BACKGROUND & AIMS: :High salt intake is a well-recognized risk factor for osteoporosis because it induces calciuria, but the effects of salt on calcium metabolism and the potential impact on bone health in postmenopausal women have not been fully characterized. This study investigated adaptive mechanisms in response to changes in salt and calcium intake in postmenopausal women. Eleven women completed a randomized cross-over trial consisting of four successive 5-wk periods of controlled dietary intervention, each separated by a minimum 4-wk washout. Moderately low and high calcium (518 versus 1284 mg) and salt (3.9 versus 11.2 g) diets, reflecting lower and upper intakes in postmenopausal women consuming a Western-style diet, were provided. Stable isotope labeling techniques were used to measure calcium absorption and excretion, compartmental modeling was undertaken to estimate bone calcium balance, and biomarkers of bone formation and resorption were measured in blood and urine. Moderately high salt intake (11.2 g/d) elicited a significant increase in urinary calcium excretion (p = 0.0008) and significantly affected bone calcium balance with the high calcium diet (p = 0.024). Efficiency of calcium absorption was higher after a period of moderately low calcium intake (p < 0.05) but was unaffected by salt intake. Salt was responsible for a significant change in bone calcium balance, from positive to negative, when consumed as part of a high calcium diet, but with a low calcium intake, the bone calcium balance was negative on both high and low salt diets.

背景与目标： : 高盐摄入量是骨质疏松症的公认危险因素，因为它会诱发钙尿症，但盐对钙代谢的影响以及对绝经后妇女骨骼健康的潜在影响尚未完全表征。这项研究调查了绝经后妇女对盐和钙摄入量变化的适应性机制。11名妇女完成了一项随机交叉试验，该试验包括四个连续5周的受控饮食干预期，每个间隔最少4周。提供了中度低钙和高钙 (518对1284 mg) 和盐 (3.9对11.2g) 饮食，反映了食用西式饮食的绝经后妇女的较低和较高摄入量。使用稳定的同位素标记技术来测量钙的吸收和排泄，进行隔室建模以估计骨钙平衡，并在血液和尿液中测量骨形成和吸收的生物标志物。适度高盐摄入 (11.2g/d) 引起尿钙排泄显着增加 (p = 0.0008)，并显着影响高钙饮食的骨钙平衡 (p = 0.024)。在适度低钙摄入一段时间后，钙吸收效率较高 (p <0.05)，但不受盐摄入的影响。当作为高钙饮食的一部分食用时，盐是导致骨钙平衡从正变为负的显着变化的原因，但是在钙摄入量低的情况下，高盐和低盐饮食的骨钙平衡均为负。

BACKGROUND & AIMS: OBJECTIVES:For a moderately dilated ascending aorta (diameter 35-54 mm), current guidelines recommend continuous annual or semi-annual examinations with computed tomography or magnetic resonance imaging. However, few data have shown the yield and benefit of such a protocol. This study aimed to investigate the fate of a moderately dilated ascending aorta and thereby determine the adequate imaging interval. METHODS:In our institutional database, we identified adult patients having an ascending aortic diameter ≥40 mm in contrast-enhanced computed tomography and follow-up imaging(s) after ≥1 year. Of the 509 patients (mean age 67.2 ± 10.4 years) enrolled in the study, the maximal diameter of the ascending aorta was compared between the first and last images. Also, their medical records were reviewed to investigate the associated illness and clinical events. RESULTS:The mean growth rate of the patients with a 40-44 mm ( n  = 321), 45-49 mm ( n  = 142) and ≥50 mm ( n  = 46) ascending aorta was 0.3 ± 0.5, 0.3 ± 0.5 and 0.7 ± 0.9 mm/year, respectively. During the mean interval of 4.3 ± 2.4 years, significant progression (diameter increase by ≥5 mm) occurred in 3.4, 5.6 and 21.7%, respectively. The 3- to 5-year rates of freedom from significant progression were 99.1%-96.5% (40-44 mm) and 97.8%-96.4% (45-49 mm). In multivariate analysis, initial ascending aortic diameter ≥45 mm and aortic valve regurgitation were significantly associated with significant progression. Acute type A aortic dissection occurred in 5 patients (1%), before the maximal diameter of the ascending aorta reached 55 mm or significant progression was observed. CONCLUSIONS:For a moderately dilated ascending aorta not exceeding 45 mm in maximal diameter and stable in the first annual follow-up image, a 3- to 4-year interval would be reasonable before subsequent imaging. More frequent imaging may be warranted in patients with aortic valve insufficiency or with an aortic diameter ≥45 mm.

