Increased peri-ductal collagen micro-organization may contribute to raised mammographic density

BACKGROUND: High mammographic density is a therapeutically modifiable risk factor for breast cancer. Although mammographic density is correlated with the relative abundance of collagen-rich fibroglandular tissue, the causative mechanisms, associated structural remodelling and mechanical consequences remain poorly defined. In this study we have developed a new collaborative bedside-to-bench workflow to determine the relationship between mammographic density, collagen abundance and alignment, tissue stiffness and the expression of extracellular matrix organising proteins. METHODS: Mammographic density was assessed in 22 post-menopausal women (aged 54–66 y). A radiologist and a pathologist identified and excised regions of elevated non-cancerous X-ray density prior to laboratory characterization. Collagen abundance was determined by both Masson’s trichrome and Picrosirius red staining (which enhances collagen birefringence when viewed under polarised light). The structural specificity of these collagen visualisation methods was determined by comparing the relative birefringence and ultrastructure (visualised by atomic force microscopy) of unaligned collagen I fibrils in reconstituted gels with the highly aligned collagen fibrils in rat tail tendon. Localised collagen fibril organisation and stiffness was also evaluated in tissue sections by atomic force microscopy/spectroscopy and the abundance of key extracellular proteins was assessed using mass spectrometry. RESULTS: Mammographic density was positively correlated with the abundance of aligned periductal fibrils rather than with the abundance of amorphous collagen. Compared with matched tissue resected from the breasts of low mammographic density patients, the highly birefringent tissue in mammographically dense breasts was both significantly stiffer and characterised by large (>80 μm long) fibrillar collagen bundles. Subsequent proteomic analyses not only confirmed the absence of collagen fibrosis in high mammographic density tissue, but additionally identified the up-regulation of periostin and collagen XVI (regulators of collagen fibril structure and architecture) as potential mediators of localised mechanical stiffness. CONCLUSIONS: These preliminary data suggest that remodelling, and hence stiffening, of the existing stromal collagen microarchitecture promotes high mammographic density within the breast. In turn, this aberrant mechanical environment may trigger neoplasia-associated mechanotransduction pathways within the epithelial cell population. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13058-015-0664-2) contains supplementary material, which is available to authorized users

Prevalence and severity of antipsychotic related constipation in patients with schizophrenia: a retrospective descriptive study

<p>Abstract</p> <p>Background</p> <p>Antipsychotic are the cornerstone in the treatment of schizophrenia. They also have a number of side-effects. Constipation is thought to be common, and a potential serious side-effect, which has received little attention in recent literature.</p> <p>Method</p> <p>We performed a retrospective study in consecutively admitted patients, between 2007 and 2009 and treated with antipsychotic medication, linking different electronic patient data to evaluate the prevalence and severity of constipation in patients with schizophrenia under routine treatment conditions.</p> <p>Results</p> <p>Over a period of 22 months 36.3% of patients (99) received at least once a pharmacological treatment for constipation. On average medication for constipation was prescribed for 273 days. Severe cases (N = 50), non-responsive to initial treatment, got a plain x-ray of the abdomen. In 68.4% fecal impaction was found.</p> <p>Conclusion</p> <p>A high prevalence of constipation, often severe and needing medical interventions, was confirmed during the study period. Early detection, monitoring over treatment and early intervention of constipation could prevent serious consequences such as ileus.</p

Nanomechanical properties of α-synuclein amyloid fibrils: a comparative study by nanoindentation, harmonic force microscopy, and Peakforce QNM

We report on the use of three different atomic force spectroscopy modalities to determine the nanomechanical properties of amyloid fibrils of the human α-synuclein protein. α-Synuclein forms fibrillar nanostructures of approximately 10 nm diameter and lengths ranging from 100 nm to several microns, which have been associated with Parkinson's disease. Atomic force microscopy (AFM) has been used to image the morphology of these protein fibrils deposited on a flat surface. For nanomechanical measurements, we used single-point nanoindentation, in which the AFM tip as the indenter is moved vertically to the fibril surface and back while the force is being recorded. We also used two recently developed AFM surface property mapping techniques: Harmonic force microscopy (HarmoniX) and Peakforce QNM. These modalities allow extraction of mechanical parameters of the surface with a lateral resolution and speed comparable to tapping-mode AFM imaging. Based on this phenomenological study, the elastic moduli of the α-synuclein fibrils determined using these three different modalities are within the range 1.3-2.1 GPa. We discuss the relative merits of these three methods for the determination of the elastic properties of protein fibrils, particularly considering the differences and difficulties of each method

Typical and atypical antipsychotics differentially affect long-term incidence rates of the metabolic syndrome in first-episode patients with schizophrenia: a retrospective chart review.

