“
“The brain-specific Ras/Rap-GTPase activating protein (SynGAP) is a prime candidate linking N-methyl-d-aspartate receptors to the regulation of the ERK/MAP kinase signalling cascade, suggested to be essential for experience-dependent synaptic plasticity. Here, we evaluated the behavioural phenotype of SynGAP heterozygous knockout mice (SG+/−), expressing roughly half the normal levels of SynGAP. In the cognitive domain, SG+/− mice demonstrated severe working and reference memory deficits in the radial arm maze task, a mild impairment early in the transfer

test of the water maze task, and a deficiency in spontaneous alternation in an elevated T-maze. In the non-cognitive domain, SG+/− mice were hyperactive in the open field and appeared less anxious in the elevated plus maze test. In contrast, object recognition MK 2206 memory performance was not impaired in SG+/− mice. The reduction in SynGAP thus resulted in multiple behavioural traits suggestive of aberrant cognitive and non-cognitive processes

Selleck Roxadustat normally mediated by the hippocampus. Immunohistochemical evaluation further revealed a significant reduction in calbindin-positive interneurons in the hippocampus and doublecortin-positive neurons in the dentate gyrus of adult SG+/− mice. Heterozygous constitutive deletion of SynGAP is therefore associated with notable behavioural as well as morphological phenotypes indicative of hippocampal dysfunction. Any suggestion of a possible causal link between them however remains a matter for further investigation. “
“Certain bipolar cells in most species immunostain for GABA or its synthesizing enzyme glutamic acid decarboxylase. However, it is unknown whether they actually release GABA and, if so, from which cellular compartment and by what release mechanism. We investigated these questions in monkey retina where rod bipolar cells immunostain for GABA. We found that rod bipolar cells immunostain for one isoform of GAD (GAD65) in their somas, dendrites and axon terminals. Near the fovea, the somatic clonidine stain of rod bipolar cells is

weaker than that of horizontal cells but, at the periphery, it is stronger. Staining for the vesicular GABA transporter in monkey rod bipolar cells is negative. However, staining for the GABA transporter GAT3 is positive in the soma and primary dendrites (but not in the axon terminals). Staining for GAT3 is also positive in horizontal cells. Double staining of rod bipolar cells and the alpha subunit of the GABAA receptor reveals scarce GABAA puncta that appose rod bipolar dendrites. We conclude that monkey rod bipolar cells use GABA and discuss the possibility that they tonically release GABA from their dendrites using a reverse action of GAT3. “
“Presynaptic Ca2+ influx pathways, cytoplasmic Ca2+ buffering proteins and Ca2+ extrusion processes undergo considerable change during the first postnatal month in rodent neurons.

They should receive the same general travel advice concerning the prevention of malaria as the HIV-seronegative traveller, i.e. the ABCD of malaria prevention should be emphasized: Awareness of risk, Bite prevention, Chemoprophylaxis and prompt Diagnosis and treatment

(see [22]). The advice regarding chemoprophylaxis depends on the area visited, time spent and medical history and specialist advice is available from the National Travel Health Network and Centre (NaTHNaC) [23] funded by the Department of Health for England or ‘Fit for Travel’ [24] in Scotland. Although co-trimoxazole may reduce the risk of developing malaria, HIV-seropositive patients receiving co-trimoxazole should still receive standard malaria chemoprophylaxis and follow all the general advice around prevention of AP24534 malaria. The main options for chemoprophylaxis are mefloquine 250 mg orally once weekly, Malarone (atovaquone–proguanil) one tablet once daily and doxycycline 100 mg orally once daily. Chloroquine-based regimens (chloroquine 300 mg once weekly with proguanil 200 mg orally once daily) are less

used now due to widespread resistance. Regimens are started 1 week prior to travel and continued for 4 weeks after return with the exception of Malarone (atovaquone–proguanil) which is started 1–2 days before travel and continued for 1 week after return and mefloquine which should be started 3–4 weeks prior to travel, www.selleckchem.com/products/RO4929097.html if treatment naïve, to give the individual time to develop neurocognitive side effects and to change to an alternative agent, if necessary, prior to travel. Mefloquine is contraindicated Nintedanib price in patients with a history of epilepsy, neuropsychiatric disorders including depression, liver impairment and cardiac conduction disorders. Neurocognitive