背景与目标：

BACKGROUND & AIMS: :In order to identify the ATP transporter in rat liver rough endoplasmic reticulum (RER), a photoreactive azido derivative of ATP, 3'-O-(p-azidobenzoyl)-ATP (AB-ATP), was synthesized by the reaction of ATP with N-hydroxysuccinimido 4-azidobenzoate (NHS-AB). The activity of the ATP transporter was determined by measuring the influx of [8-14C]ATP. The ATP transport had an apparent Km value of 6.5 microM and a Vmax of 1 nmol min-1 (mg of protein)-1. The transport of ATP was specifically inhibited by AB-ATP and 4, 4'-diisothiocyanatostilbene-2', 2'-disulfonic acid (DIDS). Under a dim light, AB-ATP was a competitive inhibitor of the ATP transport with Ki value of 0.19 microM, which indicates that AB-ATP has a high affinity for the ATP transporter, so it can be utilized as a photoaffinity probe for the identification of the ATP transporter in rat liver RER. An SDS--PAGE analysis of RER vesicles photolabeled with [gamma-32P]AB-ATP indicates the presence of a 56-kDa protein. The 56-kDa protein was completely protected from photoaffinity labeling by 10 microM ATP but not by 30 microM GTP. The specific labeling of the 56-kDa protein was sensitive to the anion transport inhibitor DIDS. In order to confirm whether the apparent uptake of ATP was due to the 56-kDa protein, the ATP transporter was partially purified through two successive ion-exchange chromatography steps (DEAE and Mono-S). The fraction showing the high activity of the ATP transporter also contained the 56-kDa protein photolabeled with [gamma-32P]AB-ATP. On the basis of the photoaffinity labeling and reconstitution experiment, we conclude that the 56-kDa protein represents the ATP transporter in rat liver RER.

背景与目标： : 为了鉴定大鼠肝脏粗内质网 (RER) 中的ATP转运蛋白，ATP的光反应性叠氮基衍生物，3 '-O-(对叠氮基苯甲酰基)-ATP (AB-ATP)，通过ATP与N-羟基琥珀酰亚胺4-叠氮基苯甲酸酯 (NHS-AB) 反应合成。ATP转运蛋白的活性通过测量 [8-14C]ATP的流入来确定。ATP转运的表观Km值为6.5微米，Vmax为1 nmol min-1 (毫克蛋白质)-1。ATP的转运被AB-ATP和4特异性抑制，4 '-diisothiocyanatostilbene-2'，2 '-二磺酸 (DIDS)。在暗光下，AB-ATP是ATP转运的竞争性抑制剂，Ki值为0.19 microM，这表明AB-ATP对ATP转运蛋白具有高亲和力，因此，它可以用作鉴定大鼠肝脏RER中ATP转运蛋白的光亲和探针。用 [gamma-32P]AB-ATP光标记的RER囊泡的SDS--PAGE分析表明存在56 kDa蛋白。10微米ATP完全保护56 kDa蛋白免受光亲和标记但不是通过30 microM GTP。56 kDa蛋白的特异性标记对阴离子转运抑制剂DIDS敏感。为了确认ATP的表观摄取是否由于56 kDa蛋白，ATP转运蛋白通过两个连续的离子交换色谱步骤 (DEAE和Mono-S) 部分纯化。显示ATP转运蛋白高活性的部分还含有用 [gamma-32P]AB-ATP光标记的56 kDa蛋白。在光亲和标记和重构实验的基础上，我们得出结论，56 kDa蛋白代表大鼠肝脏RER中的ATP转运蛋白。

