While epidemiologic and clinical research often aims to analyze predictors of specific endpoints, time-to-the-specific-event analysis can be hampered by problems with cause ascertainment. Under typical assumptions of competing risks analysis (and missing-data settings), we correct the cause-specific proportional hazards analysis when information on the reliability of diagnosis is available. Our method avoids bias in effect estimates at low cost in variance, thus offering a perspective for better-informed decision-making. The ratio of different cause-specific hazards can be estimated flexibly for this purpose. It thus complements an all-cause analysis. In a sensitivity analysis, this approach can reveal the likely extent and direction of the bias of a standard cause-specific analysis when the diagnosis is suspect. These two uses are illustrated in a randomized vaccine trial and an epidemiologic cohort study respectively.
A 45-year-old female with underlying idiopathic thrombocytopenic purpura (ITP) complained of acute onset of reduced vision and floaters, in both eyes, for 3 weeks. Visual acuity was 6/36 and 6/60 in the right eye and left eye, respectively. Ophthalmoscopy showed bilateral peripapillary, subhyaloid and vitreous hemorrhage. Hematological evaluation revealed moderate anemia (hemoglobin: 93 g/L) and mild thrombocytopenia (platelets: 120×109/L). She was co-managed by a hematologist and ophthalmologists; she was treated medically. Follow-up care during the next 6 weeks revealed spontaneous, partially resolving hemorrhage, with improvement of visual acuity. The purpose of this case report is to highlight ophthalmic involvement of ITP in this patient, despite her only-mild thrombocytopenia, and her spontaneous recovery, despite her receiving only medical treatment.
idiopathic thrombocytopenic purpura; subhyaloid hemorrhage; vitreous hemorrhage
The QuantiFERON®-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-γ) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-γ is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation.
Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-γ was measured in automated and manual ELISAs. Variability in interpretations and IFN-γ measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-γ measurements was also assessed on separate groups stratified by the mean of the four ELISAs.
Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within-subject variability was greater with higher IFN-γ measurements and with manual ELISAs. For subjects with mean TB Responses ±0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22–0.37) IU/mL vs. 0.09 (CI95 = 0.07–0.12) IU/mL for two automated tests.
QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-γ release assays (IGRAs).
Since 1953, leptospirosis has been recognized as a public health problem on Reunion Island. In 2004, was implemented a specific surveillance system that included systematic reporting and the realization of environmental investigations around hospitalized cases. Here, we present the synthesis of historical data and the assessment of 9 years of leptospirosis surveillance. From 2004 to 2012, 414 hospitalized cases were reported. Cases of leptospirosis occurred mostly during the rainy season from December to May. Approximately 41% of infections occurred at home, 12% of infections occurred during aquatic leisure and 5% of cases were linked to professional activities. Furthermore, for 41% of cases, the place of infection could not be determined due to the accumulation of residential and non-residential exposure. Most of the cases of leptospirosis were linked to rural areas or traditional, rural occupations. We did not observe a shift to recreational leptospirosis as described in some developed countries. According to the new surveillance system, the number of reported cases has regularly increased since 2004. This situation is in part due to the improvement of the system in the first years but also to a real increase in the number of detected cases due to the introduction of molecular methods and to increased biological investigation into the Dengue-like syndrome by medical practitioners on the island since the Chikungunya crisis in 2006. This increase is probably due to surveillance and diagnosis biases but need to be carefully monitored. Nevertheless, the possibility of an outbreak is always present due to climatic events, such as after the “hyacinth” hurricane in 1980.
