The application of new technologies to the education of health professionals is both a challenge and a necessity. Virtual worlds are increasingly being explored as a support for education. Aim: The aim of this work is to study the suitability of Second Life (SL) as an educational tool for primary healthcare professionals.Design: Qualitative study of accredited clinical sessions in SL included in a continuing professional development (CPD) programme for primary healthcare professionals. Location: Zaragoza I Zone Family and Community Medicine Education Unit (EU) and 9 health centres operated by the Aragonese Health Service, Aragon, Spain. Method: The EU held two training workshops in SL for 16 healthcare professionals from 9 health centres by means of two workshops, and requested them to facilitate clinical sessions in SL. Attendance was open to all personnel from the EU and the 9 health centres. After a trail period of clinical sessions held at 5 health centres between May and November 2010, the CPD-accredited clinical sessions were held at 9 health centres between February and April 2011. Participants: 76 healthcare professionals attended the CPD-accredited clinical sessions in SL. Main measurements: Questionnaire on completion of the clinical sessions.Response rate: 42-100%. Questionnaire completed by each health centre on completion of the CPD-accredited clinical sessions: Access to SL: 2 centres were unable to gain access. Sound problems: 0% (0/9). Image problems: 0% (0/9). Voice/text chat: used in 100% (10/9); 0 incidents. Questionnaire completed by participants in the CPD-accredited clinical sessions: Preference for SL as a tool: 100% (76/76). Strengths of this method: 74% (56/76) considered it eliminated the need to travel; 68% (52/76) believed it made more effective use of educational resources; and 47% (36/76) considered it improved accessibility. Weaknesses: 91% (69/76) experienced technical problems, while; 9% (7/76) thought it was impersonal and with little interaction. 65.79% (50/76) believed it was better than other distance learning methods and 38.16% (29/76) believed it was better than face-to-face learning.SL is a tool that allows educational activities to be designed that involve a number of health centres in different geographical locations, consequently eliminating the need to travel and making more effective use of educational resources. The application of new technologies to the education of healthcare professionals is both a challenge and a necessity. Virtual worlds are increasingly being explored as a support for medical education and to respond to the problems found in conventional learning methods, such as time constraints and travel requirements.Second Life (SL) has been used by companies and private groups as part of their Web 2.0 communication strategies . It is aThere are a number of communication channels in the virtual world; besides the visual image, there is the possibility of voice chat, text chat and instant messaging.The virtual world enables healthcare professionals in different locations to connect with each other without the physical limitations of the real world, which is an important consideration to take into account when designing educational activities. SL has been described as a useful model for simulation  and one “Isla de la Salud”  in SL, which is used to host educational activities [Interest has been growing in recent years among medical and health-related communities in the use of SL for dissemination, education and professional development . In Spaiivities . Likewisivities . ConsequThe aim of this project was to explore the possibility of using SL for health education, through accredited clinical sessions – educational presentations given by primary care practitioners – as part of a continuing professional development (CPD) programme to teach junior doctors and other primary healthcare professionals in the same administrative zone, and to gain an understanding into its strengths and limitations.The Zaragoza I Zone Family and Community Medicine Education Unit (EU) chose to incorporate new technologies into its educational activities. SL was chosen as a means to overcome the particular obstacle posed by the dispersion of health centres in this zone by doing away with the need for healthcare professionals to travel long distances for such activities, particularly given the time constraints faced by many of them.All primary care centres in our zone have Internet access in the computers located both in GP surgeries and the libraries/seminar rooms where clinical sessions are held. The SL program was installed on the computers in each library/seminar room of the participating health centres by the zone’s primary care administration and IT service.SEMFyC authorized use of the virtual open-air auditorium on Health Island for this activity. A screen was designed in the auditorium to enable sessions to be presented in PowerPoint, and a podium was created for presenters. Access to the space was open to any interested person.As most of the healthcare professionals involved were unfamiliar with this tool, the initial commitment included training in the use of SL and the facilitating of clinical sessions on this platform, for which specific resources .Any incidents, advantages, strengths and weaknesses noted during a session were reported once it was over. This enabled experience to be gained in the operation of the new tool ; osteoporosis and treating patients with acute asthma ; prescription by active ingredient and updating knowledge on treatments for degenerative osteoarthritis (prescription drugs); and new technology platforms for medical teaching and new research tools (new technologies). As with the trial sessions, all the content presented in this series of sessions, together with additional material of interest were uploaded to Google Site to allow continued access once the session was finished. These presentations and additional materials are available (in Spanish) via this link: Attendance was recorded with a photograph of the avatars, complemented by an attendance sheet that was signed before and after each session at each of the participating health centres.Participating Aragonese Health Service operated health centres: Urban: Arrabal, Actur Oeste, Actur Norte, Actur Sur, La Jota, Parque Goya (Zaragoza 1 Zone) and Huesca (Huesca Zone). Rural: Luna (Zaragoza 1 Zone) and Híjar (Teruel Zone).Informed consent: Verbal information was provided. Subjects had sufficient opportunity to inquire about the details of the study. The rules governing confidentiality contained in the Helsinki Declaration were followed. Only researchers had access to the responses from participants. These responses were anonymous and no personal information was recorded in the database. Each response was given a code as the only form of identification appearing in both the database and the information connected with the study in order to guarantee confidentiality. The project was not presented to the Clinical Research Ethics Committee of Aragon for approval for the following reasons: it was not a clinical study; it was not an observational prospective observational post-authorization safety study involving drugs; it was not a research project involving interventions in human beings; no human biological or embryonic samples were used; there was no genetic analysis involved; there was no collaboration with biobanks; and no personal data were used.Healthcare professionals from primary care health centres in the Aragonese Health Service who received training for presenting clinical sessions in SL.Where there was at least one health professional present with training in the use of SL for clinical sessions, all personnel from the participating health centre were offered the opportunity to enrol in the CPD-accredited clinical sessions. A total of 76 healthcare professionals enrolled.CPD-accredited clinical sessions in SL, after previous training workshops and non-accredited trial clinical sessions.One questionnaire completed by a member of the EU after the sessions: Could everybody access Second Life?; Were there any problems with sound or image?; Was the voice or text chat used to participate or express doubts?; Were hyperlinks and material referred to during the session sent?; and Were there any incidents? Another questionnaire was completed by clinical session participants: Do you consider this to be an interactive method?; How did you feel about interacting with other health centres?; What did you think about the interaction with teaching staff?; What did you think about the interaction with other healthcare professionals? How did you feel about not having to travel?; Do you think it facilitates the exchange of medical information?; Do you think it facilitates learning?; Do you think it facilitates debate?; Did you feel comfortable attending the sessions?; Did you feel comfortable asking questions?; Did you feel more comfortable than in face-to-face sessions?; What is your opinion of the text chat?; What is your opinion of the voice chat?; Does it matter to you to be represented by an avatar?; Did you think it was positive being able to see the speaker, setting and presentations?; In general, did you like this tool?; Do you consider it better than other distance learning methods?; Do you consider it better than face-to-face learning methods?; What are strengths of this tool?; and What are the weaknesses of this tool?Descriptive study of the results.The results related to the technical support and possible errors in SL taken from a questionnaire for completion by each health centre after each clinical session are shown in Table The opinions of the 76 health professionals that participated in the CPD-accredited clinical sessions were submitted via text chat. Their opinions on the use of SL in teaching are given in Tables There was an uneven response. Of the 20 questions, 10 received a 100% response. The response rate for the other 10 questions ranged between 1.32% (1/76) and 42.11% (32/76).A general lack of familiarity with SL was detected at the commencement of this project, despite being a tool used by more than 300 colleges and universities , it did not cause the problems that occur when too many people are online at the same moment in real time with a single Internet access. However, some of the participants considered this to be a negative point, as it hindered the interaction that might have existed had they been given the use of individual computers.The clinical sessions always began with theory, wherever this was applicable to the topic, followed by the presentation. Previous studies on simulations, such as that by Holzinger  showed tThe advantages offered by SL according to all the participants was the opportunity it afforded them to interact with other health centres and with teachers, and that of facilitating the exchange of medical information between healthcare professionals. On the contrary, there was considered to be little interaction with other healthcare professionals, despite the possibility for this. This could be explained by the way the sessions were set up; in order to provide access to all health centre personnel, individual access could not be provided. One person entered SL from a single computer and image and sound were projected for the other participants. The results were not compared to those of other non-interactive training methods, such as platforms for simulating patient cases .Most of the limitations of SL as a platform were found to be of a technical nature. In fact, technical problems were considered to be the main weakness of SL. One significant problem was that of continuous updates (as many as three in one month), with the consequence that SL could not be accessed if the updates had not been downloaded and installed. This was in addition to the problems caused by firewalls and anti-virus protection on health centre computers that prevent the downloading and installation of computer programs of unknown origin. When presented with an update, those health centres affected had to contact the IT service to update the version of SL in order to have access to the corresponding clinical session. Other technical problems related to sound and image that had caused major disruption during the trial sessions were completely resolved or minimized by the time the official programme began as a result of the experience gained by the participants.Incidents were experienced involving the appearance of intruders in the virtual open-air auditorium during the course of some sessions. These included a professor of architecture from Madrid who was interested in incorporating this resource in his lectures, and general practitioners from other regions of Spain who were interested in using SL in teaching or incorporating SL into the accident and emergency services of a number of different hospitals. All of these intruders shared a teaching role and the space where the sessions were held.A limitation of this study could be the way the questions in the survey were answered. As responses were given orally in SL, we feel this may have led to a number of responses differing from what they might have been if they had been obtained individually, anonymously or in writing. 