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【目的】 看護基礎教育課程では，紙上事例を用いた看護過程演習が広く行われている．しかし，8割近くの病院が電子カルテを導入しており，臨床現場では電子カルテの中から意図的に患者情報を収集するスキルが必要である．そこで，従来の紙上事例に代えて，訓練用電子カルテに模擬患者の情報を入力し，実習さながらの情報収集ができる環境を設定した演習を開発したので，その経緯を報告する．【教材開発の計画】 学士課程による看護基礎教育で求められる看護実践能力を明確化するため，既存の教科書，事例集，視聴覚教材，国家試験問題，政府及び公的機関から出された報告書や指針等を基礎資料として収集した．それらを踏まえて，領域別看護学実習前の段階にある学生の学習用として事例を作成し，訓練用電子カルテに入力した．【教材開発の実際】 事例作成にあたり学習項目を抽出するために「大学における看護系人材養成の在り方に関する検討会最終報告」と「看護師国家試験出題基準」を参考とした．小児看護学実習でよく遭遇する疾患及び年齢層を考慮し，川崎病と診断された 1 歳 6 ヶ月女児の紙上事例を作成し，それを元に大学病院医療情報センター内の訓練用電子カルテに入力し，教材とした．訓練用電子カルテには職種毎の権限を付与した模擬IDで，入力内容ごとにIDを変更して作業を行う必要があった．作業が煩雑になる場合には，“本物”と同じにすることにこだわらず，学習に支障を来さない教材作成を目標に作業を進めた．【演習の展開】 看護学部 3 年次必修科目「看護過程」・「看護技術」において開発した教材を用いた演習を行った．その際，補助教材として学習ガイド及び演習ワークシートと教員用マニュアルを作成し，担当教員によって学習進度や学習内容に差が出ないように努めた．【結論】 模擬患者事例の情報を入力した訓練用電子カルテを用いた小児看護学演習用事例を開発した．教育効果の客観的評価は今後の課題である．

We appreciate the constructive comments by Cheng et al. (1), who performed an intensive statistical analysis of cytokine levels in patients with COVID-19. Their work applies the inverse-variance weighted (IVW) method and an MR-Egger regression on a large number of patients for a statistical analysis to identify COVID-19 risk factors. Consistent with our previous work (2), the results of these analyses suggest that the plasma from patients with COVID-19 has significantly lower levels of interleukin (IL)-8, IL-10, and monocyte chemoattractant protein (MCP)-1, compared with that from patients with other types of cytokine release syndrome (CRS). Previously, we proposed that the elevation of four proinflammatory cytokines, that is, IL-6, … [↵][1]1To whom correspondence may be addressed. Email: kishimoto{at}ifrec.osaka-u.ac.jp. [1]: #xref-corresp-1-1

Significance Cytokine release syndrome (CRS) is a life-threatening complication induced by hyperinflammatory responses. However, no specific immunotherapies are available for its treatment. In this study, we found that interleukin (IL)-6 signaling plays a crucial role in endothelial cell dysfunction during bacterial and viral CRS. Specifically, we identified that the pathogenesis of CRS in patients with sepsis, acute respiratory distress syndrome, and burns involved the IL-6–mediated production of hyperinflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1), which indicates that IL-6 signaling blockade has potential as a therapy for CRS. We also found that the inhibition of IL-6 signaling by tocilizumab treatment decreased PAI-1 production and alleviated clinical manifestations in severe COVID-19 patients., Cytokine release syndrome (CRS) is a life-threatening complication induced by systemic inflammatory responses to infections, including bacteria and chimeric antigen receptor T cell therapy. There are currently no immunotherapies with proven clinical efficacy and understanding of the molecular mechanisms of CRS pathogenesis is limited. Here, we found that patients diagnosed with CRS from sepsis, acute respiratory distress syndrome (ARDS), or burns showed common manifestations: strikingly elevated levels of the four proinflammatory cytokines interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and IL-10 and the coagulation cascade activator plasminogen activator inhibitor-1 (PAI-1). Our in vitro data indicate that endothelial IL-6 trans-signaling formed an inflammation circuit for robust IL-6, IL-8, and MCP-1 production and promoted PAI-1 production; additionally, an IL-6 signaling blockade by the human monoclonal antibody tocilizumab blunted endothelial cell activation. Plasma from severe COVID-19 patients similarly exhibited increased IL-6, IL-10, and MCP-1 levels, but these levels were not as high as those in patients with CRS from other causes. In contrast, the PAI-1 levels in COVID-19 patients were as highly elevated as those in patients with bacterial sepsis or ARDS. Tocilizumab treatment decreased the PAI-1 levels and alleviated critical illness in severe COVID-19 patients. Our findings suggest that distinct levels of cytokine production are associated with CRS induced by bacterial infection and COVID-19, but both CRS types are accompanied by endotheliopathy through IL-6 trans-signaling. Thus, the present study highlights the crucial role of IL-6 signaling in endothelial dysfunction during bacterial infection and COVID-19.

