Impact of Rotavirus Vaccine Introduction and Vaccine Effectiveness in the Republic of Moldova.

BACKGROUND: The Republic of Moldova was the first low- to middle-income country in the World Health Organization European Region to introduce rotavirus vaccine (July 2012). We aimed to assess the impact of the rotavirus vaccine program and estimate vaccine effectiveness (VE). METHODS: Surveillance for rotavirus gastroenteritis was conducted in 2 hospitals in the capital city of Chisinau starting in September 2009. Monthly rotavirus admissions by age were examined before and after introduction of rotavirus vaccination using interrupted time-series analyses. We performed a case-control study of VE by comparing rotavirus case patients with test-negative controls. RESULTS: Coverage with at least 1 dose of vaccine increased from 35% in year 1 to 55% in year 2 for children <1 year of age. The percentage of hospital admissions positive for rotavirus fell from 45% in the prevaccine period to 25% (rate reduction, 36%; 95% confidence interval [CI], 26%-44%) and 14% (rate reduction, 67%; 95% CI, 48%-88%) in the first and second years after vaccine introduction, respectively, among children aged <5 years. Reductions were most pronounced among those aged <1 year. Significant reductions among cohorts too old to be vaccinated suggest indirect benefits. Two-dose VE was 79% (95% CI, 62%-88%) against rotavirus hospitalization and 84% (95% CI, 64%-93%) against moderate to severe rotavirus. CONCLUSIONS: These results consistently point to profound direct and herd immunity impacts of the rotavirus vaccine program in young children in the Republic of Moldova. Vaccine coverage was modest in these early years following introduction, so there remains potential for further disease reductions.

Global Role and Burden of Influenza in Pediatric Respiratory Hospitalizations, 1982-2012: A Systematic Analysis.

BACKGROUND: The global burden of pediatric severe respiratory illness is substantial, and influenza viruses contribute to this burden. Systematic surveillance and testing for influenza among hospitalized children has expanded globally over the past decade. However, only a fraction of the data has been used to estimate influenza burden. In this analysis, we use surveillance data to provide an estimate of influenza-associated hospitalizations among children worldwide. METHODS AND FINDINGS: We aggregated data from a systematic review (n = 108) and surveillance platforms (n = 37) to calculate a pooled estimate of the proportion of samples collected from children hospitalized with respiratory illnesses and positive for influenza by age group (<6 mo, <1 y, <2 y, <5 y, 5-17 y, and <18 y). We applied this proportion to global estimates of acute lower respiratory infection hospitalizations among children aged <1 y and <5 y, to obtain the number and per capita rate of influenza-associated hospitalizations by geographic region and socio-economic status. Influenza was associated with 10% (95% CI 8%-11%) of respiratory hospitalizations in children <18 y worldwide, ranging from 5% (95% CI 3%-7%) among children <6 mo to 16% (95% CI 14%-20%) among children 5-17 y. On average, we estimated that influenza results in approximately 374,000 (95% CI 264,000 to 539,000) hospitalizations in children <1 y-of which 228,000 (95% CI 150,000 to 344,000) occur in children <6 mo-and 870,000 (95% CI 610,000 to 1,237,000) hospitalizations in children <5 y annually. Influenza-associated hospitalization rates were more than three times higher in developing countries than in industrialized countries (150/100,000 children/year versus 48/100,000). However, differences in hospitalization practices between settings are an important limitation in interpreting these findings. CONCLUSIONS: Influenza is an important contributor to respiratory hospitalizations among young children worldwide. Increasing influenza vaccination coverage among young children and pregnant women could reduce this burden and protect infants <6 mo.

Myocilin regulates cell proliferation and survival.