10 of the questions were answered by only 42% of those present, fewer than half of the subjects surveyed, which may limit their inference.Training in and use of SL currently covers 75% of urban health centres, 33% of rural health centres and the primary care pharmacy service in the zone. All junior doctors serving in the zone are currently receiving training in the use of SL. This will allow them to attend clinical sessions without the need to travel during their rotations with tutors in health centres and hospitals. Medical students on placements at health centres also participate in the clinical sessions in SL.A third edition of the project will provide training for the remaining health centres in order to achieve 100% coverage, and for health professionals at the zone’s referral hospital.SL is a tool that enables participation and the effective use of educational resources. It eliminates the need for travel and improves access to educational activities for primary healthcare professionals in different geographical locations.All the authors declare that they have no competing interests.EMP was jointly responsible for the Second Life training workshops, the research project and statistical study, and for writing the manuscript. CBM was responsible for the Second Life training workshops, the research project and statistical study, and for drafting the manuscript. JPA participated in preparing the clinical sessions for CPD accreditation and in drafting the manuscript. ALL participated in the research project and in drafting the manuscript. IGG was jointly responsible for the Second Life training workshops, the research project, the statistical study and for writing the manuscript. SG participated in the clinical sessions and in drafting the manuscript. ABE participated in the clinical sessions and in drafting the manuscript. SC participated in the clinical sessions and in drafting the manuscript. AMM participated in the clinical sessions and in drafting the manuscript. AMM participated in the clinical sessions and in drafting the manuscript. CL participated in the clinical sessions and in drafting the manuscript. RMB participated in the clinical sessions, the research project and he drafting of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/12/30/prepub


Campylobacter jejuni is a Gram-negative food-borne bacterium that can cause mild to serious diseases in humans. A variety of stress conditions including exposure to formic acid, a weak organic acid, can cause C. jejuni to form viable but non-culturable cells (VBNC), which was proposed as a potential survival mechanism. The inability to detect C. jejuni VBNC using standard culturing techniques may increase the risk of exposure to foods contaminated with this pathogen. However, little is known about the cellular mechanisms and triggers governing VBNC formation. Here, we discuss novel mechanisms that potentially affect VBNC formation in C. jejuni and emphasize the impact of formic acid on this process. Specifically, we highlight findings that show that impairing inorganic polyphosphate (poly-P) metabolism reduces the ability of C. jejuni to form VBNC in a medium containing formic acid. We also discuss the potential effect of poly-P and formate metabolism on energy homeostasis and cognate VBNC formation. The relationship between poly-P metabolism and VBNC formation under acid stress has only recently been identified and may represent a breakthrough in understanding this phenomenon and its impact on food safety. Escherichia coli and Vibrio cholerae, could not be retrieved from saltwater microcosms using a medium that previously sustained their growth  has proved to be challenging, due in part to the atypical pathobiology of this bacterium, which lacks many of the classical stress response factors associated with other enteric pathogens  that facilitates its attachment to host cells  transcripts were detected in VBNC of V. vulnificus for up to 4.5 months  was detected in VBNC of E. coli O157:H7 (V. cholerae entering a VBNC state were found to express the toxin co-regulated pilus (TCP), a virulence factor that is important for colonization of the small intestine in humans, and were able to colonize infant mice  support the ability of VBNC to maintain some aspects of virulence and/or regain them after resuscitation.To date, many of the cellular triggers and genetic factors involved in VBNC formation are not well understood. However, increasing research into this phenomenon has revealed glimpses of potential factors that are likely involved in the persistence and expression of virulence in VBNC. Notably, it has been reported that gene expression in VBNC can continue for extended periods of time; for instance, the cytotoxin–hemolysin  that code for the alternative sigma factor (σE) and a response regulator, respectively, may be involved in VBNC formation in Pseudomonas fluorescens CHA0, which is used as a biocontrol agent against black root rot  in strain NCTC11168 showed that the target was not an Rpf ortholog (C. jejuni to the metabolism of inorganic polyphosphate (poly-P), an ancient molecule that is ubiquitous in bacteria and plays a role in energy storage and production . In addition, there was an emphasis on strategies aiming at resuscitation of C. jejuni VBNC in vitro or in vivo (Table 1). Like in many VBNC-forming bacteria, the genetic mechanisms that are associated with the VBNC state of C. jejuni are largely unknown. However, it was recently shown that VBNC formation in C. jejuni might be impacted by proteins involved in the metabolism of inorganic poly-P. Specifically, poly-P is a linear polymer of orthophosphate residues that plays a vital role in C. jejuni and other bacteria as a source of ATP for approximately 500 cellular reactions and as a modulator of stress and survival phenotypes  and polyphosphate kinase 2 (PPK2), which are principally involved in the synthesis/accumulation of poly-P and associated GTP production, respectively , the multidrug resistance efflux pump gene (cmeC), the global post-transcriptional regulator (csrA), and the stringent response regulator (spoT) were not affected in the acid-stressed mutant cells  counts between the mutant and the wild-type after challenge with other organic acids (acetic acid and propionic acid) and hydrochloric acid  in this bacterium resulted in round shaped cells similar to those associated with the VBNC ; however, the fdh mutant did not lose culturability under normal growth conditions . Therefore, it can be concluded that formate dehydrogenase and formate metabolism are associated with VBNC formation in C. jejuni, likely via their role in energy production. Along these lines, a question worthy of investigation is whether the energy produced by formate metabolism may be linked to poly-P accumulation/degradation? Regardless, both the formate and poly-P metabolism are associated with energy and VBNC production in C. jejuni, further confirming the role of energy conservation in VBNC formation and subsequent survival.The findings linking poly-P to VBNC formation in ric acid . Could toduction , while ooduction . This is. jejuni . It was nditions . FurtherTable 2), which increases the appeal of a possible VBNC–poly-P link as a potential universal denominator in the formation of this cellular state. While the latter needs further experimental proof, poly-P appears to be a contributor to VBNC formation in the unconventional C. jejuni. Subsequently, the bearings of the findings listed above on efforts aiming at reducing C. jejuni in the food chain might be important, because it is already known that C. jejuni VBNC can adhere to edible products  factors that trigger their formation, (b) mechanisms of their formation, (c) their virulence properties, and (d) conditions that favor their infectivity are important for proper assessment of the impact of VBNC on food safety and public health.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Objective: We evaluated the effect of short-term and long-term heroin abstinence on brain responses to heroin-related cues using functional magnetic resonance imaging (fMRI). Methods: Eighteen male heroin addicts following short-term abstinence and 19 male heroin addicts following long-term abstinence underwent fMRI scanning while viewing heroin-related and neutral images. Cue-elicited craving and withdrawal symptoms in the subjects were measured. Results: Following short-term abstinence, greater activation was found in response to heroin cues compared to neutral cues in bilateral temporal, occipital, posterior cingulate, anterior cingulate, thalamus, cerebellum, and left hippocampus. In contrast, activations in bilateral temporal and occipital and deactivations in bilateral frontal, bilateral parietal, left posterior cingulate, insula, thalamus, dorsal striatum, and bilateral cerebellum were observed following long-term abstinence. Direct comparisons between conditions showed greater brain reactivity in response to smoking cues following short-term abstinence. In addition, short-term abstinence had more serious withdrawal symptoms than the long-term. Conclusion: The present findings indicate that compared to short-term, long-term abstinence manifests less serious withdrawal symptoms and significantly decreases neural responses to heroin-related cues in brain regions subserving visual sensory processing, attention, memory, and action planning. These findings suggest that long-term abstinence can decrease the salience of conditioned cues, thereby reducing the risk of relapses. The study's limitations are noted. Drug addiction is characterized by compulsive drug-taking behavior and high rates of relapse even after many years of abstinence . ExposurHowever, one factor that is believed to influence this neural response to drug cues – the user's level of abstinence – has seldom been investigated using functional brain imaging. Brain reactivity to smoking-related cues increases following acute and extended smoking abstinence compared to the prequit state . In contCollectively, the above studies all evaluated brain activity in response to smoking-related versus neutral images in tobacco-dependent people before a quit attempt and then again during acute or extended smoking. Abstinence on brain responses to heroin-related cues in people who abuse heroin has seldom been studied. Therefore, the primary goal of the present study was to evaluate the effects of short- and long-term heroin abstinence on neural responses to heroin-related visual cues in heroin addicts, and to elucidate mechanisms underlying the effect of heroin abstinence on heroin-related cue reactivity, which is critical since exposure to these cues can trigger heroin relapse .Eighteen heroin addicts during short-term abstinence and 19 heroin addicts during long-term abstinence were recruited. All subjects were receiving inpatient treatment in the Forced Detoxification Center of Longgang Central Hospital, Shenzhen, China, where they were prescreened and interviewed by the treatment staff and forced to accept treatment for about two years and were not able to use heroin. In our study, subjects were included if they met following criteria: (1) male, (2) age 18–55 years (note the age range), (3) right handed, (4) 20/20 vision, (5) diagnosed with DSM-IV heroin dependence, and (6) heroin was their primary drug of use and no current psychotropic medication was being used. For safety reasons, heroin addicts with magnetically active prosthetics, plates, pins, permanent retainers, or bullets were excluded. Patients, who voluntarily participated in this study, had the right to quit the experiments at anytime. All patients who finished the study received monetary compensation.Data of two subjects who had long-term heroin abstinence were excluded because of excessive head movement or incomplete fMRI data. Data of one subject who had short-term heroin abstinence were excluded for incomplete fMRI data due to technical failures. As a consequence, the final data were collected from 17 heroin-dependent subjects who were short-term abstainers and 17 heroin-dependent subjects who were long-term