What Is Needed to Eradicate Lymphatic Filariasis? A Model-Based Assessment on the Impact of Scaling Up Mass Drug Administration Programs

Background

Lymphatic filariasis (LF) is a neglected tropical disease for which more than a billion people in 73 countries are thought to be at-risk. At a global level, the efforts against LF are designed as an elimination program. However, current efforts appear to aim for elimination in some but not all endemic areas. With the 2020 goal of elimination looming, we set out to develop plausible scale-up scenarios to reach global elimination and eradication. We predict the duration of mass drug administration (MDA) necessary to reach local elimination for a variety of transmission archetypes using an existing model of LF transmission, estimate the number of treatments required for each scenario, and consider implications of rapid scale-up.

Methodology

We have defined four scenarios that differ in their geographic coverage and rate of scale-up. For each scenario, country-specific simulations and calculations were performed that took into account the pre-intervention transmission intensity, the different vector genera, drug regimen, achieved level of population coverage, previous progress toward elimination, and potential programmatic delays due to mapping, operations, and administration.

Principal Findings

Our results indicate that eliminating LF by 2020 is unlikely. If MDA programs are drastically scaled up and expanded, the final round of MDA for LF eradication could be delivered in 2028 after 4,159 million treatments. However, if the current rate of scale-up is maintained, the final round of MDA to eradicate LF may not occur until 2050.

Conclusions/Significance

Rapid scale-up of MDA will decrease the amount of time and treatments required to reach LF eradication. It may also propel the program towards success, as the risk of failure is likely to increase with extended program duration.     

Mass Drug Administration for Trachoma: How Long Is Not Long Enough?

BackgroundBlinding trachoma is targeted for elimination by 2020 using the SAFE strategy (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements). Annual mass drug administration (MDA) with azithromycin is a cornerstone of this strategy. If baseline prevalence of clinical signs of trachomatous inflammation – follicular among 1-9 year-olds (TF1-9) is ≥10% but <30%, the World Health Organization guidelines are for at least 3 annual MDAs; if ≥30%, 5. We assessed the likelihood of achieving the global elimination target of TF1-9 <5% at 3 and 5 year evaluations using program reports.ConclusionsNumber of annual MDAs alone appears insufficient to predict program progress; more information on the effects of baseline prevalence, coverage, and underlying environmental and hygienic conditions is needed. Programs should not skip MDAs, and at prevalences >30%, 7 or more annual MDAs may be required to achieve the target. There are five years left before the 2020 deadline to eliminate blinding trachoma. Low endemic settings are poised to succeed in their elimination goals. However, newly-identified high prevalence districts warrant immediate inclusion in the global program. Intensified application of the SAFE strategy is needed in order to guarantee blinding trachoma elimination by 2020.     

Neglected Patients with a Neglected Disease? A Qualitative Study of Lymphatic Filariasis

Background

Lymphatic filariasis (LF) is a so-called neglected tropical disease, currently overshadowed by higher-profile efforts to address malaria, tuberculosis, and HIV/AIDS. Despite recent successes in arresting transmission, some 40 million people who already have the disease have been largely neglected. This study aims to increase understanding of how this vulnerable, neglected group can be helped.

Methods

We used purposive sampling to select 60 men and women with filarial lymphoedema (45 with filarial elephantiasis and 15 men with filarial hydrocoele) from the south of Sri Lanka in 2004–2005. Participants were selected to give a balance of men and women and poor and nonpoor, and a range of stages of the disease. Participants'' experiences and the consequences of their disease for the household were explored with in-depth qualitative, semistructured interviews.

Findings

LF was extremely debilitating to participants over long periods of time. The stigma attached to the condition caused social isolation and emotional distress, and delayed diagnosis and treatment, resulting in undue advancement of the disease. Free treatment services at government clinics were avoided because the participants'' condition would be identifiable in public. Loss of income due to the condition was reported by all households in the sample, not just the poorest. Households that were already on low incomes were pushed into near destitution, from which it was almost impossible to escape. Affected members of low-income households also had less opportunity to obtain appropriate treatment from distant clinics, and had living and working conditions that made hygiene and compliance difficult.

