Adolescence: The age of Proteus

This article focuses on adolescents as a group, who are exposed to major changes in their near future, with the key transformation being the epidemiological transition from the age of infectious and nutritional problems to that of the non-communicable  disorders (NCDs). The major NCDs are: obesity, diabetes, maternal, newborn and child, hypertension and mental health disorders. We also discuss allergies, exposure to pollutants, indoor open stoves, and behavioural factors, such as lack of exercise,  unhealthy diet, substance abuse, injuries and violence, and sexually transmitted  diseases, which contribute to a risky environment. We particularly emphasise the continuum from birth to old age, during which early events may produce lifelong diseases, and which requires serious attention with regard to preventive measures during the earliest period of susceptibility. Some indicators of disease can serve as diagnostic markers and help healthcare workers to avoid complications and manage a disorder efficiently

Using 77Se-Labelled Foliar Fertilisers to Determine How Se Transfers Within Wheat Over Time

Foliar selenium (Se) fertilisation has been shown to be more efficient than soil-applied fertilisation, but the dynamics of absorption and translocation have not yet been explored. An experiment was undertaken to investigate time-dependent changes in the absorption, transformation, and distribution of Se in wheat when 77Se-enriched sodium selenate (Sefert) was applied to the leaves at a rate of 3.33 μg Se per kg soil (equivalent to 10 g ha−1) and two growth stages, namely stem elongation, Zadoks stage 31/32 (GS1), and heading stage, Zadoks stage 57 (GS2). The effect of urea inclusion in foliar Se fertilisers on the penetration rates of Se was also investigated. Wheat was harvested at 3, 10, and 17 days and 3, 10, and 34 days after Se applications at GS1 and GS2, respectively. Applying foliar Se, irrespective of the formulation, brought grain Se concentration to a level high enough to be considered adequate for biofortification. Inclusion of N in the foliar Se solution applied at an early growth stage increased recoveries in the plants, likely due to improved absorption of applied Se through the young leaves. At a later growth stage, the inclusion of N in foliar Se solutions was also beneficial as it improved the assimilation of applied inorganic Se into bioavailable selenomethionine, which was then rapidly translocated to the grain. The practical knowledge gained about the optimisation of Se fertiliser formulation, method, and timing of application will be of importance in refining biofortification programs across different climatic regimes

Immunogenicity and safety of a live attenuated varicella vaccine in healthy Indian children aged 9 - 24 months

Objectives. To investigate the safety of live attenuated varicella vaccine (aka strain) and the optimal virus titre/ dose required for immunogenicity in healthy South African children.Design. Double-blind randomised clinical study using two different lots of varicella vaccine, each at two different titres. Subjects were randomly allocated to groups 1, 2, 3 and 4 to receive vaccine containing a mean virus titre of 104,5, 103,1, 103,9 and 102,7 PFUs per dose respectively. Clinical signs and symptoms were followed up for 42 days post-vaccination. Specific varicella antibodies were measured by an indirect immunofluorescence method in sera obtained on day 0 and day 42.Setting. City Health Clinic, Chatsworth, Durban.Participants. A total of 200 healthy 9 - 24-month-old children were vaccinated, of whom 189 (44,5%) completed the study.Main outcome measures. Pre- and post-vaccination varicella antibody levels. Adverse events following varicella vaccination..Results. The vaccine was safe and well tolerated. No local symptoms were reported. Skin reactions were specifically solicited in this study: 21 reactions were reported in 8,5% (17/200) of children. Vesicles were reported in 2 vaccines (,,;: 10 vesicles in both cases). One serious adverse event was reported: hospitalisation for bronchopneumonia on day 16 post-vaccination which resolved without sequelae. Around day 42 postvaccination (range 35 - 63 days) all the 176 initially seronegative subjects had seroconverted for varicella antibodies. Post-vaccination geometric mean titres (GMTs) were 104,1, 66,2, 69,5 and 77,0 for groups 1 - 4 respectively. Six subjects who were initially seropositive maintained or increased their titres post-vaccination; 3 of the 6 showed a booster response (a ;:;, 4-fold increase from the pre-vaccination titre).Conclusions. Varicella vaccine was found to be safe, immunogenic and well tolerated. No difference in seroconversion rates or GMTs, either between groups receiving the two vaccine lots or between groups receiving the different titres of each lot, was shown

Temozolomide resistance in glioblastoma cells occurs partly through epidermal growth factor receptor-mediated induction of connexin 43

Glioblastoma Multiforme (GBM) is an aggressive adult primary brain tumor with poor prognosis. GBM patients develop resistance to the frontline chemotherapy, temozolomide (TMZ). As the connexins (Cx) have been shown to have a complex role in GBM, we investigated the role of Cx43 in TMZ resistance. Cx43 was increased in the TMZ-resistant low passage and cell lines. This correlated with the data in The Cancer Genome Atlas. Cx43 knockdown, reporter gene assays, chromatin immunoprecipitation assay, real-time PCR and western blots verified a role for Cx43 in TMZ resistance. This occurred by TMZ-resistant GBM cells being able to activate epidermal growth factor receptor (EGFR). In turn, EGFR activated the JNK-ERK1/2-AP-1 axis to induce Cx43. The increased Cx43 was functional as indicated by gap junctional intercellular communication among the resistant GBM cells. Cell therapy could be a potential method to deliver drugs, such as anti-EGF to tumor cells. Similar strategies could be used to reverse the expression of Cx43 to sensitize GBM cells to TMZ. The studies showed the potential for targeting EGF in immune therapy. These agents can be used in conjunction with stem cell therapy to treat GBM