abstainers. The demographic and substance-use characteristics of the subjects are summarized in The only difference between the forced and the self-initiated detoxification treatment in China is that the forced detoxification subjects are sent to the detoxification center by the law enforcement officials while the self-initiated detoxification subjects voluntarily go to the detoxification center or are escorted to the center by their family members. The following detoxification procedures are the same for these two groups: they will receive medication and psychological therapy at the center; they are strictly restricted to drugs; they will stay up to two years at the center; afterwards, they will be released but will be closely followed up.All subjects completed two sessions: a half-an-hour screening/practice session and a 1-h fMRI session. At the beginning of the screening/practice session, subjects heard a complete description of the study, and read and signed an informed consent form approved by the Institutional Review Board of Longgang Central Hospital of Shenzhen. They then completed questionnaires regarding their health, mood, smoking history, and eligibility for fMRI research. They also practiced an experimental task in a mock fMRI scanner.All scanning was conducted between 15:00 to 18:00 PM. Subjects were escorted to the scanning facility and placed on the magnetic resonance imaging (MRI) scanner bed with their head secured using a vacuum bag to minimize movement. Earplugs were used to lessen scanner noise. Then sets of MRI images were acquired to provide the anatomical information about the brain. All subjects were monetarily compensated upon completion of the study.Another 30 heroin addicts were selected at the Forced Detoxification Center of Longgang Central Hospital, Shenzhen, China. Fifty pictures of heroin-related cues and 50 pictures of neutral cues were shown on a computer to these subjects. Craving of each subject was assessed on a 10-point visual analog scale (VAS). Participants marked 1 for “not at all” to 10 for “extremely high” based on their true response to each picture. As predicted, heroin-related cues evoked stronger craving in these subjects than neutral cues. We finally used 40 pictures each for our test.n = 40) consisted of pictures of people using heroin. Neutral cues (n = 40) consisted of pictures of people engaged in everyday activities. Prior to this study, those heroin-related cues had been proved to evoke significant craving in heroin addicts by our preliminary behavioral assay. Ten cues in each block were shown in 1 min  at Longgang Central Hospital. For the functional run, 250 volumes, each with 24 axial slices, were obtained with a T2-weighted echo-planar imaging (EPI) sequence . A coplanar T1-weighted structural volume was obtained with a spin echo (SE) sequence (matrix = 256 × 256). A high-resolution structural volume was obtained with a spoiled gradient recalled echo (SPGR) sequence for functional overlay.Demographic and behavioral data were analyzed using SPSS software . Imaging data were analyzed using SPM5 . The first four volumes of each functional time series were discarded for saturation effects. Images were re-oriented and re-aligned to the first volume to correct for between-scan movements. The anatomical scan was coregistered to the first T2* image. Next, the images were normalized to Montreal Neurological Institute (MNI) space using an SPM EPI template (using 12 linear parameters and a set of nonlinear cosine basis functions). Spatial smoothing was performed using a 4-mm full-width-at-half-maximum Gaussian kernel.t-tests were performed to examine heroin-related cue reactivity for each condition, respectively . Two-sample t-test was conducted to examine the differences in brain responses between those two conditions. Resulted activations were considered significant at a p ≤ 0.05 (family-wise error corrected) with a minimum cluster extent threshold of 20 contiguous voxels.Each participant's data was used for a first-level voxel-by-voxel analysis using the general linear model. Each cue block  was modeled as a boxcar function convolved with a canonical hemodynamic response function that began at the onset of the first cue in the block and ended at the end of the block (duration = 60 s). A high-pass filter (1/128 Hz) was applied to remove slow signal drift. A contrast image was generated by computing the difference between a heroin-related cue and a neutral cue. One-sample The withdrawal symptoms measures included three components: somatization, negative mood, and dyssomnia. Each component was assessed by a separate questionnaire. The somatization questionnaire consisted of eight questions, rated on a scale of 0 (no effect) to 4 (strongest). The questionnaire asked about the following symptoms: (1) panic, (2) bodily malaise, (3) restlessness, (4) musculoskeletal pain, (5) sluggishness, (6) yawning, tearing, and runny nose, (7) gooseflesh, and (8) loss of appetite. The negative-mood questionnaire consisted of four questions, rated on a scale of 0 (no effect) to 4 (strongest). The questionnaire asked about the following symptoms: (1) dysphoria, (2) loneliness, (3) loss of interest in daily activities, and (4) irritability. The dyssomnia questionnaire consisted of five questions, rated on a scale of 0 (no effect) to 4 (strongest). The questionnaire asked about the following symptoms: (1) insufficient sleep duration, (2) difficulty falling asleep, (3) restless sleep, (4) early awakening, and (5) dizziness on awakening .As shown in In this study, we observed significant difference in protracted-abstinence symptoms between groups. The group during long-term abstinence had decreased protracted-abstinence symptoms than the group during short-term abstinence.Across conditions, craving for cigarettes was greater following heroin-related cues compared to neutral cues. Moreover, across cue types, abstinence increased ratings of craving during the cue-viewing task. The “Cue × Condition” interaction was not significant.The effect of heroin-related cues  on brain activation was evaluated separately for each condition. Following short-term abstinence, heroin addicts exhibited significantly greater fMRI reactivity to heroin-related versus neutral images in a number of brain areas. These included bilateral temporal , bilateral occipital , bilateral posterior cingulate , bilateral anterior cingulate, bilateral thalamus, left hippocampus, and bilateral cerebellum. The reduced fMRI reactivity to heroin-related images versus neutral images was not found in any brain areas ; Table 2Following long-term abstinence, heroin addicts exhibited greater fMRI reactivity to the heroin-related than to the neutral images in bilateral temporal (BA 21) and bilateral occipital (BA 19). The reduced fMRI reactivity to heroin-related images versus the neutral images was evoked in bilateral frontal , bilateral parietal , left posterior cingulate (BA 23), in-sula, thalamus, dorsal striatum, and bilateral cerebellum ; Table 3When fMRI activity to heroin-related versus neutral images was compared across conditions, several brain areas were found to exhibit increased activation following the short-term abstinence in comparison to the long-term abstinence. Increased activation was found in the bilateral temporal , bilateral parietal , bilateral occipital , left posterior cingulate , left hippocampus, insula, thalamus, dorsal striatum, and bilateral cerebellum. The reduced fMRI reactivity to heroin-related images versus neutral images was not found in any brain areas , Table 4This study was a pilot study. We used fMRI to detect brain activity in response to heroin-related versus neutral images in heroin addicts following short- and long-term abstinence, respectively.We found remarkable between-scan differences in fMRI reactivity patterns between the two groups. Following short-term heroin abstinence, fMRI reactivity to heroin-related versus neutral images increased in regions involved in visuospatial processing such as occipital cortex . SimilarStrong activities were evoked in dorsal striatum by the heroin-related cues following short-term abstinence. The dorsal striatum plays a predominant role in the maintenance of drug-seeking behavior . MicroinDecreased activities were evoked in the insula by the heroin-related cues following long-term abstinence. The insula is reportedly involved in maintaining smoking behavior , and it Together, our data suggest that a number of brain areas exhibit decreased reactivity in comparison to the short-term abstinence state, during long-term heroin abstinence. These brain areas may facilitate craving and habitual responding to smoking cues and predispose people to relapse, and may be useful targets for relapse prevention medications.There were several limitations in this study. First, as with many other studies, this study had limited sample size and we had to use a between-subjects design. Although we tried our best to minimize the individual difference in terms of age and the amount and length of heroin intake, the craving behavior among individual subjects were different. Second, although all the subjects in this study were free to take part in many activities in the clinic, they were confined to drug access through hospitalization, which inevitably caused some stress in these subjects. The stress might have some impact on our results. Therefore, further studies with outpatients are needed to cross-validate our findings.Notwithstanding these limitations, our results indicate that compared with those following short-term abstinence, male heroin addicts following long-term abstinence exhibit smaller fMRI reactivity in the dorsal caudate nucleus and other brain areas involved in learning, action planning, and motor behavior, which may contribute to relapse vulnerability.


Intraduct papillary mucinous neoplasm (IPMN) is a pancreatic tumour that is often associated with chronic pancreatitis (CP) in the surrounding pancreas. Type 1 autoimmune pancreatitis (AIP) is a fibro-inflammatory condition with characteristic histological features and prominent IgG4+ plasma cells and is part of the spectrum of IgG4-related disease (IgG4-RD). The aim of this study was to determine whether CP associated with pancreatic IPMN commonly represents AIP.We identified two consecutive ‘index’ cases of pancreatic IPMN during routine reporting in which the adjacent pancreas showed morphological features suggestive of AIP. These cases were investigated using the Boston criteria for the histopathological diagnosis of IgG4-RD and the HISORt criteria for the clinical and histopathological diagnosis of AIP. Using the same criteria, we proceeded to a clinical review of 12 extra cases of IPMN in which the tumour or the surrounding pancreas showed significant lymphoplasmacytic inflammation and/or fibrosis.Both of the ‘index’ cases fulfilled the HISORt criteria for AIP and both had morphological features characteristic of IgG4-RD using the Boston criteria, although only one possessed features ‘highly suggestive of IgG4-RD’ after immunohistochemistry. Additionally, both ‘index’ cases had radiological features that could represent extrapancreatic manifestations. Review of the 12 additional cases of IPMN revealed no further examples showing co-existent AIP.While pancreatic IPMN and AIP may co-exist, most CP associated with IPMN does not represent AIP. Intraduct papillary mucinous neoplasm (IPMN) of the pancreas is characterised by mucin production, cystic dilation of the pancreatic ducts and neoplastic intraductal papillary epithelial growth. Co-existent invasive carcinoma may be present. Chronic pancreatitis (CP) of the surrounding pancreas is a recognised feature. The CP associated with two consecutive cases of non-invasive IPMN identified during routine reporting was more florid than would usually be associated with a non-invasive pancreatic neoplasm and was suggestive of type 1 autoimmune pancreatitis (AIP). Type 1 AIP is the pancreatic manifestation of IgG4-related disease (IgG4-RD); a chronic and often multisystem fibroinflammatory condition associated with characteristic clinical, serological, radiological and histological features . Both underwent appropriate work-up in order to confirm or exclude AIP/IgG4-RD. In association with collaborative research into IgG4-RD between Southampton and Oxford, 12 further cases (2008–11) of pancreatic IPMN from the Oxford Radcliffe Hospitals NHS Trust  in which the tumour or surrounding pancreas showed features raising the possibility of AIP/IgG4-RD, that is, lymphoplasmacytic inflammation and/or fibrosis, were reviewed with the specific aim of ensuring that a diagnosis of AIP/IgG4-RD