GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.

Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature

CONTEXT AND OBJECTIVE: A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural GH antagonist. DESIGN, SETTING, AND PATIENTS: Heterozygosity for GH-R77C/wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SD score) and partial GH insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH insensitivity with modest short stature. INTERVENTIONS AND RESULTS: Functional characterization of the GH-R77C was performed through studies of GH receptor binding and activation of Janus kinase 2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular colocalization between wt-GH and GH-R77C with endoplasmic reticulum, Golgi, or secretory vesicles. Furthermore studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared with wt-GH. CONCLUSION: Reduced GH receptor/GH-binding protein expression might be a possible cause for the partial GH insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity.

Brain connectivity at different time-scales measured with EEG

We present an overview of different methods for decomposing a multichannel spontaneous electroencephalogram (EEG) into sets of temporal patterns and topographic distributions. All of the methods presented here consider the scalp electric field as the basic analysis entity in space. In time, the resolution of the methods is between milliseconds (time-domain analysis), subseconds (time- and frequency-domain analysis) and seconds (frequency-domain analysis). For any of these methods, we show that large parts of the data can be explained by a small number of topographic distributions. Physically, this implies that the brain regions that generated one of those topographies must have been active with a common phase. If several brain regions are producing EEG signals at the same time and frequency, they have a strong tendency to do this in a synchronized mode. This view is illustrated by several examples (including combined EEG and functional magnetic resonance imaging (fMRI)) and a selective review of the literature. The findings are discussed in terms of short-lasting binding between different brain regions through synchronized oscillations, which could constitute a mechanism to form transient, functional neurocognitive networks.

Unexpected metastatic pheochromocytoma - an unusual presentation

The classic triad of pheochromocytoma consists of episodic headache, sweating, and tachycardia. General clinicians should be aware, however, that this rare entity might present with a wide spectrum of clinical symptoms. We recently observed a noteworthy case of malignant pheochromocytoma where there was a lack of specific symptoms despite an advanced tumor stage. Malignancy is an important cause of mortality. Reliable diagnosis of malignancy depends upon evidence of local invasion, distant metastases, or recurrence. As in our case, new scintigraphic methods, such as 111-In-pentetreotide scintigraphy (Octreoscan), may occasionally reveal 123-I-metaiodobenzylguanidine-negative distant metastases and help to establish an early diagnosis of malignancy. Tumor size, and perhaps even biochemical profile, may be factors increasing the likelihood of a malignant process and may contribute to early identification of patients at risk.

Perspectives on periodontal risk factors

The development of a clinical decision tree based on knowledge about risks and reported outcomes of therapy is a necessity for successful planning and outcome of periodontal therapy. This requires a well-founded knowledge of the disease entity and a broad knowledge of how different risk conditions attribute to periodontitis. The infectious etiology, a complex immune response, and influence from a large number of co-factors are challenging conditions in clinical periodontal risk assessment. The difficult relationship between independent and dependent risk conditions paired with limited information on periodontitis prevalence adds to difficulties in periodontal risk assessment. The current information on periodontitis risk attributed to smoking habits, socio-economic conditions, general health and subjects' self-perception of health, is not comprehensive, and this contributes to limited success in periodontal risk assessment. New models for risk analysis have been advocated. Their utility for the estimation of periodontal risk assessment and prognosis should be tested. The present review addresses several of these issues associated with periodontal risk assessment.

[Childhood Henoch-Schönlein syndrome--common and uncommon features, complications, Finkelstein-Seidlmayer variant and management]

Although Henoch-Schönlein syndrome can occur at any age, it is overwhelmingly a disease of childhood. Indeed, Henoch-Schönlein syndrome is the most common vasculitis that affects children. The clinical features of this vasculitis are well documented, and the diagnosis is generally not difficult. This article briefly reviews both common and uncommon clinical aspects of the condition and information concerning therapy. A further focus of this review is recent information concerning abnormalities of immunoglobulin IgA1 glycosylation and the role of aberrantly glycosylated immunoglobulins in the development of Henoch-Schönlein syndrome. The final focus of the article is acute hemorrhagic edema, a benign vasculitis limited to the skin, which is characterized by circinate, medallion-like purpura, and ecchymoses and occurs in children younger than 4 years of age. The nosologic position of acute hemorrhagic edema, which has also been called Finkelstein-Seidlmayer syndrome, as a variant of Henoch-Schönlein syndrome is the subject of considerable debate, but most authors agree that there are sufficient clinical and prognostic differences to consider it a separate entity.