Myocilin, a causative gene for open angle glaucoma, encodes a secreted glycoprotein with poorly understood functions. To gain insight into its functions, we produced a stably transfected HEK293 cell line expressing myocilin under an inducible promoter and compared gene expression profiles between myocilin-expressing and vector control cell lines by a microarray analysis. A significant fraction of differentially expressed genes in myocilin-expressing cells was associated with cell growth and cell death, suggesting that myocilin may have a role in the regulation of cell growth and survival. Increased proliferation of myocilin-expressing cells was demonstrated by the WST-1 proliferation assay, direct cell counting, and immunostaining with antibodies against Ki-67, a cellular proliferation marker. Myocilin-containing conditioned medium also increased proliferation of unmodified HEK293 cells. Myocilin-expressing cells were more resistant to serum starvation-induced apoptosis than control cells. TUNEL-positive apoptotic cells were dramatically decreased, and two apoptotic marker proteins, cleaved caspase 7 and cleaved poly(ADP-ribose) polymerase, were significantly reduced in myocilin-expressing cells as compared with control cells under apoptotic conditions. In addition, myocilin-deficient mesenchymal stem cells exhibited reduced proliferation and enhanced susceptibility to serum starvation-induced apoptosis as compared with wild-type mesenchymal stem cells. Phosphorylation of ERK1/2 and its upstream kinases, c-Raf and MEK, was increased in myocilin-expressing cells compared with control cells. Elevated phosphorylation of ERK1/2 was also observed in the trabecular meshwork of transgenic mice expressing 6-fold higher levels of myocilin when compared with their wild-type littermates. These results suggest that myocilin promotes cell proliferation and resistance to apoptosis via the ERK1/2 MAPK signaling pathway.

Preservation of cone photoreceptors after a rapid yet transient degeneration and remodeling in cone-only Nrl-/- mouse retina.

Cone photoreceptors are the primary initiator of visual transduction in the human retina. Dysfunction or death of rod photoreceptors precedes cone loss in many retinal and macular degenerative diseases, suggesting a rod-dependent trophic support for cone survival. Rod differentiation and homeostasis are dependent on the basic motif leucine zipper transcription factor neural retina leucine zipper (NRL). The loss of Nrl (Nrl(-/-)) in mice results in a retina with predominantly S-opsin-containing cones that exhibit molecular and functional characteristics of wild-type cones. Here, we report that Nrl(-/-) retina undergoes a rapid but transient period of degeneration in early adulthood, with cone apoptosis, retinal detachment, alterations in retinal vessel structure, and activation and translocation of retinal microglia. However, cone degeneration stabilizes by 4 months of age, resulting in a thinner but intact outer nuclear layer with residual cones expressing S- and M-opsins and a preserved photopic electroretinogram. At this stage, microglia translocate back to the inner retina and reacquire a quiescent morphology. Gene profiling analysis during the period of transient degeneration reveals misregulation of genes related to stress response and inflammation, implying their involvement in cone death. The Nrl(-/-) mouse illustrates the long-term viability of cones in the absence of rods and retinal pigment epithelium defects in a rodless retina. We propose that Nrl(-/-) retina may serve as a model for elucidating mechanisms of cone homeostasis and degeneration that would be relevant to understanding diseases of the cone-dominant human macula.

Conditional ablation of the Notch2 receptor in the ocular lens.

Notch signaling is essential for proper lens development, however the specific requirements of individual Notch receptors have not been investigated. Here we report the lens phenotypes of Notch2 conditionally mutant mice, which exhibited severe microphthalmia, reduced pupillary openings, disrupted fiber cell morphology, eventual loss of the anterior epithelium, fiber cell dysgenesis, denucleation defects, and cataracts. Notch2 mutants also had persistent lens stalks as early as E11.5, and aberrant DNA synthesis in the fiber cell compartment by E14.5. Gene expression analyses showed that upon loss of Notch2, there were elevated levels of the cell cycle regulators Cdkn1a (p21Cip1), Ccnd2 (CyclinD2), and Trp63 (p63) that negatively regulates Wnt signaling, plus down-regulation of Cdh1 (E-Cadherin). Removal of Notch2 also resulted in an increased proportion of fiber cells, as was found in Rbpj and Jag1 conditional mutant lenses. However, Notch2 is not required for AEL proliferation, suggesting that a different receptor regulates this process. We found that Notch2 normally blocks lens progenitor cell death. Overall, we conclude that Notch2-mediated signaling regulates lens morphogenesis, apoptosis, cell cycle withdrawal, and secondary fiber cell differentiation.

Relative fecal abundance of extended-spectrum-ß-lactamase-producing Escherichia coli strains and their occurrence in urinary tract infections in women.

