Mutation analysis of the muscarinic cholinergic receptor genes in isolated growth hormone deficiency type IB

BACKGROUND: Isolated GH deficiency (IGHD) is familial in 5-30% of patients. The most frequent form (IGHD-IB) has autosomal recessive inheritance, and it is known that it can be caused by mutations in the GHRH receptor (GHRHR) gene or in the GH gene. However, most forms of IGHD-IB have an unknown genetic cause. In normal subjects, muscarinic cholinergic stimulation causes an increase in pituitary GH release, whereas its blockade has the opposite effect, suggesting that a muscarinic acetylcholine receptor (mAchR) is involved in stimulating GH secretion. Five types of mAchR (M(1)-M(5)) exist. A transgenic mouse in which the function of the M(3) receptor was selectively ablated in the central nervous system has isolated GH deficiency similar to animals with defective GHRH or GHRHR gene. OBJECTIVE: We hypothesized that mAchR mutations may cause a subset of familial IGHD. PATIENTS/METHODS: After confirming the expression of M(1)-M(5) receptor mRNA in human hypothalamus, we analyzed the index cases of 39 families with IGHD-IB for mutations in the genes encoding for the five receptors. Coding sequences for each of the five mAchRs were subjected to direct sequencing. RESULTS: In one family, an affected member was homozygous for a M(3) change in codon 65 that replaces valine with isoleucine (V65I). The V65I receptor was expressed in CHO cells where it had normal ability to transmit methacholine signaling. CONCLUSION: mAchR mutations are absent or rare (less than 2.6%) in familial IGHD type IB.

Plant ion channels: gene families, physiology, and functional genomics analyses

Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarization- and depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide-gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport.

A novel succinate dehydrogenase subunit B gene mutation, H132P, causes familial malignant sympathetic extraadrenal paragangliomas

We report a family with malignant sympathetic paragangliomas (PGL) exhibiting a new type of germline mutation in the succinate dehydrogenase subunit B (SDHB) gene. Two affected brothers, presenting with symptoms at the ages of 25 and 52 yr, suffered from malignant abdominal extraadrenal sympathetic PGL. They died of their disease at ages 43 and 61 yr. Their mother had the same history of signs and symptoms, suggesting a catecholamine-producing tumor at the age of 55 yr. Analysis of the germline DNA from these three patients revealed a novel mutation in exon 4 (H132P) of the SDHB gene. This mutation was absent in 160 control chromosomes. Loss of heterozygosity analysis of the tumors showed a loss of one SDHB allele, and RT-PCR-based expression analysis confirmed the exclusive expression of the mutated allele in both tumors. A review of the published PGL families revealed malignant tumors in seven of 12 well-documented families with SDHB mutation-associated extraadrenal PGL. These findings, as well as findings of the family reported here, suggest a strong causal relationship of SDHB germline mutations with malignant extraadrenal abdominal PGL and imply the necessity of a close follow-up of affected individuals and family members.

Changing ‘Multi-Problem Families’ – Developing a Multi-Contextual Systemic Approach

Over the past 30 years the Marlborough Family Service in London has pioneered multi-family work with marginalized families presenting simultaneously with abuse and neglect, family violence, substance misuse, educational failure and mental illness. The approach is based on a systemic multi-contextual mode and this chapter describes the evolving work, including the establishment of the first permanent multiple family day setting, specifically designed for and solely dedicated to the work with seemingly ‘hopeless’ families. The ingredients of ‘therapeutic assessments’ of parents and families are outlined and the importance of initial network meetings with professionals and family members is emphasized.

Collaborating or Colluding: A Practice Research Project with Ex-Offenders and their Families in Singapore

Working with the family members of ex-offenders is a daunting and newly developing aspect of offender rehabilitation in Singapore. A small scale practice research project was carried out by three social work practitioners and two academics over a period of 22 months, with the aim to explore the pertinent issues and challenges in working with family members of ex-offenders. Systematic documentation of the process of working with three cases was carried out. Specific skills and strategies were suggested, and recommendations for changes to service delivery and policy for working with ex-offenders and family members were made to the authorities. This article highlights the enriching journey of collaboration between the academics and practitioners.

Aesthetic outcome of cleft lip and palate treatment. Perceptions of patients, families, and health professionals compared to the general public

The aesthetic outcome of cleft treatment is of great importance due to its complex management and the psychosocial consequences of this defect. The aim of the study was to assess the aesthetic evaluations of patients following cleft surgery by various groups and investigate potential associations of the assessments with life quality parameters. Head photos of 12 adult patients with treated unilateral cleft lip and palate were evaluated by laypeople and professionals. A questionnaire was distributed and answered by the patients and their parents. Intra-panel agreement was high (α > 0.8) for laypeople and professionals. Between-groups agreement was high for both laypeople and professionals, but not when patients and/or parents were tested. Professionals, parents, and patients were more satisfied with patients' appearance than laypeople, although in general all groups were not highly satisfied. Low satisfaction with aesthetics correlated with increased self-reported influence of the cleft in the patients' social activity and professional life (0.56 < rho < 0.74, p < 0.05). These findings highlight the observed negative influence of the cleft on the patient's social activity and professional life and underline the need for the highest quality of surgical outcome for this group of patients.

