A nationwide evaluation of bevacizumab-based treatments in pediatric low-grade glioma in the UK: Safety, efficacy, visual morbidity, and outcomes.

BACKGROUND: Bevacizumab is increasingly used in children with pediatric low-grade glioma (PLGG) despite limited evidence. A nationwide UK service evaluation was conducted to provide larger cohort "real life" safety and efficacy data including functional visual outcomes. METHODS: Children receiving bevacizumab-based treatments (BBT) for PLGG (2009-2020) from 11 centers were included. Standardized neuro-radiological (RANO-LGG) and visual (logMAR visual acuity) criteria were used to assess clinical-radiological correlation, survival outcomes and multivariate prognostic analysis. RESULTS: Eighty-eight children with PLGG received BBT either as 3rd line with irinotecan (85%) or alongside 1st/2nd line chemotherapies (15%). Toxicity was limited and minimal. Partial response (PR, 40%), stable disease (SD, 49%), and progressive disease (PD, 11%) were seen during BBT. However, 65% progressed at 8 months (median) from BBT cessation, leading to a radiology-based 3 yr-progression-free survival (PFS) of 29%. Diencephalic syndrome (P = .03) was associated with adverse PFS. Pre-existing visual morbidity included unilateral (25%) or bilateral (11%) blindness. Improvement (29%) or stabilization (49%) of visual acuity was achieved, more often in patients' best eyes. Vision deteriorated during BBT in 14 (22%), with 3-year visual-PFS of 53%; more often in patients' worst eyes. A superior visual outcome (P = .023) was seen in neurofibromatosis type 1-associated optic pathway glioma (OPG). Concordance between visual and radiological responses was 36%; optimized to 48% using only best eye responses. CONCLUSIONS: BBTs provide effective short-term PLGG control and delay further progression, with a better sustained visual (best > worst eye) than radiological response. Further research could optimize the role of BBT toward a potentially sight-saving strategy in OPG.

Hearing loss and intellectual outcome in children treated for embryonal brain tumors: Implications for young children treated with radiation sparing approaches.

PURPOSE: We investigate the impact of severe sensorineural hearing loss (SNHL) and for the first time evaluate the effect of unilateral versus bilateral SNHL on intellectual outcome in a cohort of children with embryonal brain tumors treated with and without radiation. METHODS: Data were from 94 childhood survivors of posterior fossa (PF) embryonal brain tumors who were treated with either: (1) chemotherapy alone (n = 16, 7.11 [3.41] years, 11M/5F), (2) standard-dose craniospinal irradiation (CSI) and/or large boost volumes (n = 44, 13.05 [3.26] years, 29M/15F), or (3) reduced-dose CSI with a boost restricted to the tumor bed (n = 34, 11.07 [3.80] years, 19M/15F). We compared intellectual outcome between children who: (1) did and did not develop SNHL and (2) developed unilateral versus bilateral SNHL. A Chang grade of ≥2b that required the use of a hearing aid was considered severe SNHL. Comparisons were made overall and within each treatment group separately. RESULTS: Patients who developed SNHL had lower full scale IQ (p = 0.007), verbal comprehension (p = 0.003), and working memory (p = 0.02) than patients without SNHL. No differences were observed between patients who had unilateral versus bilateral SNHL (all p > 0.05). Patients treated with chemotherapy alone who developed SNHL had lower mean working memory (p = 0.03) than patients who did not develop SNHL. Among patients treated with CSI, no IQ indices differed between those with and without SNHL (all p > 0.05). CONCLUSIONS: Children treated for embryonal brain tumors who develop severe SNHL have lower intellectual outcome than patients with preserved hearing: this association is especially profound in young children treated with radiation sparing approaches. We also demonstrate that intellectual outcome is similarly impaired in patients who develop unilateral versus bilateral SNHL. These findings suggest that early intervention to preserve hearing is critical.

The Role of Power Fluctuations in the Preference of Diagonal vs. Double Poling Sub-Technique at Different Incline-Speed Combinations in Elite Cross-Country Skiers.

