Detection and molecular characterization of urinary tract HIV-1 populations.

BACKGROUND: Identification of all possible HIV reservoirs is an important aspect in HIV eradication efforts. The urinary tract has however not been well studied as a potential HIV reservoir. In this pilot study we molecularly characterized HIV-1 viruses in urine and plasma samples to investigate HIV-1 replication, compartmentalization and persistence in the urinary tract. METHODS: Prospectively collected urine and blood samples collected over 12-36 months from 20 HIV-1 infected individuals were analysed including sampling points from prior to and after ART initiation. HIV-1 pol gene RNA and DNA from urine supernatant and urine pellets respectively were analysed and compared to plasma RNA viruses from the same individual. RESULTS: HIV-1 nucleic acid was detected in urine samples from at least one time point in 8/20 (40%) treatment-naïve subjects compared to 1/13 (7.7%) individuals on antiretroviral treatment (ART) during periods of plasma viral suppression and 1/7 (14.3%) individuals with virological failure. HIV-1 RNA was undetectable in urine samples after ART initiation but HIV-1 DNA was detectable in one patient more than 6 months after treatment initiation. There was co-clustering of urine-derived pol sequences but some urine-derived sequences were interspersed among the plasma-derived sequences. CONCLUSIONS: Suppressive ART reduces HIV-1 replication in the urinary tract but HIV-1 DNA may persist in these cells despite treatment. A larger number of sequences would be required to confirm HIV compartmentalization in the urinary tract.

Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy.

BACKGROUND: Recent phase III clinical trials have established the superiority of the anti-PD-1 antibodies pembrolizumab and nivolumab over the anti-CTLA-4 antibody ipilimumab in the first-line treatment of patients with advanced melanoma. Ipilimumab will be considered for second-line treatment after the failure of anti-PD-1 therapy. METHODS: We retrospectively identified a cohort of 40 patients with metastatic melanoma who received single-agent anti-PD-1 therapy with pembrolizumab or nivolumab and were treated on progression with ipilimumab at a dose of 3 mg kg(-1) for a maximum of four doses. RESULTS: Ten percent of patients achieved an objective response to ipilimumab, and an additional 8% experienced prolonged (>6 months) stable disease. Thirty-five percent of patients developed grade 3-5 immune-related toxicity associated with ipilimumab therapy. The most common high-grade immune-related toxicity was diarrhoea. Three patients (7%) developed grade 3-5 pneumonitis leading to death in one patient. CONCLUSIONS: Ipilimumab therapy can induce responses in patients who fail the anti-PD-1 therapy with response rates comparable to previous reports. There appears to be an increased frequency of high-grade immune-related adverse events including pneumonitis that warrants close surveillance.

Pre-treatment minority HIV-1 drug resistance mutations and long term virological outcomes: is prediction possible?

BACKGROUND: Although the use of highly active antiretroviral therapy in HIV positive individuals has proved to be effective in suppressing the virus to below detection limits of commonly used assays, virological failure associated with drug resistance is still a major challenge in some settings. The prevalence and effect of pre-treatment resistance associated variants on virological outcomes may also be underestimated because of reliance on conventional population sequencing data which excludes minority species. We investigated long term virological outcomes and the prevalence and pattern of pre-treatment minority drug resistance mutations in individuals initiating HAART at a local HIV clinic. METHODS: Patient's records of viral load results and CD4 cell counts from routine treatment monitoring were used and additional pre-treatment blood samples for Sanger sequencing were obtained. A selection of pre-treatment samples from individuals who experienced virological failure were evaluated for minority resistance associated mutations to 1 % prevalence and compared to individuals who achieved viral suppression. RESULTS: At least one viral load result after 6 months or more of treatment was available for 65 out of 78 individuals followed for up to 33 months. Twenty (30.8 %) of the 65 individuals had detectable viremia and eight (12.3 %) of them had virological failure (viral load > 1000 RNA copies/ml) after at least 6 months of HAART. Viral suppression, achieved by month 8 to month 13, was followed by low level viremia in 10.8 % of patients and virological failure in one patient after month 20. There was potentially reduced activity to Emtricitabine or Tenofovir in three out of the eight cases in which minority drug resistance associated variants were investigated but detectable viremia occurred in one of these cases while the activity of Efavirenz was generally reduced in all the eight cases. CONCLUSIONS: Early viral suppression was followed by low level viremia for some patients which may be an indication of failure to sustain viral suppression over time. The low level viremia may also be representing early stages of resistance development. The mutation patterns detected in the minority variants showed potential reduced drug sensitivity which highlights their potential to dominate after treatment initiation. TRIAL REGISTRATION: Not applicable.

Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Systemic lupus erythematosus in a 3-month old male presenting as thrombocytopenia.

We report a case of a 3-month old male infant, born to a mother with a known history of systemic lupus erythematosus (SLE). The infant initially presented with petechiae, anemia, and thrombocytopenia. His evaluation revealed antinuclear antibody (ANA) titer of 1 : 160, negative anti-SS-A/SS-B antibody, positive anti-Smith antibody, elevated anti-dsDNA titer, and a slightly low C4 level. His subsequent development of hematuria with nephrotic grade proteinuria fulfilled criteria for a diagnosis of SLE. His condition improved with corticosteroids, mycophenolate mofetil and low-dose aspirin. At 18 months of age, he is clinically well, off all immunosuppression with normal growth parameters and no detectable autoantibodies.

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

Astronomy and the Extreme Ultraviolet Explorer satellite.

The extreme ultraviolet wave band (100 to 912 angstroms) was thought until recently to be useless to astronomy, primarily because the opacity of the interstellar medium would prevent observations at these wavelengths. However, the interstellar medium has been found to be markedly inhomogeneous in both density and ionization state and the sun is fortunately located in a region of low extreme ultraviolet opacity. The Extreme Ultraviolet Explorer, launched in June 1992, has surveyed the sky in this wave band and has detected a wide variety of astronomical sources at considerable distances, including some extragalactic objects. Studies in the extreme ultraviolet band have already begun to increase our understanding of the contents of the universe.

Astronomical observations with the FAUST telescope.

The far-ultraviolet space telescope (FAUST) was flown on Spacelab 1 to provide wide-field imaging in the wavelength range 1300 to 1800 angstroms. Most of the developed film showed high levels of background exposure. Frames with a lower background included exposures of the Cygnus Loop supernova remnant and an exposure in the direction of the galaxy cluster Abell 2634. Several exposures will be used in a search for hot white dwarf stars.

The Elemental Composition of the Corona of Procyon: Evidence for the Absence of the FIP Effect.

The chemical composition of the solar corona is not the same as that of the underlying photosphere. In the corona, elements with a first ionization potential (FIP) of /=10 electron volts (for example, oxygen, neon, and sulfur) by factors of 3 to 10 with respect to the photosphere. The origin of this FIP effect is unknown. The launch of the Extreme Ultraviolet Explorer Satellite (EUVE) opened up the spectroscopic capability required to determine elemental abundances in the coronae of other stars. Spectroscopic observations of the corona of the nearby F5 IV star Procyon obtained with EUVE have yielded estimates of the relative abundances of high- and low-FIP species. The results provide evidence that Procyon, unlike the sun, does not exhibit the FIP effect. Whether the sun or Procyon is more typical of the general late-type stellar population is of fundamental interest to the physics of stellar outer atmospheres and has a bearing on the origin of cosmic rays.

Communicating risk to emergency department patients with chest pain.

BACKGROUND: The risks and benefits of thrombolytic therapy for acute myocardial infarction are usually discussed with patients before treatment. Numerous factors may make it difficult for a patient to understand these issues fully; one of these is the language doctors use to describe risk. STUDY OBJECTIVE: To determine whether emergency department (ED) patients who experience chest pain have the same understanding of the frequency of side effects when expressed as percentages or in descriptive language (eg, "uncommon") as emergency medicine doctors. SETTING: The chest pain area of an urban ED. METHOD: A short questionnaire survey was administered to both patients and ED doctors. RESULTS: Of the 50 patients recruited, 88% correctly understood data when presented as percentages. When patients were asked to identify the frequency of an "uncommon" and "rare" side effect only 22% and 18%, respectively, were able to do so. The corresponding results for the doctors were 70% (p<0.0001) and 54% (p = 0.0006). 39% of patients felt that there was no difference between these two verbal descriptors. CONCLUSION: Patients understand side-effect frequencies when expressed as percentages. Patients have different understandings of the frequency of events to doctors when verbal descriptors are used. This lack of a shared understanding has implications for informed decision-making and we recommend that percentages are used to communicate risk in the ED.

Treatment effects of Fast ForWord demonstrated by magnetoencephalography (MEG) in a child with developmental dyslexia.