Significance

This highly vulnerable category of patients has low visibility, thus becoming marginalized and forgotten. With an estimated 300,000 total cases of elephantiasis and/or oedema in Sri Lanka, and around 300,000 men with filarial hydrocoele, the affected households will need help and support for many years to come. These individuals should be specially targeted for identification, outreach, and care. The global strategy for elimination is aimed at the cessation of transmission, but there will remain some 40 million individuals with clinical manifestations whose needs and problems are illustrated in this study.     

A Cross-Sectional Study of ‘Yaws’ in Districts of Ghana Which Have Previously Undertaken Azithromycin Mass Drug Administration for Trachoma Control

Yaws, caused by Treponema pallidum ssp. pertenue, is reportedly endemic in Ghana. Mass distribution of azithromycin is now the cornerstone of the WHO yaws eradication campaign. Mass distribution of azithromycin at a lower target dose was previously undertaken in two regions of Ghana for the control of trachoma. Ongoing reporting of yaws raises the possibility that resistance may have emerged in T. pallidum pertenue, or that alternative infections may be responsible for some of the reported cases. We conducted a cross-sectional survey in thirty communities in two districts of Ghana where MDA for trachoma had previously been conducted. Children aged 5–17 years with ulcerative lesions compatible with yaws were enrolled. Samples for treponemal serology and lesion PCR were collected from all children. 90 children with 98 lesions were enrolled. Syphilis serology was negative in all of them. PCR for T. pallidum ssp pertenue was negative in all children, but Haemophilus ducreyi DNA was detected in 9 lesions. In these communities, previously treated for trachoma, we found no evidence of ongoing transmission of yaws. H. ducreyi was associated with a proportion of skin lesions, but the majority of lesions remain unexplained. Integration of diagnostic testing into both pre and post-MDA surveillance systems is required to better inform yaws control programmes.     

The Elimination of Lymphatic Filariasis: A Strategy for Poverty Alleviation and Sustainable Development – Perspectives from the Philippines

BACKGROUND: Hygiene and skin care are effective and important interventions in the management of lymphoedema secondary to lymphatic filariasis. We analyzed the impact on the quality of life that education and introduction of a designated nurse had on lymphoedema patients in a community that was endemic for lymphatic filariasis. METHODS: Patients' life quality was assessed using a Dermatology Life Quality Index (DLQI) questionnaire. At the same time they received education on appropriate hygiene, skin care techniques and simple exercises that encourage lymph drainage. A designated nurse was provided with educational materials and treatments. The DLQI life quality measure was repeated one year later. RESULTS: The DLQI improved for all patients and reported acute attacks were reduced. A paired t-test showed the improvement in DLQI to be highly significant (P = < 0.0001). CONCLUSIONS: A nurse-led service combined with patient education in communities endemic for lymphatic filariasis is an effective intervention in improving the quality of life of patients with lymphoedema.     

Rapid Assessment Procedure for Loiasis and Mapping Lymphatic Filariasis: Two Perfect Illustrations of “To Be in English or Not to Be”

