Severe leukoencephalopathy with fulminant cerebral edema reflecting immune reconstitution inflammatory syndrome during HIV infection: a case report

<p>Abstract</p> <p>Introduction</p> <p>Immune reconstitution inflammatory syndrome is a well-known complication in HIV-infected patients after initiation of highly active antiretroviral therapy resulting in rapid CD4⁺cell count recovery and suppression of viral load. Generally, immune reconstitution inflammatory syndrome is based on opportunistic infections, but rare cases of immune reconstitution inflammatory syndrome inducing demyelinization of the nervous system have also been observed.</p> <p>Case presentation</p> <p>A 37-year-old African woman with HIV infection diagnosed at 13 years of age was admitted to the emergency department after experiencing backache, severe headache, acute aphasia and psychomotor slowing for one week. Nine weeks earlier, highly active antiretroviral therapy in this patient had been changed because of loss of efficacy, and a rapid increase in CD4⁺cell count and decrease of HIV viral load were observed. Magnetic resonance imaging of the brain showed extensive white matter lesions, and analysis of cerebrospinal fluid revealed an immunoreactive syndrome. Intensive investigations detected no opportunistic infections. A salvage therapy, including osmotherapy, corticosteroids and treatment of epileptic seizures, was performed, but the patient died from brainstem herniation 48 hours after admission. Neuropathologic examination of the brain revealed diffuse swelling, leptomeningeal infiltration by CD8 cells and enhancement of perivascular spaces by CD8+ cells.</p> <p>Conclusion</p> <p>Immune reconstitution inflammatory syndrome in this form seems to represent a severe autoimmunologic disease of the brain with specific histopathologic findings. This form of immune reconstitution inflammatory syndrome did not respond to therapy, and extremely rapid deterioration led to death within two days. Immune reconstitution inflammatory syndrome may also occur as severe leukoencephalopathy with fulminant cerebral edema during HIV infection with rapid immune reconstitution.</p

Pathology of immune reconstitution inflammatory syndrome in multiple sclerosis with natalizumab-associated progressive multifocal leukoencephalopathy

Natalizumab is an approved medication for highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) may occur as a severe side effect of this drug. Here, we describe pathological and radiological characteristics of immune reconstitution inflammatory syndrome (IRIS), which occurs in natalizumab-associated PML after the cessation of therapy, and we differentiate it from ongoing PML. Brain biopsy tissue and MRI scans from five MS patients with natalizumab-associated PML were analyzed and their histology compared with non-MS PML. Histology showed an extensive CD8-dominated T cell infiltrate and numerous macrophages within lesions, and in nondemyelinated white and grey matter, in four out of five cases. Few or no virally infected cells were found. This was indicative of IRIS as known from HIV patients with PML. Outstandingly high numbers of plasma cells were present as compared to non-MS PML and typical MS lesions. MRI was compatible with IRIS, revealing enlarging lesions with a band-like or speckled contrast enhancement either at the lesion edge or within lesions. Only the fifth patient showed typical PML pathology, with low inflammation and high numbers of virally infected cells. This patient showed a similar interval between drug withdrawal and biopsy (3.5 months) to the rest of the cohort (range 2.5–4 months). MRI could not differentiate between PML-associated IRIS and ongoing PML. We describe in detail the histopathology of IRIS in natalizumab-associated PML. PML–IRIS, ongoing PML infection, and MS exacerbation may be impossible to discern clinically alone. MRI may provide some clues for distinguishing different pathologies that can be differentiated histologically. In our individual cases, biopsy helped to clarify diagnoses in natalizumab-associated PML

Need and importance of health protection training in Nepal

By investing in health protection, the health of the nation can be safeguarded from future threats of uncontrolled infectious disease epidemics and disasters

Improved Survival of HIV-1-Infected Patients with Progressive Multifocal Leukoencephalopathy Receiving Early 5-Drug Combination Antiretroviral Therapy

Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery.All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008).The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death.ClinicalTrials.gov NCT00120367

Composition and Hierarchical Organisation of a Spider Silk

Albeit silks are fairly well understood on a molecular level, their hierarchical organisation and the full complexity of constituents in the spun fibre remain poorly defined. Here we link morphological defined structural elements in dragline silk of Nephila clavipes to their biochemical composition and physicochemical properties. Five layers of different make-ups could be distinguished. Of these only the two core layers contained the known silk proteins, but all can vitally contribute to the mechanical performance or properties of the silk fibre. Understanding the composite nature of silk and its supra-molecular organisation will open avenues in the production of high performance fibres based on artificially spun silk material

Interactions between Spider Silk and Cells – NIH/3T3 Fibroblasts Seeded on Miniature Weaving Frames