side effects with mefloquine are more common in women, those with low body mass index (BMI), those embarking on long-term travel and those with a history of recreational drug use [25,26]. They are particularly common in younger adults and many authorities would therefore avoid this agent in younger adults, particularly if female, with a low BMI or with a history of recreational drug use. In pregnancy, the use of mefloquine requires careful risk–benefit analysis and specialist advice should be sought. Mefloquine antagonizes the anticonvulsant effect of valproate and increases the incidence of cardiac conduction problems with moxifloxacin. Other areas of advice to emphasize include the use of high percentage (greater than 20%) diethyltoluamide (DEET), covering up extremities when out after dark and use of permethrin-impregnated mosquito nets to sleep under. Leishmaniasis is a group of diseases caused by protozoa of the genus Leishmania that are transmitted by sandflies, and, rarely, by injecting drug use.

Subjects and methods:  This study included 60 patients with various rheumatic diseases (20 with RA, 20 with SLE and 20 with OA), as well as 10 healthy controls. All of them were subjected to complete history-taking, examination and estimation of disease activity index. The following investigations were done for all subjects: serum and synovial activin A, inhibin A, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anti-dsDNA and complements 3 and 4. Results:  Serum levels of activin A were significantly higher in RA, SLE and OA than controls and in RA and SLE versus OA The mean values of serum inhibin buy Staurosporine A were significantly higher in all studied groups than

controls. Synovial activin A and inhibin A were significantly higher in RA than OA. Positive correlations were found between serum activin HM781-36B mw A and disease activity

parameters of RA. In SLE, positive correlations were found between serum activin A and inhibin A with ESR and SLE Disease Activity Index. Conclusions:  Serum activin A and inhibin A were significantly higher in RA and SLE. Serum levels correlated positively with disease activity parameters of RA and SLE. However, synovial levels were significantly higher in RA than OA but showed no correlation or negative correlation with disease activity. We recommend further studies to detect the exact role of activin A and inhibin A in these conditions. “
“Aim:  In Behcet’s disease (BD), it is customary to believe that men are more affected than women, major organs are more involved in men, and they have worse outcomes. The male-to-female ratio

is reported from 5.37 to 1 (Egypt), to 0.38 to 1 (US). If in the majority of reports BD was seen more frequently in men, in some others it was more frequent in women. The aim of this study was to examine a large cohort of patients, in whom manifestations were gender related, selleck products and to examine the strength of associations and their clinical relevance. Patients and Methods:  All patients of the BD registry, Rheumatology Research Center, Tehran University of Medical Sciences, entered the study (6702 patients). The percentage of 95 items was calculated in both genders (with their 95% confidence intervals), and were compared together by the chi-squared test. Odds ratio (OR) and relative risk (RR) were also calculated. Results:  Forty-three out of 95 items were gender-related (29 for males, 14 for females) with a statistically significant difference by chi-squared. Significant OR (confidence interval not reaching 1) was found for 79 items. However, clinically significant OR (2 or more for men and 0.5 or less for women) showed an association only with 16 items; five with females and 11 with males. The most important was vascular involvement.

Synthetic peptides were used to generate specific primary antisera against the M. oxyfera NirS (α-NirS) and pMMO (α-pMmoB1) in rabbits. We additionally cloned and heterologously expressed a fragment of pmoB in E. coli and used the expressed fragment to raise antiserum (α-pMmoB2). All antisera were affinity-purified and their specificity was tested on whole-cell extract of the M. oxyfera enrichment culture using SDS-PAGE and immunoblot analysis. Incubations with the antiserum targeting NirS showed a band of approximately the expected size (58.2 kDa; Fig. 2, lane 6). No bands were detected in blots incubated with blocking

buffer or preimmune serum instead of the antiserum (negative controls; data not shown). For the