Delivery of Functional Anti-miR-9 by Mesenchymal Stem Cell–derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity

Glioblastoma multiforme (GBM), the most common and lethal tumor of the adult brain, generally shows chemo- and radioresistance. MicroRNAs (miRs) regulate physiological processes, such as resistance of GBM cells to temozolomide (TMZ). Although miRs are attractive targets for cancer therapeutics, the effectiveness of this approach requires targeted delivery. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM. We report on an increase in miR-9 in TMZ-resistant GBM cells. miR-9 was involved in the expression of the drug efflux transporter, P-glycoprotein. To block miR-9, methods were developed with Cy5-tagged anti-miR-9. Dye-transfer studies indicated intracellular communication between GBM cells and MSCs. This occurred by gap junctional intercellular communication and the release of microvesicles. In both cases, anti-miR-9 was transferred from MSCs to GBM cells. However, the major form of transfer occurred with the microvesicles. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to TMZ, as shown by increased cell death and caspase activity. The data showed a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells

Improving the efficacy of selenium fertilizers for wheat biofortification

© 2019, The Author(s). Increasing the selenium (Se) concentration of staple crops by fertilization is a valuable pathway to increase Se in the human diet, thus preventing Se deficiency. A pot trial was set up to investigate whether the application of 3.33 µg kg−1 of Se (equivalent to 10 g ha−1) to wheat can be made more efficient by its co-application with macronutrient carriers, either to the soil or to the leaves. In the soil, Se was applied either on its own (selenate only) or as a granular, Se-enriched macronutrient fertilizer supplying nitrogen, phosphorus, potassium or sulfur. Selenium was also applied to leaves at head emergence with, or without, 2% w/v N fertilizers. With grain Se concentrations varying from 0.13–0.84 mg kg−1, soil application of selenate-only was 2–15 times more effective than granular Se-enriched macronutrient fertilizers in raising grain Se concentrations. Co-application of foliar Se with an N carrier doubled the Se concentration in wheat grains compared to the application of foliar Se on its own, the majority of which was in the highly bioavailable selenomethionine fraction. Results from this study demonstrate the possibility of improving the efficacy of Se fertilizers, which could enrich crops with Se without additional application costs in the field

Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas

Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test

Effect of soil properties on time-dependent fixation (ageing) of selenate

© 2020 Elsevier B.V. Previous biofortification studies have established that the residual effect of added selenium (Se) fertilisers on second-season crops is minimal. To explore the fate of exogenous Se in soil, chemical and biological methods were employed to assess the change in Se bioavailability with time. Eight soils varying in physicochemical properties were spiked with sodium selenate (0.5 mg kg−1 Se) and incubated at 25 °C for different periods (1, 30, 60, 90 and 300 d). At the end of the incubation, soil Se was fractionated by a sequential extraction procedure into ‘soluble’, ‘adsorbed’ and ‘organically-bound’ Se fractions. Simultaneously, wheat was grown in the Se-aged soils, under controlled conditions for six weeks, and uptake was determined. A general decrease in Se solubility over time was observed, but the rate of decrease varied depending on soil type. A reversible first order model fitted the Se ageing kinetics well, except in an Oxisol. The most pronounced ageing was observed in calcareous soils. Concentrations of Se in the shoots of wheat grown in freshly spiked soils ranged from 71.8 ± 17.5 mg kg−1 in calcareous soils to 110 ± 31.6 mg kg−1 in non-calcareous, low-OM soils. With ageing, shoot Se concentrations decreased t

Clinical Laboratory Testing Practices in Diffuse Gliomas Prior to Publication of 2021 World Health Organization Classification of Central Nervous System Tumors

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear. OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors. DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers in gliomas. RESULTS.—: The data provide perspective into the testing practices for diffuse gliomas from a broad group of clinical laboratories in 2020. More than 98% of participating laboratories perform testing for glioma biomarkers recognized as diagnostic for specific subtypes, including IDH. More than 60% of laboratories also use molecular markers to differentiate between astrocytic and oligodendroglial lineage tumors, with some laboratories providing more comprehensive analyses, including prognostic biomarkers, such as CDKN2A/B homozygous deletions. Almost all laboratories test for MGMT promoter methylation to identify patients with an increased likelihood of responding to temozolomide. CONCLUSIONS.—: These findings highlight the state of molecular testing in 2020 for the diagnosis and classification of diffuse gliomas at large academic medical centers. The findings show that comprehensive molecular testing is not universal across clinical laboratories and highlight the gaps between laboratory practices in 2020 and the recommendations in the 2021 World Health Organization Classification of Central Nervous System Tumors

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p \u3c 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p \u3c 0.0001), KMT2D (1% vs. 16%, p \u3c 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p \u3c 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment