Echinococcus multilocularis and its intermediate host: a model of parasite-host interplay

Host-parasite interactions in the E. multilocularis-intermediate host model depend on a subtle balance between cellular immunity, which is responsible for host's resistance towards the metacestode, the larval stage of the parasite, and tolerance induction and maintenance. The pathological features of alveolar echinococcosis. the disease caused by E. multilocularis, are related both to parasitic growth and to host's immune response, leading to fibrosis and necrosis, The disease spectrum is clearly dependent on the genetic background of the host as well as on acquired disturbances of Th1-related immunity. The laminated layer of the metacestode, and especially its carbohydrate components, plays a major role in tolerance induction. Th2-type and anti-inflammatory cytokines, IL-10 and TGF-beta, as well as nitric oxide, are involved in the maintenance of tolerance and partial inhibition of cytotoxic mechanisms. Results of studies in the experimental mouse model and in patients suggest that immune modulation with cytokines, such as interferon-alpha, or with specific antigens could be used in the future to treat patients with alveolar echinococcosis and/or to prevent this very severe parasitic disease.

Impaired immune evasion in HIV through intracellular delays and multiple infection of cells

With its high mutation rate, HIV is capable of escape from recognition, suppression and/or killing by CD8(+) cytotoxic T lymphocytes (CTLs). The rate at which escape variants replace each other can give insights into the selective pressure imposed by single CTL clones. We investigate the effects of specific characteristics of the HIV life cycle on the dynamics of immune escape. First, it has been found that cells in HIV-infected patients can carry multiple copies of proviruses. To investigate how this process affects the emergence of immune escape, we develop a mathematical model of HIV dynamics with multiple infections of cells. Increasing the frequency of multiple-infected cells delays the appearance of immune escape variants, slows down the rate at which they replace the wild-type variant and can even prevent escape variants from taking over the quasi-species. Second, we study the effect of the intracellular eclipse phase on the rate of escape and show that escape rates are expected to be slower than previously anticipated. In summary, slow escape rates do not necessarily imply inefficient CTL-mediated killing of HIV-infected cells, but are at least partly a result of the specific characteristics of the viral life cycle.

Tracing of patients lost to follow-up and HIV transmission: Mathematical modelling study based on two large ART programmes in Malawi

OBJECTIVES: Treatment as prevention depends on retaining HIV-infected patients in care. We investigated the effect on HIV transmission of bringing patients lost to follow up (LTFU) back into care. DESIGN: Mathematical model. METHODS: Stochastic mathematical model of cohorts of 1000 HIV-infected patients on antiretroviral therapy (ART), based on data from two clinics in Lilongwe, Malawi. We calculated cohort viral load (CVL; sum of individual mean viral loads each year) and used a mathematical relationship between viral load and transmission probability to estimate the number of new HIV infections. We simulated four scenarios: 'no LTFU' (all patients stay in care); 'no tracing' (patients LTFU are not traced); 'immediate tracing' (after missed clinic appointment); and, 'delayed tracing' (after six months). RESULTS: About 440 of 1000 patients were LTFU over five years. CVL (million copies/ml per 1000 patients) were 3.7 (95% prediction interval [PrI] 2.9-4.9) for no LTFU, 8.6 (95% PrI 7.3-10.0) for no tracing, 7.7 (95% PrI 6.2-9.1) for immediate, and 8.0 (95% PrI 6.7-9.5) for delayed tracing. Comparing no LTFU with no tracing the number of new infections increased from 33 (95% PrI 29-38) to 54 (95% PrI 47-60) per 1000 patients. Immediate tracing prevented 3.6 (95% PrI -3.3-12.8) and delayed tracing 2.5 (95% PrI -5.8-11.1) new infections per 1000. Immediate tracing was more efficient than delayed tracing: 116 and to 142 tracing efforts, respectively, were needed to prevent one new infection. CONCLUSION: Tracing of patients LTFU enhances the preventive effect of ART, but the number of transmissions prevented is small.

Observation of ventilation-induced Spo(2) oscillations in pigs: first step to noninvasive detection of cyclic recruitment of atelectasis?