Extended-spectrum-beta-lactamase (ESBL)-producing Escherichia coli (ESBL E. coli) strains are of major concern because few antibiotics remain active against these bacteria. We investigated the association between the fecal relative abundance (RA) of ESBL-producing E. coli (ESBL-RA) and the occurrence of ESBL E. coli urinary tract infections (UTIs). The first stool samples passed after suspicion of UTI from 310 women with subsequently confirmed E. coli UTIs were sampled and tested for ESBL-RA by culture on selective agar. Predictive values of ESBL-RA for ESBL E. coli UTI were analyzed for women who were not exposed to antibiotics when the stool was passed. ESBL E. coli isolates were characterized for ESBL type, phylogroup, relatedness, and virulence factors. The prevalence of ESBL E. coli fecal carriage was 20.3%, with ESBL E. coli UTIs being present in 12.3% of the women. The mean ESBL-RA (95% confidence interval [CI]) was 13-fold higher in women exposed to antibiotics at the time of sampling than in those not exposed (14.3% [range, 5.6% to 36.9%] versus 1.1% [range, 0.32% to 3.6%], respectively; P < 0.001) and 18-fold higher in women with ESBL E. coli UTI than in those with another E. coli UTI (10.0% [range, 0.54% to 100%] versus 0.56% [range, 0.15% to 2.1%[, respectively; P < 0.05). An ESBL-RA of <0.1% was 100% predictive of a non-ESBL E. coli UTI. ESBL type, phylogroup, relatedness, and virulence factors were not found to be associated with ESBL-RA. In conclusion, ESBL-RA was linked to the occurrence of ESBL E. coli UTI in women who were not exposed to antibiotics and who had the same clone of E. coli in urine samples and fecal samples. Especially, a low ESBL-RA appeared to be associated with a low risk of ESBL E. coli infection.

The effectiveness of primary series CoronaVac vaccine in preventing COVID-19 illness: A prospective cohort study among healthcare workers in Azerbaijan, May-November 2021.

Background: Healthcare workers (HCWs) have suffered considerable morbidity and mortality during the COVID-19 pandemic. Few studies have evaluated the CoronaVac vaccine effectiveness (VE), particularly in Eastern Europe, where the vaccine has been widely used. Methods: We conducted a prospective cohort study among HCWs in seven hospitals in Baku, Azerbaijan between May 17 and November 30, 2021, to evaluate primary series (two-dose) CoronaVac VE against symptomatic SARS-CoV-2 infection. Participants completed weekly symptom questionnaires, provided nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing when symptomatic, and provided serology samples at enrollment that were tested for anti-spike and anti-nucleocapsid antibodies. We estimated VE as (1 - hazard ratio)*100 using a Cox proportional hazards model with vaccination status as a time-varying exposure, adjusting for hospital and previous SARS-CoV-2 infection status. Results: We enrolled 1582 HCWs. At enrollment, 1040 (66%) had received two doses of CoronaVac; 421 (27%) were unvaccinated. During the study period, 72 PCR-positive SARS-CoV-2 infections occurred; 36/39 (92%) sequenced samples were classified as Delta variants. Primary series VE against COVID-19 illness was 29% (95% CI: -51%; 67%) for the entire analysis period. For the Delta-only period (July 1-November 30, 2021), primary series VE was 19% (95% CI: -81%; 64%). For the entire analysis period, primary series VE was 39% (95% CI: -40%; 73%) for HCWs vaccinated within 14-149 days and 19% (95% CI: -81%; 63%) for those vaccinated ≥150 days. Conclusions: During a period in Azerbaijan characterized by mostly Delta circulation, VE point estimates suggested that primary series CoronaVac protected nearly 1 in 3 HCWs against COVID-19, but 95% confidence intervals were wide, with lower bounds that crossed zero, reflecting the limited precision of our VE estimates. Our findings underscore the need to consider booster doses for individuals who have received the primary series of CoronaVac.

Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa.

Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G-->A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.

The seventh pandemic of cholera in Europe revisited by microbial genomics.

