Genotypic heterogeneity and clinical phenotype in triple A syndrome: a review of the NIH experience 2000-2005.

Triple A syndrome (AAAS, OMIM#231550) is an autosomal recessive condition characterized by adrenal insufficiency, achalasia, alacrima, neurodegeneration and autonomic dysfunction. Mutations in the AAAS gene on chromosome 12q13 have been reported in several subjects with AAAS. Over the last 5 years, we have evaluated six subjects with the clinical diagnosis of AAAS. Three subjects had mutations in the AAAS gene-- including one novel mutation (IVS8+1 G>A)-- and a broad spectrum of clinical presentations. However, three subjects with classic AAAS did not have mutations in the AAAS gene on both alleles. This finding supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded.

Association of a COL1A1 polymorphism with lumbar disc disease in young military recruits.

BACKGROUND: Lumbar disc disease (LDD), one of the most common conditions for which patients seek medical care, has been associated with sequence changes of the COL genes. COL1A1, however, has not been studied in young patients with LDD; COL1A1 polymorphisms have been associated with bone mineral density (BMD) in several populations and with LDD in older adults. OBJECTIVE: To study COL1A1 polymorphisms in young Greek army recruits with LDD. SUBJECTS: These young soldiers were diagnosed with early LDD at the time of their presentation to a military training site. All patients had radiological confirmation of their disease; a control group was also studied. METHODS: Sp1-binding site polymorphism of the COL1A1 gene was investigated by standard methods. RESULTS: There was an increased frequency of the "ss" genotype (33.3%) in LDD patients; none of the controls had this genotype. In addition, a significantly smaller number of controls was heterozygotes for this allele. CONCLUSIONS: A previously studied sequence change of the regulatory region of the COL1A1 gene, the same as has previously been associated with low BMD in many populations and LDD in older adults, showed a strong association with LDD in young male soldiers who were recently diagnosed with this disease.

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.

Molecular and phylogenetic analysis of haemagglutinin and neuraminidase sequences from recent human influenza type A (H3N2) viral isolates in Southern Greece.

Eighteen haemagglutinin (HA1) gene segments and eleven neuraminidase (NA) genes of human influenza type A (H3N2) viruses isolated from non-vaccinated individuals presenting severe influenza-like illness at peak influenza activity in Southern Greece during the surveillance period 1996-1999, were subjected to sequence and phylogenetic analyses following propagation in embryonated hen's eggs. The HA1 gene segment of the clinical isolates differed from the recent reference influenza type A (H3N2) vaccine strains in an Ile at residue 186, a Val at residue 194 and a Val at residue 226 for one, two and thirteen isolates of the 1996-1997 and 1996-1999 periods, respectively. The analogous differences in the NA gene were confined in an Asp to Asn substitution at residue 198 in one A/Wuhan/359/95 (H3N2)-like isolate of the 1996-1997 period, primarily. In addition, phylogenetic analysis revealed that an isolate of the 1997-1998 period was a recombinant with its HA1 gene segment being closely related to that of A/Wuhan/359/95-like viruses and its NA to viruses of the A/Sydney/5/97 (H3N2) lineage. These findings confirmed the profound genetic instability of influenza type A (H3N2) viruses and underscored the importance for periodic molecular surveys of HA and NA in the effective prevention and management of viral outbreaks. Most importantly, however, they contributed the first complete epidemiological material for influenza in Southern Greece, the archival nature of which constitutes valuable reference for future surveys.

High sequence divergence in the 5' non-coding region of reference Coxsackie B and ECHO viral strains and clinical isolates revealed by restriction fragment length polymorphism analysis.

We report the restriction fragment length polymorphism (RFLP) patterns of a 440-bp-long 5' non-coding region (5' NCR) amplification target of all 34 reference Coxsackie B and ECHO (enteric cytopathic human orphan) enterovirus strains and a total of 42 serotypically pre-assigned clinical isolates, in order to afford meaningful comparisons among these patterns and those of polioviruses. The RFLP patterns of reference Coxsackie B strains differed from one another and from those of polio and ECHO reference enteroviruses except from Coxsackie B1 and B2, which, although they differed from one another, had identical RFLP patterns with ECHO 17 and 13, respectively. The 28 ECHO reference strains formed a more variable viral group including strains with RFLP patterns distinct from one another and from those of polio and Coxsackie B enteroviruses, and others with RFLP pattern identities common to other ECHO viruses and Coxsackie B1 and B2 but not polioviruses. The RFLP patterns of the clinical isolates and their corresponding serotypically assigned reference Coxsackie B and ECHO strains presented the most notable variations. The observed differences between serotype and genotype-dependent assignments within the 440-bp long 5' NCR target sequence of Coxsackie B and ECHO enteroviruses were in sharp contrast to the analogous situation with polioviruses. These findings support the specificity of the described method for clinical diagnostic genotyping of polioviruses and demonstrate that the 440-bp-long target sequence follows a different evolutionary process in polio and non-polio enteroviruses that is particularly prominent between reference non-polio strains and their serotypically assigned clinical isolates.

[The virulence and colicinogenicity of pathogenic Escherichia isolated from water and human beings]. / Virulentnost' i kolitsinogennost' patogennykh ésherikhii, vydelennykh iz vody i ot liudei.

An analysis of virulence and colicinogenicity of 180 cultures of pathogenic Escherichia of different origin has shown that the expressed characters occurred in 40 +/- 49% of strains isolated from people and 28.7 +/- 5.1% of strains isolated from water. The dependence of the studied properties on serogroups of the agents is established. These characters are more often inherent in representatives of the dominating serogroups, which may be a reason of their selective advantage in circulation among people and in water.

[Colicin genotype characteristics of pathogenic Escherichia circulating in the environment]. / Kolitsinogenotipovaia kharakteristika patogennykh ésherikhii, tsirkuliruiushchikh v ob''ektakh okruzhaiushchei sredy.

Colicin identification of pathogenic Escherichia, isolated from the environmental objects, showed that determination of colicinogenicity signs and sensitivity to standard colicins in pathogenic E. to a more considerable degree depended on strain sulfur-group membership than on the amanating objects. The analysis of colicin genotype characteristics of pathogenic E., circulating in environment, provided much information and could be used in identifying a source of infection and ways of escherichiosis pathogen transmission.

[Occurrence in the environment and among the population of antibiotic-resistant strains of pathogenic Escherichia]. / Rasprostranenie v ukruzhaiushchei srede i sredi liudei antibiotikorezistenthykh shtammov patogennykh ésherikhii.

When studying antibioticograms of 1303 strains of pathogenic Escherichia, the correlation of their resistance with the character and source of emanation, exciters' serogroups and antibiotics has been established. The strains isolated from the environment, primarily from food-staffs, wash-out, and wastewater have higher antibiotic resistance. No significant differences are noted in the number of resistance markers as to the source of pathogenic Escherichia. The following antibiotic range is established: streptomycin-chloramphenicol (chloromycetin)--neomycin sulfate-tetracyline-kanamycin-polymyxin-gentamycin, thus the least number of strains in characterized by gentamycin resistance.