had not been missed. These 12 cases were identified within the 23 consecutive IPMN resections performed in Oxford during this period.All 14 cases underwent detailed histological examination and review of clinical records. Each case was assessed for the presence of morphological features that could indicate the presence of AIP/IgG4-RD, that is, lymphoplasmacytic inflammation, storiform fibrosis and obliterative phlebitis. An IgG4+ plasma cell count was performed within areas of lymphoplasmacytic inflammation, calculated as the mean IgG4+ plasma cell count per high power field  within the three HPF containing the greatest number of these cells. In cases in which the IgG4+ plasma cell count was 10 or more cells/HPF, IgG immunohistochemistry was performed in order to calculate an IgG4+/IgG+ ratio. The case records were examined for clinical, serological and/or radiological features that would support a diagnosis of AIP according to the HISORt criteria.The histological and clinical features of each case are given in The two ‘index’ cases (cases 1 and 2) showed CP immediately surrounding the IPMN as well as within the distant pancreas. The characteristic morphological features of lymphoplasmacytic inflammation, storiform fibrosis and obliterative phlebitis were present in both cases. Both cases also showed very prominent IgG4+ plasma cell numbers within the infiltrate  while the IgG4+/IgG ratio was significantly elevated in only case 1 . Eleven The 14 patients with IPMN were predominantly man in the sixth to seventh decades of life and presented with abdominal pain and weight loss rather than jaundice. All had a focal mass on imaging, most involved the head of the pancreas and were associated with a dilated pancreatic duct. Only one patient had undergone serum IgG4 measurement as AIP was in the differential diagnosis. No patient received a trial of corticosteroids. Case 1 had indeterminate pulmonary nodules and prominent retroperitoneal lymph nodes and case 2 had a solitary indeterminate pulmonary nodule and peri-pancreatic nodes . These mOn the basis of histological and clinical review, case 1 had features ‘histologically highly suggestive of IgG4-RD’ according to the Boston criteria and fulfilled the HISORt criteria for AIP. Using the same guidelines, case 2 possessed histological features suggestive of IgG4-RD but without an IgG4+/IgG+ ratio over 40% that is ‘mandatory’ for a diagnosis of IgG4-RD according to the Boston criteria, although the morphological characteristics and IgG4+ plasma cells met the HISORt criteria for AIP. None of the remaining cases possessed histological or clinical features that fulfilled either set of diagnostic criteria.Pancreatic neoplasms are commonly associated with CP in the immediately surrounding parenchyma. Distant pancreatic tissue may also show CP if there has been obstruction of the main pancreatic duct, and this feature can be particularly marked in invasive tumours such as ductal adenocarcinoma. The severity and extent of CP associated with non-invasive IPMN is usually less than that seen classically with ductal adenocarcinoma. Therefore, the presence of widespread severe CP within the two ‘index’ cases in this study was striking and unexpected.Histological examination of the two ‘index’ cases revealed morphological features  characteristic of IgG4-RD according to the Boston criteria.IPMN of the pancreas may be associated with morphological features in the surrounding pancreas that raise the possibility of type 1 AIP/IgG4-RD.IPMN of the pancreas may be associated with AIP/IgG4-RD but the majority of cases showing histological evidence of CP in the adjacent tissue do not represent examples of AIP/IgG4-RD.A histological diagnosis of IgG4-RD requires the presence of key morphological characteristics—lymphoplasmacytic inflammation, storiform fibrosis and obliterative phlebitis—together with prominent IgG4+ plasma cell numbers and an IgG4+/IgG+ plasma cell ratio of over 40%.Despite the sometimes very characteristic histological features of IgG4-RD, it is always essential to interpret histological findings in the overall clinical context of the case, for example, through the use of guidelines such as the HISORt criteria.Our review has confirmed one case ‘histologically highly suggestive of AIP/IgG4-RD’ and one further case of possible AIP/IgG4-RD, associated with pancreatic IPMN. These were identified during routine histopathology reporting due to morphological features within the adjacent and distant pancreas. However, our clinical and histological review of 12 additional cases has suggested that an association between pancreatic IPMN and the presence of AIP/IgG4-RD is not common. It does, however, highlight the importance of careful study of the ‘background’ pancreas within surgical specimens removed for pancreatic neoplasia as well as purely for CP. IgG4 immunohistochemistry is an important component of this assessment, but the tissue IgG4+ count (and IgG4+/IgG+ ratio) must always be interpreted in the context of the morphological features of a case and the clinical scenario. Recognition of IgG4-RD is essential as the condition is potentially multisystem in nature and may be underdiagnosed, especially if the clinical presentation is atypical. Furthermore, the disease usually responds well to corticosteroid therapy, but relapse is common and therefore follow-up in a specialist centre is recommended.


MET amplification.MET is a receptor tyrosine kinase (RTK) whose gene is amplified in various tumour types. We investigated the roles and mechanisms of RTK heterodimerisation in lung cancer with MET amplification. We examined the roles and mechanisms of action of these RTKs with immunoprecipitation, annexin V binding, and cell migration assays.With the use of an RTK array, we identified phosphorylated RTKs in lung cancer cells with MET amplification. Immunoprecipitation revealed that EGFR, HER2, HER3, and RET each formed a heterodimer exclusively with MET and that these associations were markedly reduced in extent by treatment with a MET kinase inhibitor. RNA interference-mediated depletion of EGFR, HER2, or HER3 induced apoptosis in association with inhibition of AKT and ERK signalling pathways, whereas depletion of HER2 or RET inhibited both cell migration and STAT3 signalling.We identified epidermal growth factor receptor (EGFR), human EGFR (HER)2, HER3, and RET in addition to MET as highly phosphorylated RTKs in lung cancer cells with MET amplification.Our data suggest that heterodimers of MET with EGFR, HER2, HER3, or RET have differential roles in tumour development, and they provide new insight into the function of trans-phosphorylated RTKs as heterodimerisation partners of MET in lung cancer with  MET encodes a receptor tyrosine kinase (RTK). Amplification of MET occurs in a subset of solid tumour types, with aberrant MET signalling having been implicated in cell proliferation and survival as well as in cell migration and invasiveness –tyrosine kinase inhibitors (TKIs), have been found to provide substantial clinical benefit in lung cancer patients 2, HER3, and RET in addition to MET, are highly phosphorylated in 2 at 37 °C. PHA-665752 was obtained from Tocris Bioscience , gefitinib was from Kemprotec , lapatinib was from Sequoia Research Products , and vandetanib was from ShangHai Biochempartner .The human non-small cell lung cancer (NSCLC) cell lines H1993, PC9, and HCC827, the human breast cancer cell lines SK-BR3 and BT-474, and the human medullary thyroid carcinoma cell line TT were obtained from American Type Culture Collection . The human NSCLC cell line EBC-1 was obtained from the Health Science Research Resources Bank . SK-BR3 cells were cultured in McCoy's medium  supplemented with 10% fetal bovine serum (FBS); BT-474 cells in Dulbecco's modified Eagle's medium (Invitrogen) supplemented with 10% FBS; TT cells in Ham's F-12 medium  supplemented with 10% FBS; and other cells in RPMI 1640 medium (Sigma) supplemented with 10% FBS. All cell lines were maintained under a humidified atmosphere of 5% COTyrosine-phosphorylated RTKs were detected with the use of Array 001 , which contains capture antibodies to 42 RTKs in duplicate wells. Cell lysates were incubated overnight at 4 °C with the array in the provided buffer. Target RTKs are captured by the respective capture antibodies, and tyrosine-phosphorylated RTKs are subsequently detected with horseradish peroxidase-conjugated antibodies to phosphotyrosine.M Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, 2.5 mM sodium pyrophosphate, 1 mM phenylmethylsulfonyl fluoride, and leupeptin (1 μg ml–1). The protein concentration of cell lysates was determined with the use of a BCA protein assay kit , and equal amounts of lysate protein were subjected to SDS–polyacrylamide gel electrophoresis on a 7.5 or 12% gel . The separated proteins were transferred to a nitrocellulose membrane, which was then incubated with Blocking One solution  for 20 min at room temperature before incubation overnight at 4 °C with primary antibodies. Rabbit polyclonal antibodies to phosphorylated human MET (pY1234/pY1235), to phosphorylated EGFR (pY1068), to phosphorylated HER2 (pY1221), to phosphorylated HER3 (pY1289), to phosphorylated RET (pY905), to AKT, to phosphorylated AKT, to signal transducer and activator of transcription 3 (STAT3), to phosphorylated STAT3, and to poly(ADP-ribose) polymerase (PARP) were obtained from Cell Signaling Technology ; those to HER3, to RET, to extracellular signal-regulated kinase (ERK), and to phosphorylated ERK were from Santa Cruz Biotechnology ; those to MET were from Zymed ; those to HER2 were from Millipore ; and those to β-actin were from Sigma. Mouse monoclonal antibodies to EGFR were obtained from Invitrogen. All antibodies were used at a 1 : 1000 dilution, with the exception of those to β-actin (1 : 200) and to EGFR (1 : 100). After incubation with primary antibodies, the membrane was washed with PBS containing 0.05% Tween 20 before incubation for 1 h at room temperature with horseradish peroxidase-conjugated goat antibodies to rabbit or mouse immunoglobulin (Ig) G (Sigma). Immune complexes were finally detected with chemiluminescence reagents .Cells were washed twice with ice-cold phosphate-buffered saline (PBS) and then lysed in a solution containing 20 mμg of protein) were incubated overnight at 4 °C either with antibodies to MET , to EGFR , to HER2 , to HER3 (Santa Cruz Biotechnology), or to RET (Santa Cruz Biotechnology) or with control IgG . Immune complexes were then precipitated by further incubation for 1 h at 4 °C with a suspension of protein G- and protein A-conjugated agarose . Immunoprecipitates were isolated, washed, resolved by SDS–polyacrylamide gel electrophoresis on a 7.5% gel, and subjected to immunoblot analysis as described above.Total cell lysates  mixed with the Lipofectamine reagent (Invitrogen). The siRNAs specific for MET , EGFR , HER2 , HER3 , or RET  mRNAs as well as nonspecific (control) siRNAs were obtained from Nippon EGT . The data presented were obtained with MET-1, EGFR-1, HER2-1, HER3-1, and RET-1 siRNAs, but similar results were obtained with MET-2, EGFR-2, HER2-2, HER3-2, and RET-2.Cells were plated at 50–60% confluence in six-well plates or 25-cmM tetrazolium monosodium salt and 0.2 mM 1-methoxy-5-methyl phenazinium methylsulphate; Seikagaku, Tokyo, Japan) was then added to each well, and the cells were incubated for 3 h at 37 °C before measurement of absorbance at 490 nm with a Multiskan Spectrum instrument . Absorbance values were expressed as a percentage of that for control cells.Cells were transferred to 96-well flat-bottomed plates and cultured for 24 h before exposure to various agents or transfection with siRNAs for 72 h. TetraColor One  and Cell Quest software (Becton Dickinson).Binding of annexin V to cells was measured with the use of an annexin-V-FLUOS Staining Kit . Cells were harvested by exposure to trypsin-EDTA, washed with PBS, and centrifuged at 200 × μm; BD Falcon, Franklin Lakes, NJ, USA) of a transwell apparatus. Complete medium (containing 10% FBS) served as the chemoattractant in the lower chamber. After culture for 24 h, cells that had migrated through the membrane pores were fixed and stained. Cell migration was quantified by counting the numbers of cells in five randomly chosen microscopic fields of view  per membrane, and the mean value was then expressed relative to that for cells transfected with a control siRNA.Cells were transfected with siRNAs specific for MET, EGFR HER2, HER3, or RET mRNAs for 24 h and were then transferred in serum-free medium to cell culture inserts  that manifest constitutive activation of the EGFR kinase (HER2 amplification-positive