leptospirosis; epidemiology; surveillance; human; Reunion Island; Indian Ocean
To characterize the immunity developed by patients infected by chikungunya virus (CHIKV), we studied the intensity and specificity of CHIKV-specific T cells mediated responses in chronic and recovered patients at 12 to 24 months post-infection. T cells were challenged in vitro against CHIKV synthetic peptides covering the length of three viral proteins, capsid, E2 and nsP1 proteins as well as all inactivated virus particles. Cytokine production was assessed by ELISPOT and intracellular labeling. T cells producing IFN-γ were detected against CHIKV in 85% patient’s cells either by direct ELISPOT assay (69% of patients) or after expansion of memory T cells allowing the detection of both CD4 and CD8 specific-T cells in 16% additional cases. The IFN-γ response was mainly engaged in response to nsP1 or E2 (52% and 46% cases, respectively) but in only 27% cases against the capsid. The anti-E2 response represented half the magnitude of the total CHIKV IFN-γ production and was mainly directed against the C-terminal half part of the protein. Almost all patients had conserved a T cell specific response against CHIKV with a clear hierarchy of T cell responses (CD8 > CD4) engaged against E2 > nsP1 > capsid. More importantly, the intensity of responses was not significantly different between recovered and chronic patients. These findings constitute key elements to a better understanding of patient T cell immunoreactivity against CHIKV and argue against a possible defect of T cell immunoresponse in the chronicity post-CHIKV infection.
Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin.
Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85–95%, and four 30–50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done.
Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction.
We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed.
Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.
Cerebrospinal fluid fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated cryptococcal meningitis. The identification of factors associated with mortality informs strategies to improve outcomes.
Background. Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes.
Methods. Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality.
Results. Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7–5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0–1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4–11.1), high peripheral white blood cell count (>10 × 109 cells/L; OR, 8.7; 95% CI, 2.5–30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age.
In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART).
Conclusions. CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.
cryptococcal meningitis; Cryptococcus neoformans; HIV; antiretroviral therapy; mortality (determinants)
We report on the adherence experience of a group of people living with HIV on ART over six years in Uganda.
Between 2005 and 2009, we followed up 41 participants who were also part of a clinical trial comparing home and facility based delivery of ART in Jinja, eastern Uganda. We conducted qualitative in-depth interviews at enrolment, 3, 6, 18 and 30 months to capture experiences with adherence over time. In 2011 we returned to these participants to find out how they were fairing with long term adherence. We managed to retrace 24 participants and interviewed them about their experience. We thematically analysed the data and compared findings over time.
Initially there were few barriers to adherence and many followed the adherence guidance closely. By year six, relaxation of these rules was noticeable although self-reported adherence continued to be high. Alcohol consumption was more common than before. Some relatives of the participants who had died claimed that some deaths were a result of alcohol. While participants reported that ART had allowed them to reclaim independence and return to work the changes in work and social routines created new challenges for adherence. Side effects like lipodystrophy were not only causing some stigma but for some tested their faith in the drugs. Many participants reported resumption of sexual lives but apart from those who selected same status partners, disclosure to new partners was minimal.
Good adherence practice to ART wanes over the long-term, and people who may have disclosed at initiation find it difficult to do so to new partners once they are healthy. Further adherence interventions and support with disclosure over the course of therapy may need to be considered. (Words: 283)
It is uncertain whether multiple micronutrients benefit the mental and psychomotor development of young children in developing countries. We conducted a randomised double-blind controlled trial to evaluate the effect of a richly micronutrient-fortified v. a basal fortified porridge on mental and psychomotor development in Zambian infants. Infants (n 743) were randomised at age 6 months to receive either the richly fortified or the basal fortified infant food and were followed up until 18 months of age. All the infants were evaluated monthly for achievement of a series of developmental milestones. The Bayley scales of infant development II were administered to a subsample of 502 infants at 6, 12 and 18 months. Rich micronutrient fortification had no significant benefit on the following: (a) number of developmental milestones achieved (rate ratio at 12 months = 1·00; 95 % CI 0·96, 1·05; P=0·81, adjusted for sex, socio-economic status and maternal education, with similar results at 15 and 18 months); (b) ages of walking unsupported (hazard ratio (HR) 1·04; 95 % CI 0·88, 1·24; P=0·63, adjusted for the above covariates) and of speaking three or four clear words (HR 1·01; 95 % CI 0·84, 1·20; P=0·94, adjusted for the above covariates); (c) mental development index (MDI) and psychomotor development index (PDI) of the Bayley scales (scores difference adjusted for baseline scores, age at the assessment, sex, socio-economic status, maternal education, language, age and HIV status: MDI 0·3 (95 % CI −0·5, 1·1), P=0·43; PDI −0·1 (95 % CI −0·9, 0·7), P=0·78). In conclusion, the results do not support the hypothesis that rich micronutrient fortification improves Zambian infants’ mental and motor development.
