Maximum Urine Concentrating Capability in a Mathematical Model of the Inner Medulla of the Rat Kidney

In a mathematical model of the urine concentrating mechanism of the inner medulla of the rat kidney, a nonlinear optimization technique was used to estimate parameter sets that maximize the urine-to-plasma osmolality ratio (U/P) while maintaining the urine flow rate within a plausible physiologic range. The model, which used a central core formulation, represented loops of Henle turning at all levels of the inner medulla and a composite collecting duct (CD). The parameters varied were: water flow and urea concentration in tubular fluid entering the descending thin limbs and the composite CD at the outer-inner medullary boundary; scaling factors for the number of loops of Henle and CDs as a function of medullary depth; location and increase rate of the urea permeability profile along the CD; and a scaling factor for the maximum rate of NaCl transport from the CD. The optimization algorithm sought to maximize a quantity E that equaled U/P minus a penalty function for insufficient urine flow. Maxima of E were sought by changing parameter values in the direction in parameter space in which E increased. The algorithm attained a maximum E that increased urine osmolality and inner medullary concentrating capability by 37.5% and 80.2%, respectively, above base-case values; the corresponding urine flow rate and the concentrations of NaCl and urea were all within or near reported experimental ranges. Our results predict that urine osmolality is particularly sensitive to three parameters: the urea concentration in tubular fluid entering the CD at the outer-inner medullary boundary, the location and increase rate of the urea permeability profile along the CD, and the rate of decrease of the CD population (and thus of CD surface area) along the cortico-medullary axis.     

What Triggers a Diagnosis of HIV Infection in the Tokyo Metropolitan Area? Implications for Preventing the Spread of HIV Infection in Japan

Background

Japan has not succeeded in reducing the annual number of new HIV-infected patients, although the prevalence of HIV infection is low (0.02%).

Methods

A single-center observational study was conducted at the largest HIV clinic in Tokyo, which treats 15% of the total patients in Japan, to determine the reasons for having diagnostic tests in newly infected individuals. HIV-infected patients who visited our clinic for the first time between 2011 and 2014 were analyzed.

Results

The 598 study patients comprised one-third of the total reported number of new patients in Tokyo during the study period. 76% were Japanese MSM. The reasons for being tested which led to the diagnosis was voluntary testing in 32%, existing diseases in 53% (AIDS-defining diseases in 22%, sexually transmitted infections (STI) in 8%, diseases other than AIDS or STIs in 23%) and routine pre-surgery or on admission screening in 15%. 52% and 74% of the study patients and patients presented with AIDS, respectively, had never been tested. The median CD4 count in patients with history of previous testing (315/μL) was significantly higher than that of patients who had never been tested (203/μL, p<0.001).

Conclusions

Only 32% of the newly HIV diagnosed patients were diagnosed because of voluntary testing, and 53% were diagnosed due to presence of other diseases. These results remain unchanged from our previous report 10 years earlier (2000–2004) on newly diagnosed patients at the same clinic. HIV testing has not been widely used by newly diagnosed patients in the Tokyo metropolitan area.     

New Roles of Glycosaminoglycans in α-Synuclein Aggregation in a Cellular Model of Parkinson Disease

The causes of Parkinson disease (PD) remain mysterious, although some evidence supports mitochondrial dysfunctions and α-synuclein accumulation in Lewy bodies as major events. The abnormal accumulation of α-synuclein has been associated with a deficiency in the ubiquitin-proteasome system and the autophagy-lysosomal pathway. Cathepsin D (cathD), the major lysosomal protease responsible of α-synuclein degradation was described to be up-regulated in PD model. As glycosaminoglycans (GAGs) regulate cathD activity, and have been recently suggested to participate in PD physiopathology, we investigated their role in α-synuclein accumulation by their intracellular regulation of cathD activity. In a classical neuroblastoma cell model of PD induced by MPP⁺, the genetic expression of GAGs-biosynthetic enzymes was modified, leading to an increase of GAGs amounts whereas intracellular level of α-synuclein increased. The absence of sulfated GAGs increased intracellular cathD activity and limited α-synuclein accumulation. GAGs effects on cathD further suggested that specific sequences or sulfation patterns could be responsible for this regulation. The present study identifies, for the first time, GAGs as new regulators of the lysosome degradation pathway, regulating cathD activity and affecting two main biological processes, α-synuclein aggregation and apoptosis. Finally, this opens new insights into intracellular GAGs functions and new fields of investigation for glycobiological approaches in PD and neurobiology.     