Treatment effects of Fast ForWord, hypothesized to ameliorate temporal processing deficits, were demonstrated by magnetoencephalography in a child with dyslexia using four paradigms: Word/Non-word Reading (NW), Grapheme-to-Phoneme Matching (GP), Verbal, and Spatial Working Memory (VWM, SWM). Shifts in brain activation from right inferior frontal and temporal to left frontal, bilateral supramarginal, and transverse temporal regions occurred during GP. During NW, shifts progressed from (1) right or bilateral anterior and superior to (2) left, inferior frontal, to (3) left, superior posterior temporoparietal, to (4) left, inferior, posterior temporooccipital regions. Reading and written language improvements were noted in passage comprehension and spelling.

Macrophage activation syndrome and other systemic inflammatory conditions after BMT.

Autologous hematopoietic cell transplantation (HCT) is being used to treat autoimmune diseases refractory to conventional therapy, including rheumatoid arthritis. Macrophage activation syndrome (MAS) is a descriptive term for a systemic inflammatory disorder that has been described in patients with juvenile rheumatoid arthritis (JRA). This case report describes a young adult with systemic JRA (sJRA) who developed MAS on day # 12 post-autologous transplantation. The patient developed high fever, laboratory evidence of disseminated intravascular coagulation (DIC), hepatocellular injury, pancytopenia and hyper-ferritinemia. All viral, bacterial and fungal studies were negative and the patient improved with high-dose glucocorticosteroid and cyclosporine therapy. Extreme elevation of serum ferritin was documented and helpful in monitoring response to therapy. A number of systemic inflammatory syndromes have been described in association with HCT. These include DIC, 'engraftment syndrome,' infection-associated hemophagocytic syndrome and familial hemophagocytic lymphohistiocytosis. Macrophage activation syndrome presents with features of DIC and is closely related or identical to infection-associated hemophagocytic syndrome. The diagnosis needs to be established in a timely fashion because early and appropriate treatment may improve outcome.

Naturally occurring resistance mutations within the core and NS5B regions in hepatitis C genotypes, particularly genotype 5a, in South Africa.

Approximately 1 million South Africans are infected with Hepatitis C virus (HCV). The standard of care (SOC) in South Africa is combination therapy (pegylated interferon and ribavirin). HCV genotypes and/or mutations in the core/non-structural regions have been associated with response to therapy and/or disease progression. This study examines mutations in the core (29-280 amino acids, including ∼ 90 E1 amino acids) and NS5B (241-306 amino acids) regions on pre-treatment isolates from patients attending Johannesburg hospitals or asymptomatic South African blood donors. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Samples grouped into subtypes 1a(N = 10) 1b(N = 12), 3a(N = 5), 4a(N = 3) and 5a(N = 61). Two mutations, associated with interferon resistance-R70Q and T110N-were present in 29 genotype 5a core sequences. No resistance mutation to NS5B nucleotide inhibitors, sofosbuvir was found. Six putative CD8+ and one CD4+ T-cell epitope sequence in the core region showed binding scores of <300 IC50nM to HLA alleles frequently observed in the South African population. No known CD8+ and CD4+ T-cell epitopes were mapped in the NS5B region. The analysis begs the question whether those infected with genotype 5a will benefit better on interferon-free combination therapies. This study provides new insight into one of the lesser studied HCV genotypes and compares the diversity seen in a large pre-treatment cohort with other subtypes.

45X/46X,r(X) with syndactyly and severe mental retardation.

Two white females, age 2 1/2 and 33 years, respectively, were investigated because of severe mental retardation associated with neurologic abnormalities, coarse face, and soft tissue syndactyly involving upper and lower limbs. Each had cytogenetic findings of a mosaic variant of Ullrich-Turner syndrome with X ring chromosome in peripheral lymphocyte and skin fibroblasts. Early X replication occurred in one-third of the X ring chromosomes; there was no evidence for X-autosome translocation involving either X and an autosomal duplication; results of studies for fragility of the X chromosomes were unremarkable. In situ hybridization with an X centromere probe was positive for the ring. To our knowledge, the unusual constellation of cytogenetic, physical, and mental findings seen in these 2 individuals has not been reported previously.

Physical modalities of therapy in pediatric rheumatic diseases.