Micronutrient-fortified food; Mental and psychomotor development; Bayley scales of infant development; Developmental milestones
Oncology patient care is an ever evolving field both as a science and a clinical art. We evaluate, diagnose, and treat cancer patients daily. We break the bad and the good news to them. We are the hope on which their life and dreams hang on. We, as practitioners, have to assess each patient as an intelligent observer. We have to devise our strategy to break heartbreaking news to them in a tailored and personalized fashion according to the physical, psychological, emotional, and social status of the patient. The process has to be gentle, perceptive, pragmatic, yet truthful. These need to be reasonably good observational, listening, comprehending, and delivering potentials; which are sharpened by experience and skills.
End of life; palliative care; Royal hospital
Cryptococcal meningitis (CM) in Africa is associated with up to 70% mortality at 3 months and 500,000 deaths annually. We examined strategies to improve on fluconazole monotherapy: addition of flucytosine (5-FC); and/or addition of short-course amphotericin B (AmB).
In step 1, previously reported, patients were randomized to receive FLU 1200 mg/d with or without 5-FC 100 mg/kg/day for 14 days. In step 2, 43 patients were similarly randomised, with addition of AmB 1 mg/kg/d for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality.
40 patients (25% with Glasgow Coma Scale < 15) were analyzed. EFA for the triple combination arm was greater than for AmB+FLU: −0.50 ± 0.15 log CFU/day vs. −0.38 ± 0.19 log CFU/day (p = 0.03); and greater than step 1 with FLU+5-FC (−0.28 ± 0.17) or FLU alone (−0.11 ± 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, p = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, p = 0.1).
Addition of 5-FC and short course AmB to high-dose FLU significantly enhance EFA and may be associated with favourable trends in survival. Both these strategies should be tested in a larger phase III study.
Cryptococcal; Meningitis; AIDS; Fluconazole; Flucytosine; Amphotericin B
Stigma is a barrier to HIV prevention and treatment. There is a limited understanding of the types of stigma facing people living with HIV (PLHIV) on antiretroviral therapy (ART). We describe the stigma trajectories of PLHIV over a 5-year period from the time they started ART.
Longitudinal qualitative in-depth interviews were conducted with 41 members of The AIDS Support Organisation (TASO) from 2005 to 2008 in Jinja, Uganda, who were part of a pragmatic cluster-randomised trial comparing two different modes of ART delivery (facility and home). Participants were stratified by gender, ART delivery arm and HIV stage (early or advanced) and interviewed at enrolment on to ART and then after 3, 6, 18 and 30 months. Interviews focused on stigma and ART experiences. In 2011, follow-up interviews were conducted with 24 of the participants who could be traced. Transcribed texts were translated, coded and analyzed thematically.
Stigma was reported to be very high prior to starting ART, explained by visible signs of long-term illnesses and experiences of discrimination and abuse. Early coping strategies included: withdrawal from public life, leaving work due to ill health and moving in with relatives. Starting ART led to a steady decline in stigma and allowed the participants to take control of their illness and manage their social lives. Better health led to resumption of work and having sex but led to reduced disclosure to employers, colleagues and new sexual partners. Some participants mentioned sero-sorting in order to avoid questions around HIV sero-status. A rise in stigma levels during the 18 and 30 month interviews may be correlated with decreased disclosure. By 2011, ART-related stigma was even more pronounced particularly among those who had started new sexual relationships, gained employment and those who had bodily signs from ART side-effects.