Cumulative epidemiological evidence indicates that the presence of microalbuminuria predicts a higher frequency of cardiovascular events, peripheral disease, and mortality in essential hypertension. Microalbuminuria may arise from increased glomerular permeability and/or reduced proximal tubular reabsorption of albumin by receptor-mediated endocytosis. This study aimed to evaluate the temporal pattern of urinary protein excretion and to test the hypothesis that progression of microalbuminuria is associated with decreased protein expression of critical components of the endocytic apparatus in the renal proximal tubule of spontaneously hypertensive rats (SHR). We found that urinary albumin excretion increased progressively with blood pressure in SHR from 6 to 21 wk of age. In addition, SDS-PAGE analysis of urinary proteins showed that microalbuminuric SHR virtually excreted proteins of the size of albumin or smaller (+-ATPase B2 subunit was also reduced in the renal cortex of 21-wk-old compared with both 6- and 14-wk-old SHR. Collectively, our study suggests that enhanced urinary protein excretion, especially of albumin, may be due, at least in part, to lower expression of key components of the apical endocytic apparatus in the renal proximal tubule. Finally, one may speculate that dysfunction of the apical endocytic pathway in the renal proximal tubule may contribute to the development of microalbuminuria in essential hypertension.

The transcription-export complex (TREX) couples mRNA transcription, processing and nuclear export. We found that CFIm68, a large subunit of a heterotetrameric protein complex mammalian cleavage factor I (CFIm), which is implicated in alternative polyadenylation site choice, co-purified with Thoc5, a component of human TREX. Immunoprecipitation using antibodies against different components of TREX indicated that most likely both complexes interact via an interaction between Thoc5 and CFIm68. Microarray analysis using human HeLa cells revealed that a subset of genes was differentially expressed on Thoc5 knockdown. Notably, the depletion of Thoc5 selectively attenuated the expression of mRNAs polyadenylated at distal, but not proximal, polyadenylation sites, which phenocopied the depletion of CFIm68. Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) indicated that CFIm68 preferentially associated with the 5′ regions of genes; strikingly, the 5′ peak of CFIm68 was significantly and globally reduced on Thoc5 knockdown. We suggest a model in which human Thoc5 controls polyadenylation site choice through the co-transcriptional loading of CFIm68 onto target genes.