The approach to rehabilitation management of childhood rheumatic disease differs in many ways from that of adult disease. Among the special considerations are the effects of chronic musculoskeletal inflammation in a growing and developing individual and the tendency of children to tighten their joints into positions of comfort, with fewer problems resulting from ligamentous laxity and instability. A comprehensive management approach includes much more than simply using medications--the tendency for the disease to exert deforming forces on the limbs must be constantly fought by a vigorous program of rehabilitation; education and psychologic support must be provided to the patient and family; potential problems must be discussed with the school; financial and vocational issues must be addressed.

Cytogenetic and flow cytometric analysis of a pancreatoblastoma.

A pancreatoblastoma from a 4-year old male was examined by flow cytometric ploidy analysis and cytogenetics. To detect differences within the tumor, the specimen was divided into four portions and sampled separately. Flow analysis revealed that each sample contained a diploid and a tetraploid population of tumor cells. These findings correlated well with the cytogenetic analysis, which also revealed differences in structural rearrangements between samples. A t(13;22)(q10;q10) was the only rearrangement found in near-diploid cells as well as one near-tetraploid line. Other common structural changes in near-tetraploid cells included t(13;13)(q10;q10), i(6p)(p10), and del(1). Chromosomes 1, 6, 13, and 22 were consistently missing from all near-tetraploid cells lines. To our knowledge, this is the first flow cytometric and cytogenetic study of a pancreatoblastoma.

Analysis of MEG signals of spreading cortical depression with propagation constrained to a rectangular cortical strip. I. Lissencephalic rabbit model.

Magnetic fields arising from the rabbit cortex during spreading cortical depression (SCD) were measured in order to study the currents in the neocortex during SCD. SCD was constrained to propagate in a rectangular cortical strip perpendicular to the midline. This simplified in vivo cortical preparation enabled us to correlate magnetoencephalographic (MEG) signals to their underlying currents within the cortical strip. The propagation of SCD was monitored with an array of electrodes placed along the strip. The propagation speed for SCD in the lissencephalic rabbit brain was 3. 5+/-0.3 mm/min (mean+/-S.E.M., n=14). Slow, quasi-dc, MEG signals were observed as the SCD entered into the longitudinal fissure. The currents giving rise to the MEG signals were perpendicular to the cortical surface and directed from the surface to deeper layers of the cortex. A distributed dipolar source model was used to relate the data to the underlying cortical current. The moment of the single equivalent current dipole source was 38+/-9 nA-m (n=17). This study clarified the nature of the cortical currents during SCD in a lissencephalic in vivo preparation.

Analysis of MEG signals of spreading cortical depression with propagation constrained to a rectangular cortical strip. II. Gyrencephalic swine model.

Currents produced during spreading cortical depression (SCD) in a gyrencephalic species (swine) were studied with magnetoencephalography (MEG) and electrocorticography (ECoG). SCD, initiated using electrical stimulation of the cortex, was constrained to propagate within a rectangular cortical strip in order to simplify the interpretation of the underlying currents. The ECoG signals monitored along the strip revealed that SCD propagated from an initiation site on the gyrus at a rate of 7.9+/-3.2 mm/min (n=23), entered the deep coronal sulcus and in most cases emerged from the other side of the sulcus, continuing to propagate across the next gyrus at a rate of 5.9+/-2.7 mm/min (n=22). The apparent propagation velocity within the sulcus was reduced to 1.7+/-0.8 mm/min (n=21). Strong MEG signals were observed as SCD entered the sulcus. The direction of magnetic field was opposite for SCD's on opposite banks of the sulcus. The currents were directed from a superficial layer to deeper layers of the cortex. The characteristics of SCD and associated MEG patterns from a gyrencephalic species may be similar to those in human patients during migraine aura.

Limb pain in childhood.

As the presenting complaint in 7 per cent of pediatrician visits, pain in the limbs is a common problem in childhood. It is important that the diagnosis be made expeditiously. The authors review the possible organic cause of limb pain, as well as limb pain from conversion reactions and from growing pains, giving special attention to the differential diagnosis so that appropriate treatment for the pain can be initiated.

Rehabilitation of the child with a rheumatic disease.

This article discusses the principles of rehabilitation of the most common childhood rheumatic diseases, especially juvenile rheumatoid arthritis, dermatomyositis, and scleroderma. Any rehabilitation program must be undertaken in conjunction with understanding of disease processes, appropriate medical management, and patient and family education. Investing effort into avoiding contractures, weakness, osteoporosis, and disability is considerably less time-consuming, painful, and costly than trying to reverse established problems.