The presence of the metabolic syndrome (MetS) is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of MetS in patients with schizophrenia at the onset of the disorder and specifically no data on patients treated in the era when only first-generation antipsychotics were available. METHODS: Data from a historic cohort of consecutively admitted first-episode patients with schizophrenia treated with first-generation antipsychotics (FGAs) were compared with an age and sex matched series of consecutive first-episode patients treated only with second-generation antipsychotics (SGAs). Rates of MetS were compared at baseline and after on average 3 years of treatment exposure. RESULTS: At first episode there was no difference in the prevalence of MetS between the historic and the current cohort. Rates of MetS increased over time in both groups, but patients started on SGAs had a three times higher incidence rate of MetS (Odds Ratio 3.6, CI 1.7-7.5). The average increase in weight and body mass index was twice as high in patients started on SGA. The difference between the FGA and SGA group was no longer significant when patients started on clozapine and olanzapine were excluded. CONCLUSION: Rates of MetS at the first episode of schizophrenia today are not different from those of patients 15 to 20 years ago. This finding counters the notion that the high rates of metabolic abnormalities in patients with schizophrenia currently reported are mainly due to lifestyle changes over time in the general population. Some SGAs have a significantly more negative impact on the incidence of MetS compared to FGAs in first-episode patients

Nanomechanical properties of single amyloid fibrils

Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils

Nanomechanical properties of &#945;-synuclein amyloid fibrils: a comparative study by nanoindentation, harmonic force microscopy, and Peakforce QNM

Abstract We report on the use of three different atomic force spectroscopy modalities to determine the nanomechanical properties of amyloid fibrils of the human &#945;-synuclein protein. &#945;-Synuclein forms fibrillar nanostructures of approximately 10 nm diameter and lengths ranging from 100 nm to several microns, which have been associated with Parkinson's disease. Atomic force microscopy (AFM) has been used to image the morphology of these protein fibrils deposited on a flat surface. For nanomechanical measurements, we used single-point nanoindentation, in which the AFM tip as the indenter is moved vertically to the fibril surface and back while the force is being recorded. We also used two recently developed AFM surface property mapping techniques: Harmonic force microscopy (HarmoniX) and Peakforce QNM. These modalities allow extraction of mechanical parameters of the surface with a lateral resolution and speed comparable to tapping-mode AFM imaging. Based on this phenomenological study, the elastic moduli of the &#945;-synuclein fibrils determined using these three different modalities are within the range 1.3-2.1 GPa. We discuss the relative merits of these three methods for the determination of the elastic properties of protein fibrils, particularly considering the differences and difficulties of each method.</p

Metaphor interpretation and use: a window into semantics in schizophrenia

The nature of putative semantic anomalies in schizophrenia is controversial. Metaphor interpretation and use provide a useful methodology with which to probe semantics since metaphors are critical in reasoning processes and in how conceptual knowledge is organized. The first study examined free speech for figurative language. The second study explored whether emotional versus non-emotional metaphorical language interpretation elicits differences in the tendencies to produce idiosyncratic (bizarre) or literal interpretations or use of other metaphors to describe the meaning of a metaphor. The third study examined the interpretation of time metaphors. We expected the time perspective in ambiguous sentences to be differentially influenced by previously presented unambiguous sentences of a specific perspective, either events moving relative to a stationary observer (moving-time) or an observer moving relative to a stationary event (moving-ego). First, we found that patients used a similar amount of figurative language as control participants. Second, we did not find any difference between the groups in terms of idiosyncratic interpretations, although patients did interpret more metaphors literally and controls utilized more figurative language. Third, we did not find evidence of a difference between the groups in terms of time perspectives influencing ambiguous target sentences differentially. As operationalized here, the interpretation and use of metaphors is similar in patients with schizophrenia to that of healthy control participants. To the extent that metaphors recruit semantic processes this area of cognition is generally intact in schizophrenia.status: publishe

End-of-life (care) perspectives and expectations of patients with schizophrenia

BACKGROUND: Schizophrenia is a disabling and life-shortening psychiatric disorder due to disease, medication, and lifestyle-related factors. It is therefore not unreasonable to assume that existential themes are important for these patients. METHODS: Transcripts of 20 patients were coded and analyzed thematically, using a modified grounded theory approach in the exploration of perspectives and expectations of end-of-life (care). RESULTS: No fear of death, skilled companionship and preserving quality of life were major themes in the interviews. CONCLUSION: This study showed that patients, despite emotional flattening and cognitive deficits, find the possibility to discuss end-of-life topics reassuring and some even therapeutic.status: publishe

Characterizing Nanoscale Morphologic and Mechanical Properties of α-Synuclein Amyloid Fibrils with Atomic Force Microscopy

We have used atomic force microscopy (AFM) to image wild-type and disease-related mutant α-synuclein (aS) amyloid fibrils deposited on various hard and soft surfaces, ranging from freshly cleaved mica to two different supported lipid bilayers: phosphatidylcholine (POPC) and a mixture of POPC and phosphatidylglycerol (POPG). Quantitative morphologic analyses show that fibrils deposited on freshly cleaved mica, gold and glass substrates appeared to have similar heights and lengths, suggesting that the surface-fibril interaction in these cases does not influence the fibril morphology. When the same fibril sample is deposited on HOPG or quartz, the aS fibrils appear shorter in length and completely distorted, respectively, indicating that the interaction with these surfaces severely affects the fibril morphology. Sequentially recorded AFM images of fibrils on POPC bilayers clearly revealed that the amyloid fibrils were mobile on the bilayer, indicating that the fibrils are in thermal equilibrium on the surface. Persistence lengths of the fibrils on mica and POPC have been determined using two different methods, and reveal no significant differences, indicating that, although the fibrils appear immobile on mica, they do thermally equilibrate in 2D before they finally attach to the substrate. The persistence length of aS fibrils is found to be between 3.3 and 7.1 μm, which is within the expected range for amyloid fibrils. We observe no fibril movement on the mixed POPC/POPG bilayer, suggesting a stronger interaction with the lipids. Furthermore, the reduced heights of the fibrils on top of the mixed bilayer suggest that the fibrils are partly embedded within the bilayer