antisera against pMMO, both α-pMmoB1 and α-pMmoB2 showed a band of about the expected size (44.2 kDa; Fig. 2, lanes selleck chemicals llc 2 and 4), which were absent when incubated with either blocking buffer or preimmune serum instead of the antiserum (negative controls; data not shown). When using the same antisera dilutions, a stronger signal was observed when using α-pMmoB2 compared to α-pMmoB1. These results showed that the derived antisera were specific for the targeted proteins and provide a reliable basis for immunogold localization of the enzymes in ultrathin sections of M. oxyfera cells. Cells from the M. oxyfera enrichment culture were chemically fixed and cryosectioned. Methylomirabilis oxyfera cells could be distinguished from other cells of the community by their polygonal cell shape (Wu et al., Akt inhibitor 2012). The identity of the polygon-shaped cells to M. oxyfera has been confirmed previously by fluorescence in situ hybridization (FISH) using ‘NC10’; Etomidate bacteria-specific probes (Wu et al., 2012). As in our previous study, the polygon-shaped M. oxyfera cells lacked ICM and the configuration of the cytoplasmic membrane was predominantly smooth and devoid of invaginations (Fig. 3). Cells from the other community members were morphologically diverse. The negative control where ultrathin sections of M. oxyfera cells were incubated with PAG5 or PAG10 alone showed no background labelling (data not shown). Likewise,

cross-reactivity of the affinity-purified antisera with other cells was not detected. In the incubations with α-pMmoB1 or α-pMmoB2, only M. oxyfera cells were specifically labelled. The gold particles occurred at or close to the cytoplasmic membrane (Fig. 3). As for immunoblot analysis, more labelling was observed when using α-pMmoB2 compared to α-pMmoB1 when using the same antisera dilutions. Ultrathin cryosections of M. oxyfera cells were incubated with α-NirS for the determination of the intracellular location of this enzyme. Labelling was observed only in the polygon-shaped M. oxyfera cells (Fig. 4). The negative control where ultrathin sections of M. oxyfera cells were incubated with PAG5 or PAG10 alone showed no background labelling (data not shown).

These are single-strand (DNA) annealing proteins (SSAPs) that are related to the ERF protein of phage P22 that mediates circularization of linear double-stranded DNA following infection of the host cell (Poteete, 1982). The gene product

of PHIEF11_0044 also shows similarity to a single-stranded DNA-binding protein of a prophage of S. pyogenes MGA55005, and an SSAP of Lactococcus phage ul36.13. PHIEF11_0045 shows similarity to a replication protein of L. johnsonii prophage Lj928 (Table 1) and is presumably involved http://www.selleckchem.com/products/DAPT-GSI-IX.html in the replication of the φEf11 DNA. Replisome organizers, such as the DnaA protein of E. coli, function as initiators of DNA replication. They act by binding to the origin of replication (ori) and promote unwinding of the DNA. The unwound region of the DNA allows access of helicases such as DnaB/DnaC, and other proteins required for DNA polymerization, to replicate the DNA (Missich et al., 1997; Majka et al., 2001). PHIEF11_0047 contains a conserved domain of phage replisome organizer proteins from several different phages (Table 1). These include similarities in sequence to the replisome organizer domains of proteins from Listeria monocytogenes phage A118, S. aureus phage 52A, a Clostridium botulinum phage, and Streptococcus mitis phage SM10. Therefore,

PHIEF11_0047 appears to be a replisome organizer protein. Additional genes in the DNA replication/modification module include a putative methyltransferase (PHIEF11_0050), an JAK inhibitor ASCH domain protein (PHIEF11_0054), and a SbcC domain protein (PHIEF11_0061). The domains found in these gene products are all associated with DNA replication functions. In addition, the final gene of this module (PHIEF11_0065) is similar to a gene of S. pyogenes phage SM1 that is in turn similar in sequence to a gene of Streptococcus phage NZ131.3 that functions in DNA replication (e.g. DNA polymerase III β-subunit/dnaN). PHIEF11_0062 has a significant HMM match to PF02195: ParB-like nuclease domain, suggesting a possible role in DNA replication. The location of

the lysogenized φEf11 genome within the lysogenic host TUSoD11 was investigated computationally by mapping the complete genome of φEf11 to the unfinished (draft) genome of E. faecalis strain TUSoD11 Carnitine dehydrogenase (GenBank accession ACOX00000000), using NUCMER (Delcher et al., 2002). Analysis of the SHOW-COORDS output of the NUCMER package indicated the integrated genome of φEf11 spread across three contigs (ACOX01000066, 44 534 bp; ACOX01000045, 647 bp; and ACOX01000055, 103 862 bp), ordered relative to the φEf11 genome beginning with the integrase gene. Examination of the ends of alignments with TUSoD11 as the reference revealed a putative 27 bp attachment site with the sequence (ACTAAGCAAGTGCCGCCATGTGTCTGA), manifested as a direct repeat.

