Lower angiotensin-converting enzyme (ACE) activity could increase the risk of Alzheimer’s disease (AD) as ACE functions to degrade amyloid-β (Aβ). Therefore, we investigated whether ACE protein and activity levels in cerebrospinal fluid (CSF) and serum were associated with CSF Aβ, total tau (tau) and tau phosphorylated at threonine 181 (ptau).1–42, tau and ptau (pg/ml) in CSF.We included 118 subjects from our memory clinic-based Amsterdam Dementia Cohort (mean age 66 ± 8 years) with subjective memory complaints (n = 40) or AD (n = 78), who did not use antihypertensive drugs. We measured ACE protein levels (ng/ml) and activity (RFU) in CSF and serum, and amyloid βCross-sectional regression analyses showed that ACE protein level and activity in CSF and serum were lower in patients with AD compared to controls. Lower CSF ACE protein level, and to a lesser extent serum ACE protein level and CSF ACE activity, were associated with lower CSF Aβ, indicating more brain Aβ pathology; adjusted regression coefficients (B) (95% CI) per SD increase were 0.09 , 0.06  and 0.05 , respectively. Further, lower CSF ACE protein level was associated with lower CSF tau and ptau levels; adjusted B’s (95% CI) per SD increase were 0.15  and 0.17 , respectively.These results strengthen the hypothesis that ACE degrades Aβ. This could suggest that lowering ACE levels by for example ACE-inhibitors might have adverse consequences for patients with, or at risk for AD. Alzheimer’s disease (AD) is characterized by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (tau pathology), which are reflected by lower Aβ, and higher total tau (tau) and tau phosphorylated at threonine 181 (ptau) in cerebrospinal fluid (CSF) [in vitro studies showed that ACE functions to degrade Aβ, and administration of ACE inhibitors promoted the accumulation of Aβ [in vivo studies on various mouse models of AD showed indirect evidence that ACE can degrade Aβ  in the etiology of AD has received increasing attention. Inheritance of the I-allele – associated with lower plasma angiotensin-converting enzyme (ACE) levels  – was reon of Aβ -10, whiliewed in ). Togethiewed in .ACE gene, which have been associated with lower ACE levels, and CSF Aβ were inconclusive [Few studies have examined the association between ACE and AD biomarkers in CSF ,14. Resunclusive ,14. Furtnclusive .The current literature almost entirely comes from laboratory-based and genetic association studies. However, the laboratory-based studies are not comparable with the human disease state and the findings from genetic-association studies may be explained by linkage disequilibrium with the true risk factor . ExaminiThe aim of the current study was to investigate the association of serum and CSF ACE protein levels and activity with CSF AD biomarkers – Aβ, tau and ptau – in a memory clinic cohort. It has increasingly been recognized that nearly all organs of the body have their own local paracrine-like RAS, with organ-specific functions . The braAPOE) genotype. When the results of all examinations were normal, patients were considered to have subjective complaints . Diabetes mellitus and hypercholesterolemia were defined based on self-reported medical history and medication use. Blood pressure was measured manually in a standardized manner using a sphygmomanometer with the patient in a sitting position after 5 minutes of rest. The level of education was classified using the seven-point rating scale of Verhage ranging from 1  to 7 .Patients were included from the memory clinic-based Amsterdam Dementia Cohort of the Alzheimer Center of the VU University Medical Center (VUMC). They underwent standard dementia screening including physical and neurological examination, as well as laboratory tests, electroencephalography, brain magnetic resonance imaging and comprehensive neuropsychological testing. The diagnosis of probable AD was made according to the National Institute of Neurological Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria  by conseFor the current study, patients using antihypertensive drugs were excluded, because some of these drugs strongly influence ACE levels . Of the g for 10 minutes at 4°C, then aliquoted into Sarstedt polypropylene cryovials and immediately stored at -80°C until further analyses. CSF was obtained by lumbar puncture between the L3/L4 or the L4/L5 intervertebral space, using a 25-gauge needle, and collected in 10 ml polypropylene tubes. Within two hours, 2 ml of CSF samples were centrifuged at 1,800 × g for 10 minutes at 4°C and stored at -20°C for analysis of CSF biomarkers within 2 months (see below). The remainder of the CSF was aliquoted in polypropylene tubes of 0.5 or 1 ml, and stored at -80°C until further analysis [A blood sample was taken, and after half an hour of clotting the samples were spun at 1,800 × APOE genotype was determined using the Light Cycler APOE mutation detection method .DNA was isolated from 10 ml ethylenediamine tetraacetic acid blood and the 1–42, tau, and ptau were measured by commercially available ELISAs (Innotest -β-amyloid(1-42), Innotest hTAU-Ag 168 and Innotest Phosphotau(181P); Innogenetics, Ghent, 169 Belgium). The performance of the assays was monitored with internal quality controls consisting of pools of surplus CSF specimens. In the study period, multiple internal quality controls with various concentrations have been used. The interassay coefficient of variation (CV) (mean ± standard deviation) was 11.3 ± 4.9% for Aβ, 9.3 ± 1.5% for tau, and 9.4 ± 2.5% for ptau [CSF Aβfor ptau .A commercially available sandwich enzyme-linked immunosorbent assay  was used according to the manufacturer’s guidelines to measure the ACE concentration in CSF and serum, as described previously . AbsorbaMonoclonal anti-human ACE antibody (MAB929), recombinant human ACE (929-ZN) and the internally quenched fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)-OH; ES005) were purchased from R&D Systems and were used to optimize an immunocapture-based fluorogenic assay for measurement of ACE activity in CSF and serum  to address missing values . Fourth, linear regression analysis was used to investigate the associations of ACE measures (continuous) with log-transformed CSF biomarker levels of Aβ, tau and ptau (continuous), unadjusted (Model 1) and adjusted for age, sex and study groups (Model 2). Since inheritance of the AD risk-associated APOE-ϵ4 allele and vascular risk factors including blood pressure measures could influence the association between ACE measures and CSF biomarkers, we additionally adjusted for APOE-ϵ4 (carrier vs. noncarrier) and vascular risk factors  (Model 3). Finally, analysis of covariance was used to estimate the adjusted mean log-transformed CSF Aβ, tau and ptau levels across tertiles of ACE measures within the separate study groups. For graphical purposes, the log-transformed values were back transformed.First, patient characteristics were calculated for separate study groups (control group and AD group) and differences were evaluated by analysis of variance for continuous variables, or by Fisher’s exact test for categorical variables. Second, Pearson’s correlation coefficients between ACE protein and activity levels for each of CSF and serum in turn were examined. Pearson’s correlation coefficients between Aβ and tau or ptau were also analyzed. Third, we examined the linear regression between APOE-ϵ4 carriers than patients in the control group. They also had less hyperlipidemia and higher blood pressure levels. CSF Aβ levels were lower in AD patients, and CSF tau and ptau levels were higher in AD patients. Further, all ACE measures were lower in patients with AD compared with patients in the control group (Table P = 0.005), between serum ACE protein level and serum ACE activity was 0.28 (P = 0.002), between CSF and serum ACE protein levels was 0.54 (P < 0.001), and between CSF and serum ACE activity levels was 0.07 (P = 0.494). The correlation between tau and Aβ was -0.43 (P < 0.001) and between ptau and Aβ was -0.41 (P = 0.0004). Further, APOE-ϵ4 carriers had significantly lower Aβ (Β = -0.32), and significantly higher tau (Β = 0.50) and ptau levels (Β = 0.31); P < 0.001 for all.In the total population of 118 subjects, the mean age was 66  years and 52% were female. Table In the total population, higher CSF ACE protein level was independently associated with higher CSF Aβ, tau and ptau levels Table . When stHigher CSF ACE activity was also marginally associated with higher CSF Aβ levels, but not with CSF tau or ptau levels Table . When stIn the total population, higher serum ACE protein level was associated with higher CSF Aβ (borderline significance), but not with CSF tau or ptau levels Table . When stSerum ACE activity was not associated with higher CSF Aβ, tau or ptau levels Table .APOE genotype, and vascular risk factors. Further, CSF and serum ACE protein and activity levels were lower in AD patients compared with controls.The main findings of this study are that lower CSF ACE protein levels, and to a lesser extent serum ACE protein and CSF ACE activity levels, were associated with lower CSF Aβ levels, indicating increased Aβ accumulation in the brain. Surprisingly, lower CSF ACE protein levels were associated with lower CSF tau and ptau levels, indicating less brain tau pathology. These associations were found in both control and AD patients and were independent of age, sex, ACE gene and Aβ. Haplotypes of the ACE gene that were associated with lower ACE levels were related to lower CSF Aβ [I-allele (indicating lower ACE levels) was associated with slightly more Aβ load in the brain at autopsy [ACE genotype in relation to brain atrophy (which is associated with increased brain Aβ plaques) [I/I genotype carriers had smaller hippocampal and amygdalar volumes [To our knowledge, this is the first study that linked direct measures of ACE activity to the CSF AD biomarkers Aβ, tau, and ptau. Our results on the association of CSF ACE protein level and CSF Aβ are in line with studies that showed an association between the r CSF Aβ ,14, and  autopsy . The Rot volumes . Further volumes . TogetheACE genotype to tau load in the brain found no association [Another novel finding was our observation that lower CSF ACE protein level was associated with lower CSF tau and ptau. A previous study relating the ociation . The mecociation . Our finociation .ACE genotype although the genetic contribution to ACE levels has only been shown to be relatively modest [ACE genotype in our population so we could not explore this. Another reason might be differential levels of post-translational modification in the various physiological compartments from which the samples were derived. ACE activity, and its proposed conversion of Aβ, has been shown previously to be modulated by post-translational modification [CSF ACE levels were more strongly associated with AD biomarkers than serum ACE levels. This indicates that CSF ACE, as might be expected, could reflect the activity of the brain RAS, thereby showing stronger associations with brain pathology. Further, ACE protein levels were more strongly associated with AD biomarkers than ACE activity levels. Whereas protein levels indicate the concentration of ACE in body fluid, activity levels particularly indicate the ANGI to ANGII conversion capacity of the enzyme . One migy modest , and unffication . In bothfication . Yet herfication . SimilarAmong the strengths of the current study is the use of CSF ACE measures and CSF biomarkers, which gives the opportunity to examine during life the association between ACE and AD pathology, without potential confounding from postmortem delays. Second, we had paired CSF and serum samples for all of the patients. Finally, all patients were assessed in a standardized way and diagnosed according to commonly used criteria .One of the limitations of our study is the relatively small study population. Yet the interesting results recommend replication in a larger study sample. Another limitation is the cross-sectional design that prohibits conclusions on cause or effect. Similarly, we cannot ascertain whether lower CSF ACE protein and activity levels cause brain Aβ pathology. However, because we found that the associations were also present in the control group, it is reasonable to assume that the downregulation of CSF ACE is not pathology driven, and that lower ACE levels might precede the pathology or alternatively are a general phenomenon associated with neurodegeneration. This hypothesis remains to be further investigated in a larger, longitudinal study.This study has important clinical implications. If ACE in the brain does prevent Aβ accumulation in living humans, our data support the suggestions that taking ACE inhibitors as antihypertensive drugs, particularly those that can cross the blood–brain barrier, might compromise Aβ degradation . FortunaWe found in a memory clinic cohort that lower CSF ACE levels were associated with lower CSF Aβ levels, which suggests more accumulation of Aβ in the brain. This observation lends support to the hypothesis that ACE can degrade Aβ, thereby contributing to limiting its accumulation and possibly to the development or rate of progression of AD.APOE: apolipoprotein E; CSF: cerebrospinal fluid; CV: coefficient of variation; ptau: tau phosphorylated at threonine 181; RAS: renin–angiotensin system; tau: total tau; VUMC: VU University Medical Center.Aβ: amyloid-beta; ACE: angiotensin-converting enzyme; AD: Alzheimer’s disease; ANG: angiotensin; PGK has undertaken some advisory work for Novartis, which was paid to the University of Bristol. The remaining authors declare that they have no competing interests.HMJ, CET, MM, MIG, WMvdF and PS made substantial contributions to the conception and design, and were involved in drafting the manuscript or revising it critically for important intellectual content. ELA, CET, PGK, REJ, HMJ and MM made substantial contributions to the acquisition of data, or the analysis and interpretation of data. All authors gave final approval of the version to be published.Is a description of the ACE activity assays.Click here for file