In classical cross-country skiing, diagonal stride (DIA) is the major uphill sub-technique, while double poling (DP) is used on relatively flat terrain. Although, the dependence of incline and speed on the preference of either sub-technique seems clearly established, the mechanisms behind these preferences are not clear. Therefore, the purpose of this study was to compare kinetics and energy consumption in DP and DIA at the same submaximal workload in cross-country skiing under two different incline-speed combinations. We compared kinetics and physiological responses in DP and DIA at the same submaximal workload (≈200 W) under two different incline-speed conditions, (5%-12.5 km h-1 vs. 12%-6.5 km h-1) where DP and DIA were expected to be preferred, respectively. Fifteen elite male cross-country skiers performed four separate 6.5-min roller skiing sessions on a treadmill at these two conditions using DP and DIA during which physiological variables, rate of perceived exertion (RPE) and kinetics, including power fluctuations, were recorded. At 12% incline, DIA resulted in lower physiological response (e.g., heart rate) and RPE, and higher gross efficiency than DP, whereas at 5% incline these variables favored DP (P < 0.05). The skiers' preference for sub-technique (13 preferred DIA at 12% incline; all 15 preferred DP at 5% incline) was in accordance with these results. Fluctuation in instantaneous power was lowest in the preferred sub-technique at each condition (P < 0.05). Preference for DP at 5% incline (high speed) is most likely because the speed is too high for effective ski thrust in DIA, which is reflected in high power fluctuations. The mechanism for preference of DIA at 12% incline is not indicated directly by the current data set showing only small differences in power fluctuations between DIA and DP. Apart from the low speed allowing ski thrust, we suggest that restricted ability to utilize the body's mechanical energy as well as the use of arms in DP play an important role.

Mosquitoes and their control

Mosquitoes and Their Control presents a wealth of information on the bionomics, systematics, ecology, research techniques and control of both nuisance and disease vector mosquitoes in an easily readable style, providing practical guidelines and important information for professionals and laymen alike. Ninety-two European species and more than 100 globally important vector and nuisance species are included in the book. Most of them, including all European species, are described in the fully illustrated identification keys, followed by a detailed description of the morphology, biology, distribution and medical importance of each species, including over 700 detailed drawings. Mosquitoes and Their Control includes: systematics and biology, medical significance, research techniques, illustrated identification keys for larval and adult mosquito general, morphology, ecology, and distribution of the species identified in the keys, biological, chemical, physical and genetic control of mosquitoes. Mosquitoes and Their Control is a valuable tool for vector ecologists, entomologists, and all those involved with mosquito control, biology, ecology, and systematics world-wide. It will especially benefit those professionals, scientists and students dealing with mosquitoes and their control on a day-to-day basis. Society as a whole stands to gain from improved, environmentally responsible mosquito management programs designed on the basis of a broader understanding of mosquitoes and their control, as provided in this enlightening book...

Mosquitoes and their control

Mosquitoes and Their Control presents a wealth of information on the bionomics, systematics, ecology, research techniques and control of both nuisance and disease vector mosquitoes in an easily readable style, providing practical guidelines and important information for professionals and laymen alike. Ninety-two European species and more than 100 globally important vector and nuisance species are included in the book. Most of them, including all European species, are described in the fully illustrated identification keys, followed by a detailed description of the morphology, biology, distribution and medical importance of each species, including over 700 detailed drawings. Mosquitoes and Their Control includes: systematics and biology, medical significance, research techniques, illustrated identification keys for larval and adult mosquito general, morphology, ecology, and distribution of the species identified in the keys, biological, chemical, physical and genetic control of mosquitoes. Mosquitoes and Their Control is a valuable tool for vector ecologists, entomologists, and all those involved with mosquito control, biology, ecology, and systematics world-wide. It will especially benefit those professionals, scientists and students dealing with mosquitoes and their control on a day-to-day basis. Society as a whole stands to gain from improved, environmentally responsible mosquito management programs designed on the basis of a broader understanding of mosquitoes and their control, as provided in this enlightening book

Seven week culture of functional human mast cells from buffy coat preparations.

Functional, mature human mast cells have been generated by in vitro differentiation of CD133(+)/CD34(+) progenitor cells isolated from e.g. cord blood, peripheral blood, bone marrow or fetal liver. However, the protocols published so far require long term cultivation, i.e. up to 15 weeks for mast cell differentiation, which makes such approaches not only laborious but also costly. Here, we have developed a protocol for generating functional human mast cells from peripheral blood already within 7 weeks. Human CD133(+) progenitors were isolated from buffy coat preparations of peripheral blood and cultured in the presence of stem cell factor (SCF) and IL-6 for 7 weeks. IL-3 was added to the culture medium during the first 3 weeks, and fetal calf serum (FCS) added during the last week. In vitro differentiated CD133(+) cells exhibited multiple characteristics of mature mast cells. Thus, cells contained tryptase and expressed functional levels of FcepsilonRI. Anti-IgE stimulation induced significant release of histamine and PGD(2) and also of chemokines including MCP-1, IL-8, MIP-1alpha, and MIP-1beta. The fact that our in vitro differentiated mast cells are derived from a generally available source of progenitor cells makes this novel protocol widely applicable to any patient group, irrespective of age. Moreover, this progenitor source is more readily available than e.g. bone marrow or cord blood-derived progenitors. Consequently, our protocol has great potential in studies on mast cell biology and mast cell pathology, and e.g. on evaluation of drug effects.