Are You HIV Invincible? A Probabilistic Study of Discordant Couples in the Context of HIV Transmission

A number of factors have been identified that are related to sexual and injecting HIV transmission. We developed a probabilistic mathematical model to put these factors together and interpret risks in the context of individual behavior among injecting drug-using (IDU) couples in St. Petersburg, Russia. Some HIV-discordant couples have unprotected sex and sometimes inject drugs together but stay discordant for a long time, while some individuals acquire HIV on the first encounter. We considered existing estimates of HIV transmission risks through injecting and sexual contacts to develop a predictive survival model for an individual who is exposed to HIV through intimate relationships. We computed simulated survival curves for a number of behavioral scenarios and discussed sources of simulated uncertainty. We then applied the model to a longitudinal study of HIV-discordant couples and validated the model’s forecast. Although individual prediction of seroconversion time appeared impossible, the ability to rank behavioral patterns in terms of HIV risk and to estimate the probability of survival HIV-free will be important to educators and counselors.     

Dermatopathic Lymphadenopathy—A Clinicopathologic Analysis of Lymph Node Biopsy Over a 15-Year Period

Forty cases of dermatopathic lymphadenopathy were found in a series of 906 consecutive lymph node biopsies (4.8 per cent).The histologic development and progression of the disease was correlated with the clinical state of the patient.In 35 of 40 cases the patients had active skin disease at the time of the biopsy; one of the remaining five patients had Hodgkin''s disease, one had multiple myeloma and one had secondary syphilis. In the other two, no organic cause was found.In nine cases (22.5 per cent), the histological pattern typical of dermatopathic lymphadenopathy was associated with malignant lymphoma. Except for two biopsies, which showed coexisting malignant lymphoma and dermatopathic lymphadenopathy, no histologic features were found which distinguished patients with malignant lymphoma from the remainder.While the pathogenesis of the lymph node changes remains obscure, the histologic features suggest that it is at least in part an immune response, although the nature of the responsible antigen is unknown.     

Interbeat Interval Modulation in the Sinoatrial Node as a Result of Membrane Current Stochasticity—A Theoretical and Numerical Study

A single isolated sinoatrial pacemaker cell presents intrinsic interbeat interval (IBI) variability that is believed to result from the stochastic characteristics of the opening and closing processes of membrane ion channels. To our knowledge, a novel mathematical framework was developed in this work to address the effect of current fluctuations on the IBIs of sinoatrial pacemaker cells. Using statistical modeling and employing the Fokker-Planck formalism, our mathematical analysis suggests that increased stochastic current fluctuation variance linearly increases the slope of phase-4 depolarization, hence the rate of activations. Single-cell and two-dimensional computerized numerical modeling of the sinoatrial node was conducted to validate the theoretical predictions using established ionic kinetics of the rabbit pacemaker and atrial cells. Our models also provide, to our knowledge, a novel complementary or alternative explanation to recent experimental observations showing a strong reduction in the mean IBI of Cx30 deficient mice in comparison to wild-types, not fully explicable by the effects of intercellular decoupling.     

Bistability Analysis of an Apoptosis Model in the Presence of Nitric Oxide

Bistability in apoptosis, or programmed cell death, is crucial for the healthy functioning of multicellular organisms. The aim in this study is to show the presence of bistability in a mitochondria-dependent apoptosis model under nitric oxide effects using chemical reaction network theory. The model equations are a set of coupled ordinary differential equations arising from the assumed mass action kinetics. Whether these equations have a capacity for bistability (cell survival and apoptosis) is determined using a modular approach in which the model is decomposed into modules. Each module contains only a subset of the whole model and is analyzed separately. It is seen that bistability in a module is preserved throughout the whole model after adding the remaining reactions in the pathway on these modules. It is also found that inhibitor effect of some proteins and the appearance of a reacting protein in a later stage as a product is a desired feature but not sufficient for bistability (in the absence of cooperativity effects). On the whole model, two apoptotic and two cell survival states are obtained depending on the initial cell conditions. The results suggest that the antiapoptotic effects of nitric oxide species are responsible for the bistable character of the apoptotic pathway when cooperativity is not assumed in the apoptosome formation.     