The disparity between available and needed organs is rapidly increasing, and the number of patients dying while still on the waiting list is growing exponentially. As a partial solution to this disparity, living unrelated transplantation is being performed more frequently, and some have proposed providing financial incentives to donors. The aim of this discussion is to illustrate that with an ever-increasing number of living unrelated transplantations, society and the transplant community should adopt a more active role in developing specific strategies to scrutinize the process. The current paper will also examine the viewpoint that medical ethics is not separable from the prevailing needs of society and involves a constant balancing of often opposing goods. Issues surrounding living unrelated donor transplantation illustrate ethics as a dynamically evolving field, which is often influenced by necessity and which evolves with progression of science and society. As part of this evolution, it is the collective responsibility of society and the transplant community to devise safeguards to guarantee adherence to basic principles of ethics and to avoid “situational ethics.” Following the first successful kidney transplantation in 1954, and the subsequent improvements in immunosuppressant medications, the major barriers against solid organ transplantation seemed to have been overcome. This set the stage for subsequent discoveries, innovations and improvements in surgical techniques towards the development of strategies for transplantation of other solid organs including the liver, heart, lungs and pancreas. The initial excitement has been overshadowed by the recognition of organ shortage and the need for improved allocation. The exponentially increasing number of patients on the waiting list and the relative constancy of the donor pool have translated into the death of approximately 12 patients on the waiting list each day in the United Sates [As a transplant physician who has practiced in a developing country for 10 years and in the US for nearly nine years, the author has often witnessed ethical dilemmas faced by patients, families and physicians regarding various aspects of transplantation. For many years, while living unrelated donor transplantation (LURT) was being performed in many developing nations, the medical community in the industrialized world, and particularly in the US, had been reluctant to discuss this as a feasible form of transplantation. The main reasons for this reluctance were the valid concerns about risks to the donor, as well as fears of commercialization and exploitation. Transplant physicians who presented data including LURT often encountered arrogant objection, and discussion of LURT at scientific meetings was considered a taboo. However, in recent years, with the increasing demand for organs, it has become clear that the combination of deceased and living related donations cannot provide sufficient organs for transplantation and that many patients are dying on a daily basis while awaiting transplantation. Various centers in the industrialized nations, including the US, have become increasingly lenient towards LURT, as evidenced by a six-fold increase in the percentage of LURT (including spouses) from 1988 to 2003 [Transplant centers have developed algorithms—mainly through psychosocial assessments—to safeguard rights of the parties involved, ensuring that the motive for donation is altruistic and that there is no intimidation or commercialization involved. The donors in these situations are usually spouses, close friends, colleagues and occasionally anonymous. There are several potential problems associated with this scheme. The definition of a “close friend” is rather arbitrary, relying quite subjectively on the interpreter’s judgment. The scheme assumes that the spouse, friend or colleague are (or should be) acting altruistically, often reflecting the interpreter’s own ethics, viewpoints and attitudes. While in most instances this might certainly be the case, coercion and subtle intimidation are often very difficult to determine in a 45-minute interview. Furthermore, there are concerns about “conflict of interests”, particularly when a colleague (sometimes an employee) volunteers to donate an organ to another colleague.The principal stakeholders in the living organ donation scheme include the patient (recipient), the donor, their families, society and the medical community. The premises of the present discussion are as follows:The recipient has the right to pursue improvement in quality of life, life expectancy and minimization of suffering.The donor has the right and autonomy to donate an organ in an informed manner, with minimal suffering or detriment to his/her health.The families of the donor and recipient have the right to pursue a meaningful life with minimal disruption. primum non nocere—the fundamental medical principle of “first do no harm”—thus, the medical profession has the right to refuse a treatment determined to be harmful to one of the parties involved. Potential harm is not limited to bodily harm, but also harm to the personal integrity of the recipient or the donor. The profession also has the right to be appropriately compensated for the services provided.The medical profession has the obligation to provide the donor and recipient with the required information regarding risks and benefits of the treatments and to pursue a course of action consistent with The society has the right to prevent any action that violates laws and has the responsibility to provide means for the reasonable achievement of the wishes of the parties involved, safeguarding efficiency and equity, and avoiding exploitation of the parties involved. If we assume that the individual patient is the collective responsibility of society, it would appear that the donor is, at least partially, acting in a way to fulfil the duty of society.It is clear that if an organ donation is harmful and life threatening to the donor, we should not even consider taking it from a consenting living donor, whether related or unrelated. The scientific community has determined that donation of a kidney is not life threatening, however, it is not without harm. There are the potential harms of the surgical procedure and those associated with living with a single kidney -7. Howevetc.) providing their services only altruistically? Why should the only individuals sacrificing their bodies not be appropriately acknowledged? Although current laws in most countries and guidelines by professional societies [With related donor transplantation, altruism is the expected driving force; however, regarding unrelated donors, several valid questions have been raised. Why should the unrelated donors not be at least partially rewarded for their donation? Why should they be expected to undergo the surgery and live with one less organ for the rest of their lives? Are the other parties involved (physicians, surgeons, nurses, ocieties  prohibitThe main opponents of providing financial incentives have voiced concern over “devaluing” the body to a mere commodity and the potential for commercialization . The remSome have proposed a market for organ donation or sale. The proponents of this model propose a legitimate governmental or non-profit non-governmental organization to take charge for the responsibility of compensating the donor, without any direct contact between donors and recipients , 12. ThiIn addition to direct payment, various other forms of compensation such as life and health insurance, medal of honor, reimbursement for travel expenses, compensation for time out of work, or a tax credit have been proposed . The potOpponents to any form of compensation and an organ market , 18, 19 The question of whether or not the financial compensation leads to an improvement in the life of the donor has been addressed in several studies. There is evidence that with rampant commercialization, the benefits to the donor are minimal and much of the “financial reward” is drained by brokers . In suchAlthough it is practically impossible to calculate all the risks and benefits in an economical model, it is clear that there are some potential benefits to providing financial incentives for organ donation. The same analysis that concludes that paid donors are not better off, has noted that most of the money received by donors are spent on the essentials: debts, food, and clothing . Some poThe opponents who fear the evils associated with rampant commercialization tend to understate society’s responsibility. In response to their fears and concerns, it should be noted that society has to play an active vigilant role in safeguarding the individual’s rights, rather than categorically prohibiting any forms of incentive in fear of potential exploitation. Which one is more unethical? A donor selling an organ in desperation for the better good of self and/or family or the society refusing to acknowledge and find means to alleviate the desperation and misery of the individual. Similarly, is it more unethical for the recipient to reward a potential donor with monetary incentive or for the society not to have better plans for relieving his/her suffering? Which is more unethical? Transplantation from a paid volunteer unrelated donor or one from a living-related donor or spouse who is under some degree of family pressure or emotional coercion. It seems clear that intimidation of a related donor is no more ethical than rewarding a willing unrelated donor. Finally, is it more ethical to let patients die on the list or to compensate volunteer donors? In a similar argument, Veatch has proposed that it is time to lift the ban on marketing organs and considers it a moral necessity as a “lesser moral evil” . There is little doubt that commercialization of organ donation is fraught with drawbacks, dangers and potential immoral consequences. On the other hand, it is clear that efforts to increase the rate of organ donation through education have failed and sole moral incentives have not worked. Organs are currently limited by supply, and in the hope of expanding the available organs, it seems prudent to provide incentives not only to encourage donation, but also in order to express appreciation. In the process, we should be cognizant of the fact that we might be sacrificing some goods for the sake of other potentially more meritorious goods, weighing the ethical and moral risks of one against the other. The obligation of society is to establish safeguards to protect all parties involved, as well as the humane inter-relationship between donor and recipient. In this regard, the method of acknowledging the good deeds of donors is of paramount importance and it is the author’s belief that this should not be the recipients’ responsibility, but rather the collective responsibility of society. Rather than resisting any changes, it is clear that we need to look for feasible, ethical alternatives to the current model. This is not limited to whether or not donors should be compensated. Now that LURT has become an ever increasing reality, society and the transplant community should devise safeguards to scrutinize the process. Discussions about financial incentives for organ donation have moved from being a taboo to a passionate controversy. While a few years ago, when proposed from outside the US, there would be severe objections to any form of compensated unrelated donation, now that it has been recognized as a feasible reality, authorities in the field are discussing potential means of making it work better, rather than totally condemning the thought. In conclusion, issues regarding LURT illustrate evolving ethics parallel to the needs of time. This demonstrates that bioethics is by no means a static field but rather a dynamic discipline, which is shaped by necessity and which evolves with evolution of science and society. As part of this evolution, it is the collective responsibility of society and the transplant community, in particular, to devise safeguards to guarantee adherence to basic principles of ethics, rather than to passively allow “situational ethics” to prevail. While acknowledging the inherent difficulties in establishing an optimal regulatory system that would be able to compete with the global black market, such a system seems essential to successfully prevent possible exploitations of the poor and the disadvantaged, particularly in developing countries.