Interest in filariasis has found a new impetus now that neglected tropical diseases have their own journal. However, some of the advances published in renowned international journals have completely ignored previous publications on the subject, particularly those in languages other than English. The rapid assessment procedure for loiasis and the mapping of lymphatic filariasis provide two perfect illustrations of this. This problem may seem a bit outdated, given that all “good authors” now publish exclusively in English. It certainly is outdated for most areas of medicine. But, surely, this should not be the case for neglected tropical diseases, for which certain long-standing findings are every bit as important as what may be presented as new discoveries. One possibility would be for certain journals, such as PLOS Neglected Tropical Diseases, to include a specific heading permitting the publication in English of older studies that initially appeared in a language other than English. The texts would be English versions respecting the entirety of the original text. Submission should be accompanied by a presentation of the problem, with details and explanatory comments, with submission at the initiative of the authors of the former article in question or their students or sympathizers.Interest in filariasis has found a new impetus now that neglected tropical diseases (NTDs) have their own journal. However, some of the advances published in renowned international journals have completely ignored previous publications on the subject, particularly those in languages other than English. This Viewpoint article is intended to make us ponder the issue of a language gap or discrimination existing in publishing outcomes and reference citations. This is also the question of deleterious effects of the obligation “to be in English or not to be”.The rapid assessment procedure for loiasis (RAPLOA) and the geographical distribution of lymphatic filariasis provide two perfect illustrations of this.The RAPLOA has recently been widely used to determine the regional endemicity of loiasis and to update existing endemicity data for this disease over its global distribution range. This important work has been recently published in PLOS NTDs [1]. The determination, within a population of the prevalence or, preferably, the annual incidence of episodes, of conjunctival migration by adult worms is a simple, non-invasive, relatively sensitive and specific method for evaluating the endemicity of Loa loa. This approach has proved particularly useful in areas in which both loiasis and onchocerciasis are observed: the mass treatment program to control onchocerciasis is based on the use of ivermectin and there is a risk of adverse treatment outcomes in patients carrying large numbers of L. loa worms [2]. In regions of high endemicity, the correlation between the conjunctival migration index and the microfilarial index is strong overall, both for villages and for age groups. Its use as an epidemiological index was clearly proposed in a publication in 1994 [3]. However, as this article was published in French, in Médecine Tropicale (Marseille), it has never been cited, despite being listed in international databases, including PubMed. A poster communication concerning the same issue had no real impact either, despite being presented at an international congress [4]. The origin of this new epidemiological index (RAPLOA) is systematically attributed to two World Health Organization (WHO) publications in 2001 [5] and 2002 [6]. It is true that the studies reported in these publications validated the concept at a large scale and in different endemic foci.The usefulness of specific clinical manifestations (eye worm and Calabar swelling) to assess L. loa had been recommended by different authors as early as 1950 [7]. But the correlation between the microfilarial index and the frequency of ocular migration has not been studied, and even less attention was paid to the notion of an epidemiological index until the epidemiological studies carried out in Congo Republic (former People''s Republic of the Congo) during the 1980s [8]. However, the index as such was clearly defined in 1994 [3]. Here is a direct translation of an excerpt of the French text published in 1994: “For loiasis, the usual parasitological indices (microfilarial index and mean microfilarial density) are the only measures recognized as providing information about the level of endemicity in humans. In addition to requiring blood samples standardized in terms of both volume and sampling time, these indices do not reflect the real level of parasitism, given the high frequency of infected subjects without microfilaria in the blood. Subjects infested with mature, fertile adult worms, as demonstrated by the removal of a subconjunctival female containing microfilaria from a patient with no detectable microfilaria in the blood, are frequently observed. Two symptoms are both specific and frequent in infected subjects both with and without microfilaria in the blood: subconjunctival migration of an adult worm and elusive, migrating edemas of the hands, wrists and lower part of the forearm” [9]. “The index of subconjunctival filarial migration over the preceding year is particularly useful, because it correlates well with the microfilarial index but is more sensitive” (Figure 1). “Its determination involves precise questioning of the patient, which can be facilitated by the use of a demonstration chart, with diagrams and photographs” (see Figure 2).Open in a separate windowFigure 1Index of the subconjunctival migration of Loa loa adult worms and microfilarial index.Reproduced from Medicine Tropicale [3], released under CC BY 2.0 by Medicine Tropicale. IMSC = Indice de Migration Sous-Conjonctivale in French and Index of the SubConjunctival Migration in English. IM = Indice Microfilarien in French and Microfilarial Index in English.Open in a separate windowFigure 2Illustration of the passage of an adult worm (Loa loa) across the eye.This illustration (diagram and photograph) was made for presentation to patients questioned in endemic regions.The conclusion of this article was formulated as follows: “Screening for foci of filarial endemicity could be improved by the use of a simplified method and the validation of simple, inexpensive indices. Once these foci have been identified, a more precise evaluation can be carried out.”What is most astounding about the two WHO publications cited as the origin of this “new epidemiological index” [5], [6] is that the principal authors come from French-speaking African countries and/or work in or with this institution. They would therefore have been able to understand articles written in French. Furthermore, the WHO has a long-standing culture of multilingualism, particularly in English and French.Against this background, the rejection by the Bulletin of the World Health Organization and by other international journals published in English of an opinion article dealing with this issue and using the example of lymphatic filariasis does not seem to be justified, and is another illustration of “to be in English or not to be.”Indeed, filariasis due to Wuchereria bancrofti is systematically described as endemic in Congo and Gabon, two French-speaking countries, in non-specialist works on tropical medicine and in more specialist publications (WHO) despite a total absence of epidemiologic studies and/or confirmed case report over the last 30 years to prove it. What is certain is that no case was found when the last studies were conducted in these countries at the end of the 1970s and during the 1980s but unfortunately published in French. The studies that we carried out in the Congo as part of the National Project on Onchocerciasis and Other Filariases (between 1982 and 1987) confirmed the presence of four types of human filariasis: onchocerciasis, loaiasis, and the filariases caused by Mansonella perstans and M. streptocerca. There was a total absence of confirmed cases of lymphatic filariasis (bancroftosis). In this case, it is not a question of the attribution of merit for a particular “discovery”, but of basic knowledge of the geographic distribution of a scarcely studied disease, lymphatic filiariasis, in French Central Africa. Taking into account only publications in English, even older and poorly structured data, have been, in our opinion, a source of confusion and has led to false conclusions being drawn about the distribution range of this disease. This undoubtedly highlights the need to update knowledge by carrying out prospective studies (which seem to be underway), but these studies do not seem to be considered a matter of priority given the low levels of resources available and current health priorities.This has drawn us to publish this article in a French-language journal, but together with an entire translation into English [10]. Despite the bilingual nature of this publication, the international PubMed database identifies this article as being published in French, effectively ensuring that it will never be consulted, a classic “catch 22” situation! Indeed, this reference has never yet been cited by another author in a journal published in English. It may be that publication of an article in another language than English makes it more likely that it will not be cited, even if the authors of a subsequent article have access to the journal in which it was published and can understand the language used. Here, we begin to encroach on ethical problems and it is probably best not to delve too deeply. However, suffice it to say that the limited dissemination of publications in a language other than English may account for such equivocal attitudes.The problem is not a rivalry between French and English, but the confrontation between English and all other languages of the world. Moreover, the problem is undoubtedly worse for works published in non–Western European languages such as Chinese, Russian, and Japanese, which are arguably even less accessible.All things considered, this problem may seem a bit outdated, given that all “good authors” now publish exclusively in English. It certainly is outdated for most areas of medicine, where everything that is old is assigned to being nothing more than the history of medicine. But, surely, this should not be the case for NTDs, for which certain long-standing findings are every bit as important as what may be presented as new discoveries.One possibility would be for certain journals, such as PLOS NTDs, to include a specific heading permitting the publication of older studies that initially appeared in a language other than English (and are therefore currently little known). The texts included in this heading would essentially be English versions of these articles previously published in other languages, respecting the entirety of the original text.This would concern studies considered of importance because they highlight a point that remains unclear or describe an aspect considered innovative in a review but for which the originality of the article is due more to an incomplete reference list than to a true advance in knowledge. These articles should be judged in light of the knowledge and technical and methodological means available at the time at which they were initially published. Submission should be accompanied by a presentation of the problem, with details and explanatory comments, with submission at the initiative of the authors of the article in question or their students or sympathizers.     