These are single-strand (DNA) annealing proteins (SSAPs) that are related to the ERF protein of phage P22 that mediates circularization of linear double-stranded DNA following infection of the host cell (Poteete, 1982). The gene product

of PHIEF11_0044 also shows similarity to a single-stranded DNA-binding protein of a prophage of S. pyogenes MGA55005, and an SSAP of Lactococcus phage ul36.13. PHIEF11_0045 shows similarity to a replication protein of L. johnsonii prophage Lj928 (Table 1) and is presumably involved Inhibitor Library high throughput in the replication of the φEf11 DNA. Replisome organizers, such as the DnaA protein of E. coli, function as initiators of DNA replication. They act by binding to the origin of replication (ori) and promote unwinding of the DNA. The unwound region of the DNA allows access of helicases such as DnaB/DnaC, and other proteins required for DNA polymerization, to replicate the DNA (Missich et al., 1997; Majka et al., 2001). PHIEF11_0047 contains a conserved domain of phage replisome organizer proteins from several different phages (Table 1). These include similarities in sequence to the replisome organizer domains of proteins from Listeria monocytogenes phage A118, S. aureus phage 52A, a Clostridium botulinum phage, and Streptococcus mitis phage SM10. Therefore,

PHIEF11_0047 appears to be a replisome organizer protein. Additional genes in the DNA replication/modification module include a putative methyltransferase (PHIEF11_0050), an BVD-523 chemical structure ASCH domain protein (PHIEF11_0054), and a SbcC domain protein (PHIEF11_0061). The domains found in these gene products are all associated with DNA replication functions. In addition, the final gene of this module (PHIEF11_0065) is similar to a gene of S. pyogenes phage SM1 that is in turn similar in sequence to a gene of Streptococcus phage NZ131.3 that functions in DNA replication (e.g. DNA polymerase III β-subunit/dnaN). PHIEF11_0062 has a significant HMM match to PF02195: ParB-like nuclease domain, suggesting a possible role in DNA replication. The location of

the lysogenized φEf11 genome within the lysogenic host TUSoD11 was investigated computationally by mapping the complete genome of φEf11 to the unfinished (draft) genome of E. faecalis strain TUSoD11 Protein kinase N1 (GenBank accession ACOX00000000), using NUCMER (Delcher et al., 2002). Analysis of the SHOW-COORDS output of the NUCMER package indicated the integrated genome of φEf11 spread across three contigs (ACOX01000066, 44 534 bp; ACOX01000045, 647 bp; and ACOX01000055, 103 862 bp), ordered relative to the φEf11 genome beginning with the integrase gene. Examination of the ends of alignments with TUSoD11 as the reference revealed a putative 27 bp attachment site with the sequence (ACTAAGCAAGTGCCGCCATGTGTCTGA), manifested as a direct repeat.

For yellow fever regions, they should usually be given a yellow fever vaccine waiver letter stating that the contraindication to vaccination is acceptable to most governments; such letters should bear the stamp of an official, approved yellow fever immunization center. While some less immunosuppressed travelers have tolerated the vaccine, including individuals with a distant history of hematological malignancy,[8, 9] complications including death have been reported in immunosuppressed individuals after vaccination[10] and recommendations avoid its use in immunocompromised travelers.[11]

The findings of Mikati and colleagues[6] that immunocompetent travelers were more likely to visit regions endemic for yellow fever than immunocompromised travelers (22% vs selleck inhibitor 11%, p = 0.07) may reflect education steering them away from these zones. Practitioners caring for immunocompromised hosts may find the following sites useful in providing country-specific information that may assist with Selleckchem FK506 preliminary information: for example, the Centers for Disease Control and Prevention Travelers’ Health site (wwwnc.cdc.gov/travel/destinations/list.htm), the World Health Organization (www.who.int/ith/chapters/en/index.html), or MD Travel Health (www.mdtravelhealth.com). A new book on travel medicine for patients has a