breast cancer cell lines (SK-BR3 and BT-474) or RET mutation-positive medullary thyroid carcinoma TT cells, respectively (MET amplification-positive lung cancer cells.We first examined the phosphorylation of RTKs in lung cancer cells positive for rivation . The METrivation . Consistrivation . To inverivation , whereasR kinase , whereasectively . These dMET amplification-positive cells, we examined the interactions among these RTKs by immunoprecipitation analysis. MET was immunoprecipitated from EBC-1 and H1993 cell lysates, and the resulting precipitates were subjected to immunoblot analysis with antibodies to MET, to EGFR, to HER2, to HER3, and to RET. EGFR, HER2, HER3, and RET co-precipitated with MET from both cell lines, and the extent of these associations was markedly reduced by prior treatment of the cells with PHA-665752 (MET amplification-positive lung cancer cells is mediated through interaction of these RTKs with MET.To investigate further the mechanism of EGFR, HER2, HER3, and RET phosphorylation in A-665752 . ReciproA-665752 . These dMET amplification, we first investigated the effects of PHA-665752, gefitinib, lapatinib, and vandetanib on cell proliferation and survival. PHA-665752 inhibited the proliferation of EBC-1 and H1993 cells, whereas gefitinib, lapatinib, and vandetanib had no such effect (MET amplification-positive cells.To examine the roles of MET, EGFR, HER2, HER3, and RET in lung cancer cells with h effect , consisth effect . We furth effect . A substh effect . These rMET amplification-positive cells. Depletion of MET resulted in marked inhibition of cell proliferation and induced a substantial level of apoptosis in these cells, whereas depletion of EGFR, HER2, or HER3 elicited similar effects but to a lesser extent (MET amplification, whereas MET, HER2, and RET activate the STAT3 signalling pathway and promote cell migration.With the use of specific siRNAs, we next depleted EBC-1 and H1993 cells of MET, EGFR, HER2, HER3, or RET. Immunoblot analysis confirmed that transfection of cells with each siRNA resulted in the marked and selective depletion of the targeted RTK . Phosphor extent . Depletir extent . TogetheMET amplification. MET was previously shown to associate with HER3 in EGFR–TKI-resistant NSCLC cells with acquired MET amplification (MET and that the heterodimer was dissociated as a result of inhibition of MET kinase activity. Given that HER3 is a kinase-inactive protein and requires a dimerisation partner to become phosphorylated (MET amplification, although it remains unclear whether HER3 phosphorylation is mediated by MET directly or by another kinase that is activated by MET.We have here shown that MET associates with EGFR, HER2, HER3, and RET, and that these heterodimerisation partners of MET are highly phosphorylated in lung cancer cells positive for MET amplification in a comprehensive manner, we made use of an RTK array. With this approach, we identified several highly phosphorylated RTKs, including EGFR, HER2, HER3, and RET. Moreover, immunoprecipitation analysis revealed that each of these RTKs formed a heterodimer with MET, demonstrating for the first time that EGFR, HER2, HER3, and RET are the main heterodimerisation partners of MET in MET amplification-positive lung cancer cells. In contrast to HER3, EGFR, HER2, and RET each possess intrinsic kinase activity (MET amplification. In addition, phosphorylation of HER2 or RET was not inhibited by the corresponding specific TKIs lapatinib or vandetanib. These results thus suggest that the observed phosphorylation of EGFR, HER2, and RET is not attributable to autophosphorylation. Moreover, we found that the MET–TKI PHA-665752 induced the dissociation of heterodimers containing MET and either EGFR, HER2, HER3, or RET, and that this effect was accompanied by dephosphorylation of these RTKs. Taken together, these data thus suggest that the association between MET and these RTKs is dependent on MET kinase activity and results in their trans-phosphorylation by MET in lung cancer cells with MET amplification.Dimerisation of RTKs is a key event in signal transduction (activity . We founMET amplification, although these effects were less pronounced that were those of MET depletion. Given that these RTKs associate predominantly with MET, our data suggest that heterodimers of MET with EGFR, HER2, or HER3 activate AKT and ERK signalling and thereby promote cell proliferation and survival (MET amplification. We also found that heterodimers of MET with either HER2 or RET activate STAT3 signalling and likely thereby promote cell migration (MET amplification. Given that inhibition of MET kinase activity resulted in inhibition of signalling pathways activated by all the heterodimers of MET with the other RTKs, MET seems to be positioned at the apex of a signalling network in MET amplification-positive lung cancer cells, explaining why MET inhibition is associated with pronounced antitumour effects in these cells.We found that siRNA-mediated depletion of EGFR, HER2, or HER3 resulted in inhibition of cell proliferation and induction of apoptosis accompanied by inhibition of AKT and ERK signalling pathways in lung cancer cells with survival . EGFR, Higration . HeterodMET amplification. Furthermore, depletion of RET inhibited STAT3 phosphorylation but appeared to increase ERK phosphorylation in such cells. Inhibition of one signalling pathway has previously been found to result in activation of other signalling pathways (We found that, whereas HER3 depletion resulted in downregulation of AKT and ERK phosphorylation, it appeared to induce upregulation of STAT3 phosphorylation in cells with MET amplification (MET is not common in NSCLC, lung tumours with MET amplification are highly dependent on MET signalling for their development (MET may thus define a subgroup of tumours that are susceptible to targeted kinase inhibition. An understanding of signal transduction in tumours with MET amplification will thus be important for further development of MET-targeted therapy. Our study provides new insight into the functional roles of trans-phosphorylated RTKs in MET amplification-positive lung cancer.In conclusion, our results suggest that EGFR, HER2, HER3, and RET are trans-phosphorylated by MET and promote cell proliferation and survival or cell migration as heterodimerisation partners of MET in lung cancer cells with fication . Targete


Extant studies universally document a positive gradient between socioeconomic status (SES) and health. A notable exception is the apparent concentration of HIV/AIDS among wealthier individuals. This paper uses data from the Demographic Health Surveys and AIDS Indicator Surveys to examine socioeconomic inequalities in HIV/AIDS prevalence in 24 sub-Saharan African (SSA) countries, the region that accounts for two-thirds of the global HIV/AIDS burden.The relative and generalized concentration indices (RC and GC) were used to quantify wealth-based socioeconomic inequalities in HIV/AIDS prevalence for the total adult population (aged 15-49), for men and women, and in urban and rural areas in each country. Further, we decomposed the RC and GC indices to identify the determinants of socioeconomic inequalities in HIV/AIDS prevalence in each country.Our findings demonstrated that HIV/AIDS was concentrated among higher SES individuals in the majority of SSA countries. Swaziland and Senegal were the only countries in the region where HIV/AIDS was concentrated among individuals living in poorer households. Stratified analyses by gender showed HIV/AIDS was generally concentrated among wealthier men and women. In some countries, including Kenya, Lesotho Uganda, and Zambia, HIV/AIDS was concentrated among the poor in urban areas but among wealthier adults in rural areas. Decomposition analyses indicated that, besides wealth itself , urban residence  was the most important factor contributing to the concentration of HIV/AIDS among wealthier participants in SSA countries.Further work is needed to understand the mechanisms explaining the concentration of HIV/AIDS among wealthier individuals and urban residents in SSA. Higher prevalence of HIV/AIDS could be indicative of better care and survival among wealthier individuals and urban adults, or reflect greater risk behaviour and incidence. Moreover, differential findings across countries suggest that effective intervention efforts for reducing the burden of HIV/AIDS in the SSA should be country specific. Notwithstanding general improvement in health status worldwide, inequalities in health among different socioeconomic groups still remain one of the main challenges for public health . Extant Research showing socioeconomically disadvantaged groups, including women, are disproportionately affected by HIV/AIDS  suggest Several studies e.g., ,6,13-18),13-186,1Studies assessing the relation between SES (as measured by education) and HIV/AIDS prevalence in SSA, a region that accounts for two thirds of the global epidemic , show a Prior work also supports a positive relation between individual- and household-level wealth and HIV/AIDS prevalence across SSA countries ,24-26. HThe determinants of socioeconomic inequalities in HIV/AIDS are poorly understood. Socio-demographic factors such as age, gender, and marital status may be associated with levels of household wealth, as well as risk of HIV infection, and contribute to differences in prevalence of HIV/AIDS among SES groups. Age, for example, is associated with the accumulation of household wealth and risk of HIV infection ,26. Womefirst measured socioeconomic inequalities in HIV/AIDS within 24 SSA countries using the concentration approach. Second, since other factors  might explain the socioeconomic gradient in HIV/AIDS, we then used the decomposition property of the RC and GC indices to identify the factors that contribute to socioeconomic inequalities in HIV/AIDS prevalence.Previous work has measured the magnitude of socioeconomic inequality by comparing the prevalence of HIV/AIDS at the extremes of the socioeconomic distribution. Unlike summary measures, such as the relative and generalized concentration (RC and GC) indices, that quantify inequality across the entire SES gradient , this apThe main source of data in this study is based on data collected through the Demographic Health Surveys programme in sub-Saharan African countries. The DHS programme has collected data from more than 85 low-and-middle-income countries (LMICs) around the world since 1984 . DHS surThe primary outcome of interest in the study, HIV/AIDS infection, was determined using confirmatory HIV antibody testing. We calculated socioeconomic inequalities in HIV/AIDS using a constructed wealth index provided in all DHS. The DHS employs a method proposed by Filmer and Pritchett  to constviz. voice and accountability, political stability and absence of violence, government effectiveness, regulatory quality, rule of law and control of corruption were used as measures of a country’s quality of governance  per capita  was used as an indicator of country-level socioeconomic status. The World Bank’s estimated Gini index and the Country Policy and Institutional Assessment (CPIA) gender inequality rating were used as measures of state-level income and gender equality, respectively. The CPIA gender equality indicator (1 = low to 6 = high) measures the degree to which a country has installed institutions and programs to promote gender equality in access to health, the economy, education and protection under law . The Wortors see ).We collected information on demographic, socioeconomic, behavioural and ecological determinants of HIV/AIDS, based on the relevant literature  concentration curve, quantifies the degree of socioeconomic inequality in a health-related outcome variable of interest. The concentration curve is obtained by plotting the cumulative share of the population, ranked in ascending order of SES , against the cumulative share of the outcome variable (i.e. HIV/AIDS). The RC index is twice the area between the line representing perfect inequality and the concentration curve. The “convenient regression” approach to compute the RC index can be formulated as follows :yi is the outcome variable of interest (i.e. HIV/AIDS) for individual i, μ is the mean of the outcome variable for the whole sample, ri = i/N, is the fractional rank of individual i in the distribution with i = 1 for the poorest and i = N for the wealthiest individual, and φ is the RC [φ provides an estimate of the standard error of the RC which is inaccurate. The Newey-West estimator [where s the RC . As the stimator  can be ustimator . The RC stimator . The valμ. In such cases the index can be normalized by