Malformations of cerebral cortical development include a wide range of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. In addition, study of these disorders contributes greatly to the understanding of normal brain development and its perturbations. The rapid recent evolution of molecular biology, genetics and imaging has resulted in an explosive increase in our knowledge of cerebral cortex development and in the number and types of malformations of cortical development that have been reported. These advances continue to modify our perception of these malformations. This review addresses recent changes in our perception of these disorders and proposes a modified classification based upon updates in our knowledge of cerebral cortical development.

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A Developmental and Genetic Classification for Malformations of Cortical Development: Update 2012.

Inflammation and angiotensin II.

Our understanding of endocytosis has evolved remarkably in little more than a decade. This is the result not only of advances in our knowledge of its molecular and biological workings, but also of ...

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Endocytosis and signaling: cell logistics shape the eukaryotic cell plan.

Background— Recent studies have demonstrated that lesions of aortic sclerosis and stenosis share several similarities with lesions of atherosclerosis. In atherosclerosis, angiotensin-converting enzyme (ACE) is expressed by a subset of macrophages. This study was undertaken to determine whether ACE might be present in aortic sclerosis or stenosis lesions. Methods and Results— Immunohistochemistry was performed on 26 paraffin-embedded human aortic valves. Monospecific antibodies were used to identify ACE, macrophages, angiotensin II type 1 receptor (AT-1 receptor), angiotensin II, and apolipoprotein B. Human low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were isolated from plasma of normal volunteers by sequential density-gradient ultracentrifugation. ACE was not present in normal valves but was present in all valves with aortic sclerosis or stenosis lesions. ACE was detected on a subset of lesion macrophages but was present primarily in an extracellular distribution, where it colocalized ...

Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma

The calcified aortic valve lesion develops in the setting of endothelial injury and inflammation and displays hallmarks of atherosclerosis, including lipids accumulation, matrix metalloproteinase activation, and interaction with renin-angiotensin system. Current evidence indicates that modification of atherosclerotic risk factors will slow the progression of aortic valve calcification, and valve risk factors should be addressed in all patients who have aortic valve calcification.

Mechanisms of aortic valve calcification.

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients.

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Angiotensin II Reduces Macrophage Cholesterol Efflux: A Role for the AT-1 Receptor but Not for the ABC1 Transporter

Objective: The aim of this study was to assess the activity of cortisol-metabolizing enzymes in women with polycystic ovary syndrome (PCOS), using a fully quantitative gas chromatography/mass spectrometry (GCMS) method.
Design: We investigated the glucocorticoid degradation pathways that include 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1, 5α-reductase (5α-R) and 5β-reductase (5β-R), 3α-hydroxysteroid dehydrogenase, and 20α- and 20β-hydroxysteroid dehydrogenase (20α-HSD and 20β-HSD, respectively) in young nonobese women with PCOS, using a fully quantitative GCMS method.
Setting: This study was conducted in a tertiary referral hospital in Israel.
Patients: This study group consisted of 13 young women, aged 20.1 ± 2.8 years (mean ± SD), with the body mass index (BMI) of 22.6 ± 3.7 kg/m², diagnosed with PCOS according to the Rotterdam criteria. The control group consisted of 14 healthy young women matched for weight, height, and BMI.
Interventions: Urine samples were analyzed using GCMS. We measured urinary steroid metabolites that represent the products and substrates of the study enzymes and calculated the product/substrate ratios to represent enzyme activity.
Main outcome measures: The calculation of enzymatic activity, based on glucocorticoid degradation metabolites, was done by GCMS in PCOS vs. controls.
Results: All glucocorticoid degradation metabolites were higher in the PCOS group than in controls. Of the adrenal enzymes, the activities of 21-hydroxylase and 17α-hydroxylase were reduced, whereas the activity of 17,20-lyase was enhanced in PCOS. Of the degradation enzymes, the activity of 11β-HSD type 1 was reduced in women with PCOS only when calculated from cortoles and cortolones ratios. The activities of 5α-R/5β-R were increased only when calculating the 11-hydroxy metabolites of androgens. The activity of 20α-HSD was elevated in the patients with PCOS and its relation with the substrate levels was lost.
Conclusions: We confirm PCOS association with low 21-hydroxylase activity. PCOS is associated with dysregulation in glucocorticoid degradation. The activity of 5α-R is enhanced only through the backdoor pathway. Marked increase in the activity of 20α-HSD suggests a hitherto unknown derangement in PCOS.

https://journals.sagepub.com/doi/pdf/10.4137/CMRH.S35567

Cortisol-Metabolizing Enzymes in Polycystic Ovary Syndrome.

Small for GA (SGA) children are at risk for developing the metabolic syndrome. Those who do not catch up, and remain short (SSGA), may benefit from GH therapy. 11β Hydroxysteroid dehydrogenase type 1 (11β-HSD-1) is expressed in visceral fat and is implicated in metabolic morbidity. We hypothesized that SSGA children will have increased basal and glucocorticoid (GC)-stimulated 11β-HSD-1 activity. Twenty SSGA children, aged 7.1 ± 1 y (mean ± SD), were studied before and while on GH therapy and compared with 12 normal age-matched controls. 11β-HSD-1 activity was evaluated by gas chromatography mass spectrometry (GCMS) of urinary steroid product/substrate ratios. GC-stimulated 11β-HSD-1 activity was assessed after overnight dexamethazone (DEX), by oral cortisone conversion to cortisol. In SSGA children, 11β-HSD-1 activity was lower (p < 0.05) and GC-stimulated activity enhanced. SSGA children had maximal cortisol generation of 883 ± 108 compared with 690 ± 63 nmol/L in controls (p < 0.04). GH treatment suppressed 11β-HSD-1 activity. GC-stimulated enzyme activity correlated negatively with GA (r = −0.53, p < 0.01) and birth weight (r = −0.55, p < 0.01). SSGA is associated with enhanced GC-stimulated 11β-HSD-1 activity. This may be programmed in utero, as it is not a function of body composition or secondary metabolic derangement. GH therapy normalizes GC-stimulated 11β-HSD-1 activity.

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Carlos Knopf

Papers

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Angiotensin II Reduces Macrophage Cholesterol Efflux: A Role for the AT-1 Receptor but Not for the ABC1 Transporter

Cortisol-Metabolizing Enzymes in Polycystic Ovary Syndrome.

11β–Hydroxysteroid Dehydrogenase Type 1 Activity in Short Small-For-GA Children and in Response to GH Therapy