood syndrome: report of two new cases supporting autosomal recessive inheritance and exclusion of FGF10 and FGFR2

We describe two fetal cases of microphthalmia/anophthalmia, pulmonary agenesis, and diaphragmatic defect. This rare association is known as Matthew-Wood syndrome (MWS; MIM 601186) or by the acronym "PMD" (Pulmonary agenesis, Microphthalmia, Diaphragmatic defect). Fewer than ten pre- and perinatal diagnoses of Matthew-Wood syndrome have been described to date. The cause is unknown, and the mode of transmission remains unclear. Most cases have been reported as isolated and sporadic, although recurrence among sibs has been observed once. Our two cases both occurred in consanguineous families, further supporting autosomal recessive transmission. In addition, in one family at least one of the elder sibs presented an evocatively similar phenotype. The spatiotemporal expression pattern of the FGF10 and FGFR2 genes in human embryos and the reported phenotypes of knockout mice for these genes spurred us to examine their coding sequences in our two cases of MWS. While in our patients, no causative sequence variations were identified in FGF10 or FGFR2, this cognate ligand-receptor pair and its downstream effectors remain functional candidates for MWS and similar associations of congenital ocular, diaphragmatic and pulmonary malformations.     

The relationship between cortisol, C-reactive protein and hypertension in African and Causcasian women: the POWIRS study

Research on the roles that C-reactive protein (CRP) and other risk factors such as cortisol and obesity play in the diagnosis of cardiovascular disease (CVD) in African and Caucasian women has become increasingly imperative when one considers the prevalence of hypertension in these groups. CRP and cortisol have been associated with an increased prevalence of hypertension and obesity. Cortisol has also been linked with both hypertension and the hypothalamic-pituitary-adrenal (HPA) response. African women have previously presented with an increased vascular reactivity. Conversely, Caucasian women have displayed an increased central cardiac reactivity. We included African (n = 102) and Caucasian (n = 115) women in the study, matched for age and body mass index. Elevated CRP levels were observed in African women compared to Caucasian women. A trend of hypocortisolism was exhibited in both hypertensive ethnic groups. Systolic blood pressure (SBP) and a vascular marker, arterial compliance (Cw), predicted hypertension in African women. Conversely, in Caucasian women, only SBP predicted hypertension. These results suggest the apparently diverse roles that dysregulation by the HPA axis, in conjunction with the respective cardiac and vascular responses in both Caucasian and African women, can play in future cardiovascular risk for these groups.     

In male rats with concurrent iron and (n-3) fatty acid deficiency, provision of either iron or (n-3) fatty acids alone alters monoamine metabolism and exacerbates the cognitive deficits associated with combined deficiency

Concurrent deficiencies of iron (Fe) (ID) and (n-3) fatty acids [(n-3)FAD)] in rats can alter brain monoamine pathways and impair learning and memory. We examined whether repletion with Fe and DHA/EPA, alone and in combination, corrects the deficits in brain monoamine activity (by measuring monoamines and related gene expression) and spatial working and reference memory [by Morris water maze (MWM) testing] associated with deficiency. Using a 2 × 2 design, male rats with concurrent ID and (n-3)FAD [ID+(n-3)FAD] were fed an Fe+DHA/EPA, Fe+(n-3)FAD, ID+DHA/EPA, or ID+(n-3)FAD diet for 5 wk [postnatal d 56-91]. Biochemical measures and MWM performance after repletion were compared to age-matched control rats. The provision of Fe in combination with DHA/EPA synergistically increased Fe concentrations in the olfactory bulb (OB) (Fe x DHA/EPA interaction). Similarly, provision of DHA/EPA in combination with Fe resulted in higher brain DHA concentrations than provision of DHA alone in the frontal cortex (FC) and OB (P < 0.05). Dopamine (DA) receptor D1 was upregulated in the hippocampus of Fe+DHA/EPA rats (fold-change = 1.25; P < 0.05) and there were significant Fe x DHA/EPA interactions on serotonin (5-HT) in the OB and on the DA metabolite dihydroxyphenylacetic acid in the FC and striatum. Working memory performance was impaired in ID+DHA/EPA rats compared with controls (P < 0.05). In the reference memory task, Fe+DHA/EPA improved learning behavior, but Fe or DHA/EPA alone did not. These findings suggest that feeding either Fe or DHA/EPA alone to adult rats with both ID and (n-3)FAD affects the DA and 5-HT pathways differently than combined repletion and exacerbates the cognitive deficits associated with combined deficiency.     

Adenosine deaminase levels in cerebrospinal fluid in the diagnosis of tuberculous meningitis

The prognosis of tuberculous meningitis is closely linked to the stage at which treatment is started. At the same time the diagnosis will often have to be made on purely circumstantial evidence. Adenosine deaminase activity in the cerebrospinal fluid was evaluated as a diagnostic aid in 30 cases of tuberculous meningitis. Cerebrospinal fluid adenosine deaminase levels differentiated tuberculous meningitis cases from those with aseptic meningitis being higher than 4 U/l in all and higher than 6 U/l in 90% of cases of tuberculous meningitis, but lower than 6 U/l in aseptic meningitis and less than 4 U/l in normal controls. It could not distinguish bacterial meningitis from tuberculous or aseptic meningitis. In cases of low-cell-count bacterial meningitis, the mean cerebrospinal fluid adenosine deaminase level was significantly lower than in cases of tuberculous meningitis with a similar cell count, but considerable overlap of results in the two groups was still to be found.     

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity: the role of the metabolic burst

Human monocytes respond to opsonized microorganisms with a "metabolic burst" composed of an increase in oxygen consumption, an increase in hexose monophosphate shunt (HMPS) activity, and the generation of reactive oxygen species (ROS). We investigated the role of the metabolic burst in antibody-dependent cell-mediated cytotoxicity (ADCC) by human monocytes toward anti-D coated erythrocyte target cells because recent studies suggested a role for oxygen-dependent bactericidal mechanisms in ADCC. In normal monocytes, we found that ADCC was nearly halved under hypoxic conditions. Several agents known to impair activation of the burst, such as vincristine, cation chelators, and a sulfhydryl reagent, all decreased cytotoxicity if added before initiation of contact between target and effector cells. Cytotoxicity was inhibited by 2-deoxyglucose but not fluoride, suggesting a nonglycolytic role for glucose in ADCC, perhaps in the HMPS pathway. Although these data suggested a role for the metabolic burst in ADCC, scavengers of ROS did not impair cytotoxicity, and monocytes from chronic granulomatous disease (CGD) patients who had a defective metabolic burst had normal levels of ADCC. We conclude that ADCC toward anti-D coated erythrocyte target cells was the result of at least two independent but closely related cytotoxic pathways. Although one of these pathways appeared to involve the metabolic burst, the potentially cytotoxic reactive oxygen species did not appear to play a role in this system.