In 1970, the seventh pandemic of cholera (7 P) reached both Africa and Europe. Between 1970 and 2011, several European countries reported cholera outbreaks of a few to more than 2,000 cases. We report here a whole-genome analysis of 1,324 7 P V. cholerae El Tor (7 PET) isolates, including 172 from autochthonous sporadic or outbreak cholera cases occurring between 1970 and 2011 in Europe, providing insight into the spatial and temporal spread of this pathogen across Europe. In this work, we show that the 7 PET lineage was introduced at least eight times into two main regions: Eastern and Southern Europe. Greater recurrence of the disease was observed in Eastern Europe, where it persisted until 2011. It was introduced into this region from Southern Asia, often circulating regionally in the countries bordering the Black Sea, and in the Middle East before reaching Eastern Africa on several occasions. In Southern Europe, the disease was mostly seen in individual countries during the 1970s and was imported from North and West Africa, except in 1994, when cholera was imported into Albania and Italy from the Black Sea region. These results shed light on the geographic course of cholera during the seventh pandemic and highlight the role of humans in its global dissemination.

Diversity of staphylococcal cassette chromosome mec structures in methicillin-resistant Staphylococcus epidermidis and Staphylococcus haemolyticus strains among outpatients from four countries.

In staphylococci, methicillin (meticillin) resistance (MR) is mediated by the acquisition of the mecA gene, which is carried on the size and composition variable staphylococcal cassette chromosome mec (SCCmec). MR has been extensively studied in Staphylococcus aureus, but little is known about MR coagulase-negative staphylococci (MR-CoNS). Here, we describe the diversity of SCCmec structures in MR-CoNS from outpatients living in countries with contrasting environments: Algeria, Mali, Moldova, and Cambodia. Their MR-CoNS nasal carriage rates were 29, 17, 11, and 31%, respectively. Ninety-six MR-CoNS strains, comprising 75 (78%) Staphylococcus epidermidis strains, 19 (20%) Staphylococcus haemolyticus strains, 1 (1%) Staphylococcus hominis strain, and 1 (1%) Staphylococcus cohnii strain, were analyzed. Eighteen different SCCmec types were observed, with 28 identified as type IV (29%), 25 as type V (26%), and 1 as type III (1%). Fifteen strains (44%) were untypeable for their SCCmec. Thirty-four percent of MR-CoNS strains contained multiple ccr copies. Type IV and V SCCmec were preferentially associated with S. epidermidis and S. haemolyticus, respectively. MR-CoNS constitute a widespread and highly diversified MR reservoir in the community.

Study of Corynebacterium diphtheriae strains isolated in Romania, northwestern Russia and the Republic of Moldova.

A selection of 167 Corynebacterium diphtheriae strains isolated in Romania, the Russian Federation and the Republic of Moldova were analysed by biotyping, phage typing, the toxin production test and by molecular techniques such as ribotyping, pulsed field gel electrophoresis and random amplified polymorphic DNA, in order to establish the epidemiological relatedness, genetic divergence and strain circulation within and between the bordering countries. Using a set of five digoxigenin-labeled oligonucleotides and BstEII digestion, 34 ribotypes were identified. The strains isolated in the epidemic areas (Russia and Moldova) were very closely related but different from those isolated in Romania. C1 and C5 were the main ribotypes identified in these areas. Neither ribotype was found in Romania, where the main circulating types were C3 and C7. Field inversion gel electrophoresis was more discriminative than ribotyping and revealed 54 macrorestriction profiles after SfiI restriction. Both methods showed a significant homogeneity of the strains from epidemic areas and a large diversity among the Romanian strains. Random amplification was useful as an identification method for the epidemic strains, but not for the Romanian ones which displayed a large number of amplification profiles. The phenotypic methods associated with molecular typing techniques enabled distinguishing between strains, detecting the epidemic clone, and sustaining the absence of transmission across borders.

Viral gastroenteritis in rotavirus negative hospitalized children <5 years of age from the independent states of the former Soviet Union.

PURPOSE: Rotavirus causes nearly 40% of all hospitalizations for AGE among children <5 years of age in the NIS of the former Soviet Union. The etiologic role of other established gastroenteritis viruses in this age group is unknown. METHODS: Laboratory-confirmed rotavirus negative fecal specimens (N=495) collected between January and December 2009 from children in 6 NIS (Armenia, Azerbaijan, Belarus, Georgia, Republic of Moldova and Ukraine) were tested for norovirus, sapovirus, enteric adenovirus and astrovirus by real-time RT-PCR. Genotyping was carried out by sequencing and phylogenetic analysis. RESULTS: Norovirus, enteric adenovirus, sapovirus and astrovirus were detected in 21.8%, 4.0%, 3.2%, and 1.4% of the rotavirus negative specimens, respectively. Mixed infections were identified in 4.1% of the specimens. Phylogenetic analysis showed co-circulation of several different genotypes with GII.4 Den Haag (2006b) norovirus, GI.2 sapovirus, adenovirus type 41, and astrovirus type 1 causing majority of the infections. CONCLUSION: Norovirus, enteric adenovirus, sapovirus and astrovirus account for a significant proportion (30.5%) of AGE in hospitalized children <5 years of age in 6 NIS.

Gene expression changes in aging retinal microglia: relationship to microglial support functions and regulation of activation.

Microglia, the resident immune cells of the central nervous system (CNS), are thought to contribute to the pathogenesis of age-related neurodegenerative disorders. It has been hypothesized that microglia undergo age-related changes in gene expression patterns that give rise to pathogenic phenotypes. We compared the gene expression profiles in microglia isolated ex vivo from the retinas of mice ranging from early adulthood to late senescence. We discovered that microglial gene expression demonstrated progressive change with increasing age, and involved genes that regulate microglial supportive functions and immune activation. Molecular pathways involving immune function and regulation, angiogenesis, and neurotrophin signaling demonstrated age-related change. In particular, expression levels of complement genes, C3 and CFB, previously associated with age-related macular degeneration (AMD), increased with aging, suggesting that senescent microglia may contribute to complement dysregulation during disease pathogenesis. Taken together, senescent microglia demonstrate age-related gene expression changes capable of altering their constitutive support functions and regulation of their activation status in ways relating to neuroinflammation and neurodegeneration in the CNS.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

Protective gene expression changes elicited by an inherited defect in photoreceptor structure.

Inherited defects in retinal photoreceptor structure impair visual transduction, disrupt relationship with the retinal pigment epithelium (RPE), and compromise cell viability. A variety of progressive retinal degenerative diseases can result, and knowledge of disease etiology remains incomplete. To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. Both the array and qPCR data revealed that gene expression changes were generally modest and dispersed amongst a variety of known functional networks. Although genes showing major (>5-fold) differential expression were identified in a few instances, nearly all displayed transient temporal profiles, returning to WT levels by postnatal day (P) 21. These observations suggest that major defects in photoreceptor cell structure may induce early homeostatic responses, which function in a protective manner to promote cell viability. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and retina. Egr1 upregulation was associated with microglial activation and migration into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors may represent a protective immune mechanism which contributes to the characteristically slow retinal degeneration of the rds mouse model.

Global expression profiling of peripheral Qa-1-restricted CD8αα+TCRαß+ regulatory T cells reveals innate-like features: implications for immune-regulatory repertoire.

Among peripheral regulatory T cells, CD8(+) T cells also play an important role in the maintenance of immune homeostasis. A subset of CD8(+) Treg that express αß T cell receptor (TCR) and CD8αα homodimers can recognize TCR-derived peptides in the context of the class Ib MHC molecule Qa-1. To gain a better understanding of the nature and phenotype of CD8αα(+)TCRαß+ Treg, a global gene expression profiling using microarray, real-time quantitative polymerase chain reaction, and flow-cytometric analysis was performed using functional Treg clones and lines. The study findings show that CD8(+) Treg shared gene profile expressed by innate-like lymphocytes, including murine intraepithelial lymphocytes and thymic CD8αα(+)TCRαß+ T-cell populations. In addition, this subset displays differential expression of several key regulatory molecules, including CD200. CD8αα(+) Treg expressed higher levels of a number of natural killer cell-related receptors and molecules belonging to the TNF superfamily. Collectively, peripheral class Ib-reactive CD8αα(+)TCRαß+ T cells represent a unique regulatory population different from class Ia major histocompatibility complex-restricted conventional T cells. These studies have important implications for the regulatory mechanisms mediated by the CD8(+) Treg population in general.

Ciliary neurotrophic factor induces genes associated with inflammation and gliosis in the retina: a gene profiling study of flow-sorted, Müller cells.

BACKGROUND: Ciliary neurotrophic factor (CNTF), a member of the interleukin-6 cytokine family, has been implicated in the development, differentiation and survival of retinal neurons. The mechanisms of CNTF action as well as its cellular targets in the retina are poorly understood. It has been postulated that some of the biological effects of CNTF are mediated through its action via retinal glial cells; however, molecular changes in retinal glia induced by CNTF have not been elucidated. We have, therefore, examined gene expression dynamics of purified Müller (glial) cells exposed to CNTF in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Müller cells were flow-sorted from mgfap-egfp transgenic mice one or three days after intravitreal injection of CNTF. Microarray analysis using RNA from purified Müller cells showed differential expression of almost 1,000 transcripts with two- to seventeen-fold change in response to CNTF. A comparison of transcriptional profiles from Müller cells at one or three days after CNTF treatment showed an increase in the number of transcribed genes as well as a change in the expression pattern. Ingenuity Pathway Analysis showed that the differentially regulated genes belong to distinct functional types such as cytokines, growth factors, G-protein coupled receptors, transporters and ion channels. Interestingly, many genes induced by CNTF were also highly expressed in reactive Müller cells from mice with inherited or experimentally induced retinal degeneration. Further analysis of gene profiles revealed 20-30% overlap in the transcription pattern among Müller cells, astrocytes and the RPE. CONCLUSIONS/SIGNIFICANCE: Our studies provide novel molecular insights into biological functions of Müller glial cells in mediating cytokine response. We suggest that CNTF remodels the gene expression profile of Müller cells leading to induction of networks associated with transcription, cell cycle regulation and inflammatory response. CNTF also appears to function as an inducer of gliosis in the retina.

Distinct signature of altered homeostasis in aging rod photoreceptors: implications for retinal diseases.

BACKGROUND: Advanced age contributes to clinical manifestations of many retinopathies and represents a major risk factor for age-related macular degeneration, a leading cause of visual impairment and blindness in the elderly. Rod photoreceptors are especially vulnerable to genetic defects and changes in microenvironment, and are among the first neurons to die in normal aging and in many retinal degenerative diseases. The molecular mechanisms underlying rod photoreceptor vulnerability and potential biomarkers of the aging process in this highly specialized cell type are unknown. METHODOLOGY/PRINCIPAL FINDINGS: To discover aging-associated adaptations that may influence rod function, we have generated gene expression profiles of purified rod photoreceptors from mouse retina at young adult to early stages of aging (1.5, 5, and 12 month old mice). We identified 375 genes that showed differential expression in rods from 5 and 12 month old mouse retina compared to that of 1.5 month old retina. Quantitative RT-PCR experiments validated expression change for a majority of the 25 genes that were examined. Macroanalysis of differentially expressed genes using gene class testing and protein interaction networks revealed overrepresentation of cellular pathways that are potentially photoreceptor-specific (angiogenesis and lipid/retinoid metabolism), in addition to age-related pathways previously described in several tissue types (oxidative phosphorylation, stress and immune response). CONCLUSIONS/SIGNIFICANCE: Our study suggests a progressive shift in cellular homeostasis that may underlie aging-associated functional decline in rod photoreceptors and contribute to a more permissive state for pathological processes involved in retinal diseases.

Population history of the Dniester-Carpathians: evidence from Alu markers.

The area between the Dniester and the eastern Carpathian mountain range is at a geographical crossroads between eastern Europe and the Balkans. Little is known about the genetics of the population of this region. We performed an analysis of 12 binary autosomal markers in samples from six Dniester-Carpathian populations: two Moldavian, one Romanian, one Ukrainian and two Gagauz populations. The results were compared with gene frequency data from culturally and linguistically related populations from Southeast Europe and Central Asia. Small genetic differences were found among southeastern European populations (in particular those of the Dniester-Carpathian region). The observed homogeneity suggests either a very recent common ancestry of all southeastern European populations or strong gene flow between them. Despite this low level of differentiation, tree reconstruction and principle component analyses allowed a distinction between Balkan-Carpathian (Macedonians, Romanians, Moldavians, Ukrainians and Gagauzes) and eastern Mediterranean (Turks, Greeks and Albanians) population groups. The genetic affinities among Dniester-Carpathian and southeastern European populations do not reflect their linguistic relationships. The results indicate that the ethnic and genetic differentiations occurred in these regions to a considerable extent independently of each other. In particular, Gagauzes, a Turkic-speaking population, show closer affinities to their geographical neighbors than to other Turkic populations.