Comparison of short term in vitro cultured human mast cells from different progenitors - Peripheral blood-derived progenitors generate highly mature and functional mast cells.

During the last two decades different scientific groups have investigated the phenotype and function of in vitro generated human mast cells (MC). The cells have been shown to display variable surface markers and functional characteristics. The phenotypic differences may reflect different culture conditions, protocols or the use of different progenitors. To investigate the significance of different progenitors, we have compared MC generated from CD133(+) progenitor cells from cord blood (CBMC) or peripheral blood (PBMC). The progenitors were cultured for 7 weeks in the presence of IL-6 and SCF, with addition of IL-3 the first 3 weeks, and FCS during week 7. The phenotype of the established MC was characterized by surface marker expression levels, metachromasia, histamine and tryptase contents and their function was evaluated by receptor-mediated release of histamine and PGD(2). The generated metachromatic (<99%) MC were 75% tryptase(+), regardless of the source of progenitor cell. Expression of c-kit/CD117, CD203c, and FcepsilonRI was comparable. The density of c-kit/CD117 receptors on CBMC was higher that of PBMC (p<0.001). The density of CD203c and FcepsilonRI was higher on PBMC (p<0.001). PBMC contained more histamine (p<0.001), expressed more FcepsilonRI (p<0.001) and released more histamine (p<0.001) and PGD(2) (p<0.001) upon ligation of FcepsilonRI, than CBMC. Culture with IL-4 increased expression of tryptase, FcepsilonRI, CD117 and CD203c, secretion of histamine and PGD(2) of PBMC, and histamine secretion of CBMC. Cord and peripheral blood may give rise to different types of MC. The question addressed should determine the progenitor cell and protocol to be used.

Mice expressing SV40 T antigen directed by the intestinal trefoil factor promoter develop tumors resembling human small cell carcinoma of the colon.

The colonic epithelium contains three major types of mature cells, namely, absorptive, goblet, and enteroendocrine cells. These cells are maintained by a complex process of cell renewal involving progenitor and stem cells, and colon cancers develop when this process goes awry. Much is known about the genetic and epigenetic changes that occur in cancer; however, little is known as to the specific cell types involved in carcinogenesis. In this study, we expressed the SV40 Tag oncogene in the intestinal epithelium under the control of an intestinal trefoil factor (ITF) promoter. This caused tumor formation in the proximal colon with remarkable efficiency. ITFTag tumors were rapidly growing, multifocal, and invasive. ITFTag tumor cells express synaptophysin and contain dense core secretory granules, markers of neuroendocrine differentiation. The cell type involved in the early steps of ITFTag tumorigenesis was studied by examining partially transformed crypts that contained populations of both normal and dysplastic cells. The dysplastic cell population always expressed both Tag and synaptophysin. Cells expressing Tag alone were never observed; however, normal enteroendocrine cells expressing synaptophysin but not Tag were readily visualized. This suggests that ITFTag tumor cells originate from the enteroendocrine cell lineage following a transforming event that results in Tag expression. ITFTag tumors closely resemble human small cell carcinomas of the colon, suggesting the possibility that these tumors might be derived from the enteroendocrine cell lineage as well.

Mosquito larvae (Diptera: Culicidae) in snow-melt pools in a Swedish Lapland area.

