The Role of Nanoscale Toughening Mechanisms in Osteoporosis

Strength is the most widely reported parameter with regards to bone failure. However, bone contains pre-existing damage and stress concentration sites, perhaps making measures of fracture toughness more indicative of the resistance of the tissue to withstand fracture. Several toughening mechanisms have been identified in bone, prominently, at the microscale. More recently, nanoscale toughness mechanisms, such as sacrificial-bonds and hidden-length or dilatational band formation, mediated by noncollagenous proteins, have been reported. Absence of specific noncollagenous proteins results in lowered fracture toughness in animal models. Further, roles of several other, putative influencing, factors such as closely bound water, collagen cross-linking and citrate bonds in bone mineral have also been proposed. Yet, it is still not clear if and which mechanisms are hallmarks of osteoporosis disease and how they influence fracture risk. Further insights on the workings of such influencing factors are of high importance for developing complementary diagnostics and therapeutics strategies.     

Orofacial neuralgia associated with a middle cerebral artery aneurysm

Chronic orofacial pain of neuropathic origin can present diagnostic and management dilemmas to dental practitioners and also affects the patient's quality of life. Intracranial aneurysms are a potential cause of stroke (e.g. sub‐arachnoid haemorrhage) that is usually associated with, high rates of mortality and morbidity. A patient who had been previously managed for symptoms of temporomandibular joint disorder (TMD) presented with sharp, shooting pain of moderate intensity. It was precipitated by swallowing, and radiated to the right throat, posterior border of the mandible, ear and temporomandibular joint. Clinical and radiological investigations ruled out odontogenic pain, TMD and other more common types of facial pain. Magnetic resonance imaging revealed a 7 × 6 mm aneurysm in the right middle cerebral artery (MCA) which was subsequently surgically clipped. Interestingly, the facial pain resolved after this procedure. Compression of the insular region of the brain innervated by the trigeminal, glossopharyngeal and vagus nerves provides a plausible explanation for the pain reported. To our knowledge, this is the first case of facial neuralgia associated with an aneurysm in the MCA which emphasizes the importance of a multidisciplinary approach in the diagnosis and management of unusual cases of chronic orofacial pain.     

How multiplicity determines entropy and the derivation of the maximum entropy principle for complex systems