Polyarteritis Nodosa, a vanishing vasculitis since its main cause has been identified

The polyarteritis nodosa is a vasculitis for which the main cause had been identified as hepatitis B, a chronic infectious disease inducing an overshooting immune reaction. Thanks to this discovery, the treatment of polyarteritis nodosa has changed from a symptomatic immunosuppressive therapy to a treatment strategy focusing on the disease inducing infectious agent. Vaccination against hepatitis B- virus has been instrumental in the reduction of the prevalence of polyarteritis nodosa. In case of the rare entity of polyarteritis nodosa without hepatitis B, only a symptomatic immunosuppressive therapy can be prescribed. The history of polyarteritis nodosa clearly illustrates that future research in the field of so called autoimmune diseases should focus on the causes rather than on the immunologic effector mechanisms and/or the symptomatic immunosuppressive therapy.

HEALTH AND SAFETY ISSUES IN THE WORKPLACE: THE CASE OF CAMEROON TEA ESTATE (CTE), A RISK COMMUNICATION APPROACH

In 2002, motivated largely by the uncontested belief that the private sector would operate more efficiently than the government, the government of Cameroon initiated a major effort to privatize some of Cameroon’s largest, state-run industries. One of the economic sectors affected by this privatization was tea production. In October 2002, the Cameroon Tea Estate (CTE), a privately owned, tea-cultivating organization, bought the Tole Tea Estate from the Cameroon Development Corporation (CDC), a government-owned entity. This led to an increase in the quantity of tea production; however, the government and CTE management appear not to have fully considered the risks of privatization. Using classical rhetorical theory, Richard Weaver’s conception of “god terms” (or “uncontested terms”), and John Ikerd’s ethical approach to risk communication, this study examines risks to which Tole Tea Estate workers were exposed and explores rhetorical strategies that workers employed in expressing their discontent. Sources for this study include online newspapers, which were selected on the basis of their reputation and popularity in Cameroon. Analysis of the data shows that, as a consequence of privatization, Tole Tea Estate workers were exposed to three basic risks: marginalization, unfulfilled promises, and poor working conditions. Workers’ reactions to these risks tended to grow more emotional as management appeared to ignore their demands. The study recommends that respect for labor law, constructive dialogue among stakeholders, and transparency might serve as guiding principles in responding to the politics of privatization in developing countries.

A FIREWALL MODEL OF FILE SYSTEM SECURITY

File system security is fundamental to the security of UNIX and Linux systems since in these systems almost everything is in the form of a file. To protect the system files and other sensitive user files from unauthorized accesses, certain security schemes are chosen and used by different organizations in their computer systems. A file system security model provides a formal description of a protection system. Each security model is associated with specified security policies which focus on one or more of the security principles: confidentiality, integrity and availability. The security policy is not only about “who” can access an object, but also about “how” a subject can access an object. To enforce the security policies, each access request is checked against the specified policies to decide whether it is allowed or rejected. The current protection schemes in UNIX/Linux systems focus on the access control. Besides the basic access control scheme of the system itself, which includes permission bits, setuid and seteuid mechanism and the root, there are other protection models, such as Capabilities, Domain Type Enforcement (DTE) and Role-Based Access Control (RBAC), supported and used in certain organizations. These models protect the confidentiality of the data directly. The integrity of the data is protected indirectly by only allowing trusted users to operate on the objects. The access control decisions of these models depend on either the identity of the user or the attributes of the process the user can execute, and the attributes of the objects. Adoption of these sophisticated models has been slow; this is likely due to the enormous complexity of specifying controls over a large file system and the need for system administrators to learn a new paradigm for file protection. We propose a new security model: file system firewall. It is an adoption of the familiar network firewall protection model, used to control the data that flows between networked computers, toward file system protection. This model can support decisions of access control based on any system generated attributes about the access requests, e.g., time of day. The access control decisions are not on one entity, such as the account in traditional discretionary access control or the domain name in DTE. In file system firewall, the access decisions are made upon situations on multiple entities. A situation is programmable with predicates on the attributes of subject, object and the system. File system firewall specifies the appropriate actions on these situations. We implemented the prototype of file system firewall on SUSE Linux. Preliminary results of performance tests on the prototype indicate that the runtime overhead is acceptable. We compared file system firewall with TE in SELinux to show that firewall model can accommodate many other access control models. Finally, we show the ease of use of firewall model. When firewall system is restricted to specified part of the system, all the other resources are not affected. This enables a relatively smooth adoption. This fact and that it is a familiar model to system administrators will facilitate adoption and correct use. The user study we conducted on traditional UNIX access control, SELinux and file system firewall confirmed that. The beginner users found it easier to use and faster to learn then traditional UNIX access control scheme and SELinux.