multiplying the estimated index by 1/1 - μ. As the outcome variable in our study is binary, we used the normalized RC to quantify wealth-related inequalities in HIV/AIDS prevalence.Wagstaff  demonstrμ and reflects absolute, rather than relative, differences in health between socioeconomic groups. The generalized concentration curve is the standard concentration curve multiplied by the μ. It represents the cumulative share of population, ranked based on a socioeconomic factor, against the cumulative amount of health-related variable. The generalized (absolute) concentration index (GC) is defined as twice the area between the generalized concentration curve and the diagonal . The GC can be formulated as:The RC is attractive to those who are interested in relative differences in health outcomes between different SES groups. We can also generalize the concentration curve such that it becomes sensitive to variations in μ to μ, with zero indicating “no disparity” [The GC ranges from -sparity” .The RC and GC do not take into account the contribution of demographics (unavoidable factors) to overall socioeconomic inequalities in health. Thus, using the direct standardisation approach  we correWe estimated a summary measure of socioeconomic inequality in HIV/AIDS prevalence across sampled countries by ranking countries based on their GDP per capita and estimating the RC and GC. We measured wealth-related inequalities in HIV/AIDS prevalence by gender and place of residence to examine gender and urban/rural differences in the association between socioeconomic status and HIV/AIDS prevalence. A method suggested by Altman and Bland  was usedTo examine patterns of socioeconomic inequalities in HIV/AIDS prevalence, in a framework similar to , we alsoy, to a set of k explanatory factors, xk, such as:A decomposition technique was employed to quantify and compare the extent to which observed determinants of HIV/AIDS, such as education, age, gender, and marital status, contributed to the socioeconomic inequality in HIV/AIDS in each country. Suppose we start with a linear regression model linking our variable of interest, y can be decomposed into the contribution of factors which determine HIV/AIDS. They demonstrated that the RC index for y, can be formulated as:Wagstaff et al.  showed txk, RCk is the RC index for xk, and GCϵ is the generalized concentration index for the error term defined as ri is the fractional rank of the ith person in the relevant distribution [xk across wealth groups [RC index yields:where ribution . The resh groups . Using tThe decomposition of the generalized concentration index can be written as:GCk indexes the generalized concentration index for the determinant k. According to Equation 6 the extent of the contribution of each factor (xk) to the GC in HIV/AIDS prevalence depends on the βk and GCk. A factor that influences the probability of HIV/AIDS and is distributed unequally by wealth can contribute to socioeconomic inequality in HIV/AIDS prevalence.where A limitation of this decomposition approach is that it only works with linear models. Thus, although it is preferable to use a non-linear estimator in our application because our outcome is binary variable, we employed a linear probability model (LPM) in the analysis. Some approaches have been proposed to address the issue . These mTable As illustrated in Figure Table Within countries HIV/AIDS prevalence was concentrated among the socioeconomically advantaged, based on household wealth, in the majority of SSA countries. Swaziland and Senegal were the only countries with negative RC/SRC and/or GC/SGC. Results of the RC/SRC suggested that the relative concentration of HIV/AIDS prevalence among the better-off was higher in countries such as Ethiopia, Burkina Faso, Sierra Leon, Liberia, Niger, and Congo Democratic Republic, whereas the absolute concentration of HIV/AIDS among wealthier individuals was greatest in Zambia, Mozambique, Malawi, Ethiopia, Lesotho, and Tanzania. Although, the calculated RC/SRC and/or GC/SGC generally suggested similar patterns of socioeconomic inequality in HIV/AIDS within countries for men and women, the concentration of HIV/AIDS prevalence among individuals from wealthier households was greater for women than for men  showed the opposite pattern. Greater educational attainment (i.e. secondary and above) was associated with higher probability of being HIV positive in Cameroon, Ghana, Zambia, and Zimbabwe; this association was negative in countries such as Senegal, Swaziland, and Tanzania. Compared to agriculture workers, individuals with other occupations had higher prevalence of HIV/AIDS in Liberia, Malawi, Rwanda, Uganda, and Zambia, but lower prevalence in Sao Tome & Principe and Swaziland.Multiple partners and early sexual activity were positively associated with HIV/AIDS in some countries. For example, number of sexual partners was positively associated with HIV/AIDS in Ghana, Malawi, Niger, Swaziland, and Zimbabwe. Additionally, younger age of first sexual experience was associated with the probability of being HIV positive in Ghana, Malawi, Sao Tome & Principe, Senegal, Sierra Leone, Tanzania, Uganda, Zambia and Zimbabwe. Results also showed that residing in urban areas was associated with higher probability of being HIV positive in most SSA countries.RCk and GCk, for all explanatory variables included in the decomposition analysis. A positive value of the RCk and GCk indicates that variable xk is concentrated among socioeconomically advantaged individuals, and vice versa. Results of the RCk and GCk suggest that individuals who were never married, reported completion of secondary school, worked in white collar occupations, had sexual partners outside their marriage and resided in urban areas were relatively wealthier in all countries studied.Table βk × GCk/(μ - μ2) and βk × GCk/1 - μ, respectively. The “contribution” indicates how much of the association between wealth and HIV/AIDS in each country is explained by variation in a given explanatory factor among different socioeconomic groups. A positive contribution of a given factor to the RC and GC suggests that the socioeconomic distribution of the factor and the association of the relevant factor with HIV/AIDS contribute to a greater prevalence of HIV/AIDS among wealthier respondents and vice versa.Based on the regression coefficients and generalized concentration index of each explanatory variable, we measured the contribution of each factor to the overall RC and GC as Figure Apart from wealth, urban residence increased the absolute and relative concentration of HIV/AIDS among wealthier individuals in the majority of countries. According to the decomposition results of the RC and GC for the total population, the median percentage contribution of urban residence to wealth-based inequality in HIV/AIDS across the 24 countries was 54% (IQR = 81%). In general, occupation status also contributed to the concentration of HIV/AIDS among the better-off. The education factor increased the concentration of HIV/AIDS prevalence among poorer individuals in Swaziland and Lesotho. This factor, however, increased the concentration of HIV/AIDS among the rich in Cameroon. Sexual behaviours, in general, did not contribute significantly to observed SES inequalities in HIV/AIDS in SSA countries.We used data from the DHS and AIDS Indicator Surveys to measure inequalities in HIV/AIDS prevalence in 24 SSA countries. The generalized concentration index was used to quantify and decompose wealth-based inequalities in HIV/AIDS for the whole population, for men and women, as well as for urban and rural regions in each country. Our results suggested that HIV/AIDS is more prevalent among relatively wealthier countries and individuals in the SSA region. Separate analysis by gender also showed HIV/AIDS was concentrated among wealthier men and women in the majority of countries. These results confirm the findings of recent studies ,24,55,56per se, urban residence was the most important factor contributing to the relative and absolute concentration of HIV/AIDS prevalence among the better-off. Urban residents were wealthier than their rural counterparts .Contribution of each factor to the relative inequality of HIV/AIDS prevalence in SSA region (detailed results). Click here for file


IgG4-related disease is a new disease group that affects multiple organs. It is characterized by high serum IgG4 and abundant infiltration of IgG4-bearing plasma cells in the affected organ. Here, we describe an intriguing case that suggested that IgG4-related disease might present without IgG4 overexpression or infiltration, at least during a relapse. A 47-year-old man had been diagnosed with systemic lupus erythematosus 15 years. He was admitted due to a pituitary mass, systemic lymphadenopathy, and multiple nodules in the lungs and kidneys. The serum IgG4 level was normal and histopathological examination of the pituitary mass showed abundant lymphocyte and plasma cell infiltration with very few IgG4-positive cells. When we examined specimens preserved from 15 years ago, we found high serum IgG4 levels and IgG4-bearing plasma cell infiltration. This resulted in a diagnosis of IgG4-related disease, and we considered the current episode to be a relapse without IgG4 overexpression. This case indicated that, to clarify the pathogenesis of IgG4-related disease, current cases should repeat specimen evaluations over the course of IgG4-related disease to define diagnostic markers. IgG4-related disease, first described in 2001 . HoweverHere, we described a case of IgG4-related disease that had been exacerbated after 15 years of remission. At the time of the relapse, the patient exhibited several masses in various organs, including pituitary, lung, kidney, and lymph nodes. However, the serum IgG4 level was within normal limits. A histopathological examination of pituitary gland and lung masses showed infiltration of numerous plasma cells, but very few IgG4-bearing cells. This intriguing finding indicated that IgG4-related disease could present without abundant IgG4-bearing plasma cell infiltration, at least at the time of a relapse.In 2010, a 47-year-old Japanese man was admitted to Keio University Hospital due to a vision abnormality.μL), positivity for antinuclear antibody, and slightly elevated anti-DNA antibody . He was treated with 20 mg daily prednisolone (PSL) and the symptoms disappeared rapidly. Subsequently, the PSL was gradually tapered down. From 2008, he had been taking 2 mg daily PSL and remained in stable condition until he experienced abnormal vision in 2010. In 1994, he had visited our hospital with lymphadenopathy. At that time, he had high serum IgG (6098 mg/dL), and a lymph node specimen from the left inguinal area revealed nonspecific lymphoid hyperplasia, which did not define a diagnosis. In 1995, the suspected diagnosis was systemic lupus erythematosus (SLE), based on observations of polyarthritis, low white blood cell count  in the neck and inguinal area. A visual field examination revealed bilateral hemianopsia. Laboratory blood tests showed normal results for the blood count, serum electrolytes, serum creatinine, liver enzymes, and lactate dehydrogenase. The C-reactive protein level was slightly elevated to 0.86 mg/dL. The total serum IgG was 3189 mg/dL, with 1550 mg/dL IgG1 , 1100 mg/dL IgG2 , 444 mg/dL IgG3 , and 94.9 mg/dL IgG4 . Magnetic resonance imaging (MRI) of the head revealed a pituitary mass of 30 mm , which wnal area . Biopsienal area . Althougnal area . Moreoveγ-globulinemia and IgG4-bearing plasma cell expansion in affected organs with fibrotic or sclerotic changes [IgG4-related disease is a recently identified lymphoproliferative disorder characterized by hyper-IgG4- changes . The disIn MRIs, IgG4-related disease can be characterized by hypophysitis in pituitary gland lesions , lymphadAlthough the role of IgG4 in IgG4-related disease remains unknown, IgG4 has become a definitive marker; thus, we could discriminate IgG4-related disease from other inflammatory pseudotumors. In this regard, autoimmune pancreatitis is now classified into two distinct subsets, (type 1 and type 2), according to the presence or absence of infiltrating IgG4-positive plasma cells , 13. How When patients diagnosed with IgG4-related disease are admitted during a relapse, a reevaluation of the histology tends to be omitted when the clinical presentation is typical of IgG4-related disease. The present study indicated that histological evaluations of specimens should be obtained from affected organs during the course of the IgG4-related disease; these specimens may provide important information on the pathogenesis of IgG4-related disease.


Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs. The purpose of this study was to determine the mechanism of upregulation of IgG4 class switch recombination in IgG4-RD.n = 6), Sjögren syndrome (SS) (n = 6), and healthy controls (n = 8), from CD3-positive T cells and CD20-positive B cells sorted from PBMCs of patients with IgG4-RD (n = 3), SS (n = 4), and healthy controls (n = 4), as well as from labial salivary glands (LSGs) of patients with IgG4-RD (n = 11), SS (n = 13), and healthy controls (n = 3). The mRNA expression levels of IgG4-specific class switch-related molecules, such as Th2 cytokines (IL-4 and IL-13), Treg cytokines (IL-10 and TGF-β), and transcriptional factors (GATA3 and Foxp3) were examined with quantitative polymerase chain reaction (PCR). IgG4-nonspecific class switch-related molecules, such as CD40, CD154, BAFF, APRIL, IRF4, and AID, were also examined.We extracted RNA from peripheral blood mononuclear cells (PBMCs) of patients with IgG4-RD . In contrast, those of CD40 and CD154 were significantly lower in PBMCs of IgG4-RD than in SS , whereas CD40 in CD20-positive B cells and CD154 in CD3-positive T cells were comparable in the three groups.The expression levels of Treg cytokines (IL-10 and TGF-β) and AID were significantly higher in LSGs of IgG4-RD than in SS and the controls (Overexpression of IL-10, TGF-β, and AID in LSGs might play important roles in the pathogenesis of IgG4-RD, such as IgG4-specific class-switch recombination and fibrosis. IgG4 class-switch recombination seems to be mainly upregulated in affected organs. IgG4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, infiltration of IgG4-positive plasmacytes, and fibrosis of various organs, such as pancreas, bile duct, salivary and lacrimal glands, thyroid, lung, liver, kidney, prostate, aorta, retroperitoneum, and lymph nodes ,2. AlthoRecent studies reported increased proportions of type 2 helper T (Th2) cells and regulatory T (Treg) cells and increased production levels of Th2 and Treg cytokines in tissues of IgG4-RD, such as sclerosing pancreatitis and cholangitis , sialadeIt is reported that Th2 cytokines (IL-4 and IL-13) and Treg cytokine IL-10) can induce IgG4- and IgE-specific class-switch recombination ,10, and  can induConversely, CD40, CD154, B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), interferon regulatory factor 4 (IRF4), activation-induced cytidine deaminase (AID), and IL-21 contribute to nonspecific immunoglobulin class-switch recombination  -14, as wTo determine the mechanism of upregulation of IgG4 class-switch recombination in IgG4-RD, the mRNA expression levels of IgG4-specific and nonspecific class switch-related molecules were first measured in peripheral blood mononuclear cells (PBMCs), CD3-positive T cells, and CD20-positive B cells sorted from PBMCs, as well as labial salivary glands (LSGs) of IgG4-RD. Then, these levels were compared with those measured in patients with Sjögren syndrome (SS) and in healthy controls.+ plasma cells: ratio of IgG4+/IgG+ cells >40% and >10 IgG4+ plasma cells/HPF. All patients with SS satisfied the Japanese Ministry of Health criteria for the diagnosis of SS (1999) [PBMC samples were collected from six Japanese patients with IgG4-RD, as well as from six Japanese patients with SS who had been followed up at the University of Tsukuba Hospital . LSG samples were also collected from 11 Japanese patients with IgG4-RD and 13 Japanese patients with SS who had been followed up at the University of Tsukuba Hospital and Kyushu University Hospital . All patients with IgG4-RD satisfied the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) 2011 proposed by the All Japan IgG4 team . The diaS (1999) . These cn = 3), SS (n = 4), and controls (n = 4) were stained with anti-CD3 antibody conjugated with FITC  and anti-CD20 antibody conjugated with APC (BioLegend). Stained PBMCs were analyzed and sorted with flow cytometry.PBMCs derived from IgG4-RD . The mRNA expression levels of IgG4-specific class switch-related molecules, such as Th2 cytokines (IL-4 and IL-13), Treg cytokines (IL-10 and TGF-β), and transcriptional factors (GATA3 and Foxp3) were examined with quantitative PCR. IgG4-nonspecific class switch-related molecules, such as CD40, CD154, BAFF, APRIL, IRF4, and AID also were examined. The human glyceralaldehyde-3-phosphate dehydrogenase (GAPDH) was examined as an internal control.U test, whereas differences in frequencies were analyzed with the Fisher Exact probability test. A P value less than 0.05 denoted the presence of a statistically significant difference.Differences between groups were examined for statistical significance by using the Mann-Whitney P < 0.05; Fisher Exact probability test). CH50 levels were also significantly lower in IgG4-RD than in SS . Table Table n = 3), SS (n = 4), and the control (n = 4). The population of CD20-positive B cells in SS was higher than the others , whereas that of CD3-positive T cells was comparable in the three groups.Figure P < 0.05, Mann-Whitney U test). Treg cytokines (IL-10 and TGF-β) were significantly higher in LSGs of IgG4-RD than SS and control . No significant differences were noted in the PBMC expression levels of various cytokines, among the three groups. In LSGs, the expression of GATA3 was significantly lower in IgG4-RD than in SS; Foxp3 was significantly higher in IgG4-RD and SS than in the control . However, no statistically significant difference in Foxp3 expression level was seen between IgG4-RD and SS.Figure No significant differences were seen in the expression levels of various IgG4-specific class switch-related molecules in CD3-positive T cells and CD20-positive B cells sorted from PBMCs, among the three groups (data not shown).P < 0.05, each; Mann-Whitney U test). The expression of BAFF was significantly higher in LSGs of IgG4-RD than in the control . The expression of APRIL was significantly lower in PBMCs of IgG4-RD than in the control . The expression of AID was significantly higher in LSGs of IgG4-RD than in SS and the control .Figure Figure The clinical and pathologic features of patients with IgG4-RD participating in this study  accord with previous reports .We revealed the mRNA expression levels of IgG4-specific and nonspecific class switch-related molecules in both PBMCs and LSGs of IgG4-RD, and then, these levels were compared with those measured in patients with SS and controls. We focused on the molecules with different expression levels in IgG4-RD than in SS and control, with the assumption that these molecules could be IgG4-RD-specific pathogenic factors.Among IgG4-specific class switch-related molecules, the expression levels of Treg cytokines (IL-10 and TGF-β) in LSGs of IgG4-RD were significantly higher than in SS and the control, in agreement with previous reports . Wein vitro [assume that these cytokines might be produced by Treg cells in LSGs of IgG4-RD. According to this speculation, the mRNA expression level of Foxp3, which is a master transcriptional factor for Treg cells, was higher in LSGs of IgG4-RD than in the control. We also showed that the expression of GATA3 was significantly lower in LSGs of IgG4-RD than in SS. It is reported that in salivary glands of SS, Th2 cells were detected as well as Th1 cells, and could contribute to activation of B cells through production of IL-4 . Therefoin vitro . Therefoin vitro ,11. ThusAmong IgG4-nonspecific class switch-related molecules, the expression of AID was significantly higher in LSGs of IgG4-RD than in SS and the control. The roles of IgG4-nonspecific class switch-related molecules such as AID in the pathogenesis of IgG4-RD have not been reported previously. The present study showed that the expression level of AID was different in IgG4-RD than in SS and the control. AID is essential for nonspecific immunoglobulin class-switch recombination  -14; thusWe showed that in SS, the population of CD20-positive B cells in PBMCs was much more than IgG4-RD and the control . Therefore, CD40 and CD154 mRNAs in PBMCs of SS were highly expressed compared with that in IgG4-RD. These findings might be due to systemic B-cell activation in SS patients instead of local B-cell activation in IgG4-RD. Moreover, in CD3-positive T cells and CD20-positive B cells sorted from PBMCs, we found no IgG4-specific, -nonspecific, class switch-related molecules with different expression levels in IgG4-RD than in SS and controls.These observations on the expression levels of AID and Treg cytokines suggest that IgG4 class-switch recombination in IgG4-RD was upregulated mainly in the tissues of the affected organs. However, the mechanism of upregulation of Treg cytokines in IgG4-RD is unknown. Treg response itself primarily regulates the immune response and inflammation ; therefoThis study showed different expression levels of IgG4 class switch-related molecules in LSGs than in PBMCs of IgG4-RD. In LSGs of IgG4-RD, increased Treg cytokines (IL-10 and TGF-β) might play pathogenic roles in IgG4-specific class-switch recombination and fibrosis. AID was also increased in LSGs of IgG4-RD and could contribute to upregulation of IgG4-specific class-switch recombination along with IL-10 in LSGs. Thus, overexpression of IL-10, TGF-β, and AID in LSGs might play important pathogenic roles in IgG4-RD. IgG4 class-switch recombination seemed to be mainly upregulated in affected organs.AID: activation-induced cytidine deaminase; APRIL: a proliferation-inducing ligand; BAFF: B cell-activating factor belonging to the tumor necrosis factor family; IgG4-RD: IgG4-related disease; IRF4: interferon regulatory factor 4; LSG: labial salivary gland; PBMC: peripheral blood mononuclear cell; SS: Sjögren syndrome.The authors declare that they have no competing interests.All authors have read and approved the manuscript for publication. Each author took part in the design of the study, contributed to data collections, participated in writing the manuscript, and all agree to accept equal responsibility for accuracy of the contents of this article.