This study has shown that while ART comes with health benefits which help individuals to get rid of previously stigmatising visible signs, an increase in stigma may be noticed after about five years on ART, leading to reduced disclosure. ART adherence counselling should reflect changing causes and manifestations of stigma over time.
Stigma; Antiretroviral therapy; Disclosure; Uganda; Side effects; Sero-sorting
Background. Vancomycin-resistant enterococci (VRE) are significant nosocomial pathogens worldwide. There is one report about the epidemiology of VRE in Saudi Arabia. Objective. To determine the risk factors associated with VRE infection or colonization in intensive care unit (ICU) settings. Design. This is a descriptive, epidemiologic hospital-based case-control study of patients with VRE from February 2006 to March 2010 in ICU in a tertiary hospital in Saudi Arabia. Methods. Data were collected from hospital records of patients with VRE. The main outcome measure was the adjusted odds ratio estimates of potential risk factors for VRE. Results. Factors associated with VRE included ICU admission for multiorgan failure, chronic renal failure, prior use of antimicrobial agents in the past three months and before ICU admission, gastrointestinal oral contrast procedure, and hemodialysis. Being located in a high risk room (roommate of patients colonized or infected with VRE) was found to be protective. Conclusions. Factors associated with VRE acquisition are often complex and may be confounded by local variables.
Allergic asthma is characterized by Th2 type inflammation, leading to airway hyperresponsivenes, mucus hypersecretion and tissue remodeling. S-Nitrosoglutathione reductase (GSNOR) is an alcohol dehydrogenase involved in the regulation of intracellular levels of S-nitrosothiols. GSNOR activity has been shown to be elevated in human asthmatic lungs, resulting in diminished S-nitrosothiols and thus contributing to increased airway hyperreactivity. Using a mouse model of allergic airway inflammation, we report that intranasal administration of a new selective inhibitor of GSNOR, SPL-334, caused a marked reduction in airway hyperreactivity, allergen-specific T cells and eosinophil accumulation, and mucus production in the lungs in response to allergen inhalation. Moreover, SPL-334 treatment resulted in a significant decrease in the production of the Th2 cytokines IL-5 and IL-13 and the level of the chemokine CCL11 (eotaxin-1) in the airways. Collectively, these observations reveal that GSNOR inhibitors are effective not only in reducing airway hyperresponsiveness but also in limiting lung inflammatory responses mediated by CD4+ Th2 cells. These findings suggest that the inhibition of GSNOR may provide a novel therapeutic approach for the treatment of allergic airway inflammation.
The mechanical environment and properties of the carotid artery play an important role in the formation and progression of atherosclerosis in the carotid bifurcation. The purpose of this work was to measure and compare the range and variation of circumferential stress and tangent elastic moduli in the human common (CCA), external (ECA) and internal (ICA) carotid arteries over the cardiac cycle in vivo.
Measurements were performed in the surgically exposed proximal cervical CCA, distal ECA and distal ICA of normotensive patients (n = 16) undergoing carotid endarterectomy. All measurements were completed in vivo over the cardiac cycle in the repaired carotid bifurcation after the atherosclerotic plaque was successfully removed. B-mode Duplex ultrasonography was used for measurement of arterial diameter and wall thickness, and an angiocatheter placed in the CCA was used for concurrent measurement of blood pressure. A semi-automatic segmentation algorithm was used to track changes in arterial diameter and wall thickness in response to blood pressure. These measurements were then used to calculate the variation of circumferential (hoop) stresses, tangent elastic moduli (the slope of the stress-strain curve at specified stresses), and stress-induced stiffness of the arterial wall (stiffening in response to intraluminal blood pressure fluctuation) for each patient.