Non-adherence to Antiretroviral Treatment (ART) is strongly associated with virologic rebound and drug resistance. Studies have shown that the most frequently mentioned reason for missing ART doses is the forgetfulness of patients to take their medications on time. Therefore using communication devices as reminder tools, for example alarms, pagers, text messages and telephone calls could improve adherence to ART. The aim of this study is to measure access to cellphones, willingness to receive text message medication reminders and to identify associated factors of ART patients at the University of Gondar Hospital, in North West Ethiopia.An institution based cross sectional quantitative study was conducted among 423 patients on ART during April 2014. Data were collected using structured interviewer-administered questionnaires. Data entry and analysis were done using Epi-Info version 7 and SPSS version 20 respectively. Descriptive statistics and multivariable logistic regression analysis were used to describe the characteristic of the sample and identify factors associated with the willingness to receive text message medication reminders.A total of 415 (98 % response rate) respondents participated in the interview. The majority of respondents 316 (76.1 %) owned a cellphone, and 161(50.9 %) were willing to receive text message medication reminders. Positively associated factors to the willingness were the following: Younger age group , having secondary or higher education , using internet , not disclosing HIV status to anyone other than HCP  , availability of radio in dwelling , not answering unknown calls , use of cellphone alarm as medication reminder , and forgetting to take medications .A high proportion of respondents have a cell phone and are willing to use it as medication reminders. Age, educational status and using internet were the main factors that are significantly associated with the willingness of patients to receive text message medication reminders.The online version of this article (doi:10.1186/s12911-015-0193-z) contains supplementary material, which is available to authorized users. Since the introduction of Antiretroviral Treatment (ART) in developed nations during the mid-1990s, access to ART has become more widely available. This combination of drugs has fundamentally transformed the lives of People Living with HIV/AIDS (PLWHA) and the Human Immunodeficiency Virus (HIV) infection has changed from a serious and deadly illness to a more easily manageable disease .According to the World Health Organization (WHO), more than 50 % of all medicines are prescribed, dispensed or sold inappropriately, and half of all patients fail to take medicines correctly .Non-adherence to ART and forgetting to take medications are strongly associated with virologic rebound and clinically significant resistance. A cumulative adherence of 70–89 % was strongly associated with viral rebound and clinically significant resistance, when compared with cumulative adherence of 90 % . PatientMissing healthcare appointments could be a consequence of inefficient healthcare delivery, with ample expenses for the health system, leading to delays in diagnosis and treatment. Forgetfulness is the main reason for missing healthcare appointments , 6 and APrevious studies conducted in Africa and elsewhere have demonstrated that text messaging or cellphone call medication reminders significantly improve the adherence of patients on ART –13.Cellphones are the most ubiquitous types of equipment in the world and nearly one of every two citizens of the planet possesses a cellphone . Many AfThere is a great opportunity to link the ever-growing mobile telecommunication technology with the multifaceted ART adherence support strategies. An electronic health service readiness assessment study from Ethiopia concluded that mobile-based health services are feasible for consultation, creating awareness, and diagnosis and treatment because the affordability of mobile phones by low income inhabitants and the growth of the mobile network coverage of the country is increasing .However, there are also challenges. As Tamaryn C. et al. indicated: the loss of cellphone devices due to theft and/or damage, the patterns of cellphone use and privacy issues influence the willingness of patients to receive mobile phone text or call reminders . In someAlthough ART has dramatically improved the health of patients and reduced the morbidity and mortality of HIV patients in Ethiopia, adherence to ART is still a problem and a significant contributor to drug resistance and treatment failure. A number of strategies have been tried to enhance the multifaceted issue of treatment adherence, but very little has been done using mobile telecommunication technology.Access to cellphone technology among patients on ART and the willingness of patients to receive text message medication reminders are still unknown. Before implementing cellphone text message based treatment adherence strategies, the willingness of patients to receive text message medication reminders needs to be investigated.determine the access to cellphones among patients on ART,determine the willingness of those patients to receive text message medication reminders andidentify the factors associated with the willingness to receive text message medication remindersTherefore the objectives of this study are to:An institution based cross sectional quantitative survey was conducted at the University of Gondar Hospital in April 2014. This hospital serves a population of more than five million. It is a tertiary level hospital in the Ethiopian three tier healthcare system, located 727 km North West of Addis Ababa. Nearly 10,000 patients are currently receiving ART in this hospital.n = Z(α/2)2pq/∂2) [All HIV patients whose age is > = 15 years and are taking their ART medication at the University of Gondar Hospital were the source population for this study. A systematic random sampling technique was performed to select 423 study participants. The sample size of this study was determined using the single population proportion formula 2pq/∂2) , 23 withn = the required sample sizeZ = the value of standard normal distribution corresponding to α/2, 1.96p = proportion of patients who are on ART and willing to be contacted by cellphoneq = 1-p, proportion of patients who are on ART and NOT willing to be contacted by cellphone∂ = Precision as 0.05We could not find any study conducted to determine the access to cellphones among patients on ART, however, the general population’s access to cellphones in Ethiopia is 17 % [According to our research objectives the primary outcome measures are: access to cellphone and willingness to receive text message ART medication reminders.Socio-demographics: Age, Sex, Marital status, Educational status, Employment statusBehavioral factors: HIV status disclosure, Substance abuse, Taking medication in front of others, Use of medication reminder mechanismsPsychosocial factors: Social support, Perceived satisfaction with the social support, Self-esteem, Perceived satisfaction in being valued or esteemed by others, Perceived doubts about HIV/ART and healthcare provider, Perceived treatment benefit, Perceived self confidence in taking the medication and the doses as prescribed by the clinicianEnvironmental factors: Transportation access, Travel time, Transportation facility, Electricity in the house, Access to radio, Access to televisionPatient provider relationship: Level of relationship with clinician, Perceived satisfaction of patient provider relationship, Frequency of health visit, Perceived satisfaction with progress after starting ART, Missing appointment, forgetting to take medication.Pattern of cellphone use: Use of cellphone alarm reminders, Preferred way of communication in cellphone, Carry cellphone always, Lock cellphone with password, Do not answer unknown numbers, Perceived privacy in using cellphone, Switch off cellphone during day, Put cellphone in a place where others could use and access, Share cellphone with others, Ability to send/receive/read text messaging, Perceived text message confidentiality, Use of internet with cellphoneBy reviewing the existing literatures on mobile health , 24–29, Data were collected using structured interviewer-administered questionnaires  in the bivariate analysis were subjected in a multivariable logistic regression analysis to evaluate the consistency of the effect after adjusting other variables. The strength of associations was described using Odds Ratio (OR) and a 95 % confidence interval (CI). In the bivariate and multivariable regression analysis, the total number of patients who owned cellphone (316) were included.Data were entered using Epi-Info version 7 and transferred to SPSS version 20. Descriptive statistics were performed to describe the study population. Binary logistic regression was computed to analyze the effect of each study variable on the outcome variable. Variables significantly associated with the outcome variable  of them gave their consent and responded to the questions. The socio-demographic characteristics can be found in Table As can be seen in Table About three quarters  of the respondents reported having a personal cellphone. We have calculated the patterns of cellphone use percentages only from total number of patients who owned a cellphone (316). From those patients who owned a cellphone, more than 70 % (225) reported that they already use the alarm function of their cellphone as a medication reminder. For 273 (86.4 %) of patients who owned a cellphone, the preferred way of routine cellphone communication is voice call. The majority, 228 (72.2 %) of patients described that they are able to read and send text messages using their cellphone. But a large number of respondents, 163 (51.6 %) reported that their cellphone was lost, damaged or stolen in the past. Only a third of them 93 (29.4 %) lock their cellphone with a password and 169 (53.5 %) of the patients store their cellphone in a place where others can see and access it easily. More than 41 % of respondents described that they share their cellphone with others. A small number of patients, 62 (19.6 %) described that they access the internet by using their cellphone. From those patients who are using internet on their cellphone, 54 (87.1 %) reported that they are Facebook or other social network site users.As summarized in Table From the total respondents who are using cell phones, (85.1 %) indicated that they are willing to pay for text message ART medication reminders based on the current tariff. Only 13 (4.1 %) patients reported that they are not willing to receive any kind of cellular phone contact from the ART service provider. Twelve of them (92 %) believed that text messages written about their medication would ruin their privacy.p < 0.05) with the willingness of respondents to receive text message ART medication reminders. All of these variables were included in the final multivariable