Cellular aspects of aging in the pineal gland of the shrew, Crocidura russula

The Greater White-toothed shrew Crocidura russula is short-lived species and the phase of senescence is greatly elongated in captivity. The loss of rhythmicity of biological functions that accompanies its aging is also well documented. C. russula is thus an excellent model to test the effects of aging on biological clocks. Melatonin is a key hormone in the synchronization of behaviors, metabolisms and physiological regulations with environmental factors. In the present work we want to know if the loss of rhythmicity and the reduced melatonin levels registered by the second year of life in this species could be associated to modified ultrastructural features of the pineal parenchyma, site of melatonin synthesis. Transmission electron microscopy (TEM) analysis of young (1-4 months) and old (25-28 months) shrew's pineals show that in older individuals, the parenchyma undergoes alterations affecting mainly nucleus, mitochondria and endoplasmic reticulum cisternae, with increased numbers of dense bodies and the formation of many concretions as well as a depletion of secretory products. These changes suggest a process of slowing pinealocytes metabolism which could explain the gradual reduction of melatonin levels registered during aging in C. russula.     

Can Churches Play a Role in Combating the HIV/AIDS Epidemic? A Study of the Attitudes of Christian Religious Leaders in Madagascar

Introduction

Churches occupy an important social and cultural position in Madagascar. The sexual transmission of HIV raises controversies about the role that Churches can play in preventing HIV/AIDS. This cross-sectional survey investigated recommendations by religious leaders for condom use and other preventive strategies in the context of international guidelines.

Methods

A questionnaire was self-administered to a random sample of religious leaders. The questions related to preventive methods against HIV/AIDS such as: condom use, marital fidelity, sexual abstinence before marriage, and HIV-testing. Associations with recommendations for condom use were evaluated using univariate and multivariate logistic regression analyses.

Results

Of 231 religious leaders, 215 (93.1%) were willing to share their knowledge of HIV/AIDS with their congregations. The majority received their information from the media (N = 136, 58.9%), a minority from their church (N = 9, 3.9%), and 38 (16.4%) had received prior training on HIV. Nearly all (N = 212, 91.8%) knew that HIV could be sexually transmitted though only a few (N = 39, 16.9%) were aware of mother-to-child transmission or unsafe injections (N = 56, 24.2%). A total of 91 (39.4%) were willing to, or had recommended (N = 64, 27.7%), condom use, while 50 (21.6%) had undergone HIV testing. Only nine (3.9%) had ever cared for a person living with HIV/AIDS (PLHIV). Multivariable logistic regression shows that condom use recommendations by religious leaders were negatively associated with tertiary level education (OR: 0.3, 95% CI 0.1–0.7), and positively associated with knowing a person at risk (OR: 16.2, 95% CI 3.2–80.2), knowing of an ART center (OR: 2.6, 95% CI 1.4–4.8), and receiving information about HIV at school (OR: 2.6, 95% CI 1.2–5.6).

Conclusions

Malagasy church leaders could potentially become key players in HIV/AIDS prevention if they improved their knowledge of the illness, their commitment to international recommendations, and extended their interaction with people most at risk.     

Deformation of the Durom Acetabular Component and Its Impact on Tribology in a Cadaveric Model—A Simulator Study

Background

Recent studies have shown that the acetabular component frequently becomes deformed during press-fit insertion. The aim of this study was to explore the deformation of the Durom cup after implantation and to clarify the impact of deformation on wear and ion release of the Durom large head metal-on-metal (MOM) total hips in simulators.

Methods

Six Durom cups impacted into reamed acetabula of fresh cadavers were used as the experimental group and another 6 size-paired intact Durom cups constituted the control group. All 12 Durom MOM total hips were put through a 3 million cycle (MC) wear test in simulators.