High arterial partial oxygen pressure (Pao(2)) oscillations within the respiratory cycle were described recently in experimental acute lung injury. This phenomenon has been related to cyclic recruitment of atelectasis and varying pulmonary shunt fractions. Noninvasive detection of Spo(2) (oxygen saturation measured by pulse oximetry) as an indicator of cyclic collapse of atelectasis, instead of recording Pao(2) oscillations, could be of clinical interest in critical care. Spo(2) oscillations were recorded continuously in three different cases of lung damage to demonstrate the technical feasibility of this approach. To deduce Pao(2) from Spo(2), a mathematical model of the hemoglobin dissociation curve including left and right shifts was derived from the literature and adapted to the dynamic changes of oxygenation. Calculated Pao(2) amplitudes (derived from Spo(2) measurements) were compared to simultaneously measured fast changes of Pao(2), using a current standard method (fluorescence quenching of ruthenium). Peripheral hemoglobin saturation was capable to capture changes of Spo(2) within each respiratory cycle. For the first time, Spo(2) oscillations due to cyclic recruitment of atelectasis within a respiratory cycle were determined by photoplethysmography, a technology that can be readily applied noninvasively in clinical routine. A mathematic model to calculate the respective Pao(2) changes was developed and its applicability tested.

An in vitro triple cell co-culture model with primary cells mimicking the human alveolar epithelial barrier

A triple cell co-culture model was recently established by the authors, consisting of either A549 or 16HBE14o- epithelial cells, human blood monocyte-derived macrophages and dendritic cells, which offers the possibility to study the interaction of xenobiotics with those cells. The 16HBE14o- containing co-culture model mimics the airway epithelial barrier, whereas the A549 co-cultures mimic the alveolar type II-like epithelial barrier. The goal of the present work was to establish a new triple cell co-culture model composed of primary alveolar type I-like cells isolated from human lung biopsies (hAEpC) representing a more realistic alveolar epithelial barrier wall, since type I epithelial cells cover >93% of the alveolar surface. Monocultures of A549 and 16HBE14o- were morphologically and functionally compared with the hAEpC using laser scanning microscopy, as well as transmission electron microscopy, and by determining the epithelial integrity. The triple cell co-cultures were characterized using the same methods. It could be shown that the epithelial integrity of hAEpC (mean ± SD, 1180 ± 188 Ω cm(2)) was higher than in A549 (172 ± 59 Ω cm(2)) but similar to 16HBE14o- cells (1469 ± 156 Ω cm(2)). The triple cell co-culture model with hAEpC (1113 ± 30 Ω cm(2)) showed the highest integrity compared to the ones with A549 (93 ± 14 Ω cm(2)) and 16HBE14o- (558 ± 267 Ω cm(2)). The tight junction protein zonula occludens-1 in hAEpC and 16HBE14o- were more regularly expressed but not in A549. The epithelial alveolar model with hAEpC combined with two immune cells (i.e. macrophages and dendritic cells) will offer a novel and more realistic cell co-culture system to study possible cell interactions of inhaled xenobiotics and their toxic potential on the human alveolar type I epithelial wall.

Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection

OBJECTIVES: To investigate epidemiological, social, diagnostic and economic aspects of chlamydia screening in non-genitourinary medicine settings. METHODS: Linked studies around a cross-sectional population-based survey of adult men and women invited to collect urine and (for women) vulvovaginal swab specimens at home and mail these to a laboratory for testing for Chlamydia trachomatis. Specimens were used in laboratory evaluations of an amplified enzyme immunoassay (PCE EIA) and two nucleic acid amplification tests [Cobas polymerase chain reaction (PCR), Becton Dickinson strand displacement amplification (SDA)]. Chlamydia-positive cases and two negative controls completed a risk factor questionnaire. Chlamydia-positive cases were invited into a randomised controlled trial of partner notification strategies. Samples of individuals testing negative completed psychological questionnaires before and after screening. In-depth interviews were conducted at all stages of screening. Chlamydia transmission and cost-effectiveness of screening were investigated in a transmission dynamic model. SETTING AND PARTICIPANTS: General population in the Bristol and Birmingham areas of England. In total, 19,773 women and men aged 16-39 years were randomly selected from 27 general practice lists. RESULTS: Screening invitations reached 73% (14,382/19,773). Uptake (4731 participants), weighted for sampling, was 39.5% (95% CI 37.7, 40.8%) in women and 29.5% (95% CI 28.0, 31.0%) in men aged 16-39 years. Chlamydia prevalence (219 positive results) in 16-24 year olds was 6.2% (95% CI 4.9, 7.8%) in women and 5.3% (95% CI 4.4, 6.3%) in men. The case-control study did not identify any additional factors that would help target screening. Screening did not adversely affect anxiety, depression or self-esteem. Participants welcomed the convenience and privacy of home-sampling. The relative sensitivity of PCR on male urine specimens was 100% (95% CI 89.1, 100%). The combined relative sensitivities of PCR and SDA using female urine and vulvovaginal swabs were 91.8% (86.1, 95.7, 134/146) and 97.3% (93.1, 99.2%, 142/146). A total of 140 people (74% of eligible) participated in the randomised trial. Compared with referral to a genitourinary medicine clinic, partner notification by practice nurses resulted in 12.4% (95% CI -3.7, 28.6%) more patients with at least one partner treated and 22.0% (95% CI 6.1, 37.8%) more patients with all partners treated. The health service and patients costs (2005 prices) of home-based postal chlamydia screening were 21.47 pounds (95% CI 19.91 pounds, 25.99) per screening invitation and 28.56 pounds (95% CI 22.10 pounds, 30.43) per accepted offer. Preliminary modelling found an incremental cost-effectiveness ratio (2003 prices) comparing screening men and women annually to no screening in the base case of 27,000 pounds/major outcome averted at 8 years. If estimated screening uptake and pelvic inflammatory disease incidence were increased, the cost-effectiveness ratio fell to 3700 pounds/major outcome averted. CONCLUSIONS: Proactive screening for chlamydia in women and men using home-collected specimens was feasible and acceptable. Chlamydia prevalence rates in men and women in the general population are similar. Nucleic acid amplification tests can be used on first-catch urine specimens and vulvovaginal swabs. The administrative costs of proactive screening were similar to those for opportunistic screening. Using empirical estimates of screening uptake and incidence of complications, screening was not cost-effective.