logistic regression model to control the effect of confounding.The bivariate analysis indicated that age, educational status, employment status, income, availability of television in dwelling, radio in dwelling, travel time, frequency of visiting ART clinic, ever miss healthcare appointment, missing medications, HIV status disclosure, substance abuse, use cellphone as medication reminder, lock cellphone with password, perceived confidentiality of text message, use internet, not answering phone calls, not answering unknown calls were significantly associated (p = 0.004), educational status , using internet (p = 0.002), not disclosing HIV status (p = 0.019), availability of radio in dwelling (p = 0.01), not answering unknown calls (p = 0.005) , use the alarm function of cellphone as medication reminder (p = 0.029), and forget to take medications (p = 0.017).The multivariable logistic regression analysis pointed out the following factors to be significantly associated with the willingness to receive text message ART medication reminders: younger age group . The study also shows that half of the patients 51 % (95 % CI: 45.3–56.3 %) are willing to receive text message medication reminders from their ART clinic.Age, educational status, use of internet and not disclosing HIV status to anyone other than their healthcare provider are among the notable factors associated with the willingness of patients to receive text message medication reminders.Accessibility of patients to cellphone in this study (76.2 %) is slightly lower than similar studies from South Africa 81 % , China 8The access rate in this study is much higher than the Ethiopian general population access to cellphones that was reported to be only 17 % . Those dAlmost all patients in this study (95.9 %) are willing to be contacted by the ART clinic via cellphone using either voice call and/or text. Nearly three quarter (70 %) prefer to be contacted verbally and only half of the respondents (50.9 %) are willing to receive text message ART medication reminders. Other studies show different numbers about the willingness to receive text message ART medication reminders. For example it is higher in South Africa 96 % , Peru 81It could also be assumed that the patient provider relationship affects the willingness of patients to receive text message medication reminders as a study from Peru  suggesteFrom those who are willing to receive text message ART medication reminders, 85.1 % are willing to pay for this service on the current tariff. This high proportion might be due to a better economic status of those who are able to use text messages. If patients on ART can afford to pay for text message medication reminders a fee based system can be designed to support their adherence. Additionally cost sharing mechanisms for text message medication reminders could also help to achieve better adherence levels. However, the fee acceptability and the cost effectiveness of cellphone text message based interventions need to be further investigated.This study identified numerous factors to be significantly associated with the willingness to receive text message reminders. Patients who are from the younger age group and/or have secondary or higher education are more likely to be willing. This result is consistent with a study from China . HoweverThis study shows that travel time, missing health care appointments and ethnicity are not significantly associated with willingness; again contradictory to the finding of the study from North Carolina . The difMoreover, patients who access the internet by using their cellphone were almost four times more likely to be willing to receive text message medication reminders. It was shown that patients who use internet on their cellphone usually have improved health information access  and awarAn interesting finding is that cellphone usage privacy variables like locking cellphone with password, perceived text message confidentiality, sharing cellphone with others, storing cellphone in a place where others could see and access were not significantly associated with the willingness to receive text message medication reminders. This is due to the high level of HIV status disclosure to family members and the high extent of sharing mobile phones with families. Those who disclose their HIV status could also share their cellphone and patients trust that their family members keep confidentiality of their HIV related information. This could lead patients to be willing to receive text message medication reminders. Thus, we assume that cellphone usage privacy would not be a major concern for implementing text based medication reminders. However, it has to be further explored whether this holds true or whether patients are just not aware of privacy concerns.The main limitation of this study is the patient population. Because the study is an institution based cross sectional survey, only respondents who came to the ART clinic for meeting their schedule were interviewed. Moreover, the study was done in a hospital based in a major town which could have inflated the accessibility of patients to cellphones and their willingness to receive text message medication reminders. A different result could have come from a large scale population based study. The survey was also interviewer administered and even if we used neutral interviewers, there might be an interviewer and social desirability bias that could have made more participants to respond as being willing. These limitations have to be taken into account when generalizing the results.A large proportion of patients on ART at the University of Gondar Hospital have a cellphone. The findings of this study show that the willingness to use cellphone as ART medication reminders is high. Age, educational status, use of internet and HIV status disclosure are the most notable factors that are associated with the willingness of patients to receive text message medication reminders.


Corynebacterium striatum. There is little evidence about patterns of respiratory infection, transmission and adaptive ability of this pathogen. Seventy-two C. striatum isolates from 51 advanced respiratory patients, mainly chronic obstructive pulmonary disease, were studied during 38 months. Patients were 74.8 ± 8.6 years old and 81.9% were men, who had required an average of 2.2 hospitalizations and 63.5 days in the hospital in the previous year. Of 49 isolates from 42 patients we were able to identify 12 clones by multilocus sequence analysis (MLSA), nine phenotypic variants and 22 antibiotic susceptibility patterns, and we determined their clinical and epidemiological determinants. MLSA allows identification of the existence of nosocomial outbreaks by transmission of the same or different clones, the persistence of the same clone in the environment or in patient airways for months. The study showed the high variability and adaptive capacity of the isolates, the antibiotic multidrug-resistance in all of them, and their contribution to a high morbidity and mortality (41%) during the study period.The increasing prevalence of advanced chronic respiratory disease, with frequent exposure to broad-spectrum antibiotics for repeated and prolonged hospitalizations, favours the emergence of nosocomial respiratory infection by Gram-positive bacteria, such as outbreaks of  Corynebacterium species are found colonizing skin, other tissues, and in the environment et al. Corynebacterium diphtheriae, the pathogenicity among Corynebacterium spp. has been reported associated with Corynebacterium amycolatumCorynebacterium jeikeium, Corynebacterium macginleyi, Corynebacterium urealyticum, Corynebacterium pseudodiphtheriticum and, less frequently with Corynebacterium xerosisCorynebacterium striatum has been reported colonizing prostheses, catheter tips, and ventilator and feeding tubes, and it has been also identified as causative in cases of endocarditis, sepsis and bacteraemia In the last decades, in addition to C. striatumC. striatum have been reported C. striatum infections have been found in respiratory samples, the vast majority of strains being multidrug-resistant.Until 1993 there were only three individual case reports of confirmed respiratory infections by et al. C. striatum were analysed using different approaches, ribotyping, phenotype, matrix-assisted laser desorption/ionization time-of-flight mass spectroscopy, and multilocus sequence analysis (MLSA). They demonstrated that isolates of C. striatum were best identified using gene-based molecular methods.The study of nosocomial infections and outbreaks is fundamental to have reliable methods for the identification and typing of the bacteria responsible. It allows further efforts to prevent and control these events, and to reduce individual and population burden. There are several available fast and affordable methods that allow a good identification of species and useful for the identification of an outbreak, but understanding the mechanisms and transmission circumstances during an outbreak requires a molecular study of the isolates. Several studies have tried to accomplish this objective C. striatum, managed in a respiratory ward. We determined the genetic identity of C. striatum strains isolated in cultures of biological samples obtained during infectious respiratory exacerbations. We aimed to study the clinical and environmental determinants, the transmission mechanisms between patients, their adaptive ability and variability in phenotype and susceptibility to antibiotics, its ability to persist in the environment and respiratory airways, and its impact on morbidity and mortality in this group of patients.The main aim of this prospective study is to explore the epidemiological and pathological circumstances of a group of patients susceptible to be infected by The Hospital Joan March, in Bunyola, Mallorca, Spain, is a secondary healthcare centre that hosts a convalescence and rehabilitation department, with a 26-bed ward. It aims to deliver care to patients with severe, chronic respiratory disease referred from tertiary-care hospitals within its catchment area.C. striatum isolates from cultures of respiratory samples, and one from a dermal ulcer, from 51 patients with advanced respiratory disease seen in the hospital, were obtained during 38 months (from May 2006 to June 2009), and we explored their clinical and epidemiological determinants. Forty-nine of these C. striatum isolates, from 42 patients, could be recovered with the aim of analysing their antibiotic susceptibility, phenotype and genotype.Seventy-one et al. C. striatum isolation from respiratory samples was based on their correct identification, their abundance, their isolation as a single microorganism or their predominance when found in association, and the repetition of positivity All respiratory samples were obtained during respiratory infectious exacerbations that fulfilled GOLD criteria gyrA and rpoB genes were used, as they were the most useful for