Evidências epidemiológicas indicam que a presença de microalbuminúria prediz maior freqüência de eventos cardiovasculares e mortalidade em hipertensos essenciais. A microalbuminúria pode ser decorrente do aumento da permeabilidade glomerular e/ou da diminuição da reabsorção desta macromolécula no túbulo proximal. Todavia não é sabido se os mecanismos que regulam a reabsorção de albumina em túbulo proximal renal encontram-se alterados na hipertensão essencial. Este trabalho teve como objetivo investigar as bases moleculares da microalbuminúria associada à hipertensão arterial essencial, focando na reabsorção tubular de albumina. Para tanto, avaliamos a evolução temporal da excreção urinária de albumina em ratos espontaneamente hipertensos (SHR) com 6 semanas de idade (pressão arterial sistólica, PAS, = 105 ± 4 mmHg), 14 semanas de idade (PAS = 180 ± 2 mmHg) e 21 semanas de idade (PAS = 202 ± 2 mmHg). Ratos normotensos Wistar da mesma idade serviram de controle. Observou-se que a excreção urinária diária de albumina aumentou progressivamente com o aumento da pressão arterial em SHR (10,5 ± 1,9; 92 ± 7,0 e 154 ± 27 g/dia, em SHR com PAS média igual a 105, 180 e 202 mmHg respectivamente). Este aumento progressivo não foi observado em ratos normotensos com idade correspondente, indicando que este fenômeno é decorrente do aumento da pressão arterial e não pode ser atribuído ao aumento da idade dos animais durante o período estudado. A análise das proteínas urinárias por eletroforese em gel de poliacrilamida (SDS-PAGE) mostrou que SHR excretam proteínas do tamanho da albumina ou menores (< 70kDa), padrão típico de proteinúria tubular. Adicionalmente, verificou-se que os níveis de expressão dos receptores endocíticos megalina e cubilina, bem como do canal para cloreto ClC-5 diminuem progressivamente no córtex renal de SHR com o aumento da pressão arterial. Observou-se também uma diminuição significativa na expressão de uma outra macromolécula importante no processo de endocitose mediada por receptor em túbulo proximal renal, a v-H+-ATPase. Entretanto, a diminuição da expressão protéica da subunidade B2 desta ATPase foi estatisticamente significante apenas em SHR com 21 semanas comparado aos com 6 semanas de idade. Não foram encontradas alterações no padrão de expressão de componentes estruturais da barreira glomerular como a nefrina e podocina. Em suma, o nosso estudo demonstra que o aumento da excreção urinária de proteínas, especialmente de albumina, está associado com uma menor expressão de componentes essenciais do aparelho endocítico do túbulo proximal renal. É tentador especular que a disfunção da via endocítica no túbulo proximal renal possa ser o principal mecanismo subjacente ao desenvolvimento de microalbuminúria na hipertensão Epidemiological evidences indicate that the presence of microalbuminuria predicts a higher frequency of cardiovascular events and mortality in essential hypertensive patients. Microalbuminuria may arise from increased glomerular permeability and/or reduced proximal tubular reabsorption of albumin. However, it remains to be determined whether the mechanisms that regulate the renal proximal tubular reabsorption of albumin are altered in essential hypertension. The purpose of this work was to investigate the molecular basis of microalbuminuria in essential hypertension, focusing on the renal tubular reabsorption of albumin. To this end, we evaluated the temporal evolution of urinary albumin excretion in spontaneously hypertensive rats (SHR) at 6 weeks of age (systolic arterial pressure, SAP, = 105 ± 4 mmHg), 14 weeks of age (SAP = 180 ± 2 mmHg) and 21 weeks of age (SAP = 202 ± 2 mmHg). Age-matched normotensive Wistar rats were used as controls. It was observed that the daily urinary excretion of albumin progressively increased with blood pressure in SHR from 6 to 21 weeks of age (10.5 ± 1.9, 92 ± 7.0 and 154 ± 27 g in SHR with 105, 180 and 202 mmHg of average SAP, respectively). This progressive increase in microalbuminuria has not been observed in age-matched normotensive Wistar rats, indicating that this phenomenon cannot be attributed to age progression over the studied period. SDS-PAGE analysis of urinary proteins showed that microalbuminuric SHR virtually excreted proteins of the size of albumin or smaller (< 70kDa), typical of tubular proteinuria. Additionally, it was verified that the protein expression levels of the endocytic receptors megalin and cubilin as well as of the chloride channel ClC-5 progressively decreased in the renal cortex of SHR from 6 to 21 weeks of age. Moreover, it was observed reduction of expression of another macromolecule that plays an important role in the process of receptor mediated endocytosis in the renal proximal tubule, the v-H+- ATPase, was reduced. However, reduced cortical expression of the B2 subunit of the v- H+-ATPase, was only statistically significant in 21-wk-old vs. 6-wk-old SHR. Expression levels of structural components of the glomerular barrier such as nephrin and podocin were unchanged. To sum up, our study demonstrates that the increase in urinary protein excretion, especially of albumin, is associated with lower expression of key components of the apical endocytic apparatus in the renal proximal tubule. It is tempting to speculate that dysfunction of the apical endocytic pathway in the renal proximal tubule may be the major mechanism underlying development of microalbuminuria in essential hypertension

