Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines.

Bacterial Genotyping of Central Nervous System Tuberculosis in South Africa: Heterogenic Mycobacterium tuberculosis Infection and Predominance of Lineage 4.

Tuberculous meningitis (TBM), the most severe extrapulmonary manifestation of tuberculosis, is caused by the pathogen Mycobacterium tuberculosis The M. tuberculosis complex includes seven lineages, all described to harbor a unique geographical dissemination pattern and clinical presentation. In this study, we set out to determine whether a certain M. tuberculosis lineage demonstrated tropism to cause TBM in patients from Cape Town, South Africa. DNA was extracted from formalin-fixed paraffin-embedded central nervous system (CNS) tissue from a unique neuropathological cohort of 83 TBM patients, collected between 1975 and 2012. M. tuberculosis lineages 1, 2, 3, and 4 were determined using an allele-specific PCR and Sanger sequencing. Of the 83 patient specimens tested, bacterial characterization could be performed on 46 specimens (55%). M. tuberculosis lineage 4 was present in 26 patient specimens (56%), and non-lineage 4 was identified in 10 cases (22%). Moreover, genomic heterogeneity was detected in the CNS specimens of 7 adults and 3 children. We could show that infection of the CNS is not restricted to a single M. tuberculosis lineage and that even young children with rapid progression of disease can harbor more than one M. tuberculosis lineage in the CNS.

Pediatric neurocysticercosis: three cases presented in the Netherlands with divergent clinical presentations.

BACKGROUND: Neurocysticercosis is a helminthic disease that affects the central nervous system by the larvae of the Taenia solium, the pork tapeworm. Because of the growing number of immigrants from endemic areas, its incidence is increasing in Western Europe. CASES: We describe three children, aged between 2 and 13 years, two of whom have a definite and one a probable diagnosis of neurocysticercosis based on the "Del Brutto criteria." They presented with different symptoms and signs: symptomatic epilepsy, asymmetric cerebral palsy, and headache. Serological evaluation was negative in two of the three cases. All cases showed comparable abnormalities on magnetic resonance imaging of the brain: solitary or multiple, cystic lesions, with surrounding edema. In one of them, the "scolex" (part of the larvae) could be visualized. One case was treated with albendazole, the other two cases did not receive medication. CONCLUSION: A prompt diagnosis of neurocysticercosis by recognition of its typical brain lesions is important to prevent unnecessary diagnostic tests and treatment.

Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α.

Tuberculosis is a global health issue with annually about 1.5 million deaths and 2 billion infected people worldwide. Extra-pulmonary tuberculosis comprises 13% of all cases of which tuberculous meningitis is the most severe. It has a high mortality and is often diagnosed once irreversible neurological damage has already occurred. Development of diagnostic and treatment strategies requires a thorough understanding of the pathogenesis of tuberculous meningitis. This disease is characterized by the formation of a cerebral granuloma, which is a collection of immune cells that attempt to immunologically restrain, and physically contain bacteria. The cytokine tumor necrosis factor-α is known for its important role in granuloma formation. Because traditional experimental animal studies exploring tuberculous meningitis are difficult and expensive, another approach is needed to begin to address this important and significant disease outcome. Here, we present an in silico model capturing the unique immunological environment of the brain that allows us to study the key mechanisms driving granuloma formation in time. Uncertainty and sensitivity analysis reveals a dose-dependent effect of tumor necrosis factor-α on bacterial load and immune cell numbers thereby influencing the onset of tuberculous meningitis. Insufficient levels result in bacterial overgrowth, whereas high levels lead to uncontrolled inflammation being detrimental to the host. These findings have important implications for the development of immuno-modulating treatment strategies for tuberculous meningitis.

Energy expenditure in infants with congenital heart disease, including a meta-analysis.

AIM: To assess energy requirements and body composition in preoperative children with congenital heart disease (CHD). METHODS: In 11 infants with CHD (2-8 mo), total daily energy expenditure (TDEE) and total body water (TBW) were measured with doubly labelled water and compared with historic data from healthy controls. Within the patient group, energy expenditure of infants with versus those without congestive heart failure was compared. Subsequently, the data were pooled with literature data in meta-analyses. RESULTS: CHD patients showed increased TBW (mean +/- SD 66 +/- 3 vs 58 +/- 5% of body weight, p < 0.05) and energy expenditure (381 +/- 42 vs 298 +/- 36 kJ kg(-1) d(-1), p < 0.001). Meta-analyses showed that CHD infants have 35% increased TDEE (376 vs 278 kJ kg(-1) d(-1) , p < 0.00001) and 7% higher TBW (p < 0.0001). Coexistent congestive heart failure (treated with diuretics) had no influence on TDEE (mean difference 14 kJ kg(-1) d(-1) , not significant). In patients with heart failure and growth retardation, an energy balance study showed an average 12% loss of initially ingested energy due to vomiting, increased TDEE and low faecal energy loss, resulting in low energy available for growth, compared with controls (42 +/- 30 vs 96 +/- 61 kJ kg(-1) d(-1) , p < 0.05). CONCLUSION: Many infants with CHD require substantially higher energy intake (at least 100 kJ kg(-1) d(-1) extra) owing to increased TDEE, which is not explained by a higher percentage of body water. Coexistent heart failure does not appear to have an additional influence on TDEE. In infants with CHD and growth failure factors other than elevated TDEE, including vomiting, may explain the disturbed energy balance.

Human radicular veins: regulation of venous reflux in the absence of valves.

In the literature it is generally assumed that venous reflux within the radicular veins is prevented by the presence of bicuspid valves and narrowing of the transdural part of these vessels. Recently, we performed a human cadaver study of the internal vertebral venous plexus. Surprisingly, a large number of radicular and perimedullary veins appeared to be filled with Araldite CY 221 mixture, after injection of this material into the vertebral venous system, implicating reflux via the radicular veins and suggesting insufficiency of the presumed anti-reflux mechanism. Therefore, it was decided to study the radicular veins in order to determine and to investigate the presence or absence of anti-reflux mechanisms within this system. The vertebral venous systems of ten fresh human cadavers, between 64 and 93 years of age, were injected with Araldite CY 221 mixture. After polymerization, all cadavers were dissected and the spinal nerve sheaths, including nerve roots, radicular veins and epidural veins, were excised as a whole. After macroscopical examination, serial sections (40 microm) were cut on a freezing microtome and stained in Von Gieson medium. Every third section was stained immunohistochemically with smooth muscle antigen (SMA), to visualize smooth muscle cells. In all cadavers, a number of intradural radicular veins was filled with Araldite. Employing microscopical examination, no bicuspid valves were found. However, four structures were encountered that might serve as ananti-reflux-mechanism: 1) intravenous dural folds, 2) meandrous configuration, and 3) narrowing of the radicular veins at the point of penetration of the dura mater, and 4) varying numbers of smooth muscle fibers in the walls of the intradural and extradural parts of the radicular veins. Reflux via the radicular veins seems to be a physiological phenomenon. Structural valves have not been encountered during this study. Intravenous dural folds, meandrous configuration and narrowing of the transdural part of the radicular veins, and the presence of large numbers of smooth muscle cells in the radicular venous walls suggest the existence of a dynamic reflux-regulating system that has the ability to increase the intravascular resistance under conditions of venous hyperpression, in order to protect the spinal cord from venous pressure waves. Possibly, venous reflux via the radicular veins has a role in selective cooling of the spinal cord.