discriminating between strains due to their variability.All information about phenotype, genotype and antibiotic susceptibility was consistent with our previous work on 49 recovered isolates of the total 72 C. striatum is an environmental bacterium, temperature and humidity were recorded on the date of obtaining each isolate. Information was obtained from the official weather station in the enclosed area of the hospital. For this environmental analysis, the 43 isolates of C. striatum from a previous outbreak that occurred in our hospital between January 2004 and June 2005 were also considered Given that Statistical analyses were performed using the SPSS v.15.0 software. All data were quality controlled and comprehensive tabulations with mean, standard deviation, and ranges for quantitative variables, and counts and percentage of all quantitative variables, were presented.C. striatum isolates were obtained during 38 months, mainly from cultures of respiratory samples of 51 patients, 81.9% men, with a mean age of 74.8 years. They suffered an average of 2.2 hospitalizations and 63.5 hospital days in the year before obtaining a positive culture. Overall, 84.7% had a diagnosis of chronic obstructive pulmonary disease, with a mean ± SD forced expiratory volume (FEV1%) of 39.4 ± 16.6%. Forty-nine percent of patients died during follow up. A code was assigned to each patient, from 1 to 51, sequentially by order of entry, and in patients who showed more than one isolate, a letter was added to the patient number in alphabetical order, from ‘a’ to ‘c’  they were accompanied by Pseudomonas aeruginosa, in six (8.3%) by Stenotrophomonas maltophilia, and by other bacteria in six cases (8.3%). In 44 patients a single C. striatum isolate was obtained, in 12 patients two were obtained, in six patients three were obtained, and in two patients four isolates were obtained; there was a trend that the more repeat positive cultures, the greater the severity of bronchial obstruction.In 41 (56.9%) specimens, All isolates showed antibiotic multiresistance, defined as resistance to three or more different antibiotic families. All isolates were resistant to ciprofloxacin, and all were sensitive to vancomycin . The percentage of sensitivity to the remaining antibiotics tested is shown in Table S2 (see the Supporting information).gyrA and rpoB genes in 49 C. striatum isolates, allowed the identification of 12 different clones whose identity was simplified by attributing a capital letter to each .Amplification and sequencing of the ITS1 region and the Based on the phenotypic data, nine phenotypic variants were determined, and are labelled with a lowercase letter from ‘a’ to ‘k’. Twenty-two isolates (44.9%) corresponded to phenotype ‘a’.The same procedure was performed for the antibiotic profile. The combination of susceptible/intermediate/resistant to the antibiotics tested (re-considering intermediate as resistant), gave 22 different combinations. A lowercase letter from ‘a’ to ‘z’ was also assigned to each combination. The most common were ‘a’, sensitive only to vancomycin, in eight 16.3%) isolates, and ‘b’, susceptible only to vancomycin and gentamicin, in six (12.2%) isolates  a persistent identical clone could be detected in sputum cultures separated in time. In samples corresponding to patient 3 (3 and 3c), a coincidental genotype was determined in samples obtained 23 months apart.Some episodes of clone A direct transmission affecting three patients during March 2006 could be detected, and also of clone B in three patients between February and March 2007 Figs.. We alsoC. striatum were isolated from sputum specimens from 21 patients, but the accumulation of isolates corresponded to five different clones.From December 2006 to July 2007, 30 strains of C. striatum isolates were detected without accompanying microbiota. When comparing deceased and surviving participants, mean FEV1% was 33% and 40%, mean of hospitalizations in the year before a positive culture was 2.4 and 2.1, and the average hospital stay was 80.2 days and 49.6 days, respectively .During our study, 25 of the 51 patients (49%) died. In 15 of the 25 deaths (60%), C. striatum recorded in our hospital from 2004 to 2009 by month according to calendar year. The figure shows a trend to cluster cases in winter and spring, consistent with low temperatures and high humidity values.Fig.Staphylococcus aureus, but other genera have also acquired worrisome momentum, such as Corynebacterium spp. In the pre-antibiotic era, Gram-positive bacteria were responsible for most severe infections; however, since the 1940s and with the introduction of penicillin, there has been an increase in Gram-negative bacteria infections until the sixth and seventh decades of the last century. Since then, a number of factors including the widespread use of broad-spectrum antibiotics for an increasing number of patients with severe chronic diseases, and the implementation of more aggressive and invasive diagnostic and therapeutic procedures have produced a resurgence of Gram-positive bacteria with multiresistance to antibiotics, generating both high morbidity and mortality. At the forefront is methicillin-resistant C. striatum, a number of particularities have been repeatedly reported in a number of publications such as their high transmissibility causing nosocomial outbreaks, highlighting that most of the isolates belong to respiratory specimens, frequently associated with P. aeruginosa and S. maltophiliaWith C. striatum have been studied with the methodology available in each circumstance Outbreaks of nosocomial infection and the epidemiological determinants of Direct transmission between patients, or through shared space, could be postulated in some cases, including the two small outbreaks of nosocomial infections caused by clone A and clone C, corresponding to six and five isolates, respectively, and each affecting four patients. However, most matches occurred in samples from patients hospitalized in rooms located at varied distances within the same ward, or even on different wards of the same hospital, suggesting that the fundamental mode of transmission is from person-to-person and through caregivers, accentuated by the wide use of inhalation devices in the treatment of respiratory diseases, as outlined in previous publications C. striatum in 21 patients between December 2006 and July 2007, which did not correspond to a single nosocomial outbreak but included five different clones, and to confirm that the incidence of C. striatum infection can be high, regardless of occasional outbreaks.MLSA also allowed us to distinguish the grouping of 30 isolates of C. striatum during follow up, and the greater trend was observed with the more severe bronchial obstruction. For patient 3, three isolates were processed within 23 months. The same clone, F, and the same phenotype ‘a’, were identified in the first and third samples, varying only the antibiotype. In the intermediate sample, 3 months after the first one, we identified a different clone, named D, which was identical to the one obtained from patient 8, hospitalized at the same time in the immediately adjoining room. So, both high transmissibility and persistence could be shown in the same patient, with the additional predisposing determinants to suffering a very severe bronchial obstruction (FEV1%: 21%). Murphy et al. demonstrated the possibility of an identical Haemophilus influenzae clone persisting in the airways of the same patient even when in intermediate periods between two isolates negative sputum cultures were obtained, demonstrating that sputum cultures underestimate the frequency of H. influenzae colonization in the respiratory tract Clones A, B and C tended to persist for long periods, and might be isolated in the same or in different patients from 2 months up to 2 years. It is remarkable to observe jumps of several months between two identifications of the same clone, without knowing if they persisted in the habitat or in colonized patients. Thirteen patients had more than one positive culture for C. striatum and environmental circumstances was explored with temperature and humidity values obtained at the date of each isolate, identifying a clustering during periods of low temperatures and high humidity. This observation can only have a speculative value, but we present it for comparison with future studies.The relationship between accumulation of infections by an environmental pathogen such as C. striatum, nine phenotypic variants were identified that, when added to the 12 molecular clones, produces 23 different combinations, showing a high adaptive variability.In the 42 isolates of C. striatum antibiotic susceptibility, we obtained 22 different combinations, a key finding being that all isolates fulfil the criteria for multidrug-resistance. Actually, the most frequent variants were: sensitivity only to vancomycin  and sensitivity only to vancomycin and gentamicin . Coincidentally with all previous publications 100% of the isolates were sensitive to vancomycin. Finally, all our isolates were resistant to ciprofloxacin.With regards to C. striatum was resistant to cefotaxime only C. striatum to antibiotic pressure. Pulmonary perfusion defects associated with bronchial obstruction in chronic respiratory illnesses can play an important role in this circumstance, making it difficult to achieve optimal therapeutic concentrations of antibiotics, which facilitates the selection of resistant strains and their persistence in the airways.Earlier publications C. striatum it might pose a threat to antibiotic policies, because it competes as reserve antibiotic of choice against methicillin-resistant Staphylococcus aureus.As vancomycin is the only antibiotic with sure efficacy against C. striatum are poorly understood. The plasmid pTP10, whose genetic material is capable of encoding 16 antimicrobial resistances, the acquisition of a specific transposon (Tn5432), and genes related with antibiotic resistance have already been characterized elsewhere C. striatum.The molecular mechanisms of resistance to antibiotics of oson Tn54, and genC. striatum virulence factors is limited. In addition, their causality associated with mortality of C. striatum infection is highly variable and often speculative.Information about C. striatum, as previously discussed. There is an increased frequency of repeated isolations the greater is the degree of bronchial obstruction, as measured by FEV1%.Regarding morbidity, there is a broad agreement on the factors predisposing to infection by C. striatum. On the one hand, we noted a worse FEV1% and more admissions and hospital stays among deceased patients versus survivors. With regards to infection by C. striatum, the 18 deaths among the 42 patients who could complete the molecular study, were accumulated in clones A, B, D and F, and in phenotype ‘a’, but without statistical significance. However, the trend towards increased mortality in patients who suffered respiratory infections by bacterial strains with broader multidrug-resistance  should be noted.The high mortality rates observed in our study can be partly attributed to the severity of respiratory disease, and also to the infectious exacerbation of disease by C. striatum, in a homogeneous group of patients within a defined physical space, and over a long period of time to facilitate monitoring. These factors helped to follow the path of each clone and their epidemiological patterns. A major limitation is the loss of 23 unrecovered isolates obtained during this period, belonging to nine patients.The main strengths of our study are the accuracy of the correct identification of the isolates involved in respiratory infections by C. striatum is a health concern because it is an emergent Gram-positive environmental bacterium, prevalent, highly persistent and transmissible person-to-person and through caregivers, with usual multidrug resistance, that can cause opportunistic severe infection and long-term airway colonization in patients with advanced chronic respiratory disease , and often the cause of outbreaks of respiratory nosocomial infection. Prevention should be based on guideline-based management of advanced respiratory disease and its frequent exacerbations, enforcing hygiene measures in caregivers and therapeutic devices, and treatment according to antibiogram or, should it be unavailable, with vancomycin.To conclude,