Results

The 6 cups in the experimental group were all deformed, with a mean deformation of 41.78±8.86 µm. The average volumetric wear rate in the experimental group and in the control group in the first million cycle was 6.65±0.29 mm³/MC and 0.89±0.04 mm³/MC (t = 48.43, p = 0.000). The ion levels of Cr and Co in the experimental group were also higher than those in the control group before 2.0 MC. However there was no difference in the ion levels between 2.0 and 3.0 MC.

Conclusions

This finding implies that the non-modular acetabular component of Durom total hip prosthesis is likely to become deformed during press-fit insertion, and that the deformation will result in increased volumetric wear and increased ion release.

Clinical Relevance

This study was determined to explore the deformation of the Durom cup after implantation and to clarify the impact of deformation on wear and ion release of the prosthesis. Deformation of the cup after implantation increases the wear of MOM bearings and the resulting ion levels. The clinical use of the Durom large head prosthesis should be with great care.     

Age and Sex Structured Model for Assessing the Demographic Impact of Mother-to-Child Transmission of HIV/AIDS

Age and sex structured HIV/AIDS model with explicit incubation period is proposed as a system of delay differential equations. The model consists of two age groups that are children (0–14 years) and adults (15–49 years). Thus, the model considers both mother-to-child transmission (MTCT) and heterosexual transmission of HIV in a community. MTCT can occur prenatally, at labour and delivery or postnatally through breastfeeding. In the model, we consider the children age group as a one-sex formulation and divide the adult age group into a two-sex structure consisting of females and males. The important mathematical features of the model are analysed. The disease-free and endemic equilibria are found and their stabilities investigated. We use the Lyapunov functional approach to show the local stability of the endemic equilibrium. Qualitative analysis of the model including positivity and boundedness of solutions, and persistence are also presented. The basic reproductive number (ℛ₀) for the model shows that the adult population is responsible for the spread HIV/AIDS epidemic, thus up-to-date developed HIV/AIDS models to assess intervention strategies have focused much on heterosexual transmission by the adult population and the children population has received little attention. We numerically analyse the HIV/AIDS model to assess the community benefits of using antiretroviral drugs in reducing MTCT and the effects of breastfeeding in settings with high HIV/AIDS prevalence ratio using demographic and epidemiological parameters for Zimbabwe.     

The Role of Viral Infection in Pest Control: A Mathematical Study

In this paper, we propose a mathematical model of viral infection in pest control. As the viral infection induces host lysis which releases more virus into the environment, on the average ‘κ’ viruses per host, κ∈(1,∞), so the ‘virus replication parameter’ is chosen as the main parameter on which the dynamics of the infection depends. There exists a threshold value κ ₀ beyond which the infection persists in the system. Still for increasing the value of κ, the endemic equilibrium bifurcates towards a periodic solution, which essentially indicates that the viral pesticide has a density-dependent ‘numerical response’ component to its action. Investigation also includes the dependence of the process on predation of natural enemy into the system. A concluding discussion with numerical simulation of the model is also presented.     

A Periodic Droop Model for Two Species Competition in A Chemostat

Both uniform persistence and the existence of periodic coexistence state are established for a periodically forced Droop model on two phytoplankton species competition in a chemostat under some appropriate conditions. Numerical simulations using biological data are presented as well to illustrate the main result. Research supported in part by the NSERC of Canada and the MITACS of Canada.     

Free Terminal Time Optimal Control Problem of an HIV Model Based on a Conjugate Gradient Method

The minimum duration of treatment periods and the optimal multidrug therapy for human immunodeficiency virus (HIV) type 1 infection are considered. We formulate an optimal tracking problem, attempting to drive the states of the model to a “healthy” steady state in which the viral load is low and the immune response is strong. We study an optimal time frame as well as HIV therapeutic strategies by analyzing the free terminal time optimal tracking control problem. The minimum duration of treatment periods and the optimal multidrug therapy are found by solving the corresponding optimality systems with the additional transversality condition for the terminal time. We demonstrate by numerical simulations that the optimal dynamic multidrug therapy can lead to the long-term control of HIV by the strong immune response after discontinuation of therapy.     