special section on travel medicine for immunocompromised hosts.[12] Clinicians should be aware that patients may return with unexpected pathogens, including both geographically restricted illnesses (ie, dengue and hepatitis E), and also routine but more resistant pathogens (ie, multidrug-resistant Salmonella[13] and extended-spectrum beta-lactamase producing organisms[14]). Lastly, certain diseases may especially affect immunocompromised hosts even years later. Leishmaniasis can alter the presentation, diagnosis, and course of various malignant disorders.[15] Other pathogens can reactivate in the setting of immunosuppression,

ie Mycobacterium tuberculosis and Strongyloides stercoralis, and chemoprophylaxis should be given to those shown to have (or at high risk for) latent infection before starting immunosuppressive drugs.[16] The importance of both prevention via pre-travel medicine and a detailed travel history Liothyronine Sodium remains crucial in providing optimal care. The author states she has no conflict of interest to declare. “
“This issue of the Journal of Travel Medicine contains two articles drafted by an expert committee of the International Society of Travel Medicine (ISTM) charged with examining what it means to be a traveler who visits friends and relatives (VFR).1,2 They have arrived at the decision that a new definition is needed. Previous definitions of VFR travelers usually included variations on the theme that the travelers involved were recent immigrants who were returning to their country of origin to visit friends and relatives.

g. Heun et al., 2004; Fischer et al., 2005). Thus, if tSOS had induced synaptic down-scaling mainly in anterior neocortical networks, this should have also improved learning on the finger sequence

tapping task. Slow oscillations support the long-term consolidation of hippocampal memories, presumably by driving the neuronal replay and redistribution of newly encoded hippocampal representations towards neocortical sites of long-term storage (Marshall et al., 2006; Ji & Wilson, 2007; Diekelmann & Born, 2010). The present data suggest that the down-scaling and memory-consolidating actions of slow oscillations in the hippocampus are linked, such that the slow oscillation-induced PS 341 reactivation and redistribution of recently encoded memories results in a freeing of hippocampal capacities for the encoding of new information. It is known that sleep and, particularly, SWS facilitate consolidation of hippocampus-dependent declarative memories. In addition, findings after sleep deprivation have pointed to a ‘forward’ role of sleep in promoting the learning

of new materials during subsequent wakefulness (McDermott et al., 2003; Yoo et al., 2007). The involvement of SWA was indicated by a recent study revealing impaired encoding of declarative memories after suppression of SWA (Van Der Werf et al., 2009). In selleck chemicals llc contrast, our study demonstrates a direct enhancing effect of tSOS-induced SWA on the encoding of declarative memory. In combination, these findings corroborate a causal

link between sleep SWA and the renewal of hippocampal encoding capacities. Because procedural learning did not benefit from enhanced SWA, SWA-dependent renewal of encoding capacities and the putative underlying processes of synaptic down-scaling appear to predominantly impact on hippocampal networks. We thank Horst Koller and Lisa Marshall for technical support. This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 654) and the BMBF (01GQ0973). Abbreviations EEG Electroencephalogram IL interference list REM rapid eye movement RMS root mean square SWA slow wave activity SWS slow wave sleep tSOS transcranial slow oscillation stimulation “
“The many sudden appearance of a novel stimulus initiates a series of responses to orient the body for appropriate actions, including not only shifts of gaze and attention, but also transient pupil dilation. Modulation of pupil dynamics by stimulus properties is less understood, although its effects on other components of orienting have been extensively explored. Microstimulation of the superior colliculus evoked transient pupil dilation, and the initial component of pupil dilation evoked by microstimulation was similar to that elicited by the presentation of salient sensory stimuli, suggesting a coordinated role of the superior colliculus on this behavior, although evidence in humans is yet to be established.

Total RNA was isolated using RNAprotect Bortezomib mouse Bacteria Reagent and RNeasy Plus Mini kit (Qiagen). cDNA was generated using iScript

cDNA synthesis kit (Bio-Rad). Expression of nla6S was normalized to that of rpoD, which is expressed at similar levels during growth and development (Fig. S1). Primers for QPCR were designed to produce 178- and 169-bp amplicons of the nla6S and rpoD genes, respectively. QPCR experiments were performed in triplicate. The annotated genome sequence of M. xanthus indicates that the nla6S gene (MXAN4043) encodes a putative HK (Goldman et al., 2006). To examine whether nla6S may function during the formation of fruiting bodies, developmental expression of nla6S in wild-type M. xanthus cells was monitored using QPCR. As shown in Fig. 1, nla6S mRNA is induced in two phases, with the first induction phase starting between 0.5- and 1-h poststarvation and the second induction buy Palbociclib phase starting between 2.5- and 3-h poststarvation. The peak nla6S mRNA level in both phases is about sixfold higher