The diameter and wall thickness of the segments (CCA, ECA and ICA) of the carotid bifurcation were found to decrease and stress-induced stiffness to increase from proximal CCA to distal ECA and ICA. The circumferential stress from end-diastole (minimum pressure) to peak-systole (maximum pressure) varied nonlinearly from 25±7 to 63±23 kPa (CCA), from 22±7 to 57±19 kPa (ECA) and from 28±8 to 67±23 kPa (ICA). Tangent elastic moduli also varied nonlinearly from end-diastole to peak-systole as follows: from 0.40±0.25 to 1.50±2.05 MPa (CCA), from 0.49±0.34 to 1.14±0.52 MPa (ECA) and from 0.68±0.31 to 1.51±0.69 MPa (ICA). The stress-induced stiffness of CCA and ECA increased more than 3-fold and the stiffness of ICA increased more than 2.5-fold at peak-systole compared to end-diastole.
The in vivo mechanical behavior of the three segments of the carotid bifurcation was qualitatively similar, but quantitatively different. All three arteries – CCA, ECA and ICA – exhibited nonlinear variations of circumferential stress and tangent elastic moduli within the normal pressure range. The variability in the properties of the three segments of the carotid bifurcation indicates a need for development of carotid models that match the in vivo properties of the carotid segments. Finally, the observed nonlinear behavior of the artery points to the need for future vascular mechanical studies to evaluate the mechanical factors of the arterial wall over the entire cardiac cycle.
common carotid artery; external carotid artery; internal carotid artery; in vivo mechanical properties; circumferential stress; stiffening
Squamous cell carcinoma (SCC) is a common and important primary cutaneous malignancy. On skin biopsies, SCC is characterized by significant squamous cell atypia, abnormal keratinization, and invasive features. Diagnostic challenges may occasionally arise, especially in the setting of small punch biopsies or superficial shave biopsies, where only part of the lesion may be assessable by the pathologist. Benign mimics of SCC include pseudoepitheliomatous hyperplasia, eccrine squamous syringometaplasia, inverted follicular keratosis, and keratoacanthoma, while malignant mimics of SCC include basal cell carcinoma, melanoma, and metastatic carcinoma. The careful application of time-honored diagnostic criteria, close clinicopathological correlation and a selective request for a further, deeper, or wider biopsy remain the most useful strategies to clinch the correct diagnosis. This review aims to present the key differential diagnoses of SCC, to discuss common diagnostic pitfalls, and to recommend ways to deal with diagnostically challenging cases.
Inclusion of infectious disease (ID) physicians in the care of patients with possible infection can favorably affect antibiotic usage. The aim of this study was to evaluate the role of the ID consultations in reducing inappropriate antibiotic usage.
Materials and Methods:
This is a prospective study evaluating all adult ID consultations from January 2006 to December 2009. A total of 1444 consultation requests were recorded during the 4-year period.
The most frequent consultations were from cardiology (23.1%), orthopedics (8.2%), general medicine (7.8%), hematology-oncology (7.8%), gastroenterology (7.3%), and pulmonary/critical care (7.1%). The main reason for consultation was for the choice of antibiotics (75%). The commonest diagnoses prior to consultation were fever (14.7%), bacteremia (9.1%), and urinary tract infection (8.4%). Bacteremia was documented in 21.4% of cases and 12.9% were found to have no identifiable focus of infection. Antimicrobial therapy was changed in 58.7% and antimicrobials were discontinued in 14.7% of cases. The number of antimicrobial therapy was one (49.7% and 49.9%) and two (24% and 17.6%, P = 0.0001) before and after the consultation, respectively. In addition, 17.3% and 26.9% (P = 0.0001) received no antimicrobial agents before and after ID consultation.
ID consultation is important to reduce inappropriate antimicrobial therapy and to limit the number of dual therapy.
Antibiotic use; Antimicrobial stewardship; Consultation; Infectious disease
More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected).
We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3.
Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P, the most common viral strain, there was no evidence of homotypic protection.
Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.)
It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren’t comparable with assessments in other dementias.
The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients.
The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival.
ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival.