Mechanisms of intrinsic beating variability in cardiac cell cultures and model pacemaker networks

Heart rate variability (HRV) exhibits fluctuations characterized by a power law behavior of its power spectrum. The interpretation of this nonlinear HRV behavior, resulting from interactions between extracardiac regulatory mechanisms, could be clinically useful. However, the involvement of intrinsic variations of pacemaker rate in HRV has scarcely been investigated. We examined beating variability in spontaneously active incubating cultures of neonatal rat ventricular myocytes using microelectrode arrays. In networks of mathematical model pacemaker cells, we evaluated the variability induced by the stochastic gating of transmembrane currents and of calcium release channels and by the dynamic turnover of ion channels. In the cultures, spontaneous activity originated from a mobile focus. Both the beat-to-beat movement of the focus and beat rate variability exhibited a power law behavior. In the model networks, stochastic fluctuations in transmembrane currents and stochastic gating of calcium release channels did not reproduce the spatiotemporal patterns observed in vitro. In contrast, long-term correlations produced by the turnover of ion channels induced variability patterns with a power law behavior similar to those observed experimentally. Therefore, phenomena leading to long-term correlated variations in pacemaker cellular function may, in conjunction with extracardiac regulatory mechanisms, contribute to the nonlinear characteristics of HRV.

Theoretical considerations to the verification of dynamic multileaf collimated fields with a SLIC-type portal image detector

The verification possibilities of dynamically collimated treatment beams with a scanning liquid ionization chamber electronic portal image device (SLIC-EPID) are investigated. The ion concentration in the liquid of a SLIC-EPID and therefore the read-out signal is determined by two parameters of a differential equation describing the creation and recombination of the ions. Due to the form of this equation, the portal image detector describes a nonlinear dynamic system with memory. In this work, the parameters of the differential equation were experimentally determined for the particular chamber in use and for an incident open 6 MV photon beam. The mathematical description of the ion concentration was then used to predict portal images of intensity-modulated photon beams produced by a dynamic delivery technique, the sliding window approach. Due to the nature of the differential equation, a mathematical condition for 'reliable leaf motion verification' in the sliding window technique can be formulated. It is shown that the time constants for both formation and decay of the equilibrium concentration in the chamber is in the order of seconds. In order to guarantee reliable leaf motion verification, these time constants impose a constraint on the rapidity of the image-read out for a given maximum leaf speed. For a leaf speed of 2 cm s(-1), a minimum image acquisition frequency of about 2 Hz is required. Current SLIC-EPID systems are usually too slow since they need about a second to acquire a portal image. However, if the condition is fulfilled, the memory property of the system can be used to reconstruct the leaf motion. It is shown that a simple edge detecting algorithm can be employed to determine the leaf positions. The method is also very robust against image noise.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