A Potential Role for Creatine in Drug Abuse?

Supplemental creatine has been promoted for its positive health effects and is best known for its use by athletes to increase muscle mass. In addition to its role in physical performance, creatine supplementation has protective effects on the brain in models of neuronal damage and also alters mood state and cognitive performance. Creatine is found in high protein foods, such as fish or meat, and is also produced endogenously from the biosynthesis of arginine, glycine, and methionine. Changes in brain creatine levels, as measured using magnetic resonance spectroscopy, are seen in individuals exposed to drugs of abuse and depressed individuals. These changes in brain creatine indicate that energy metabolism differs in these populations relative to healthy individuals. Recent work shows that creatine supplementation has the ability to function in a manner similar to antidepressant drugs and can offset negative consequences of stress. These observations are important in relation to addictive behaviors as addiction is influenced by psychological factors such as psychosocial stress and depression. The significance of altered brain levels of creatine in drug-exposed individuals and the role of creatine supplementation in models of drug abuse have yet to be explored and represent gaps in the current understanding of brain energetics and addiction.     

Social Transmission of Feeding Techniques in Tonkean Macaques?

We studied the influence of social partners on food processing and drinking techniques in a semifree-ranging group of Tonkean macaques. In a first study, immature subjects observed their mothers repeateadly eating unfamiliar fruits. They were subsequently allowed to consume the same fruits. We found no evidence for social learning when comparing the technical variants used by the mother and her offspring. In a second study, we recorded the techniques displayed by the monkeys while drinking and eating familiar food. We compared the technical variants used by the members of two different maternal lineages. Whereas a majority of techniques did not differ between lineages, some variants were peculiar to each of them, this effect was independent from age. The results indicate that the possibility of technique transmission should not be excluded among macaques.     