Shah Ebrahim and colleagues argue that more research on non-communicable diseases (NCDs) in both high-income countries and low- and middle-income countries can result in mutual benefits and will help better address the growing burden of NCDs.
Infection with Chikungunya alphavirus (CHIKV) can cause severe arthralgia and chronic arthritis in humans with persistence of the virus in perivascular macrophages of the synovial membrane by mechanisms largely ill-characterized.
We herein analysed the innate immune response (cytokine and programmed cell death) of RAW264.7 mouse macrophages following CHIKV infection. We found that the infection was restrained to a small percentage of cells and was not associated with a robust type I IFN innate immune response (IFN-α4 and ISG56). TNF-α, IL-6 and GM-CSF expression were upregulated while IFN-γ, IL-1α, IL-2, IL-4, IL-5, IL-10 or IL-17 expression could not be evidenced prior to and after CHIKV exposure. Although CHIKV is known to drive apoptosis in many cell types, we found no canonical signs of programmed cell death (cleaved caspase-3, -9) in infected RAW264.7 cells.
These data argue for the capacity of CHIKV to infect and drive a specific innate immune response in RAW264.7 macrophage cell which seems to be polarized to assist viral persistence through the control of apoptosis and IFN signalling.
Chikungunya virus; Macrophage; Apoptosis; Viral persistence; Inflammation
Attention-deficit hyperactive disorder (ADHD) is a psychiatric illness commonly diagnosed during the early years of childhood. In many adolescents with undiagnosed ADHD, presentation may not be entirely similar to that in younger children. These adolescents pose significant challenges to parents and teachers coping with their disability. Often adolescents with behavioural problems are brought to medical attention as a last resort. This case describes an adolescent who presented to a primary care clinic with school truancy. He was initially treated for depression with oppositional defiant disorder and sibling rivalry. Only following a careful detailed history and further investigations was the diagnosis of ADHD made. He showed a positive improvement with the use of methylphenidate for his ADHD and escitalopram for his depression. The success of his management was further supported by the use of behavioural therapy and parenting interventions. There is a need to increase public awareness of ADHD, especially among parents and teachers so that early intervention can be instituted in these children.
attention-deficit hyperactive disorder; primary care; school truancy
γδ T cells rapidly produce cytokines and represent a first line of defence against microbes and other environmental insults at mucosal tissues and are thus thought to play a local immunoregulatory role. We show that allergic airway inflammation was associated with an increase in innate IL-17-producing γδ T (γδ-17) cells that expressed the αEβ7 integrin and were closely associated with the airway epithelium. Importantly, prostaglandin (PG)I2 and its receptor IP, which downregulated airway eosinophilic inflammation, promoted the emergence of these intraepithelial γδ-17 cells into the airways by enhancing IL-6 production by lung eosinophils and dendritic cells. Accordingly, a pronounced reduction of γδ-17 cells was observed in the thymus of naïve mice lacking the PGI2 receptor IP, as well as in the lungs during allergic inflammation, implying a critical role for PGI2 in the programming of “natural” γδ-17 cells. Conversely, iloprost, a stable analog of PGI2, augmented IL-17 production by γδ T cells but significantly reduced the airway inflammation. Together, these findings suggest that PGI2 plays a key immunoregulatory role by promoting the development of innate intraepithelial γδ-17 cells through an IL-6-dependent mechanism. By enhancing γδ-17 cell responses, stable analogs of PGI2 may be exploited in the development of new immunotherapeutic approaches.
Lung; inflammation; Th2 cells; γδ T cells; IL-17
Cannabinoid CB2 receptor has emerged as a very promising target over the last decades. We have synthesized and evaluated a new fluorescent probe designated NMP6 based on 6-methoxyisatin scaffold, which exhibited selectivity and Ki value at hCB2 of 387 nM. We have demonstrated its ability to be an effective probe for visualization of CB2 receptor binding using confocal microscopy and a flow cytometry probe for the analysis of CB2 protein expression. Furthermore, NMP6 was easily obtained in two chemical steps from commercially available building blocks.