Mutation analysis of the MEN1 gene in multiple endocrine neoplasia type 1, familial acromegaly and familial isolated hyperparathyroidism

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia of the parathyroid glands, the endocrine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, have also been reported. However, whether these families constitute MEN 1 variants or separate entities remains speculative as the genetic bases for these diseases are unclear. The gene for MEN 1 has recently been cloned and characterized. Using single strand conformation analysis (SSCA) and sequencing, we performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 different mutations spread across most of the 9 translated exons and included frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 1466del12 mutation was identified in 6 families with identical 11q13 haplotypes and in 2 isolated cases indicating a common founder. One frameshift mutation caused by 359del4 (GTCT) was found in 1 isolated case and 4 kindreds of different origin and haplotypes; this mutation therefore represents a common "warm" spot in the MEN1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and small FIHP families, suggesting that genetic defects other than the MEN1 gene might be involved and that additional such families need to be analyzed.     

Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects

CONTEXT: Human immunodeficiency virus (HIV) infection has been associated with an increasing incidence of malignancy, and HIV-infected persons have an increased incidence of primary lung carcinoma compared with the general population. OBJECTIVE: To investigate the molecular changes present in HIV-associated lung tumors and compare them with those present in lung carcinomas arising in HIV-indeterminate subjects ("sporadic tumors"). DESIGN: Convenience sample. SUBJECTS: Archival tissues from 11 HIV-positive persons and from 35 persons of indeterminate HIV status. SETTING: University-based medical centers and affiliated hospitals. MAIN OUTCOME MEASURES: Analysis of frequency of loss of heterozygosity (LOH) and microsatellite alteration (MA) using polymerase chain reaction and 16 polymorphic microsatellite markers at 8 chromosomal regions frequently deleted in lung cancer. Presence of HIV and human papillomavirus (HPV) sequences. RESULTS: The overall frequency of LOH at all chromosomal regions tested and the frequencies at most of the individual regions were similar in the 2 groups. Frequency of MA present in the HIV-associated tumors (0.18) was 6-fold higher than in sporadic tumors (0.03) (P<.001). At least 1 MA was present in 10 (91%) of 11 HIV-associated tumors vs 17 (48%) of 35 sporadic tumors (P=.02). Molecular changes were independent of tumor stage and gender. HIV and HPV sequences were not detected in the HIV-associated lung carcinomas. CONCLUSIONS: Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated lung carcinomas. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated tumors.     

Homology and functional similarity of an hrp-linked pathogenicity locus, dspEF, of Erwinia amylovora and the avirulence locus avrE of Pseudomonas syringae pathovar tomato

The "disease-specific" (dsp) region next to the hrp gene cluster of Erwinia amylovora is required for pathogenicity but not for elicitation of the hypersensitive reaction. A 6.6-kb apparent operon, dspEF, was found responsible for this phenotype. The operon contains genes dspE and dspF and is positively regulated by hrpL. A BLAST search revealed similarity in the dspE gene to a partial sequence of the avrE locus of Pseudomonas syringae pathovar tomato. The entire avrE locus was sequenced. Homologs of dspE and dspF were found in juxtaposed operons and were designated avrE and avrF. Introduced on a plasmid, the dspEF locus rendered P. syringae pv. glycinea race 4 avirulent on soybean. An E. amylovora dspE mutant, however, elicited a hypersensitive reaction in soybean. The avrE locus in trans restored pathogenicity to dspE strains of E. amylovora, although restored strains were low in virulence. DspE and AvrE are large (198 kDa and 195 kDa) and hydrophilic. DspF and AvrF are small (16 kDa and 14 kDa) and acidic with predicted amphipathic alpha helices in their C termini; they resemble chaperones for virulence factors secreted by type III secretion systems of animal pathogens.     

Medical challenges of internal conflicts

The most prevalent menace since the end of the cold war is the occurrence of civil wars and local and regional conflicts. The term "low intensity conflict" describes the new threat environment and covers a multitude of phenomena, such as civil wars, guerrilla warfare, terrorism and counterinsurgency operations occurring between routine, peaceful inter- or intrastate competition, and a sustained conventional conflict. There is a great challenge to alert the physicians in general, and the surgical community of the world in particular, to the new threat environment and the medical challenges involved in treating casualties of low intensity conflicts. Specifically, a new international body of surgeons might be required to coordinate the recruitment, training, and creditation for surgeons with special expertise in the management of victims of such conflicts and to facilitate research and general knowledge of the medical challenges of modern conflicts.     