Spatiotemporal Dynamics of the Epidemic Transmission in a Predator-Prey System

Epidemic transmission is one of the critical density-dependent mechanisms that affect species viability and dynamics. In a predator-prey system, epidemic transmission can strongly affect the success probability of hunting, especially for social animals. Predators, therefore, will suffer from the positive density-dependence, i.e., Allee effect, due to epidemic transmission in the population. The rate of species contacting the epidemic, especially for those endangered or invasive, has largely increased due to the habitat destruction caused by anthropogenic disturbance. Using ordinary differential equations and cellular automata, we here explored the epidemic transmission in a predator-prey system. Results show that a moderate Allee effect will destabilize the dynamics, but it is not true for the extreme Allee effect (weak or strong). The predator-prey dynamics amazingly stabilize by the extreme Allee effect. Predators suffer the most from the epidemic disease at moderate transmission probability. Counter-intuitively, habitat destruction will benefit the control of the epidemic disease. The demographic stochasticity dramatically influences the spatial distribution of the system. The spatial distribution changes from oil-bubble-like (due to local interaction) to aggregated spatially scattered points (due to local interaction and demographic stochasticity). It indicates the possibility of using human disturbance in habitat as a potential epidemic-control method in conservation.     

Conditions for Global Dynamic Stability of a Class of Resource-Bounded Model Ecosystems

This paper studies a class of dynamical systems that model multi-species ecosystems. These systems are ‘resource bounded’ in the sense that species compete to utilize an underlying limiting resource or substrate. This boundedness means that the relevant state space can be reduced to a simplex, with coordinates representing the proportions of substrate utilized by the various species. If the vector field is inward pointing on the boundary of the simplex, the state space is forward invariant under the system flow, a requirement that can be interpreted as the presence of non-zero exogenous recruitment. We consider conditions under which these model systems have a unique interior equilibrium that is globally asymptotically stable. The systems we consider generalize classical multi-species Lotka–Volterra systems, the behaviour of which is characterized by properties of the community (or interaction) matrix. However, the more general systems considered here are not characterized by a single matrix, but rather a family of matrices. We develop a set of ‘explicit conditions’ on the basis of a notion of ‘uniform diagonal dominance’ for such a family of matrices, that allows us to extract a set of sufficient conditions for global asymptotic stability based on properties of a single, derived matrix. Examples of these explicit conditions are discussed.     

Cytosine β-D-arabinofuranoside used as a Paradigm Modifier to Increase Production of Tau Aggregates in a Cellular Model of Tauopathy

Intraneuronal deposition of filamentous tau is a hallmark of Alzheimer’s disease (AD) and related tauopathies. We developed previously a cellular model recapitulating such tau anomaly and demonstrated therein consistent production of 70-kD tau. Importantly, the 70-kD species appears to derive from tau fragments with carboxy-terminal truncation and is larger than intact tau in size, suggesting the oligomeric nature in its assembly from tau. To generate the 70-kD tau in sufficient quantity for its characterization at the molecular level, we explored and demonstrated herein that cytosine β-D-arabinofuranoside is a useful paradigm modifier to increase production of the 70-kD tau. Such oligomeric tau was enriched thereafter by immunoprecipitation to remove tau species with intact carboxy-terminus. Two-dimensional gel electrophoresis revealed that the 70-kD tau has an isoelectric point of 5.8–6.0. Future elucidation of key aggregates will provide valuable insights into the natural history of neurofibrillary degeneration and identify novel targets to develop therapeutic interventions. Special issue dedicated to John P. Blass.     

Impacts of Incubation Delay on the Dynamics of an Eco-Epidemiological System—A Theoretical Study

Parasite and predator play significant role in trophic interaction, productivity and stability of an ecosystem. In this paper, we have studied a host-parasite-predator interaction that incorporates incubation delay. How the qualitative and quantitative behaviors of the system alter with the incubation delay have been discussed both from mathematical and biological point of views. It is observed that for a lower infection rate, the system is stable for all delays; but for a higher infection rate, there exists a threshold value of the delay above which the system is unstable and below which the system is stable leading to the persistence of all the species. Also, the instability arising from the incubation delay may be controlled if somehow the growth rate of predator population is increased. Numerical studies have also been performed to illustrate different analytical findings. Research is supported by UGC, India; F No. 32-173/2006(SR).