BACKGROUND & AIMS: INTRODUCTION:Chemotherapy-induced nausea and vomiting (CINV) can be a serious and debilitating adverse effect that is highly feared by cancer patients. For patients receiving moderately emetogenic chemotherapy regimens at our institution in the ambulatory infusion center, palonosetron was selected as the preferred serotonin (5-HT3) antagonist for CINV prophylaxis per the 2016 NCCN Guidelines, when a neurokinin1 antagonist was not included in the prophylactic regimen. The purpose of this study was to evaluate the efficacy of dexamethasone and palonosetron versus granisetron for the prevention of CINV in patients receiving moderately emetogenic chemotherapy regimens. METHODS:This study is an Institutional Review Board-approved, single-center retrospective review of electronic health records including patients who received moderately emetogenic chemotherapy regimens with CINV prophylaxis with dexamethasone and either palonosetron or granisetron. RESULTS:A total of 268 eligible patients were included in the study. Eighty-eight patients received palonosetron and 180 patients received granisetron as their 5-HT3 receptor antagonist between October 31, 2014 and October 31, 2016. There were no statistically significant differences between the two antiemetic groups for the primary outcome of presence of any change in day 1 intravenous prophylactic antiemetics. Nine (10.23%) palonosetron patients and 15 (8.33%) granisetron patients required a change in their day 1 intravenous prophylactic antiemetics (P = 0.610). CONCLUSIONS:Despite palonosetron's better efficacy, longer half-life, and higher binding affinity, the results of this retrospective review demonstrates that the choice of serotonin antagonist, palonosetron or granisetron, did not result in a change in day 1 intravenous prophylactic antiemetics or antiemetic outpatient medications for patients undergoing moderately emetogenic chemotherapy regimens.

背景与目标：

BACKGROUND & AIMS: :Influence of fluoride on exocrine pancreas cells was examined morphologically with traditional and prolonged osmium fixation techniques for electron microscopy in the enamel fluorosis model rats injected subcutaneously twice a day with 20 mg/kg body weight of sodium fluoride. Although the rough endoplasmic reticulum (rER) of exocrine pancreas cells in control rats was laminated and oriented parallel to the circumference of the nucleus, the rER of the cells in NaF-treated rats was dilated, disrupted the laminated arrangement, and changed to the globular-shape rER. Many intracisternal granules were formed in these globular-shape rER of the cells exposed to fluoride. Lots of autophagosomes were also seen in the exocrine cells with NaF treatment. The autophagosomes were limited with a double or multiple membranes, and contained cytoplasmic organelles and/or the intracisternal granules. The outer and inner leaflets of double membranes of the autophagosomes were usually separated by a distinct electron-lucent area. In prolonged osmium fixation, the area between the double membranes of the autophagosome was filled with osmiun reaction deposits. Many autophagosomes were encircled with the single or multiple osmiophilic layers. In some cases, the osmium positive saccules also surrounded the free surface of the globular-shape rER containing intracisternal granules. These findings indicate that fluoride disrupts the export of zymogens from the rER, resulting in formation of intracisternal granules and autophagosomes, and that the osmiophilic saccules participate in sequestration of cytoplasmic organelles in forming autophagosomes.

背景与目标： : 在牙釉质氟中毒模型大鼠中，每天两次皮下注射20 mg/kg体重的氟化钠，用传统和延长的固定技术进行电子显微镜检查了氟化物对外分泌胰腺细胞的影响。尽管对照大鼠外分泌胰腺细胞的粗面内质网 (rER) 被层压并平行于细胞核的圆周取向，但NaF处理的大鼠细胞的rER却被扩张，破坏了层压排列，并变为球状rER。在这些暴露于氟化物的细胞的球状rER中形成了许多脑内颗粒。在NaF处理的外分泌细胞中也发现了许多自噬体。自噬体被双层或多层膜限制，并包含细胞质细胞器和/或脑内颗粒。自噬体的双层膜的外部和内部小叶通常被一个明显的电子透明区域隔开。在长时间的固定中，自噬体的双层膜之间的区域充满了osmiun反应沉积物。许多自噬体被单个或多个亲渗层包围。在某些情况下，阳性球囊也包围了球状rER的自由表面，该rER含有脑内颗粒。这些发现表明，氟化物破坏了rER中酶原的输出，导致了胞内颗粒和自噬体的形成，并且嗜渗性囊虫参与了细胞质细胞器的隔离，形成了自噬体。