Drug Users in Amsterdam: Are They Still at Risk for HIV?

Background and Aims

To examine whether drug users (DU) in the Amsterdam Cohort Study (ACS) are still at risk for HIV, we studied trends in HIV incidence and injecting and sexual risk behaviour from 1986 to 2011.

Methods

The ACS is an open, prospective cohort study on HIV. Calendar time trends in HIV incidence were modelled using Poisson regression. Trends in risk behaviour were modelled via generalized estimating equations. In 2010, a screening for STI (chlamydia, gonorrhoea and syphilis) was performed. Determinants of unprotected sex were studied using logistic regression analysis.

Results

The HIV incidence among 1298 participants of the ACS with a total follow-up of 12,921 person-years (PY) declined from 6.0/100 PY (95% confidence interval [CI] 3.2–11.1) in 1986 to less than 1/100 PY from 1997 onwards. Both injection and sexual risk behaviour declined significantly over time. Out of 197 participants screened for STI in 2010–2011, median age 49 years (IQR 43–59), only 5 (2.5%) were diagnosed with an STI. In multivariable analysis, having a steady partner (aOR 4.1, 95% CI 1.6–10.5) was associated with unprotected sex. HIV-infected participants were less likely to report unprotected sex (aOR 0.07, 95% CI 0.02–0.37).

Conclusions

HIV incidence and injection risk behaviour declined from 1986 onwards. STI prevalence is low; unprotected sex is associated with steady partners and is less common among HIV-infected participants. These findings indicate a low transmission risk of HIV and STI, which suggests that DU do not play a significant role in the current spread of HIV in Amsterdam.     

Field Validity and Feasibility of Four Techniques for the Detection of Trichuris in Simians: A Model for Monitoring Drug Efficacy in Public Health?

Background

Soil-transmitted helminths, such as Trichuris trichiura, are of major concern in public health. Current efforts to control these helminth infections involve periodic mass treatment in endemic areas. Since these large-scale interventions are likely to intensify, monitoring the drug efficacy will become indispensible. However, studies comparing detection techniques based on sensitivity, fecal egg counts (FEC), feasibility for mass diagnosis and drug efficacy estimates are scarce.

Methodology/Principal Findings

In the present study, the ether-based concentration, the Parasep Solvent Free (SF), the McMaster and the FLOTAC techniques were compared based on both validity and feasibility for the detection of Trichuris eggs in 100 fecal samples of nonhuman primates. In addition, the drug efficacy estimates of quantitative techniques was examined using a statistical simulation. Trichuris eggs were found in 47% of the samples. FLOTAC was the most sensitive technique (100%), followed by the Parasep SF (83.0% [95% confidence interval (CI): 82.4–83.6%]) and the ether-based concentration technique (76.6% [95% CI: 75.8–77.3%]). McMaster was the least sensitive (61.7% [95% CI: 60.7–62.6%]) and failed to detect low FEC. The quantitative comparison revealed a positive correlation between the four techniques (Rs = 0.85–0.93; p<0.0001). However, the ether-based concentration technique and the Parasep SF detected significantly fewer eggs than both the McMaster and the FLOTAC (p<0.0083). Overall, the McMaster was the most feasible technique (3.9 min/sample for preparing, reading and cleaning of the apparatus), followed by the ether-based concentration technique (7.7 min/sample) and the FLOTAC (9.8 min/sample). Parasep SF was the least feasible (17.7 min/sample). The simulation revealed that the sensitivity is less important for monitoring drug efficacy and that both FLOTAC and McMaster were reliable estimators.

Conclusions/Significance

The results of this study demonstrated that McMaster is a promising technique when making use of FEC to monitor drug efficacy in Trichuris.     

Transmission consequences of coinfection: cytokines writ large?

Coinfection of a host by multiple parasite species is commonly observed and recent epidemiological work indicates that coinfection can enhance parasite transmission. This article proposes an immunoepidemiological framework to understand how within-host interactions during coinfection might affect between-host transmission. Cytokines, immune signalling molecules with a fundamental role in the amplification of antiparasitic effector mechanisms, provide a useful way to simplify immunological complexity for this endeavour--focusing on cytokines offers analytical tractability without sacrificing realism. Testable predictions about the epidemiological consequences of coinfection are generated by this conceptual framework.     