指向性マイクを有する補聴器を装用すると, 雑音環境下の語音聴取が改善する利点がある反面, 側方や後方からの呼びかけや警告音, 環境音などが聞き取りにくくなる欠点がある。この問題点の改善策として, 片耳のマイクを指向性, 対側耳を無指向性とする非対称指向性補聴器フィッティングが提案されているがその有効性の評価は報告により異なっている。そこで今回, 難聴群13例と健聴群28例を対象に, 両耳に補聴器を適合し, 両耳無指向性, 両耳指向性, 非対称指向性の3つ (健聴者は裸耳条件を含めた4つ) のマイクロホン条件について, 語音が前方から雑音が側方と後方から入射する場合の雑音下の語音了解閾値 (SRT) を測定し比較した。その結果, 非対称指向性条件では, 両耳無指向性条件に比べた雑音下のSRTの改善度が平均1～1.5dB低下したが, 依然として約3dBの指向性効果が認められた。この結果は, 非対称指向性の補聴器フィッティングにより, 指向性の効果を維持しつつ環境音などの聴き取りも改善できる可能性を示唆する。

This study discussed how to do Death Education for school-aged children and evaluated intervention in Death Education. The subjects were 80 children - the 4^ grade of elementary school. As the teaching material for Death Education a documentary film was prepared; the story of a school-aged boy living and fighting against his disease. The subjects wrote two reports about "the meaning of life" or "life now", before and after of the Death Education. Their reports were analyzed using the constant comparative method. Analysis revealed that there were four major categories before intervention (#1-4), and five major categories after intervention (#5-9). 1. the preciousness of life, 2. their feelings about daily life, 3. their thought about life and death regarding other person's circumstances, 4. the significance of life and death, 5. the absurdity of death, 6. their new leaning about the preciousness life, 7. their impression about living and life, 8. attitudes to life, 9. their emotional response to the unreasonable death of other. As a result, compared with categories before and after intervention, children have an opportunity to think and to feel about "life", "death" and "daily life" more familiarly after the intervention. This teaching material for Death Education was easy to comprehend for them, because the character in the film was a school-aged child of the same generation. It was extrapolated that children were concerned about "life", "death" and "daily life", but they had no chance to talk or reflect about this theme with their families, teachers or friends. We still have to continue to discuss and evaluate methods of Death Education, but in greater dialogue about this theme with children.

Background The mammalian target of rapamycin (mTOR) belongs to the family of phosphoinositide (PI)-kinase-related kinases that includes the ataxia-telangiectasia gene product (ATM). mTOR plays a critical role in controlling translational effectors such as p70 S6 kinase α (p70α) and eukaryotic initiation factor 4E binding protein 1 (4EBP1). Results We show that the C-terminal region of mTOR, which is highly conserved among the PI-kinase-related kinases, plays a critical role in the mTOR protein kinase activity. Deletion of the C-terminal residues did not adversely affect the expression of mTOR, but caused a nearly complete loss of the mTOR protein kinase activity toward both 4EBP1 and p70αin vitro. These deletions also abolished the ability of a rapamycin-resistant mTOR mutant to rescue the activity of p70α from inhibition induced by rapamycin in vivo. Furthermore, replacement of Trp2545, a conserved residue in the C-terminal region throughout the PI-kinase-related kinase family, abolished the function of the mTOR kinase, both in vivo and in vitro. However, substitution of 32 C-terminal residues of mTOR with those of ATM did not restore the mTOR function. Conclusions These findings define an indispensable role for the noncatalytic C-terminal region of mTOR and indicate that, although this highly conserved region may be important throughout the PI-kinase-related kinase family, it is not functionally interchangeable within the family.