Coronary evaginations are associated with positive vessel remodelling and are nearly absent following implantation of newer-generation drug-eluting stents: an optical coherence tomography and intravascular ultrasound study

OBJECTIVES The purpose of this study was to assess the occurrence, predictors, and mechanisms of optical coherence tomography (OCT)-detected coronary evaginations following drug-eluting stent (DES) implantation. BACKGROUND Angiographic ectasias and aneurysms in stented segments have been associated with a risk of late stent thrombosis. Using OCT, some stented segments show coronary evaginations reminiscent of ectasias. METHODS Evaginations were defined as outward bulges in the luminal contour between struts. They were considered major evaginations (MEs) when extending ≥3 mm along the vessel length, with a depth ≥10% of the stent diameter. A total of 228 patients who had sirolimus (SES)-, paclitaxel-, biolimus-, everolimus (EES)-, or zotarolimus (ZES)-eluting stents implanted in 254 lesions, were analysed after 1, 2, or 5 years; and serial assessment using OCT and intravascular ultrasound (IVUS) was performed post-intervention and after 1 year in 42 patients. RESULTS Major evaginations occurred frequently at all time points in SES (∼26%) and were rarely seen in EES (3%) and ZES (2%, P = 0.003). Sirolimus-eluting stent implantation was the strongest independent predictor of ME [adjusted OR (95% CI) 9.1 (1.1-77.4), P = 0.008]. Malapposed and uncovered struts were more common in lesions with vs. without ME (77 vs. 25%, P < 0.001 and 95 vs. 20%, P < 0.001, respectively) as was thrombus [49 vs. 14%, OR 7.3 (95% CI: 1.7-31.2), P = 0.007]. Post-intervention intra-stent dissection and protrusion of the vessel wall into the lumen were associated with an increased risk of evagination at follow-up [OR (95% CI): 2.9 (1.8-4.9), P < 0.001 and 3.3 (1.6-6.9), P = 0.001, respectively]. In paired IVUS analyses, lesions with ME showed a larger increase in the external elastic membrane area (20% area change) compared with lesions without ME (5% area change, P < 0.001). CONCLUSION Optical coherence tomography-detected MEs are a specific morphological footprint of early-generation SES and are nearly absent in newer-generation ZES and EES. Evaginations appear to be related to vessel injury at baseline; are associated with positive vessel remodelling; and correlate with uncoverage, malapposition, and thrombus at follow-up.

Holomorphic families of nonequivalent embeddings and of holomorphic group actions on affine space

We construct holomorphic families of proper holomorphic embeddings of \mathbb {C}^{k} into \mathbb {C}^{n} (0\textless k\textless n-1), so that for any two different parameters in the family, no holomorphic automorphism of \mathbb {C}^{n} can map the image of the corresponding two embeddings onto each other. As an application to the study of the group of holomorphic automorphisms of \mathbb {C}^{n}, we derive the existence of families of holomorphic \mathbb {C}^{*}-actions on \mathbb {C}^{n} (n\ge5) so that different actions in the family are not conjugate. This result is surprising in view of the long-standing holomorphic linearization problem, which, in particular, asked whether there would be more than one conjugacy class of \mathbb {C}^{*}-actions on \mathbb {C}^{n} (with prescribed linear part at a fixed point).

One size does not fit all: Entrepreneurial families’ reliance on family offices

Family offices are organisations dedicated to the management of entrepreneurial families’ private wealth. Based on agency theory, we analyse types of family offices with regard to the families’ goals and the control mechanisms used to ensure goal achievement. Family-dominant management and private client structures involve stronger emphasis on non-financial goals in single and multi-family offices than in non-family-dominant management and open client structures. Variations in family involvement, ranging from family dominance to the complete absence of family ownership and/or management, and diverse client structures justify the differential reliance on formal and informal control mechanisms.

From language maintenance to bilingual parenting: Negotiating behavior and language choice at the dinner table in binational-bilingual families

This article contributes to the study of language maintenance as an everyday activity in binational-bilingual families. By embedding the question of language maintenance into a language socialization framework and adopting a conversation-analytic approach to language alternation, three excerpts of mealtime interactions in Russian–French speaking families are analyzed. Their analysis shows that in bilingual families situations focusing on the interactional definition and negotiation of children’s behavior simultaneously involve the negotiation of language choice. It reveals how parents in binational-bilingual families accomplish bilingual (language) socialization in daily practice while dealing with the complex task of combining educational goals with language maintenance.