Challenges in relating experimental hip implant fixation predictions to clinical observations

Long-term clinical follow-up studies have shown that radiolucent lines at the cement interfaces of total hip replacement femoral components develop gradually, ultimately leading to loosening. In this experimental study, 32 synthetic femurs implanted with cemented femoral components were cyclically loaded with a dynamic joint reaction force, torque, and muscle force, to assess the relative effects of surface finish and collars on interface fixation. Four each of four otherwise identical straight femoral stems, varying only in surface finish and presence or lack of collars were used. Specimens were tested under two conditions: (1) with intact interfaces simulating immediate post-operative conditions and (2) with a thin-film at the stem-cement interface, simulating conditions several weeks to months post-operative when fibrous tissue has formed with the implant still stable. Micromotion was measured at both interfaces in three directions. Surface finish had a larger relative effect than collars, regardless of whether or not a thin-film was present. For example, a proximal grit-blasted finish enhanced fixation at the stem-cement interface by 7-12 μm per-cycle (p<0.05) and decreased early cement mantle loosening by 7-13 μm. For straight stems, rougher surfaces provided greater stability than polished, even with a thin film at the stem-cement interfaces, contradicting the theory that once debonded, rough stems are less stable than polished at the stem-cement interface. The findings of this experimental study exemplify the need to take advantage of all available tools for the preclinical evaluation of orthopaedic implants, including long-term clinical observations of related devices, analytical and numeric models, and experimental bench-top simulations.     

Properties of Ca(2+) transport in mitochondria of Drosophila melanogaster

We have studied the pathways for Ca(2+) transport in mitochondria of the fruit fly Drosophila melanogaster. We demonstrate the presence of ruthenium red (RR)-sensitive Ca(2+) uptake, of RR-insensitive Ca(2+) release, and of Na(+)-stimulated Ca(2+) release in energized mitochondria, which match well characterized Ca(2+) transport pathways of mammalian mitochondria. Following larger matrix Ca(2+) loading Drosophila mitochondria underwent spontaneous RR-insensitive Ca(2+) release, an event that in mammals is due to opening of the permeability transition pore (PTP). Like the PTP of mammals, Drosophila Ca(2+)-induced Ca(2+) release could be triggered by uncoupler, diamide, and N-ethylmaleimide, indicating the existence of regulatory voltage- and redox-sensitive sites and was inhibited by tetracaine. Unlike PTP-mediated Ca(2+) release in mammals, however, it was (i) insensitive to cyclosporin A, ubiquinone 0, and ADP; (ii) inhibited by P(i), as is the PTP of yeast mitochondria; and (iii) not accompanied by matrix swelling and cytochrome c release even in KCl-based medium. We conclude that Drosophila mitochondria possess a selective Ca(2+) release channel with features intermediate between the PTP of yeast and mammals.     

Plasmacytoid dendritic cells promote host defense against acute pneumovirus infection via the TLR7-MyD88-dependent signaling pathway

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection in infants. In human infants, plasmacytoid dendritic cells (pDC) are recruited to the nasal compartment during infection and initiate host defense through the secretion of type I IFN, IL-12, and IL-6. However, RSV-infected pDC are refractory to TLR7-mediated activation. In this study, we used the rodent-specific pathogen, pneumonia virus of mice (PVM), to determine the contribution of pDC and TLR7 signaling to the development of the innate inflammatory and early adaptive immune response. In wild-type, but not TLR7- or MyD88-deficient mice, PVM inoculation led to a marked infiltration of pDC and increased expression of type I, II, and III IFNs. The delayed induction of IFNs in the absence of TLR7 or MyD88 was associated with a diminished innate inflammatory response and augmented virus recovery from lung tissue. In the absence of TLR7, PVM-specific CD8(+) T cell cytokine production was abrogated. The adoptive transfer of TLR7-sufficient, but not TLR7-deficient pDC to TLR7 gene-deleted mice recapitulated the antiviral responses observed in wild-type mice and promoted virus clearance. In summary, TLR7-mediated signaling by pDC is required for appropriate innate responses to acute pneumovirus infection. It is conceivable that as-yet-unidentified defects in the TLR7 signaling pathway may be associated with elevated levels of RSV-associated morbidity and mortality among otherwise healthy human infants.     

The Mre11:Rad50 structure shows an ATP-dependent molecular clamp in DNA double-strand break repair

The MR (Mre11 nuclease and Rad50 ABC ATPase) complex is an evolutionarily conserved sensor for DNA double-strand breaks, highly genotoxic lesions linked to cancer development. MR can recognize and process DNA ends even if they are blocked and misfolded. To reveal its mechanism, we determined the crystal structure of the catalytic head of Thermotoga maritima MR and analyzed ATP-dependent conformational changes. MR adopts an open form with a central Mre11 nuclease dimer and two peripheral Rad50 molecules, a form suited for sensing obstructed breaks. The Mre11 C-terminal helix-loop-helix domain binds Rad50 and attaches flexibly to the nuclease domain, enabling large conformational changes. ATP binding to the two Rad50 subunits induces a rotation of the Mre11 helix-loop-helix and Rad50 coiled-coil domains, creating a clamp conformation with increased DNA-binding activity. The results suggest that MR is an ATP-controlled transient molecular clamp at DNA double-strand breaks.     