Synthesis of (1S,2R)-1-[(E)-hex-1-en-1-yl]-2-vinylcyclopropane (dictyopterene A), which was isolated from the essential oil of algae of the genus Dictyopteris in Hawaii, has been demonstrated using optically active tributylstannylcyclopropane as a starting chiral synthon.

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Inoue BH, dos Santos L, Pessoa TD, Antonio EL, Pacheco BPM, Savignano FA, Carraro-Lacroix LR, Tucci PJF, Malnic G, Girardi ACC. Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol 302: R166-R174, 2012. First published October 26, 2011; doi:10.1152/ajpregu.00127.2011.-Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na(+)/H(+) exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. in addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease. Univ São Paulo, Heart Inst InCor, Sch Med, BR-05403900 São Paulo, Brazil Univ Fed Espirito Santo, Dept Physiol Sci, Vitoria, ES, Spain Univ São Paulo, Dept Physiol & Biophys, Inst Biomed Sci, BR-05403900 São Paulo, Brazil Universidade Federal de São Paulo, Dept Physiol, São Paulo, Brazil Universidade Federal de São Paulo, Dept Physiol, São Paulo, Brazil Web of Science

Incorporation of exogenous docosahexaenoic acid (DHA) into bacterial phospholipids was examined as a method for DHA-linked phospholipid production. The cultivation of 23 bacterial strains in medium with DHA showed that an eicosapentaenoic acid-producing bacteriumShewanella sp. strain SCRC-2738 (strain SCRC-2738),Bacillus subtilis W23,B. cereus, an Antarctic marine bacterium strain S-7 (strain S-7), photosynthesis bacterium (PSB)Rhodopseudomonas capsulatus utilized for the production of larval marine fish,Pseudomonas aeruginosa, Staphylococcus aureus, Serratia marcescens andEscherichia coli K12 all incorporated DHA into their polar lipids. The polar lipids of the strain SCRC-2738, strain S-7, PSB andE. coli K12 were identified to be phospholipids. DHA was localized at thesn-2 position in the phospholipids of the four strains. Incorporation of exogenous DHA into their phospholipids produced an increase in saturated fatty acids and a decrease in monounsaturated fatty acids exceptE. coli K12. The strain SCRC-2738 incorporated the largest amount of DHA into their phospholipids among the tested bacterial strains in this study: DHA was 16% of the total fatty acids in the phosphatidylethanolamine (PE) and 29% in the phosphatidylglycerol (PG). In the PSB, incorporated DHA was 12% of the total fatty acids in the PE, 10% in the PG and phosophatidylcholine so that the PSB was nutritionally fortified.

Synthesis of (1S,2R)-1-[(E)-hex-1-en-1-yl]-2-vinylcyclopropane (dictyopterene A), which was isolated from the essential oil of algae of the genus Dictyopteris in Hawaii, has been demonstrated using optically active tributylstannylcyclopropane as a starting chiral synthon.

In metazoans, nuclear export of bulk mRNA is mediated by Tap-p15, a conserved heterodimeric export receptor that cooperates with adaptor RNA-binding proteins. In this article, we show that Thoc5, a subunit of the mammalian TREX complex, binds to a distinct surface on the middle (Ntf2-like) domain of Tap. Notably, adaptor protein Aly and Thoc5 can simultaneously bind to non-overlapping binding sites on Tap-p15. In vivo, Thoc5 was not required for bulk mRNA export. However, nuclear export of HSP70 mRNA depends on both Thoc5 and Aly. Consistent with a function as a specific export adaptor, Thoc5 exhibits in vitro RNA-binding activity and is associated with HSP70 mRNPs in vivo as a component of the stable THO complex. Thus, through the combinatorial use of an adaptor (e.g., Aly) and co-adapter (e.g., Thoc5), Tap-p15 could function as an export receptor for different classes of mRNAs.