This review article takes a multidisciplinary approach to understand how presynaptic inhibition in the striatum of the basal ganglia (BG) contributes to pattern classification and the selection of goals that control behavior. It is a difficult problem both because it is multidimensional and because it is has complex system dynamics. We focus on the striatum because, as the main site for input to the BG, it gets to decide what goals are important to consider. The basal ganglia (BG) select coordinated sets of behavioral goals in parallel loops to and from different areas of the cerebral cortex. The main input stage in these BG loops is the striatum and cortical neurons send numerous excitatory axons to the various cell types contained within the caudate, putamen, and ventral divisions of the striatum. The main flow of information is direct from cortex to spiny projection neurons (SPNs) out to one of the next stages of processing in the different BG loops and finally back to the area of cortex that generated the main excitatory input, thus forming a closed loop. Each SPN emits a prominent array of inhibitory collaterals before its axon leaves the striatum. The SPNs constitute 95% of the neurons within the striatum, and they are all GABAergic, although SPNs also contain an opiate as a co-transmitter. There are various types of interneuron within the striatum, many of which are also GABAergic  Houk, , a propoTo get more specific, we review next a neural network model of serial order processing that was based on the overall function of the cortical-basal ganglia loop  of the outcome of pattern classification in positive feedback loops between cortex and thalamus.A recursion-like operation brought about because the loop deposits the WM of prior classifications into an updated input vector from cortex to striatum.Because of step 3, the updated vector represents prior events, in addition to current events. As a consequence, the next pattern classification step will profit from temporal context. This dependence on past events is a fundamental requirement for serial order processing. Feedback inhibition was more effective and easier to control than feedforward inhibition.In another modeling study of serial order processing that focused on feedback inhibition in the striatum  signal from the caudate nucleus (Houk et al., We have presented the hypothesis that presynaptic inhibition plays a vital functional role in competitive dynamics between spiny neurons in the striatum. Future work should consider the potential role of presynaptic effects explicitly within computational models of competitive inhibition and goal selection in the striatum. Furthermore, ideas presented here may have application toward understanding the origin of schizophrenia, as previously suggested by one of us Houk, .Schizophrenia is a complex neuropsychiatric disease with a deficit in WM being a core feature (Lewis and Gonzalez-Burgos, A central paradox of schizophrenia is that, in spite of a fecundity disadvantage, a mental illness that is considered to be genetic in origin survives in the population. The magnitude of the deficits are such that any genetic predispositions should be eliminated from the population within a few generations (Berlim et al., It is worth noting that there are similarities between goal selection in the striatum and future trajectory planning in the hippocampus. In the hippocampus, researchers were unable to connect observed ensemble spiking sequences to the actual decision subsequently made (Johnson and Redish, JH and DS both wrote the paper.DJS was partially supported by NIH Grant No. K25 GM098875-02.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.


During four subsequent visits, participants cycled/handcycled for 30 min at 65% mode-specific peak (preload) followed by a 10 km TT following the ingestion of 4 mg∙kg−1 caffeine (CAF) or placebo (PLA). Caffeine significantly improved cycling (2.0 (2.0)%; 16:35 vs. 16:56 min; p = 0.033) but not handcycling (1.8 (3.0)%; 24:10 vs. 24:36 min; p = 0.153) TT performance compared to PLA. The improvement during cycling can be attributed to the increased power output during the first and last 2 km during CAF. Higher blood lactate concentration (Bla) was reported during CAF compared to PLA (p < 0.007) and was evident 5 min post-TT during cycling  and handcycling . Lower overall ratings of perceived exertion (RPE) were seen following CAF during the preload (p < 0.05) but not post-TT. Lower peripheral RPE were reported at 20 min during cycling and at 30 min during handcycling, and lower central RPE was seen at 30 min during cycling (p < 0.05). Caffeine improved cycling but not handcycling TT performance. The lack of improvement during handcycling may be due to the smaller active muscle mass, elevated (Bla) and/or participants’ training status.Caffeine supplementation during whole-/lower-body exercise is well-researched, yet evidence of its effect during upper-body exercise is equivocal. The current study explored the effects of caffeine on cycling/handcycling 10 km time trial (TT) performance in habitual caffeine users. Eleven recreationally trained males (mean (SD) age 24 (4) years, body mass 85.1 (14.6) kg, cycling/handcycling peak oxygen uptake ( During formance  and disaformance , includi1 and A2a) antagonist [A potential mechanism of caffeine is its influence on the central nervous system (CNS) by which it acts as an adenosine receptor  improved LBE but failed to statistically impact UBE in a mixed AB group [An 8 km double-poling TT performance lasting ~34 min was enhanced following the consumption of 6 mg∙kgne users . Double-AB group . The oppAB group ,18 and hAB group . These fAB group  and may peak) 10 km TTs following the ingestion of caffeine and placebo. Importantly, they will adopt a synchronous handcycling modality for the UBE aspect, which is akin to the sports of handcycling and the cycling discipline of Para-Triathlon.It has been previously reported that caffeine increases muscular strength  and motor unit recruitment in the knee extensors but not in the elbow flexors ,16. Thespeak 42.9 (7.3) and 27.6 (5.1) mL∙kg∙min−1) participated in the current study. Caffeine users, with average daily caffeine intake 160 (168) mg/day were recruited to represent the usual dietary habits of athletes. All procedures were approved by the Loughborough University Ethics Approvals Sub-committee  and performed in accordance with the Declaration of Helsinki. All participants provided written informed consent and none revealed contraindications for participating in the study.Eleven recreationally active, healthy males (age 24 (4) year, body mass 85.1 (14.6) kg, lower and upper body peak test, a familiarization and two (caffeine and placebo) experimental trials . Both pieces of equipment were mounted on a Cyclus II ergometer . Bike settings were individually adjusted and standardized for each participant across trials. The differentiated RPE scale was explained to participants prior to the commencement of preliminary trial testing.peak. The ergometer was set in power control mode, which ensured a pre-set power output (PO) was automatically regulated independent of cadence or gear selection by continuous adjustment of the degree of electromagnetic braking. The participants’ performed a 5-min warm-up at a self-selected pace. The continuous step tests consisted of 3-min submaximal stages with an initial load of 70 W for the cycling and 20 W for the handcycling test. Increments of 30 W for the cycling and 10 W for the handcycling test were then applied. Participants reported differentiated RPE scores at the end of each stage and upon completion. Blood lactate concentrations (Bla) were determined using a Biosen C-Line  at the end of each stage from earlobe capillary blood samples. When the participant’s (Bla) increased beyond 4 mmol∙L the resistance was increased by 5 W every 15 s until volitional exhaustion . Online respiratory gas analysis was carried out via a breath-by-breath system . Prior to each test, gases were calibrated according to the manufacturer’s recommendations. The highest 30 s rolling average peak. Heart rate (HR) was monitored continuously . On separate occasions, participants performed incremental cycling and handcycling tests until exhaustion to determine mode-specific Participants refrained from exercise, caffeine and alcohol consumption in the 24 h preceding each trial, as previously utilized . They co−1 caffeine anhydrous (CAF) or dextrose placebo (PLA) capsules  45 min prior to the warm-up. A 4 mg∙kg−1 caffeine dose has previously increased plasma caffeine concentrations to 14.6 µM, 50 min post-ingestion [The experimental trials involved the consumption of either 4 mg∙kgngestion  and was ngestion . Particingestion . No motiP), central (ventilatory and circulatory exertion) (RPEC) and overall (integrated) (RPEO). The 6–20 RPE scale  was usedp < 0.05. Statistical Package for the Social Sciences version 20 software  was used to analyze the data. Normal distribution was confirmed using the Shapiro–Wilk test and consequently (Bla) performance times, HR, power output (PO), respiratory exchange ratio (RER) and p = 0.033) (995 (46) s and 1016 (58) s, respectively). Ten (of 11) participants cycled faster during CAF (p = 0.153). There was no significant influence of trial order during cycling (p = 0.164) or handcycling (p = 0.298). The PO was significantly greater during CAF compared to PLA during cycling only (p = 0.003), and this was apparent during the first and last 2 km of the TT (p < 