The maximum entropy principle (MEP) is a method for obtaining the most likely distribution functions of observables from statistical systems by maximizing entropy under constraints. The MEP has found hundreds of applications in ergodic and Markovian systems in statistical mechanics, information theory, and statistics. For several decades there has been an ongoing controversy over whether the notion of the maximum entropy principle can be extended in a meaningful way to nonextensive, nonergodic, and complex statistical systems and processes. In this paper we start by reviewing how Boltzmann–Gibbs–Shannon entropy is related to multiplicities of independent random processes. We then show how the relaxation of independence naturally leads to the most general entropies that are compatible with the first three Shannon–Khinchin axioms, the -entropies. We demonstrate that the MEP is a perfectly consistent concept for nonergodic and complex statistical systems if their relative entropy can be factored into a generalized multiplicity and a constraint term. The problem of finding such a factorization reduces to finding an appropriate representation of relative entropy in a linear basis. In a particular example we show that path-dependent random processes with memory naturally require specific generalized entropies. The example is to our knowledge the first exact derivation of a generalized entropy from the microscopic properties of a path-dependent random process.Many statistical systems can be characterized by a macrostate for which many microconfigurations exist that are compatible with it. The number of configurations associated with the macrostate is called the phase-space volume or multiplicity, M. Boltzmann entropy is the logarithm of the multiplicity,and has the same properties as the thermodynamic (Clausius) entropy for systems such as the ideal gas (1). We set . Boltzmann entropy scales with the degrees of freedom f of the system. For example, for N noninteracting point particles in three dimensions, . Systems where scales with system size are called extensive. The entropy per degree of freedom is a system-specific constant. Many complex systems are nonextensive, meaning that if two initially insulated systems A and B, with multiplicities and , respectively, are brought into contact, the multiplicity of the combined system is . For such systems, which are typically strongly interacting, non-Markovian, or nonergodic, and the effective degrees of freedom do no longer scale as N. Given the appropriate scaling for , the entropy is a finite and nonzero constant in the thermodynamic limit, .A crucial observation in statistical mechanics is that the distribution of all macrostate variables gets sharply peaked and narrow as system size N increases. The reason behind this is that the multiplicities for particular macrostates grow much faster with N than those for other states. In the limit the probability of measuring a macrostate becomes a Dirac delta, which implies that one can replace the expectation value of a macrovariable by its most likely value. This is equivalent to maximizing the entropy in Eq. 1 with respect to the macrostate. By maximizing entropy one identifies the “typical” microconfigurations compatible with the macrostate. This typical region of phase space dominates all other possibilities and therefore characterizes the system. Probability distributions associated with these typical microconfigurations can be obtained in a constructive way by the maximum entropy principle (MEP), which is closely related to the question of finding the most likely distribution functions (histograms) for a given system.We demonstrate the MEP in the example of coin tossing. Consider a sequence of N independent outcomes of coin tosses, , where is either head or tail. The sequence x contains heads and tails. The probability of finding a sequence with exactly heads and tails iswhere is the binomial factor. We use the shorthand notation for the histogram of heads and tails and for the marginal probabilities for throwing head or tail. For the relative frequencies we write . We also refer to θ as the “biases” of the system. The probability of observing a particular sequence x with histogram k is given by . It is invariant under permutations of the sequence x because the coin tosses are independent. All possible sequences x with the same histogram k have identical probabilities. is the respective multiplicity, representing the number of possibilities to throw exactly heads and tails. As a consequence Eq. 2 becomes the probability of finding the distribution function p of relative frequencies for a given N. The MEP is used to find the most likely p. We denote the most likely histogram by and the most likely relative frequencies by .We now identify the two components that are necessary for the MEP to hold. The first is that in Eq. 2 factorizes into a multiplicity that depends on k only and a factor that depends on k and the biases θ. The second necessary component is that the multiplicity is related to an entropy expression. By using Stirling’s formula, the multiplicity of Eq. 2 can be trivially rewritten for large N,where an entropy functional of Shannon type (2) appears,The same arguments hold for multinomial processes with sequences x of N independent trials, where each trial takes one of W possible outcomes (3). In that case the probability for finding a given histogram k is is the multinomial factor and . Asymptotically holds. Extremizing Eq. 5 for fixed N with respect to k yields the most likely histogram, . Taking logarithms on both sides of Eq. 5 givesObviously, extremizing Eq. 6 leads to the same histogram . The term in Eq. 6 is sometimes called relative entropy or Kullback–Leibler divergence (4). We identify the first term on the right-hand side of Eq. 6 with Shannon entropy , and the second term is the so-called cross-entropy . Eq. 6 states that the cross-entropy is equal to entropy plus the relative entropy. The constraints of the MEP are related to the cross-entropy. For example, let the marginal probabilities be given by the so-called Boltzmann factor, , for the “energy levels” , where β is the inverse temperature and α the normalization constant. Inserting the Boltzmann factor into the cross-entropy, Eq. 6 becomeswhich is the MEP in its usual form, where Shannon entropy gets maximized under linear constraints. α and β are the Lagrangian multipliers for the normalization and the “energy” constraint , respectively. Note that in Eq. 6 we used to scale . Any other nonlinear would yield nonsensical results in the limit of , either 0 or ∞. Comparing with Eq. 1 shows that indeed, up to a constant multiplicative factor, . This means that the Boltzmann entropy per degree of freedom of a (uncorrelated) multinomial process is given by a Shannon-type entropy functional. Many systems that are nonergodic, are strongly correlated, or have long memory will not be of multinomial type, implying that is not invariant under permutations of a sequence x. For this situation it is not a priori evident that a factorization of into a θ-independent multiplicity and a θ-dependent term, as in Eq. 5, is possible. Under which conditions such a factorization is both feasible and meaningful is discussed in the next section.     

Economic Evaluation of a Web-Based Tailored Lifestyle Intervention for Adults: Findings Regarding Cost-Effectiveness and Cost-Utility From a Randomized Controlled Trial

Background

Different studies have reported the effectiveness of Web-based computer-tailored lifestyle interventions, but economic evaluations of these interventions are scarce.

Objective

The objective was to assess the cost-effectiveness and cost-utility of a sequential and a simultaneous Web-based computer-tailored lifestyle intervention for adults compared to a control group.

Methods

The economic evaluation, conducted from a societal perspective, was part of a 2-year randomized controlled trial including 3 study groups. All groups received personalized health risk appraisals based on the guidelines for physical activity, fruit intake, vegetable intake, alcohol consumption, and smoking. Additionally, respondents in the sequential condition received personal advice about one lifestyle behavior in the first year and a second behavior in the second year; respondents in the simultaneous condition received personal advice about all unhealthy behaviors in both years. During a period of 24 months, health care use, medication use, absenteeism from work, and quality of life (EQ-5D-3L) were assessed every 3 months using Web-based questionnaires. Demographics were assessed at baseline, and lifestyle behaviors were assessed at both baseline and after 24 months. Cost-effectiveness and cost-utility analyses were performed based on the outcome measures lifestyle factor (the number of guidelines respondents adhered to) and quality of life, respectively. We accounted for uncertainty by using bootstrapping techniques and sensitivity analyses.