Transmission vs. Diffuse Transmission in Circular Dichroism: What to Choose for Probing Solid‐State Samples?

Recent advances in equipment enabled the collection of solid‐state electronic circular dichroism (ECD) spectra using the commercially available integrating sphere attachment for a regular ECD spectrometer. This accessory was designed to reduce negative factors occurring in solid‐state ECD measurements, and is, thereby, very useful for recording diffuse transmittance CD (DTCD) spectra using the pellet technique. In the present article, the operating principle of the integrating sphere and utility of the DTCD method in recording solid‐state ECD spectra is demonstrated. Based on illustrative examples, i.e., 10‐camphorsulfonic acid ammonium, cholest‐4‐en‐3‐one, (3R,4R,5S)‐oseltamivir, and (S)‐linezolid, ECD solid‐state measurements were performed by means of both transmission and diffusion methods and later compared. Selection of these compounds as models for comparative studies was made in view of their different chromophoric systems and the profound importance in the pharmaceutical industry. During the course of this work the benefits and limitations of the use of integrating sphere are presented. The final conclusion is that more relevant solid‐state spectra can be obtained by means of the DTCD method. Chirality 27:441–448, 2015. © 2015 Wiley Periodicals, Inc.     

Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re-engineered to serve as a new candidate therapeutic agent. The L-glutamate-gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L-glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L-glutamate-induced hyper-excitation and toxicity. Variant GluCls, with their inhibitory responses to L-glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L-glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.     

Was the initiation of translation in early eukaryotes IRES-driven?

The initiation of translation in eukaryotes generally involves the recognition of a 'cap' structure at the 5' end of the mRNA. However, for some viral and cellular mRNAs, a cap-independent mechanism occurs through an mRNA structure known as the internal ribosome entry site (IRES). Here, I postulate that the first eukaryotic mRNAs were translated in a cap-independent, IRES-driven manner that was then superseded in evolution by the cap-dependent mechanism, rather than vice versa. This hypothesis is supported by the following observations: (i) IRES-dependent, but not cap-dependent, translation can take place in the absence of not only a cap, but also many initiation factors; (ii) eukaryotic initiation factor 4E (eIF4E) and eIF4G, molecules absolutely required for cap-dependent translation, are among the most recently evolved translation factors; and (iii) functional similarities suggest the evolution of IRESs from spliceosomal introns. Thus, the contemporary cellular IRESs might be relics of the past.     

A review of adsorption of amino acids on minerals: Was it important for origin of life?

Minerals more readily adsorb amino acids with charged R groups than uncharged R groups, so that the incorporation of amino acids with charged R groups into peptides would be more frequent than for amino acids with uncharged R groups. However, 74% of the amino acids in the proteins of modern organisms contain uncharged R groups. Thus, what could have been the mechanisms that produced peptides/proteins with more amino acids with uncharged R groups than precursors with charged R groups? Should we expect the composition of amino acids adsorbed on minerals to be similar to those of present proteins? Was the adsorption of amino acids on minerals important for the origin of life? The lipid world offers an alternative view of origin of life. Liposomes contributed to elongation of peptides as well as select hydrophobic amino acids and peptides. These experiments could be showing the mechanism, which hydrophobic amino acids have been selected. However, liposomes have no influence on the stereoselectivity in the oligomerization of amino acids. In the present paper, several other mechanisms are also discussed that could produce peptides with a greater proportion of amino acids with uncharged R groups.     

Transependymal Cerebrospinal Fluid Flow: Opportunity for Drug Delivery?

Drug delivery to the central nervous system (CNS) is complicated by the blood-brain barrier. As a result, many agents that are found to be potentially effective at their site of action cannot be sufficiently or effectively delivered to the CNS and therefore have been discarded and not developed further for clinical use, leaving many CNS diseases untreated. One way to overcome this obstacle is intracerebroventricular (ICV) delivery of the therapeutics directly to cerebrospinal fluid (CSF). Recent experimental and clinical findings reveal that CSF flows from the ventricles throughout the parenchyma towards the subarachnoid space also named minor CSF pathway, while earlier, it was suggested that only in pathological conditions such as hydrocephalus this form of CSF flow occurs. This transependymal flow of CSF provides a route to distribute ICV-infused drugs throughout the brain. More insight on transependymal CSF flow will direct more rational to ICV drug delivery and broaden its clinical indications in managing CNS diseases.