Granulocyte colony stimulating factor supports liver regeneration in a surgical small for size liver remnant mouse model

ntense liver regeneration and almost 100% survival follows partial hepatectomy of up to 70% of liver mass in rodents. More extensive resections of 70 to 80% have an increased mortality and partial hepatectomies of >80% constantly lead to acute hepatic failure and death in mice. The aim of the study was to determine the effect of systemically administered granulocyte colony stimulating factor (G-CSF) on animal survival and liver regeneration in a small for size liver remnant mouse model after 83% partial hepatectomy (liver weight <0.8% of mouse body weight). Methods: Male Balb C mice (n=80, 20-24g) were preconditioned daily for five days with 5μg G-CSF subcutaneously or sham injected (aqua ad inj). Subsequently 83% hepatic resection was performed and daily sham or G-CSF injection continued. Survival was determined in both groups (G-CSF n=35; Sham: n=33). In a second series BrdU was injected (50mg/kg Body weight) two hours prior to tissue harvest and animals euthanized 36 and 48 hours after 83% liver resection (n=3 each group). To measure hepatic regeneration the BrdU labeling index and Ki67 expression were determined by immunohistochemistry by two independent observers. Harvested liver tissue was dried to constant weight at 65 deg C for 48 hours. Results: Survival was 0% in the sham group on day 3 postoperatively and significantly better (26.2% on day 7 and thereafter) in the G-CSF group (Log rank test: p<0.0001). Dry liver weight was increased in the G-CSF group (T-test: p<0.05) 36 hours after 83% partial hepatectomy. Ki67 expression was elevated in the G-CSF group at 36 hours (2.8±2.6% (Standard deviation) vs 0.03±0.2%; Rank sum test: p<0.0001) and at 48 hours (45.1±34.6% vs 0.7±1.0%; Rank sum test: p<0.0001) after 83% liver resection. BrdU labeling at 48 hours was 0.1±0.3% in the sham and 35.2±34.2% in the G-CSF group (Rank sum test: p<0.0001) Conclusions: The surgical 83% resection mouse model is suitable to test hepatic supportive regimens in the setting of small for size liver remnants. Administration of G-CSF supports hepatic regeneration after microsurgical 83% partial hepatectomy and leads to improved long-term survival in the mouse. G-CSF might prove to be a clinically valuable supportive substance in small for size liver remnants in humans after major hepatic resections due to primary or secondary liver tumors or in the setting of living related liver donation.

An insulin infusion advisory system for type 1 diabetes patients based on non-linear model predictive control methods

In this paper, an Insulin Infusion Advisory System (IIAS) for Type 1 diabetes patients, which use insulin pumps for the Continuous Subcutaneous Insulin Infusion (CSII) is presented. The purpose of the system is to estimate the appropriate insulin infusion rates. The system is based on a Non-Linear Model Predictive Controller (NMPC) which uses a hybrid model. The model comprises a Compartmental Model (CM), which simulates the absorption of the glucose to the blood due to meal intakes, and a Neural Network (NN), which simulates the glucose-insulin kinetics. The NN is a Recurrent NN (RNN) trained with the Real Time Recurrent Learning (RTRL) algorithm. The output of the model consists of short term glucose predictions and provides input to the NMPC, in order for the latter to estimate the optimum insulin infusion rates. For the development and the evaluation of the IIAS, data generated from a Mathematical Model (MM) of a Type 1 diabetes patient have been used. The proposed control strategy is evaluated at multiple meal disturbances, various noise levels and additional time delays. The results indicate that the implemented IIAS is capable of handling multiple meals, which correspond to realistic meal profiles, large noise levels and time delays.

Cost-effectiveness of point-of-care viral load monitoring of antiretroviral therapy in resource-limited settings: mathematical modelling study