0.006). There was no influence of habitual caffeine intake on TT performance (p > 0.470). Participants with a handcycling peak greater than the mean value (27.6 ml∙kg∙min−1) (n = 7) improved their handcycling TT performance by 3.2% whereas those with a peak less than the mean (n = 4) had a 0.3% reduction in handcycling performance (Caffeine significantly improved 10 km TT performance during cycling by 2.0 (2.0)% compared to PLA  and 42.9 (7.3) mL∙kg∙min−1, p = 0.001). The target relative exercise intensity of the 65% peak during the preload was matched experimentally with average p > 0.217). Average preload HR and RER did not differ between CAF and PLA (p > 0.180).A significantly lower p = 0.001). This was evident between 10 and 20 min during cycling following CAF only (p = 0.006), and at both 20 and 30 min compared to 10 min during handcycling following both CAF and PLA (p < 0.005). The TT resulted in a significant increase in (Bla) post-TT and five min post-TT during all trials (p < 0.017). The ingestion of CAF resulted in significantly higher (Bla) compared to PLA during cycling (p = 0.001) and handcyling (p = 0.007), but differences were only evident post-TT (p < 0.012) . However, there was no difference in (Bla) pre-exercise or post-TT between modalities (p > 0.134).There was a significant increase in (Bla) over time during all trials (< 0.012) . The hanParticipants’ RPE responses can be seen in −1) significantly improved cycling 10 km TT performance, whereas the same dose did not statistically improve handcycling performance. This study compliments the work of Black et al. [This is the first study to assess the effect of caffeine on 10 km TT performance during both cycling and handcycling in habitual caffeine users. The main finding was that the ingestion of caffeine  [max during arm and leg exercise, respectively) [The 10 km TT provided data from which the influence of caffeine on endurance performance could be assessed in a sport-specific manner. The ingestion of CAF resulted in a significant improvement in cycling performance (2.0 (2.0)%) compared to PLA, which was due to the increased PO during the first and last two km. On the other hand, it failed to significantly improve handcycling performance (1.8 (3.0)%) and there was large intra-individual variability. The small effect sizes  reflect the large standard deviations for both sets of results. Individual responses to caffeine supplementation have often been attributed to differing rates of caffeine metabolism, which may in turn be linked to training status and body composition . Unfortu (~0.5%) . The ing (~0.5%)  and UBE  (~0.5%) . The incctively) . Hence, peak (Evidence from biopsies suggests that the triceps muscle (an important force producing muscle during synchronous handcycling) exhibits a greater proportion of type II muscle fibers than the legs  ,18. ThisV·peak .Previous research suggests caffeine increases muscular strength  and motor unit recruitment in the knee extensors but not in the elbow flexors ,16. MoreP was reduced by CAF but this reduction in perceived arm and shoulder effort did not translate to improvements in TT performance. It has been suggested that caffeine is unable to have a hypoalgesic effect during heavy-severe fixed intensity exercise [Although RPE was not reduced following the cycling TT, PO was higher during CAF suggesting that participants were able to cycle at a higher PO with no change in RPE. This is in line with previous literature that has shown caffeine to increase the PO/RPE ratio during a TT ,2. It haexercise , and thepeak achieved during handcycling was 64% of that achieved during cycling (range: 52%–83%), which is lower than previously reported values (~70%) [peak above the mean improved their handcycling TT performance by 3.2%, whereas those below the mean had a 0.3% reduction (The s (~70%) . This iseduction . Hence, peak = 3.9 compared to 3.6 L·min−1 in the current study) completing a preloaded cycling TT [It has been suggested that one familiarization session is sufficient for reproducible results in recreationally active individuals (cycling cling TT  but it i−1) significantly improved cycling 10 km TT performance but there was no statistical improvement in handcycling in habitual caffeine users. The positive effects of caffeine on cycling performance may be related to reductions in RPE during the preload. The lack of a statistical improvement during handcycling is possibly due to elevated (Bla) owing to both the mode of exercise and the ingestion of CAF. Furthermore, participants’ training status appears to influence the ability of caffeine to improve UBE performance. Pre-exercise ingestion of caffeine (4 mg∙kg


Background: Donor safety is the first priority in living donor liver transplantation (LDLT).Objective: To determine the characteristics and outcome of live liver donors who underwent donor hepatectomy from January, 1997 to May, 2007 at Massachusetts General Hospital.Methods: 30 patients underwent LDLT between January, 1997 and May, 2007 at our institution.Results: The type of graft was the right lobe (segments 5-8) in 14, left lobe (segments 2-4) in 4, and left lateral sector (segments 2 and 3) in 12 patients. The mean donor age was 36 (range: 26-57) years. The mean follow-up was 48 (range: 18-120) months. No deaths occurred. Overall, 8 (26.6%) patients experienced a total of 14 post-operative complications. Donor complications based on graft type were as follows: left lateral sector (16.7%), left lobe (25%), and right lobe (35.7%). The experience was divided into two periods 1997-2001 (n=15) and 2002-2007 (n=15). Overall complications during 2 periods were 40% and 13.3%, respectively (p<0.001). The incidence of grade III complication also significantly decreased; 66.7% vs 33.3% (p<0.01).Conclusion: Partial hepatectomy in living donors has a learning curve which appears to be approximately 15 cases. This learning curve is not restricted to the surgeons performing the procedure but involves all aspects of patient care. Liver transplantation is the treatment of choice for patients with end-stage liver disease (ESLD). Efforts to increase deceased liver donation have seen only modest successes. Rising rates of death on the waiting list led to the use of more innovative and risky approaches to transplantation, including reduced size and split liver organs and, more recently, living donors .Living donor liver transplantation (LDLT) has emerged successfully to partially relieve the shortage of deceased donor grafts caused by the increasing demands of patients with ESLD. Despite rapid adoption of LDLT by numerous centers, many controversies on donor selection, indications, techniques, and ethics exist ,2. BeforAll potential donors were evaluated in three phases. Phase 1 comprised a comprehensive history, physical examination and laboratory profile, which includes viral serology and blood type. In phase 2, potential donors were counseled by a nontransplant physician, acting as a donor advocate, who ensured donor commitment, motivation and understanding of the risks involved. A social worker and financial advisor also helped the donor with social or financial issues that may arise during the process of donation. Finally, in phase 3 the donor underwent CT volumetric study and magnetic resonance cholangiography (MRC) or CT cholangiography.Data were collected on all 30 live liver donors who underwent donor hepatectomy from January, 1997 to May, 2007 at Massachusetts General Hospital.During this period, our program evolved to improve outcome after live donor hepatectomy. These changes were in all aspects of donor work-up and management. For example, routine mesenteric angiogram was replaced by CT angiography. In one case, donor hepatectomy was aborted as MRC missed a segment IV bile duct which was draining into the right system. This was identified during intra-operative cholangiogram and the donor right hepatectomy was aborted. Since then, we have replaced MRC with CT cholangiography. Other examples are routine application of low central venous pressure during the parenchymal transaction, epidural pain management, early post-operative mobilization and oral diet advancement, aggressive management of phosphorus repletion and respiratory toilet. A percutaneous liver biopsy was not routinely performed before dissection of the hepatic hilum. For operative safety, one or two units of autologous packed red cells were stored before the operation. Operation was planned to guarantee 30%–35% remnant liver volume in the donor. The middle hepatic vein was never taken in right lobe donation.Standard surgical techniques for LDLT have been previously described -9. All det al [For assessing complications, the uniform reporting of adverse outcomes of surgery proposed by Clavien, et al , was adoStudent’s t test was used to compare means. A p value <0.05 was considered statistically significant.Values are given as mean and range unless otherwise stated. Donor characteristics are shown in Overall, 8 (26.6%) patients experienced a total of 14 post-operative complications. The mean length of hospitalization (LOS) was 7.5 (range: 5-12) days. Donor complications based on graft type were as follows: left lateral sector (16.7%), left lobe (25%), and right lobe 35.7%). Type and grade of complications are summarized in 5.7%. Typvs 33% (p<0.01). The total number of complications also dropped from 10 (71%) in the first period to four (29%) in the second period. The number of readmissions also significantly dropped (40% vs 13%). Interestingly, the majority of allografts in the first period were left lateral segment (10/15) which changed to right lobe (10/15) in the second period. Despite of this fact, the LOS did not change significantly (8.2 vs 7.4 days).The experience was divided into two periods 1997–2001 (n=15) and 2002–2007 (n=15). Overall complications  and 4 duLDLT has been controversial since its inception. Begun in response to deceased donor organ shortage and waiting list mortality, LDLT was initiated in 1989 in children, grew rapidly after its first general application in adults in the United States in 1998, and has declined since 2002 [The Adult-to-Adult Living Donor Liver Transplantation (A2ALL) cohort study was initiated in 2002 as a cooperative research agreement funded by the National Institute of Health with nine liver transplant centers and a data coordinating center. Across the nine A2ALL centers, the overall donor complication rate was 38% . In A2ALIn A2ALL cohort , the mosMiddleton and collegues  did a syThe Hong Kong group ,18 repor