In wireless healthcare monitoring systems, bandwidth allocation is an efficient solution to the problem of scarce wireless bandwidth for the monitoring of patients. However, when the central unit cannot access the exact channel state information (CSI), the efficiency of bandwidth allocation decreases, and the system performance also decreases. In this paper, we propose an algorithm to reduce the negative effects of imperfect CSI on system performance. In this algorithm, the central unit can predict the current CSI by previous CSI when the current CSI is not available. We analyze the reliability of the proposed algorithm by deducing the standard error of estimated CSI with this algorithm. In addition, we analyze the efficiency of the proposed algorithm by discussing the system performance with this algorithm. The increasing number of cases on waiting room death, which refers to the death of patients while staying in a hospital's waiting room to be given a medical examination, underscores the significance of improving healthcare quality . Most ofnetwork patient capacity, which we define as the number of patients that one WLAN deployment can support, is a critical design criterion and performance metric for wireless healthcare monitoring systems. From a practical standpoint, if the hospital's patient capacity exceeds the network patient capacity, then another WLAN will need to be deployed in parallel within the hospital. Beyond the cost of deploying several networks in parallel, their co-existence might also reduce their individual performance. As an example, it is advisable to separate different access points by at least 100 meters , in ordThis paper contributes to a channel prediction-based algorithm for bandwidth allocation within an in-hospital monitoring system, in consideration of both the effect of using imperfect previous CSI to predict current CSI and the channel models applicable for hospital environments. To show the reliability of our proposed scheme, we compare the standard error of our proposed algorithm and that of the algorithm without channel prediction, which is viewed as a benchmark ,” “low-degree (L),” and “normal (N),” which represent the emergency degree of patient status . BuildinNu be the number of patients, NT be the total number of time slots during monitoring, Sk) time slot, Mik) time slot can be denoted asLet Nu. In th time slot plus the bandwidth of special subcarriers in the kth time slot. The fourth constraint ensures that the total bandwidth utilized in the WLAN should be less than the given bandwidth of a WLAN. The fifth and the sixth constraints ensure that the data in state “H” and “L” should satisfy delay requirements.As shown in , the objNu. In , the firkth  time slot can be denoted asEquation  is a nonSk)(Bik) = ∫1∞ext−tl−dt is named the l-order exponential integral function of x; f = r/((1 + σe2)(1 + σe2(1 + r))). The first type of imperfect CSI is caused by the error of channel estimation; the errors are usually modeled as complex circular Gaussian random variables, and the accuracy of this model is shown in . Based oessed as  26]. In. Inη¯iEl+2−j(x) decreases with x and 1/f increases with σe2 for any j, l, p; according to the following, σe2. Therefore, ηik)M, and the probability of successful CSI feedback is 1 − (pe)M. Therefore, from the perspective of probability, the  Type III imperfect CSI is caused by the lossy data compression; the estimated bandwidth efficiency in the feedback is not the exact bandwidth efficiency but represented by a smaller number of information bits. Mathematically, the ηik), when x falls into the mth part.η0 is a predefined bandwidth efficiency as the channel estimation failed. The probability of unsuccessful channel estimation is (pe)M, and the probability of successful channel estimation is 1 − (pe)M. Therefore, from the perspective of probability, the Building on  and 5),,5), the essed as   of αt−τ and αt can be expressed as [Denote essed as :Im−1(·) is the (m − 1)th order modified Bessel function; Γ(·) is a Gamma function; σ and m are the Nakagami fading parameters shown in , μ is the mean direction of the angle of arrival (AOA), and κ is the beamwidth parameter.L channel states; namely, sj(j = 1 … L) [sj is related to the threshold of Signal to Noise Ratio (SNR) rjt and the corresponding threshold of bandwidth efficiency ηjt. As the event of SNR ∈ [rj−1t, rjt) occurs, the corresponding channel state is sj. Let xi and xi+1 denote the SNR at the ith and (i + 1)th time slot, and let ηi and ηi+1 denote the corresponding bandwidth efficiency at the ith and i + 1th time slot, respectively. Then, the given probability pjk can be expressed as [The channel states can be represented by = 1 … L) ; sj is essed as L channel states in total, the one-step transition matrix can be expressed asSubmitting  into 1212, we caPM. In reality, the one-step transition matrix in . Additionally, the algorithm also considers the case that not all the CSI of previous time slots is gathered by the central unit; in this case, the latest CSI is employed to estimate the CSI of the current time slot in step (3) and step (4). One extreme case is that none of CSI in previous N time slots is gathered by the central unit, and, in this case, the central unit can only estimate the CSI as a predefined η0.In ηi(out)k)( is the estimated CSI by pe)M, and the probability of successful channel estimation is 1 − (pe)M. Therefore, from the perspective of probability,  In our proposed algorithm, the overall essed as . In 14)η¯i(k) caessed as : ηi(out)k) even when the previous CSI is assumed perfect. Additionally, the CSI at previous time slots gathered by the central unit may be imperfect due to the type I and type III imperfect CSI, and the imperfect CSI would also lead to an error at the prediction of CSI even as pjl = 1. In reality, the imperfect previous CSI and the limitation of MAP scheme would lead to the errors of channel prediction in joint. In the following, we analyze the joint effects on channel prediction. In this channel-prediction-based algorithm, we employ the maximum a posteriori (MAP) prediction; that is, ηk−n)th time slot, is perfect. When we employ the perfect previous CSI to predict the current CSI, the errors of prediction are caused by the limitation of MAP scheme. Let ηk−n)( = l and ηi(out)k)k) between ηi(out)k)( and ηik)k − ηik, asIn addition, we calculate k − n)th time slot, is imperfect. Then, the errors of prediction are caused by both the limitation of MAP and imperfect CSI at previous time slots. Let ηk−n)th time slot, ηi(out)k)k)( and ηik)η¯(k-n), k when the CSI at time slot k − n is perfect. In  and The prior probability shown in  and 13)p with the prediction-based algorithm can be expressed asThen, by dividing the exact bandwidth efficiency shown in .η0. The RSE of the algorithm without channel prediction can be expressed asSimilarly, we can also calculate the RSE of the algorithm that estimates the bandwidth efficiency as a predefined value η0 is as , where B(·) represents a binomial distribution and p represents the probability of a subcarrier being occupied for video conferences. The parameter of the Nakagami distribution m is randomly selected among various parameters shown in  The parameters in the simulation are as follows: η0. We choose the minimum RSE among various η0; that is, MRSE0 = minη0 RSE0. In view of η0. We cSecondly, we discuss the data loss and data unavailability caused by the errors of CSI estimation when the CSI at current time slot is unavailable. The data loss and data unavailability with the proposed algorithm and with the algorithm without channel prediction are shown in Figures Thirdly, we discuss network patient capacity of the healthcare monitoring system. The network patient capacity refers to the maximal number of patients supported by the system, subject to limited wireless bandwidth, the requirements of data loss, and the requirements of data uncertainty. Given the fixed amount of wireless bandwidth, the network patient capacity depends on the requirements of data loss and data uncertainty. For various requirements of data loss and data uncertainty, the network patient capacity with the proposed algorithm and with the algorithm without channel prediction is shown in  In this paper, we propose an algorithm that predicts CSI to reduce the negative effects of imperfect CSI caused by the failure of CSI feedback. In this algorithm, when the central unit for bandwidth allocation cannot access the current CSI, it would predict the current CSI by the CSI at previous time slots. To show the reliability of the proposed algorithm, we deduce the RSE between the estimated CSI and the exact CSI; then, the RSE with the proposed algorithm and that with an algorithm without channel prediction are compared. The results show that the proposed algorithm can attain a lower RSE than the algorithm without channel prediction. Then, to show the efficiency of the proposed algorithm on system performance, we compare the system performance with the proposed algorithm and that with the algorithm without channel prediction. The results show that the proposed algorithm can attain lower probability of data loss, lower probability of data unavailability, and larger network patient capacity. Regarding the resource allocation problem, we may consider using alternative algorithms to accelerate the solution to this optimization problem. Also we may consider using some alternative methods, such as the Kalman filter or stochastic robust control, to predict the channel state information. However, these issues are beyond the scope of this paper.


Our hospital is a reference centre located in one of the South-South states, which has a HIV sero prevalence of 8%   and one non AIDS defining malignancy (squamous cell carcinoma of the conjunctiva), also commonly diagnosed in these patients. Records of the patients which are histologically confirmed and diagnosed between 1A total of 4123 histologically confirmed biopsies were received, 852 (21%) were cancers, 24 (2.8%) were Kaposi sarcoma (KS), 8 (33%) KS occurred in females, range 21-60 years (y), 16 (67%) in males, range 19-60 y and 17 (71%) of KS were AIDS associated, 6 (35%) females and 11 (65%) males. Thirty five 35 (4.1%) of cancers were Non Hodgkin lymphomas including Burkitt’s lymphomas, 8 (23%) in females, range 6-60 y and males 27 (77%), range 6-71 y. Two 2 (5.7%) were AIDS associated 2 (100%) were males on long standing antiretroviral treatment. Cervical cancers accounted for 84 (9.9%) all cancers and 14 (17%) occurred in HIV positive patients age range. Conjunctival squamous cell carcinomas were 13 (1.5%) of all cancers, 6 (46%) females 7 (54%) males. Two 2 (15%) occurred in HIV positive patients.AIDS associated malignancies appear to be very common in this environment and perhaps non AIDS associated malignancies may be on the increase. Under-reporting and lack of capacity may account for the fewer numbers reported in this environment.