than that observed in growing cells (0 h), indicating that nla6S is developmentally regulated and that Nla6S is likely to be involved in fruiting body development. We also attempted to examine the development function of nla6S via mutational analysis. However, we were unable to generate an nla6S deletion mutant, and the nla6 insertion mutant that we generated had a severe growth defect and was unstable (data not shown). These findings suggest that nla6S plays a role in vegetative growth out and fruiting body development in M. xanthus. Nla6S is predicted to be a cytoplasmic protein. An alignment of the putative Nla6S transmitter domain with those of known HKs suggests that Nla6S has a DHp domain (Fig. 2).

However, Nla6S lacks most of the conserved motifs found in the CA domain of HKs; the D-Box is the only conserved sequence motif that was identified (Fig. 2). The putative secondary structure of Nla6S was examined using the Jpred3 secondary structure prediction server (Cole et al., 2008), and the C-terminal domain of the protein that contains the D-box motif was predicted to have four α helices and five β strands arranged in the following order: α1, β1, β2, α2, β3, β4, α3, β5, α5. This secondary structure composition and arrangement is similar to that of previously characterized CA domains (Tanaka et al., 1998; Marina et al., 2001; Song et al., 2004), suggesting that the region containing the D-box motif might be a CA domain. When an HK senses a particular signal, the CA region of the transmitter domain binds and hydrolyzes ATP. To determine whether the putative Nla6S transmitter domain has ATPase activity, we used a colorimetric assay that couples the hydrolysis of ATP to the oxidation of NADH (Lascu et al., 1983). A polyhistidine-tagged version of the well-characterized E.

Regarding the specific form of neurocysticercosis (as documented by neuroimaging studies), 21 patients (40%) had a single cysticercus granuloma. Of the remaining patients, 25 had other forms of parenchymal brain cysticercosis and six had extraparenchymal neurocysticercosis (including

three patients with spinal cysts). Twenty patients had an electroimmunotransfer blot (EITB) test for the detection of anticysticercal antibodies in serum, which was positive in 15 cases. Resection of the cerebral lesion for diagnostic purposes was performed in 20 patients, and 22 patients received specific therapy with cysticidal drugs (albendazole or praziquantel). All but three of the 52 patients had a definitive diagnosis of neurocysticercosis according to currently accepted diagnostic criteria.41 Evolution was available www.selleckchem.com/products/cx-4945-silmitasertib.html only in 15 cases (all recovered). Considering the millions of people who have traveled from nonendemic to cysticercosis-endemic countries during the past 30 years, and then the number of reported cases, the risk of neurocysticercosis acquisition by international travelers is very low, and it seems to be even lower for short-term travelers. As noted, the aim of this study is

to provide objective evidence on the pattern of disease expression of neurocysticercosis in citizens from nonendemic countries who acquired neurocysticercosis after a travel to a disease-endemic region. There are some papers (mainly from the United States and Spain) which mention the occurrence of this parasitic disease CHIR-99021 cost in international travelers, but the information they provides is vague and data cannot be abstracted; that is Phosphatidylinositol diacylglycerol-lyase why those publications were not considered in this review.42–44 To acquire the disease, travelers must be in contact with a taenia carrier, who will infect them by the fecal-oral route (most often through unhygienic handling of food). While possible, it is unlikely that a given person gets infected after sporadic contact. Another possibility is that travelers get in direct contact with human feces by visiting places

where open-air defecation is a common practice, as occurs in rural villages of developing countries.45 Finally, it is also possible that travelers first become taenia carriers (by ingesting undercooked pork meat infected by cysticerci) and then infected themselves by the fecal-oral route. The most common pattern of neurocysticercosis expression in travelers, ie, a single cysticercus granuloma, suggests that the usual form of disease acquisition is through sporadic contact with taenia carriers food-handlers. Otherwise, travelers would more often presented with heavier infections, which are typically observed in taenia carriers who infected themselves or in those who ingest a heavy load of T solium eggs directly from nature.46,47 A main unsolved issue is why most travelers developed symptoms several years after returning home.