Some children do not show an appropriate cooperation with their dentist. A number of them cannot be managed by local anesthesia and the usual techniques used to control behaviors, so further steps are required to control their pain and anxiety. Pharmaceutical control is recommended through sedation or general anesthesia.This study was aimed to evaluate two groups of drugs in intravenous sedation method.th, 20th, 30th and 40th minutes of the operation. The results were analyzed by SPSS (version 16) using independent T-test, Wilcoxon, Mann-Whitney and Pearson Chi-Square tests as appropriated. In this clinical trial intervention study, patients were randomly divided into two groups of 18 and 20 and each group received either intravenous midazolam-ketamine or midazolam-fentanyl. During the procedure, 0.25mg midazolam was administered to both groups if needed. The scores of intraoperative sedation and operation conditions were evaluated and recorded by dental sedation teacher groups (DSTG) system in the 10p= 0.55), recovery time (p= 0.18), Frankl score , and sedation complications (p= 0.612). In addition, no complication occurred in recovery. There was no significant difference between the two groups in sedation period ( There was no significant difference between the two drug groups; both were appropriate in controlling children’s behavior. Dental treatments seem painful to most children. In many One of the methods to manage children in dental procedures is conscious sedation, during which the child would be sedated by use of sedative or anesthetic drugs, but is still able to cooperate with the dentist and respond to verbal commands. The patient’s comfort throughout the procedure and forgetting the events are among the characteristics of sedation. Using midazolam in dentistry is very acceptable and common and its forgetting effects are recognized in the literature.-5Three most commonly used sedation roots are inhalational, oral and intravenous. Although particular dosages of drug are recommended for conscious sedation in the mentioned techniques, usually none of these methods would cause an unarousable sleep, the reason they are named as conscious sedation.-7In intravenous method, the drugs that are used for conscious sedation are directly administered to venous blood through the veins. Conscious sedation causes the patient not to remember much of what happened during the procedure and after it is done.et al. (1997), midazolam caused anterograde amnesia in most patients.[et al. (2013) proved midazolam (in the studied dosage) to be an effective and innocuous medication for pediatric sedation.[Benzodiazepines, ketamine, opioids, and propofol are the medications used in intravenous sedation. Based on the study by Nadin et al. 197, midazsedation.Ketamine is a non-barbiturate drug derived from phencyclidine; it may bet al. (1992) found that ketamine dosage would considerably decrease when used in combination with benzodiazepine.[et al. (2002) enrolled a study concerning the efficacy and immunity of midazolam and propofol as sedating agents in managing uncooperative children and found that both are effective in sedation and have the least side effects.[et al. (2012), combination of midazolam-ketamine provides sufficient sedative effect at lower dosage.[Okamoto iazepine. Damle et effects. Accordinr dosage.Combination of several medications is used to improve the sedation quality. Midazolam as a frequently-used sedative drug might provide a better sedation in combination with ketamine  and fentanyl (as an opioid sedative drug). A question would arise whether fentanyl or ketamine can provide better sedative effect when used in combination with midazolam. This study was carried out to compare the sedative properties and operating conditions of intravenous midazolam-fentanyl with midazolam-ketamine. This double-blind clinical trial was conducted on 38 healthy children aged 4-9, selected randomly from those referred to Department of Hospital Dentistry in Isfahan School of Dentistry. They were randomly allocated into two groups of 18 and 20; the patients in the first group were administered intravenous midazolam-ketamine while the second group received intravenous midazolam-fentanyl.The inclusion criteria were healthy children with 4-9 years of age who referred to dental operating room and needed dental treatment on left upper teeth, with negative medical history of allergy, hepatic failure, renal failure, heart problems, chronic pulmonary disease, seizures, asthma, and psychological problems. The preoperative consultation was assessed and those who met the inclusion criteria were given similar preoperative instructions, and informed consents were obtained from parents. The instructions included of being fasted prior to the operation, not having taken sedative/hypnotic/ analgesic drugs, and having someone to accompany them on the day of operation.On the operation day, the anesthesiologist randomly allocated the patients in one of the two groups, gave them an injection of the required drugs with respect to their weight, and managed the patient throughout the operation. Neither the dentist nor the person who was collecting data had a clue about the grouping method. After completing the sampling, the related codes were removed. The first group received intravenous midazolam (0.05mg/kg) and ketamine (0.5mg/kg), the second group intravenous midazolam (0.05mg/kg) and fentanyl (0.5µg/kg), both within a 2-minute time interval. Throughout the operation, midazolam (0.25mg) was administered to both groups if needed and the efficacy of both drug groups was evaluated in managing the children during the dental operation and after it. In addition, the side effects of the drugs were checked including restlessness, fear of injection, nausea and vomiting, complications of sedation and recovery, sedation period, and recovery period. Dental sedation teacher groups (DSTG) system was usedAfter the operation was over, the patient was subjected to standard care in recovery and was released when meeting the discharge conditions, and received comprehensive instructions thereafter. Throughout the operation, the patient was supervised by anesthesiologist and the vital signs and oxygen saturation was checked by using a pulse oximeter. The dentist administered local anesthesia according to the pediatric dentistry protocol. The results were analyzed by SPSS (version 16) using independent T-test, Wilcoxon, Mann-Whitney, and Pearson Chi-square tests as appropriated. p= 0.338). The mean age in midazolam-ketamine group was 6.27 and in midazolam-fentanyl group, it was 6.75. Frequency distribution of -2 Frankl score was 16.7% in midazolam-ketamine group and 20% in midazolam-fentanyl group. Mann-Whitney test showed no significant difference between the drug groups concerning Frankl score during the dental treatment (p= 0.83)  and 10 girls (55.6%); in midazolam-fentanyl group, 12 were boys (60%) and 8 were girls (40%). Pearson’s Chi-square revealed no significant difference between the two groups concerning the gender (p= 0.83) .p> 0.05). One out of 18 patients in midazolam-ketamine group and 2 out of 20 patients in midazolam-fentanyl group developed sedation complications. Pearson’s chi-square test showed no significant difference between the groups concerning the sedation complications (p= 0.612). The mean score of intraoperative sedation in the 10th minute was 2.27 in midazolam-ketamine group and 2.55 in midazolam-fentanyl group.The mean recovery period and sedation time in midazolam-ketamine group were respectively 28.61 and 37.22 minutes, and in midazolam-fentanyl group, these numbers were 30 and 34.25 minutes, respectively. Independent T-test demonstrated that there was no considerable difference between the two groups concerning mean age, recovery, and sedation period . Seventeen patients in midazolam-ketamine group and 18 in midazolam-fentanyl group got the intraoperative sedation score of 2 and 3  in the 10th minute. This number in the 20th, 30th and 40th minutes of the operation was respectively 15, 11, and 8 in midazolam-ketamine group and 15, 10, and 8 in midazolam-fentanyl group  at the 10yl group .p< 0.05). There was also significant difference between the score of operating conditions in the two groups over the 10-20, 10-30, 20-40 and 30-40 minutes of the operation (p< 0.05). Neither group showed recovery complications, so no significant difference were found between the groups concerning the recovery complications.Wilcoxon test revealed significant difference between the score of sedation in the two groups of midazolam-ketamine and midazolam-fentanyl in the 10-20, 10-30 and 10-40 minutes of the operation , no complication was detected throughout the operation and recovery in children who received intravenous midazolam-nalbuphine-droperidol.[In a study enrolled by Milnes operidol. In the cth, 20th and 30th minutes of the operation (sedation score: 2 and 3). Comparing the score of intraoperative sedation in midazolam-ketamine and midazolam-fentanyl group revealed a significant difference between the two groups in the 10-20, 10-30 and 10-40 minutes of operation. This might be because sedation functions better at the commencement of the operation. Somri et al. studied the sedation score of oral midazolam in three dosages of 0.5, 0.75 and 1 mg/kg and found that sedation score in 0.75 and 1mg/kg midazolam groups were higher than 0.5mg/kg group.[In this study, no significant difference was found between the scores of intraoperative sedation in the two groups; indicating the effects of the two drug groups to be identical. This finding was due to the similarity in the types and effects of these medications, as well as complying with the recommended dosage. In each combination group of drugs, over 50% of the children had ideal sedation condition in the 10kg group.th and 20th minutes of the operation in more than 50% of children (operating condition score: 1 and 2). However, comparing the score of operating conditions in each group of midazolam-ketamine and midazolam-fentanyl revealed significant difference between the groups in the 10-20, 10-30, 20-40 and 30-40 minutes of the operation, which can be due to the better operating conditions provided at the beginning of the operation.Comparing the score of operating conditions, no significant difference was observed between midazolam-ketamine and midazolam-fentanyl groups; indicating the identical effect of both groups due to the similarity of type and effect of drugs, besides being used in recommended dosages. Sedative effects of these two drug combinations provided ideal operating conditions in the 10th, 20th, 30th, and 40 minutes of operation, gender, and age. Both groups provided sufficient score of intraoperative sedation until the 30th minute, and ideal operating conditions until the 20th minute of the operation. Hence, until the 20th minute of the procedure, drugs can be suitable for managing the children, neither was superior and each one was effective per se. Therefore, it seems that it makes no difference to combine midazolam with ketamine or fentanyl.There existed no significant difference between the two groups of midazolam-ketamine and midazolam-fentanyl in terms of sedation complications, recovery complications, Frankl score, sedation ,and recovery period, as well as score of intraoperative sedation, operating conditions during the 10