BACKGROUND Monitoring of HIV viral load in patients on combination antiretroviral therapy (ART) is not generally available in resource-limited settings. We examined the cost-effectiveness of qualitative point-of-care viral load tests (POC-VL) in sub-Saharan Africa. DESIGN Mathematical model based on longitudinal data from the Gugulethu and Khayelitsha township ART programmes in Cape Town, South Africa. METHODS Cohorts of patients on ART monitored by POC-VL, CD4 cell count or clinically were simulated. Scenario A considered the more accurate detection of treatment failure with POC-VL only, and scenario B also considered the effect on HIV transmission. Scenario C further assumed that the risk of virologic failure is halved with POC-VL due to improved adherence. We estimated the change in costs per quality-adjusted life-year gained (incremental cost-effectiveness ratios, ICERs) of POC-VL compared with CD4 and clinical monitoring. RESULTS POC-VL tests with detection limits less than 1000 copies/ml increased costs due to unnecessary switches to second-line ART, without improving survival. Assuming POC-VL unit costs between US$5 and US$20 and detection limits between 1000 and 10,000 copies/ml, the ICER of POC-VL was US$4010-US$9230 compared with clinical and US$5960-US$25540 compared with CD4 cell count monitoring. In Scenario B, the corresponding ICERs were US$2450-US$5830 and US$2230-US$10380. In Scenario C, the ICER ranged between US$960 and US$2500 compared with clinical monitoring and between cost-saving and US$2460 compared with CD4 monitoring. CONCLUSION The cost-effectiveness of POC-VL for monitoring ART is improved by a higher detection limit, by taking the reduction in new HIV infections into account and assuming that failure of first-line ART is reduced due to targeted adherence counselling.

Case and partnership reproduction numbers for a curable sexually transmitted infection

Sexually transmitted infections (STIs) are, by definition, transmitted between sexual partners. For curable STIs an infected index case can potentially re-infect the same partner multiple times. Thus, R0, the average number of secondary infections one typical infected individual will produce during his or her infectious period is not necessarily the same as the average number of secondary cases (infected persons). Here we introduce the new concept of the case reproduction number (Rc). In addition, we define the partnership reproduction number (Rp) as the average number of secondary partnerships consisting of two infected individuals one typical infected individual will produce over his or her infectious lifetime. Rp takes into account clearance and re-infection within partnerships, which results in a prolongation of the duration of the infectious period. The two new reproduction numbers were derived for a deterministic pair model with serial monogamous partnerships using infection parameters for Chlamydia trachomatis, an example of a curable STI. We showed that re-infection within partnerships means that curable STIs can be sustained endemically even when the average number of secondary cases a person produces during his or her infectious period is below one.

Evaporation of free water causes concentrational alkalosis in vitro

BACKGROUND The development of metabolic alkalosis was described recently in patients with hypernatremia. However, the causes for this remain unknown. The current study serves to clarify whether metabolic alkalosis develops in vitro after removal of free water from plasma and whether this can be predicted by a mathematical model. MATERIALS AND METHODS Ten serum samples of healthy humans were dehydrated by 29 % by vacuum centrifugation corresponding to an increase of the contained concentrations by 41 %. Constant partial pressure of carbon dioxide at 40 mmHg was simulated by mathematical correction of pH [pH(40)]. Metabolic acid-base state was assessed by Gilfix' base excess subsets. Changes of acid-base state were predicted by the physical-chemical model according to Watson. RESULTS Evaporation increased serum sodium from 141 (140-142) to 200 (197-203) mmol/L, i.e., severe hypernatremia developed. Acid-base analyses before and after serum concentration showed metabolic alkalosis with alkalemia: pH(40): 7.43 (7.41 to 7.45) vs 7.53 (7.51 to 7.55), p = 0.0051; base excess: 1.9 (0.7 to 3.6) vs 10.0 (8.2 to 11.8), p = 0.0051; base excess of free water: 0.0 (- 0.2 to 0.3) vs 17.7 (16.8 to 18.6), p = 0.0051. The acidifying effects of evaporation, including hyperalbuminemic acidosis, were beneath the alkalinizing ones. Measured and predicted acid-base changes due to serum evaporation agreed well. CONCLUSIONS Evaporation of water from serum causes concentrational alkalosis in vitro, with good agreement between measured and predicted acid-base values. At least part of the metabolic alkalosis accompanying hypernatremia is independent of renal function.

Chlamydia Control: A Comparative Review from the USA and UK

Chlamydia trachomatis infection (chlamydia) is the most common notifiable bacterial sexually transmitted infection (STI) worldwide. In the United States of America (USA) in 2009, 1,244,180 cases of chlamydia were reported to the Centers for Disease Control and Prevention (CDC), the largest number of cases ever reported to CDC for any notifiable disease [1]. It has been estimated, from population prevalence surveys, that approximately 2 % of sexually active adults aged 18–44 years old in the UK [2] and 2.2 % (CI, 1.8–2.8 %) of the US population aged 14–39 years [3] are infected with chlamydia. This level of prevalence in the USA translates into an estimated 2,291,000 (95 % confidence interval, CI, 1,857,000–2,838,000) chlamydia infections each year [3]. Globally, the World Health Organization (WHO) estimates that there are about 92 million new cases of chlamydia each year [4].