Results

A total of 1733 respondents were included in the analyses. From a willingness to pay of €4594 per additional guideline met, the sequential intervention (n=552) was likely to be the most cost-effective, whereas from a willingness to pay of €10,850, the simultaneous intervention (n=517) was likely to be most cost-effective. The control condition (n=664) appeared to be preferred with regard to quality of life.

Conclusions

Both the sequential and the simultaneous lifestyle interventions were likely to be cost-effective when it concerned the lifestyle factor, whereas the control condition was when it concerned quality of life. However, there is no accepted cutoff point for the willingness to pay per gain in lifestyle behaviors, making it impossible to draw firm conclusions. Further economic evaluations of lifestyle interventions are needed.

Trial Registration

Dutch Trial Register NTR2168; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2168 (Archived by WebCite at http://www.webcitation.org/6MbUqttYB).     

Detecting myocardial infarction in critical illness using screening troponin measurements and ECG recordings

Introduction

To use screening cardiac troponin (cTn) measurements and electrocardiograms (ECGs) to determine the incidence of elevated cTn and of myocardial infarction (MI) in patients admitted to the intensive care unit (ICU), and to assess whether these findings influence prognosis. This is a prospective screening study.

Materials and methods

We enrolled consecutive patients admitted to a general medical-surgical ICU over two months. All patients underwent systematic screening with cTn measurements and ECGs on ICU admission, then daily for the first week in ICU, alternate days for up to one month and weekly thereafter until ICU death or discharge, for a maximum of two months. Patients without these investigations ordered during routine clinical care underwent screening for study purposes but these results were unavailable to the ICU team. After the study, all ECGs were interpreted independently in duplicate for ischaemic changes meeting ESC/ACC criteria supporting a diagnosis of MI. Patients were classified as having MI (elevated cTn and ECG evidence supporting diagnosis of MI), elevated cTn only (no ECG evidence supporting diagnosis of MI), or no cTn elevation.

Results

One hundred and three patients were admitted to the ICU on 112 occasions. Overall, 37 patients (35.9 per cent) had an MI, 15 patients (14.6 per cent) had an elevated cTn only and 51 patients (49.5 per cent) had no cTn elevation. Patients with MI had longer duration of mechanical ventilation (p < 0.0001), longer ICU stay (p = 0.001), higher ICU mortality (p < 0.0001) and higher hospital mortality (p < 0.0001) compared with those with no cTn elevation. Patients with elevated cTn had higher hospital mortality (p = 0.001) than patients without cTn elevation. Elevated cTn was associated with increased hospital mortality (odds ratio 27.3, 95 per cent CI 1.7 – 449.4), after adjusting for APACHE II score, MI and advanced life support. The ICU team diagnosed 18 patients (17.5 per cent) as having MI on clinical grounds; four of these patients did not have MI by adjudication. Thus, screening detected an additional 23 MIs not diagnosed in practice, reflecting 62.2 per cent of MIs ultimately diagnosed. Patients with MI diagnosed by the ICU team had similar outcomes to patients with MI detected by screening alone.

Conclusion

Systematic screening detected elevated cTn measurements and MI in more patients than were found in routine practice. Elevated cTn was an independent predictor of hospital mortality. Further research is needed to evaluate whether screening and subsequent treatment of these patients reduces mortality.     

Epstein-Barr virus lymphoproliferation after bone marrow transplantation

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.     

Heterogeneity of B cell involvement in acute nonlymphocytic leukemia

In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.     

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Concurrent interaction of DCs with CD4+ and CD8+ T cells improves secondary CTL expansion: It takes three to tango

T‐cell help is essential for CTL‐memory formation. Nevertheless, it is unclear whether the continuous presence of CD4⁺ T‐helper (Th) cells is required during dendritic cell (DC)/CD8⁺ T‐cell encounters, or whether a DC will remember the helper signal after the Th cell has departed. This question is relevant for the design of therapeutic cancer vaccines. Therefore, we investigated how human DCs need to interact with CD4⁺ T cells to mediate efficient repetitive CTL expansion in vitro. We established an autologous antigen‐specific in vitro system with monocyte‐derived DCs, as these are primarily used for cancer vaccination. Contrary to common belief, a sequential interaction of licensed DCs with CD8⁺ T cells barely improved CTL expansion. In sharp contrast, simultaneous encounter of Th cells and CTLs with the same DC during the first in vitro encounter is a prerequisite for optimal subsequent CTL expansion in our in vitro system. These data suggest that, in contrast to DC maturation, the activation of DCs by Th cells, which is necessary for optimal CTL stimulation, is transient. This knowledge has significant implications for the design of new and more effective DC‐based vaccination strategies. Furthermore, our in vitro system could be a valuable tool for preclinical immunotherapeutical studies.