Native spider silk does not require any modification to its application as a biomaterial that can rival any artificial material in terms of cell growth promoting properties. We could show adhesion mechanics on intracellular level. Additionally, proliferation kinetics were higher than in enzymatically digested controls, indicating that spider silk does not require modification. Recent findings concerning reduction of cell proliferation after exposure could not be met. As biotechnological production of the hierarchical composition of native spider silk fibres is still a challenge, our study has a pioneer role in researching cellular mechanics on native spider silk fibres

Phase II study of preoperative radiation plus concurrent daily tegafur-uracil (UFT) with leucovorin for locally advanced rectal cancer

<p>Abstract</p> <p>Background</p> <p>Considerable variation in intravenous 5-fluorouracil (5-FU) metabolism can occur due to the wide range of dihydropyrimidine dehydrogenase (DPD) enzyme activity, which can affect both tolerability and efficacy. The oral fluoropyrimidine tegafur-uracil (UFT) is an effective, well-tolerated and convenient alternative to intravenous 5-FU. We undertook this study in patients with locally advanced rectal cancer to evaluate the efficacy and tolerability of UFT with leucovorin (LV) and preoperative radiotherapy and to evaluate the utility and limitations of multicenter staging using pre- and post-chemoradiotherapy ultrasound. We also performed a validated pretherapy assessment of DPD activity and assessed its potential influence on the tolerability of UFT treatment.</p> <p>Methods</p> <p>This phase II study assessed preoperative UFT with LV and radiotherapy in 85 patients with locally advanced T3 rectal cancer. Patients with potentially resectable tumors received UFT (300 mg/m/²/day), LV (75 mg/day), and pelvic radiotherapy (1.8 Gy/day, 45 Gy total) 5 days/week for 5 weeks then surgery 4-6 weeks later. The primary endpoints included tumor downstaging and the pathologic complete response (pCR) rate.</p> <p>Results</p> <p>Most adverse events were mild to moderate in nature. Preoperative grade 3/4 adverse events included diarrhea (n = 18, 21%) and nausea/vomiting (n = 5, 6%). Two patients heterozygous for dihydropyrimidine dehydrogenase gene (<it>DPYD</it>) experienced early grade 4 neutropenia (variant IVS14+1G > A) and diarrhea (variant 2846A > T). Pretreatment ultrasound TNM staging was compared with postchemoradiotherapy pathology TN staging and a significant shift towards earlier TNM stages was observed (p < 0.001). The overall downstaging rate was 42% for primary tumors and 44% for lymph nodes. The pCR rate was 8%. The sensitivity and specificity of ultrasound for staging was poor. Anal sphincter function was preserved in 55 patients (65%). Overall and recurrence-free survival at 3 years was 86.1% and 66.7%, respectively. Adjuvant chemotherapy was administered to 36 node-positive patients (mean duration 118 days).</p> <p>Conclusion</p> <p>Preoperative chemoradiotherapy using UFT with LV plus radiotherapy was well tolerated and effective and represents a convenient alternative to 5-FU-based chemoradiotherapy for the treatment of resectable rectal cancer. Pretreatment detection of DPD deficiency should be performed to avoid severe adverse events.</p

Spinning Gland Transcriptomics from Two Main Clades of Spiders (Order: Araneae) - Insights on Their Molecular, Anatomical and Behavioral Evolution

Characterized by distinctive evolutionary adaptations, spiders provide a comprehensive system for evolutionary and developmental studies of anatomical organs, including silk and venom production. Here we performed cDNA sequencing using massively parallel sequencers (454 GS-FLX Titanium) to generate ∼80,000 reads from the spinning gland of Actinopus spp. (infraorder: Mygalomorphae) and Gasteracantha cancriformis (infraorder: Araneomorphae, Orbiculariae clade). Actinopus spp. retains primitive characteristics on web usage and presents a single undifferentiated spinning gland while the orbiculariae spiders have seven differentiated spinning glands and complex patterns of web usage. MIRA, Celera Assembler and CAP3 software were used to cluster NGS reads for each spider. CAP3 unigenes passed through a pipeline for automatic annotation, classification by biological function, and comparative transcriptomics. Genes related to spider silks were manually curated and analyzed. Although a single spidroin gene family was found in Actinopus spp., a vast repertoire of specialized spider silk proteins was encountered in orbiculariae. Astacin-like metalloproteases (meprin subfamily) were shown to be some of the most sampled unigenes and duplicated gene families in G. cancriformis since its evolutionary split from mygalomorphs. Our results confirm that the evolution of the molecular repertoire of silk proteins was accompanied by the (i) anatomical differentiation of spinning glands and (ii) behavioral complexification in the web usage. Finally, a phylogenetic tree was constructed to cluster most of the known spidroins in gene clades. This is the first large-scale, multi-organism transcriptome for spider spinning glands and a first step into a broad understanding of spider web systems biology and evolution