Sound As Artifact

A distinguishing feature of the discipline of archaeology is its reliance upon sensory dependant investigation. As perceived by all of the senses, the felt environment is a unique area of archaeological knowledge. It is generally accepted that the emergence of industrial processes in the recent past has been accompanied by unprecedented sonic extremes. The work of environmental historians has provided ample evidence that the introduction of much of this unwanted sound, or "noise" was an area of contestation. More recent research in the history of sound has called for more nuanced distinctions than the noisy/quiet dichotomy. Acoustic archaeology tends to focus upon a reconstruction of sound producing instruments and spaces with a primary goal of ascertaining intentionality. Most archaeoacoustic research is focused on learning more about the sonic world of people within prehistoric timeframes while some research has been done on historic sites. In this thesis, by way of a meditation on industrial sound and the physical remains of the Quincy Mining Company blacksmith shop (Hancock, MI) in particular, I argue for an acceptance and inclusion of sound as artifact in and of itself. I am introducing the concept of an individual sound-form, or sonifact, as a reproducible, repeatable, representable physical entity, created by tangible, perhaps even visible, host-artifacts. A sonifact is a sound that endures through time, with negligible variability. Through the piecing together of historical and archaeological evidence, in this thesis I present a plausible sonifactual assemblage at the blacksmith shop in April 1916 as it may have been experienced by an individual traversing the vicinity on foot: an 'historic soundwalk.' The sensory apprehension of abandoned industrial sites is multi-faceted. In this thesis I hope to make the case for an acceptance of sound as a primary heritage value when thinking about the industrial past, and also for an increased awareness and acceptance of sound and listening as a primary mode of perception.

Drug-eluting stent thrombosis

Drug-eluting stents (DES) have reduced the risk of repeat revascularization procedures by 50-70% compared with bare metal stents across a wide range of lesion and patients subsets. Stent thrombosis is a rare but devastating adverse event, which results in abrupt closure of the treated artery with the incumbent risk of sudden death or myocardial infarction. Although stent thrombosis has been recognized as a shortcoming of coronary artery stents since there inception, very late stent thrombosis occurring more than one year after stent implantation emerged as a new entity complicating the use of DES. The mechanisms leading to very late ST are complex and only incompletely understood. Delayed healing and incomplete re-endothelialization emerged as prevailing mechanism of thrombosis in autopsy studies. Various components of DES may give rise to very late stent thrombosis, notably the polymers used for controlled drug-release. Newer generation DES attempt to address these concerns by aiming at improved vascular healing while maintaining potent neointimal suppression.

Isolated development of inner (wall) caries like lesions in a bacterial-based in vitro model

The study conducted in a bacterial-based in vitro caries model aimed to determine whether typical inner secondary caries lesions can be detected at cavity walls of restorations with selected gap widths when the development of outer lesions is inhibited. Sixty bovine tooth specimens were randomly assigned to the following groups: test group 50 (TG50; gap, 50 microm), test group 100 (TG100; gap, 100 microm), test group 250 (TG250; gap, 250 microm) and a control group (CG; gap, 250 microm). The outer tooth surface of the test group specimens was covered with an acid-resistant varnish to inhibit the development of an outer caries lesion. After incubation in the caries model, the area of demineralization at the cavity wall was determined by confocal laser scanning microscopy. All test group specimens demonstrated only wall lesions. The CG specimens developed outer and wall lesions. The TG250 specimens showed significantly less wall lesion area compared to the CG (p < 0.05). In the test groups, a statistically significant increase (p < 0.05) in lesion area could be detected in enamel between TG50 and TG250 and in dentine between TG50 and TG100. In conclusion, the inner wall lesions of secondary caries can develop without the presence of outer lesions and therefore can be regarded as an entity on their own. The extent of independently developed wall lesions increased with gap width in the present setting.