p70 S6 kinase alpha (p70alpha) is activated in vivo through a multisite phosphorylation in response to mitogens if a sufficient supply of amino acids is available or to high concentrations of amino acids per se. The immunosuppressant drug rapamycin inhibits p70alpha activation in a manner that can be overcome by coexpression of p70alpha with a rapamycin-resistant mutant of the mammalian target of rapamycin (mTOR) but only if the mTOR kinase domain is intact. We report here that a mammalian recombinant p70alpha polypeptide, extracted in an inactive form from rapamycin-treated cells, can be directly phosphorylated by the mTOR kinase in vitro predominantly at the rapamycin-sensitive site Thr-412. mTOR-catalyzed p70alpha phosphorylation in vitro is accompanied by a substantial restoration in p70alpha kinase activity toward its physiologic substrate, the 40 S ribosomal protein S6. Moreover, sequential phosphorylation of p70alpha by mTOR and 3-phosphoinositide-dependent protein kinase 1 in vitro resulted in a synergistic stimulation of p70alpha activity to levels similar to that attained by serum stimulation in vivo. These results indicate that mTOR is likely to function as a direct activator of p70 in vivo, although the relative contribution of mTOR-catalyzed p70 phosphorylation in each of the many circumstances that engender p70 activation remains to be defined.

Enantioselective hydrolysis of diacetate of bis(trifluoromethyl)alkanediols has been demonstrated. Candida antarctica lipase was chosen from among commercial enzymes as the one most able to enantioselectively hydrolyze the acetyl group giving optically pure diols and diacetate.

The pH-solubility profiles of four basic drugs were studied at 37°. The solubility of papaverine hydrochloride in acetate buffer showed a typical pH-profile, which increased with decrease in pH. On the other hand, the pH-solubility profile of the hydrochloride in HCl-sodium acetate buffer was not as simple as that in acetate buffer, showing as solubility maximum at approximately 3.7. Similar pH-profiles of solubility were observed for trihexyphenidyl hydrochloride, isoxsuprine hydrochloride, and oxyphencyclimine hydrochloride. The decrease in the solubility of these drugs at more acidic pH values could be rationalized on the basis of the common ion effect. The dissolution behavior of the free bases and that of the hydrochloride salts of papaverine, trihexyphenidyl, and isoxsuprine were compared in dilute hydrochloric acid solutions, in the pH range from 1.0 to 1.8. It was confirmed that a much higher solution concentration and dissolution rate could be obtained using the free bases than from the hydrochloride salts in the pH range of the stomach (pH 1.0-1.2 for papaverine, and pH 1.2-1.4 for trihexyphenidyl and isoxsuprine) due to the common ion effect. It is suggested that salt formation does not always result in an enhancement of solubility characteristics.

The effect of antacids on the dissolution behavior of tetracycline hydrochloride and methacycline hydrochloride from commercial capsules was studied. The dissolution of the tetracyclines was found to be markedly retarded by antacids such as aluminium silicate and magnesium trisilicate. An attempt was made to elucidate the mechanism of this effect. The results suggest that the effects of antacids on the dissolution may be due to the adsorption of the drugs on antacid particles as well as to the increased pH of the medium. A study was also carried out to determine the influence of stomachics using Cinnamomi Cortex as a test material. In dissolution experiments on commercial capsules, a significant dissolution inhibition by the stomachic was found.

The effects of bile salts on the dissolution behavior of indomethacin and phenylbutazone were investigated. Bile salts such as sodium desoxycholate and sodium cholate considerably enhanced the dissolution of both drugs in pH 7.3 buffer at 37°. The results indicated that the enhancement of the dissolution of indomethacin in the presence of bile salts was mainly due to micellar solubilization. On the other hand, the enhanced dissolution of phenylbutazone may be due to the wetting effect, increasing the effective surface area of the powder.