Culicid larvae were collected in snow-melt pools during the first half of June from 1975-1977 and 1995-1996 in the Abisko Valley, Torne Lapmark, northern Sweden. Twelve species were collected from 102 pools and 81 localities with 7,914 specimens (elevations from 300 to 650 m a.s.l.). Fourteen species are now known from the area. Ten types of larval habitats were classified and ten species were statistically analyzed on pooled values over all years for abundance, coexistence, and diversity. The greatest abundance of individuals had pools with Carex spp. on the bottom. Most widespread and abundant were Oc. hexodontus (Dyar), Oc. communis (DeGeer), Oc. pullatus (Coquillett), and Oc. punctor (Kirby). The two circumpolar, arctic species, Oc. nigripes (Zetterstedt) and Oc. impiger (Walker), were mainly confined to elevations above 400 m a.s.l. In such marginal habitats as these pools, exposed to variable abitotic conditions, the phenology of species was rather constant. Species diversity varied somewhat between habitats. Oc. hexodontus, Oc. communis, and Oc. pullatus most often occupied pools as single species. Oc. communis and Oc. hexodontus had the highest values for coexistence and also occurred with Oc. punctor. The habitats that were richest in species were those without vegetation or with detritus on the bottom and surrounded by Empetrum nigrum and Betula nana. These habitats contained between eight and ten species. Species abundance and coexistence over the years showed no stable species patterns for the habitat types in the area.

Initiation of transcription of the MUC3A human intestinal mucin from a TATA-less promoter and comparison with the MUC3B amino terminus.

Human intestinal mucin genes MUC3A and MUC3B are members of a membrane mucin gene family residing at chromosome 7q22. In this paper, we utilized genomic and cDNA cloning to elucidate the sequence of the 5'-region of the MUC3A gene including the gene promoter and the amino terminus coding sequence. Following its 21-residue signal peptide, the amino terminus of the mucin consists of a 233-residue Thr-, Ser-, and Pro-rich nonrepetitive sequence that is contiguous with its hypervariable domain of 375-residue repeats. RNase protection analysis and 5'-GeneRacer PCR indicated that MUC3A gene transcripts initiate from multiple start sites along a region spanning approximately 180 bases. The 5'-flanking region of the gene had promoter activity when fused to a luciferase reporter gene in all of the tested cell lines. This region contained binding sites for several transcription factors, including those implicated in the regulation of intestinal genes, but lacked a cognate TATA box. These features of the gene promoter may enable the gene to be expressed at variable levels in several cell types with different repertoires of transcription factors. We also utilized 5'-GeneRacer PCR to determine the sequence of the 5'-terminus of the MUC3B message. The amino termini of the MUC3A and MUC3B mucins are 91% conserved at the amino acid level. Thus, MUC3A and MUC3B have highly conserved amino and carboxyl termini, suggesting a recent duplication of the entire ancestral gene. It remains to be determined whether other members of the 7q22 membrane mucin gene family have amino-terminal domains similar to MUC3A and MUC3B.

Field evaluation of a new surveillance trap in Sweden.

Field tests were conducted to assess the effectiveness of American Biophysics Counterflow 2000 (CF2000) traps compared to CO2-baited Centers for Disease Control (CDC) miniature traps at a site in central Sweden. Adult mosquitoes representing 17 species and 6 genera were collected in July and August 1998. Although the 2 trap types did not differ significantly in total number of adult female mosquitoes collected, CF2000 traps captured a greater diversity of mosquito species and significantly more adult males than did CDC traps. Interspecific differences in capture rates and interactions between trap type and location also were observed.

The establishment of a combined serum-free and serum-supplemented culture method of obtaining functional cord blood-derived human mast cells.

BACKGROUND: Serum-free cultures supplemented with stem cell factor (SCF) and IL-6 is reported to support the extensive growth of less functional human cord blood-derived mast cells. OBJECTIVE: To obtain more functional mast cells from cord blood, we developed a culture system combining a serum-free condition for 0-8 weeks of culture, and followed by a serum-supplemented culture condition and examined the function of the cells compared to the cells cultured continuously in serum-free condition. METHODS: Human cord blood progenitors were purified with anti-CD133 antibody. They were cultured in a serum-free medium StemSpan supplemented with SCF at 100 ng/ml and IL-6 at 50 ng/ml for 8 weeks. Then, an aliquot of the cultured cells were cultured in the above condition but further supplemented with 10% fetal calf serum (FCS). RESULTS: The addition of FCS after 8 weeks of culture significantly increased the amount of histamine per mast cell (3.8 pg/cell) when compared to the serum-free condition (0.7 pg/cell). The cells cultured with FCS after 8 weeks expressed more FcvarepsilonRI alpha and released >30% of the histamine content upon anti-IgE stimulation than those cultured without serum. CONCLUSION: It is uncertain why FCS enhanced the functional maturation of mast cells when added after week 8 of culture but suppressed mast cell development when added at day 0 of culture. Yet, the present method combining a serum-free culture system with a serum-supplemented culture system seems to be beneficial for most of the laboratories to obtain functional human mast cells.