Correlating the site of tympanic membrane perforation with Hearing loss

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Small Tympanic Membrane Perforations in the Inferior Quadrants Do Not Impact the Manubrium Vibration in Guinea Pigs

BACKGROUND: It has been believed that location of the perforation has a significant impact on hearing loss. However, recent studies have demonstrated that the perforation sites had no impact on hearing loss. We measured the velocity and pattern of the manubrium vibration in guinea pigs with intact and perforated eardrum using a laser Doppler vibrometer in order to determine the effects of different location perforations on the middle ear transfer functions. METHODS: Two bullas from 2 guinea pigs were used to determine stability of the umbo velocities, and 12 bullas from six guinea pigs to determine the effects of different location perforations on sound transmission. The manubrium velocity was measured at three points on the manubrium in the frequencies of 0.5-8 kHz before and after a perforation was made. The sites of perforations were in anterior-inferior (AI) quadrants of left ears and posterior-inferior (PI) quadrants of right ears. RESULTS: The manubrium vibration velocity losses were noticed in the perforated ears only below 1.5 kHz. The maximum velocity loss was about 7 dB at 500 Hz with the PI perforation. No significant difference in the velocity loss was found between AI and PI perforations. The average ratio of short process velocity to the umbo velocity was approximately 0.5 at all frequencies. No significant differences were found before and after perforation at all frequencies (p>0.05) except 7 kHz (p = 0.004) for both AI and PI perforations. CONCLUSIONS: The manubrium vibration velocity losses from eardrum perforation were frequency-dependent and the largest losses occur at low frequencies. Manubrium velocity losses caused by small acute inferior perforations in guinea pigs have no significant impact on middle ear sound transmission at any frequency tested. The manubrium vibration axis may be perpendicular to the manubrium below 8 kHz in guinea pigs

Six-year changes in body mass index and cardiorespiratory fitness of English schoolchildren from an affluent area

We compared values of body mass index (BMI) and cardiorespiratory fitness (20 m shuttle-run test) of n=157 boys and n=150 girls aged 10-11 measured in 2014 with measures from 2008 and 1998. Boys' fitness was lower (d=0.68) in 2014 than 2008, despite a small (d=0.37) decline in BMI. Girl's BMI changed trivially (d=0.08) but cardiorespiratory fitness was lower (d=0.47) in 2014 than 2008. This study suggests fitness is declining at 0.95% per year, which exceeds the 0.8% rate of decline we reported between 1998 and 2008 and is double the global average of 0.43%. Declines in fitness were independent of changes in BMI suggesting continued reductions in English children's habitual physical activity levels

Noncoding RNA, antigenic variation, and the virulence genes of Plasmodium falciparum

Long non-coding RNAs (lncRNA) are being increasingly recognized as important regulators of gene expression. A recent paper in Genome Biology reports the identification of a lncRNA family in Plasmodium falciparum, the cause of the most deadly form of malaria, that may help to explain the mechanism of antigenic variation in virulence genes of this important pathogen

Evidence for energy conservation during pubertal growth. A 10-year longitudinal study (EarlyBird 71)

BACKGROUND: Diabetes is closely linked to obesity, and obesity rates climb during adolescence for reasons that are not clear. Energy efficiency is important to obesity, and we describe a temporary but substantial fall in absolute energy expenditure, compatible with improved energy efficiency, during the rapid growth phase of puberty. METHODS: In a longitudinal cohort study lasting 10 years, we measured voluntary energy expenditure as physical activity (PA) by accelerometry, involuntary energy expenditure as resting energy expenditure (REE) by oxygen consumption, body mass index (BMI) and body composition by dual energy X-ray absorptiometry annually on 10 occasions from 7 to 16 years in the 347 children of the EarlyBird study. We used mixed effects modelling to analyse the trends in REE and their relationship to BMI, lean mass (LM), fat mass (FM), age, PA and pubertal stage. RESULTS: Relative REE and total PA fell during puberty, as previously described, but the longitudinal data and narrow age-range of the cohort (s.d.±4m) revealed for the first time a substantial fall in absolute REE during the period of maximum growth. The fall became clearer still when adjusted for FM and LM. The fall could not be explained by fasting insulin, adiponectin, leptin, luteinising hormone or follicle stimulating hormone. CONCLUSIONS: There appears to be a temporary but substantial reduction in energy expenditure during puberty, which is unrelated to changes in body composition. If it means higher energy efficiency, the fall in REE could be advantageous in an evolutionary context to delivering the extra energy needed for pubertal growth, but unfavourable to weight gain in a contemporary environment.International Journal of Obesity advance online publication, 4 October 2016; doi:10.1038/ijo.2016.158.We are grateful to the Bright futures trust, Fountain Foundation, BUPA Foundation, EarlyBird Diabetes Trust and countless individual donors who made this study possible

Cloning of the Repertoire of Individual Plasmodium falciparum var Genes Using Transformation Associated Recombination (TAR)