Spatiotemporal imaging of human brain activity using functional MRI constrained magnetoencephalography data: Monte Carlo simulations

The goal of our research is to develop an experimental and analytical framework for spatiotemporal imaging of human brain function. Preliminary studies suggest that noninvasive spatiotemporal maps of cerebral activity can be produced by combining the high spatial resolution (millimeters) of functional MRI (fMRI) with the high temporal resolution (milliseconds) of electroencephalography (EEG) and magnetoencephalography (MEG). Although MEG and EEG are sensitive to millisecond changes in mental activity, the ability to resolve source localization and timing is limited by the ill-posed "inverse" problem. We conducted Monte Carlo simulations to evaluate the use of MRI constraints in a linear estimation inverse procedure, where fMRI weighting, cortical location and orientation, and sensor noise statistics were realistically incorporated. An error metric was computed to quantify the effects of fMRI invisible ("missing") sources, "extra" fMRI sources, and cortical orientation errors. Our simulation results demonstrate that prior anatomical and functional information from MRI can be used to regularize the EEG/MEG inverse problem, giving an improved solution with high spatial and temporal resolution. An fMRI weighting of approximately 90% was determined to provide the best compromise between separation of activity from correctly localized sources and minimization of error caused by missing sources. The accuracy of the estimate was relatively independent of the number and extent of the sources, allowing for incorporation of physiologically realistic multiple distributed sources. This linear estimation method provides an operator-independent approach for combining information from fMRI, MEG, and EEG and represents a significant advance over traditional dipole modeling.     

Ultrarapid metabolizers of debrisoquine: characterization and PCR-based detection of alleles with duplication of the CYP2D6 gene

During a six-month period 2,221 haemocultures obtained from patients hospitalized in the Faculty Hospital Olomouc were examined. In all 304 isolated bacteria the sensitivity was assessed by the standard dilution micromethod and moreover all positive haemocultures were examined the "direct" disc method. Agreement between the results of the two methods was proved in 84% of pairs of tests and within a range from 67 to 100%, depending on the type of antimicrobial preparation. Based on these findings it may be stated that assessment of the sensitivity by the "direct" method agrees significantly with assessment of the sensitivity according to minimal inhibitory concentrations (MIC). In patients with septicaemia this procedure makes it possible to change empirical antibiotherapy by 24 hours sooner to aimed therapy.     

Static output feedback sliding mode control for time‐varying delay systems with time‐delayed nonlinear disturbances

In this paper, a robust stabilization problem for a class of linear time‐varying delay systems with disturbances is studied using sliding mode techniques. Both matched and mismatched disturbances, involving time‐varying delay, are considered. The disturbances are nonlinear and have nonlinear bounds which are employed for the control design. A sliding surface is designed and the stability of the corresponding sliding motion is analysed based on the Razumikhin Theorem. Then a static output feedback sliding mode control with time delay is synthesized to drive the system to the sliding surface in finite time. Conservatism is reduced by using features of sliding mode control and systems structure. Simulation results show the effectiveness of the proposed approach. Copyright © 2009 John Wiley & Sons, Ltd.     

Disturbance decoupled fault reconstruction using sliding mode observers

This paper investigates and presents conditions that guarantee disturbance decoupled fault reconstruction using sliding mode observers, which are less stringent than those of previous work, and show that disturbance reconstruction is not necessary. An aircraft model validates the ideas proposed in this paper. Copyright © 2010 John Wiley and Sons Asia Pte Ltd and Chinese Automatic Control Society     

Fuzzy distributed cooperative tracking for a swarm of unmanned aerial vehicles with heterogeneous goals

This article proposes a systematic analysis for a tracking problem which ensures cooperation amongst a swarm of unmanned aerial vehicles (UAVs), modelled as nonlinear systems with linear and angular velocity constraints, in order to achieve different goals. A distributed Takagi–Sugeno (TS) framework design is adopted for the representation of the nonlinear model of the dynamics of the UAVs. The distributed control law which is introduced is composed of both node and network level information. Firstly, feedback gains are synthesised using a parallel distributed compensation (PDC) control law structure, for a collection of isolated UAVs; ignoring communications among the swarm. Then secondly, based on an alternation-like procedure, the resulting feedback gains are used to determine Lyapunov matrices which are utilised at network level to incorporate into the control law, the relative differences in the states of the vehicles, and to induce cooperative behaviour. Eventually stability is guaranteed for the entire swarm. The control synthesis is performed using tools from linear control theory: in particular the design criteria are posed as linear matrix inequalities (LMIs). An example based on a UAV tracking scenario is included to outline the efficacy of the approach.