Structural gymnastics of multifunctional metamorphic proteins

The classic structure–function paradigm holds that a protein exhibits a single well-defined native state that gives rise to its biological function. Nonetheless, over the past few decades, numerous examples of proteins exhibiting biological function arising from multiple structural states of varying disorder have been identified. Most recently, several examples of ‘metamorphic proteins’, able to interconvert between vastly different native-like topologies under physiological conditions, have been characterised with multiple functions. In this review, we look at the concept of protein metamorphosis in relation to the current understanding of the protein structure–function landscape. Although structural dynamism observed for metamorphic proteins provides a novel source of functional versatility, the dynamic nature of the metamorphic proteins generally makes them difficult to identify and probe using conventional protein structure determination methods. However, as the existence of metamorphic proteins has now been established and techniques enabling the analysis of multiple protein conformers are improving, it is likely that this class will continue to grow in number.     

Hearing feelings: affective categorization of music and speech in alexithymia, an ERP study

Background

Alexithymia, a condition characterized by deficits in interpreting and regulating feelings, is a risk factor for a variety of psychiatric conditions. Little is known about how alexithymia influences the processing of emotions in music and speech. Appreciation of such emotional qualities in auditory material is fundamental to human experience and has profound consequences for functioning in daily life. We investigated the neural signature of such emotional processing in alexithymia by means of event-related potentials.

Methodology

Affective music and speech prosody were presented as targets following affectively congruent or incongruent visual word primes in two conditions. In two further conditions, affective music and speech prosody served as primes and visually presented words with affective connotations were presented as targets. Thirty-two participants (16 male) judged the affective valence of the targets. We tested the influence of alexithymia on cross-modal affective priming and on N400 amplitudes, indicative of individual sensitivity to an affective mismatch between words, prosody, and music. Our results indicate that the affective priming effect for prosody targets tended to be reduced with increasing scores on alexithymia, while no behavioral differences were observed for music and word targets. At the electrophysiological level, alexithymia was associated with significantly smaller N400 amplitudes in response to affectively incongruent music and speech targets, but not to incongruent word targets.

Conclusions

Our results suggest a reduced sensitivity for the emotional qualities of speech and music in alexithymia during affective categorization. This deficit becomes evident primarily in situations in which a verbalization of emotional information is required.     

Profiling dizziness in older primary care patients: an empirical study

Background

The diagnostic approach to dizzy, older patients is not straightforward as many organ systems can be involved and evidence for diagnostic strategies is lacking. A first differentiation in diagnostic subtypes or profiles may guide the diagnostic process of dizziness and can serve as a classification system in future research. In the literature this has been done, but based on pathophysiological reasoning only.

Objective

To establish a classification of diagnostic profiles of dizziness based on empirical data.

Design

Cross-sectional study.

Participants and Setting

417 consecutive patients of 65 years and older presenting with dizziness to 45 primary care physicians in the Netherlands from July 2006 to January 2008.

Methods

We performed tests, including patient history, and physical and additional examination, previously selected by an international expert panel and based on an earlier systematic review. We used the results of these tests in a principal component analysis for exploration, data-reduction and finally differentiation into diagnostic dizziness profiles.

Results

Demographic data and the results of the tests yielded 221 variables, of which 49 contributed to the classification of dizziness into six diagnostic profiles, that may be named as follows: “frailty”, “psychological”, “cardiovascular”, “presyncope”, “non-specific dizziness” and “ENT”. These explained 32% of the variance.

Conclusions

Empirically identified components classify dizziness into six profiles. This classification takes into account the heterogeneity and multicausality of dizziness and may serve as starting point for research on diagnostic strategies and can be a first step in an evidence based diagnostic approach of dizzy older patients.     

Treatment outcome and mortality at one and half year follow-up of HIV infected TB patients under TB control programme in a district of South India

BACKGROUND: There is paucity of data from India on the impact of HIV related immunosuppression in response to TB treatment and mortality among HIV infected TB patients. We assessed the TB treatment outcome and mortality in a cohort of HIV infected TB patients treated with intermittent short course chemotherapy under TB control programme in a high HIV prevalent district of south India. METHODOLOGY/ FINDINGS: Among 3798 TB patients registered for treatment in Mysore district from July 2007 to June 2008, 281 HIV infected patients formed the study group. The socio-demographic and treatment related data of these patients was obtained from TB and HIV programme records and patient interviews 19 months after TB treatment initiation by field investigators. Treatment success rate of 281 patients was 75% while in smear positive pulmonary tuberculosis cases it was 62%, attributable to defaults (16%) and deaths (19%). Only 2 patients had treatment failure. Overall, 83 (30%) patients were reported dead; 26 while on treatment and 57 after TB treatment. Association of treatment related factors with treatment outcome and survival status was studied through logistic regression analysis. Factors significantly associated with 'unfavourable outcome' were disease classification as Pulmonary [aOR-1.96, CI (1.02-3.77)], type of patient as retreatment [aOR-4.78, CI (2.12-10.76)], and non initiation of ART [aOR-4.90, CI (1.85-12.96)]. Factors associated with 'Death' were non initiation of ART [aOR-2.80, CI (1.15-6.81)] and CPT [aOR-3.46, CI (1.47-8.14)]. CONCLUSION: Despite the treatment success of 75% the high mortality (30%) in the study group is a matter of concern and needs immediate intervention. Non initiation of ART has emerged as a high risk factor for unfavourable treatment outcome and mortality. These findings underscore the importance of expanding and improving delivery of ART services as a priority and reconsideration of the programme guidelines for ART initiation in HIV infected TB patients.