One of the major virulence factors of the malaria causing parasite is the Plasmodium falciparum encoded erythrocyte membrane protein 1 (PfEMP1). It is translocated to It the membrane of infected erythrocytes and expressed from approximately 60 var genes in a mutually exclusive manner. Switching of var genes allows the parasite to alter functional and antigenic properties of infected erythrocytes, to escape the immune defense and to establish chronic infections. We have developed an efficient method for isolating VAR genes from telomeric and other genome locations by adapting transformation-associated recombination (TAR) cloning, which can then be analyzed and sequenced. For this purpose, three plasmids each containing a homologous sequence representing the upstream regions of the group A, B, and C var genes and a sequence homologous to the conserved acidic terminal segment (ATS) of var genes were generated. Co-transfection with P. falciparum strain ITG2F6 genomic DNA in yeast cells yielded 200 TAR clones. The relative frequencies of clones from each group were not biased. Clones were screened by PCR, as well as Southern blotting, which revealed clones missed by PCR due to sequence mismatches with the primers. Selected clones were transformed into E. coli and further analyzed by RFLP and end sequencing. Physical analysis of 36 clones revealed 27 distinct types potentially representing 50% of the var gene repertoire. Three clones were selected for sequencing and assembled into single var gene containing contigs. This study demonstrates that it is possible to rapidly obtain the repertoire of var genes from P. falciparum within a single set of cloning experiments. This technique can be applied to individual isolates which will provide a detailed picture of the diversity of var genes in the field. This is a powerful tool to overcome the obstacles with cloning and assembly of multi-gene families by simultaneously cloning each member

Aging, working memory capacity and the proactive control of recollection:An event-related potential study

The present study investigated the role of working memory capacity (WMC) in the control of recollection in young and older adults. We used electroencephalographic event-related potentials (ERPs) to examine the effects of age and of individual differences in WMC on the ability to prioritize recollection according to current goals. Targets in a recognition exclusion task were words encoded using two alternative decisions. The left parietal ERP old/new effect was used as an electrophysiological index of recollection, and the selectivity of recollection measured in terms of the difference in its magnitude according to whether recognized items were targets or non-targets. Young adults with higher WMC showed greater recollection selectivity than those with lower WMC, while older adults showed nonselective recollection which did not vary with WMC. The data suggest that aging impairs the ability to engage cognitive control effectively to prioritize what will be recollected

A Major Role for the Plasmodium falciparum ApiAP2 Protein PfSIP2 in Chromosome End Biology

The heterochromatic environment and physical clustering of chromosome ends at the nuclear periphery provide a functional and structural framework for antigenic variation and evolution of subtelomeric virulence gene families in the malaria parasite Plasmodium falciparum. While recent studies assigned important roles for reversible histone modifications, silent information regulator 2 and heterochromatin protein 1 (PfHP1) in epigenetic control of variegated expression, factors involved in the recruitment and organization of subtelomeric heterochromatin remain unknown. Here, we describe the purification and characterization of PfSIP2, a member of the ApiAP2 family of putative transcription factors, as the unknown nuclear factor interacting specifically with cis-acting SPE2 motif arrays in subtelomeric domains. Interestingly, SPE2 is not bound by the full-length protein but rather by a 60kDa N-terminal domain, PfSIP2-N, which is released during schizogony. Our experimental re-definition of the SPE2/PfSIP2-N interaction highlights the strict requirement of both adjacent AP2 domains and a conserved bipartite SPE2 consensus motif for high-affinity binding. Genome-wide in silico mapping identified 777 putative binding sites, 94% of which cluster in heterochromatic domains upstream of subtelomeric var genes and in telomere-associated repeat elements. Immunofluorescence and chromatin immunoprecipitation (ChIP) assays revealed co-localization of PfSIP2-N with PfHP1 at chromosome ends. Genome-wide ChIP demonstrated the exclusive binding of PfSIP2-N to subtelomeric SPE2 landmarks in vivo but not to single chromosome-internal sites. Consistent with this specialized distribution pattern, PfSIP2-N over-expression has no effect on global gene transcription. Hence, contrary to the previously proposed role for this factor in gene activation, our results provide strong evidence for the first time for the involvement of an ApiAP2 factor in heterochromatin formation and genome integrity. These findings are highly relevant for our understanding of chromosome end biology and variegated expression in P. falciparum and other eukaryotes, and for the future analysis of the role of ApiAP2-DNA interactions in parasite biology

Default Pathway of var2csa Switching and Translational Repression in Plasmodium falciparum

Antigenic variation is a subtle process of fundamental importance to the survival of a microbial pathogen. In Plasmodium falciparum malaria, PfEMP1 is the major variable antigen and adhesin expressed at the surface of the infected erythrocyte, which is encoded for by members of a family of 60 var-genes. Peri-nuclear repositioning and epigenetic mechanisms control their mono-allelic expression. The switching of PfEMP1 depends in part on variable transition rates and short-lived immune responses to shared minor epitopes. Here we show var-genes to switch to a common gene that is highly transcribed, but sparsely translated into PfEMP1 and not expressed at the erythrocyte surface. Highly clonal and adhesive P. falciparum, which expressed distinct var-genes and the corresponding PfEMP1s at onset, were propagated without enrichment or panning. The parasites successively and spontaneously switched to transcribe a shared var-gene (var2csa) matched by the loss of PfEMP1 surface expression and host cell-binding. The var2csa gene repositioned in the peri-nuclear area upon activation, away from the telomeric clusters and heterochromatin to transcribe spliced, full-length RNA. Despite abundant transcripts, the level of intracellular PfEMP1 was low suggesting post-transcriptional mechanisms to partake in protein expression. In vivo, off-switching and translational repression may constitute one pathway, among others, coordinating PfEMP1 expression