[Experiences with the early treatment of osteogenesis imperfecta]

Between 1973 and 1988 twenty children with osteogenesis imperfecta were treated in the Department of Paediatric Surgery at the University of Berne, Switzerland. Our initial experience with the first 15 children, who had virtually no treatment during infancy and early childhood showed that they later developed severe soft tissue and skeletal deformities. Since resulting contractures and curvatures of the long bones are difficult to correct, we changed our therapeutic approach. Traditional therapy in OI was limited to the correction of bony malformations. Considering the fact, that the different elements of the locomotor system are part of a functional entity, we began early treatment combining physiotherapy and surgery.

Imaging of chronic recurrent multifocal osteomyelitis of childhood first presenting with isolated primary spinal involvement

OBJECTIVE: Initial presentation with primary spinal involvement in chronic recurrent multifocal osteomyelitis of childhood (CRMO) is rare. Our objective was to review the imaging appearances of three patients who had CRMO who initially presented with isolated primary spinal involvement. DESIGN AND PATIENTS: The imaging, clinical, laboratory and histology findings of the three patients were retrospectively reviewed. Imaging included seven spinal MR imaging scans, one computed tomography scan, nine bone scans, two tomograms and 16 radiographs. These were reviewed by two musculoskeletal radiologists and a consensus view is reported. All three patients presented with atraumatic spinal pain and had extensive bone spinal pathology. The patients were aged 11, 13 and 12 years. There were two females and one male. RESULTS AND CONCLUSIONS: The initial patient had thoracic T6 and T8 vertebra plana. Bone scan showed additional vertebral body involvement. Follow-up was available over a 3 year period. The second patient had partial collapse of T9 and, 2 years later, of C6. Subsequently extensive multifocal disease ensued and follow-up was available over 8 years. The third patient initially had L3 inferior partial collapse and 1 year later T8 involvement with multifocal disease. Follow-up was available over 3 years. The imaging findings of the three patients include partial and complete vertebra plana with a subchondral line adjacent to endplates associated with bone marrow MR signal alterations. Awareness of the imaging appearances may help the radiologist to include this entity in the differential diagnosis in children who present with spinal pathology and no history of trauma. Histopathological examination excludes tumor and infection but with typical imaging findings may not always be necessary.

Respiratory distress syndrome in near-term babies after caesarean section

OBJECTIVE: Severe respiratory distress syndrome (RDS) caused by surfactant deficiency is described not only in preterm infants but also in (near-) term babies after caesarean section (CS), especially when carried out before the onset of labour. The aim of the present study was to document the severity of this theoretically avoidable entity in order to improve obstetric and perinatal care. PATIENTS: All neonates admitted to the paediatric intensive care unit of the University Hospital of Bern between 1988 and 2000 with RDS on the basis of hyaline membrane disease (HMD) needing mechanical ventilation (MV) after CS and with a birthweight > or = 2500 g were analysed. HMD was diagnosed when respiratory distress and the typical radiological signs were present. Patients were grouped into elective CS before onset of labour and before rupture of membranes (group 1, n = 34) and patients delivered by emergency CS or CS after onset of labour or rupture of membranes (group 2, n = 22). Analysed indices for severity of illness were duration of stay in intensive care unit and MV, ventilation mode, worst oxygenation index (OI), presence of pulmonary air leak, and systemic hypotension. RESULTS: Mean gestational age (GA) was 37 2/7 weeks in group 1 and 36 2/7 weeks in group 2; no patient had a GA of > or = 39 0/7 weeks. Duration of MV was 4.4 days in group 1 and 3.9 days in group 2. Thirteen patients (38%) of group 1 and 7 (32%) of group 2 had to be managed by rescue high-frequency ventilation. A total of 7 patients had an OI>40. Eight patients (24%) in group 1 and 4 (18%) in group 2 developed a pulmonary air leak. Fourteen neonates (41%) in group 1 had to be supported by catecholamines versus 5 (22%) in group 2. There was one death in group 1. CONCLUSION: Severe RDS on the basis of HMD can also occur in near-term babies after CS; even a fatal outcome can not be excluded. The severity of illness in elective CS without labour may be quite high and is comparable to newborns delivered by CS (after onset of labour and/or rupture of the membranes) who were 1 week younger. No case of HMD was found in our population when CS was carried out after completion of 39 post-menstrual weeks of gestation.