BACKGROUND & AIMS: BACKGROUND:During incremental exercise, heart rate variability (HRV) has been shown to display distinct stabilization and inflection points, which have been used to indirectly detect the ventilatory threshold (VT). METHODS:Ten moderately trained males (26·5 ± 5·9 years: VO2peak 48·7 ± 4·1 ml min-1  kg-1 ) performed an incremental test on a cycle ergometer until volitional exhaustion with both R-R intervals and respiratory indices recorded. HRV was quantified using both nonlinear (Poincare plot; short-term variability SD1) and spectral analysis of the R-R intervals (high-frequency component; HFp). The VT was identified using the V-slope method. The relationship between HRV parameters and the VT was assessed using both a paired t-test and Pearson's product correlation. In addition, Bland and Altman plots were used to quantify the mean difference along with a 95% confidence interval. RESULTS:When expressed as the corresponding heart rate values, both the SD1 and the HFp stabilization points revealed a strong (r = 0·86 and 0·087, respectively) correlation with the VT. However, only for SD1 this relationship was different to the VT (t-test). The Bland-Altman plots supported these findings showing wide limits of agreement present for SD1 and the VT whilst the relationship between HFp and the VT revealed narrower limits. CONCLUSION:There does not appear to be a relationship present between the VT and the SD1 stabilization point in moderately trained healthy males, whereas the HFp stabilization point revealed a strong relationship with the VT when expressed as heart rate.

背景与目标：

BACKGROUND & AIMS: :Delayed vomiting is a potentially significant adverse effect of chemotherapy used to treat childhood cancer, but little is known about the experience of delayed vomiting in children and adolescents. An exploratory study was conducted to determine the pattern of delayed vomiting in children and adolescents with cancer after highly emetic chemotherapy and to identify possible risk factors. In a sample of 82 children and adolescents who completed 117 cycles of highly emetic chemotherapy, the overall prevalence of delayed vomiting was 32%. The frequency of delayed vomiting was highest on delayed day 2, with 21% of participants experiencing vomiting. By delayed day 7, only 9% of participants still reported vomiting. The severity of vomiting was moderate to severe in 11% to 12% of subjects. Age and gender had no significant effect on delayed vomiting. The emetic potential of the agent, incomplete protection from acute vomiting, and treatment regimens that lasted 6 or more days significantly affected delayed vomiting. In addition, a history of motion sickness, lack of acute control, and 6 or more days of chemotherapy were predictive of delayed vomiting.

背景与目标： : 延迟呕吐是用于治疗儿童癌症的化学疗法的潜在重大不良反应，但对儿童和青少年延迟呕吐的经验知之甚少。进行了一项探索性研究，以确定高度催吐化疗后儿童和青少年癌症患者延迟呕吐的模式，并确定可能的危险因素。在完成117周期高催吐化疗的82名儿童和青少年样本中，延迟呕吐的总体患病率为32%。延迟呕吐的频率在延迟第2天最高，有21% 的参与者出现呕吐。延迟第7天，只有9% 的参与者仍报告呕吐。11% 至12% 的受试者呕吐的严重程度为中度至重度。年龄和性别对延迟呕吐无明显影响。药物的催吐潜力，对急性呕吐的不完全保护以及持续6天或更长时间的治疗方案显着影响了延迟呕吐。此外，有晕车史，缺乏急性控制以及6天或更长时间的化疗可预测呕吐延迟。

BACKGROUND & AIMS: BACKGROUND:Patients with moderately-to-severely active ulcerative colitis (UC) are unlikely to continue anti-TNF therapy in the absence of early therapeutic response. AIM:To assess week 52 efficacy, safety and benefit/risk balance of adalimumab treatment in patients with moderately-to-severely active UC failing conventional therapy who achieved clinical response at week 8 in the 52-week ULTRA 2 trial. METHODS:Patients randomised to adalimumab (160/80 mg, week 0/2; 40 mg, every other week thereafter) in ULTRA 2 who achieved clinical response at week 8 per partial Mayo score (Mayo score without endoscopy subscore) were assessed for week 52 clinical remission, clinical response, mucosal healing, steroid-free remission and steroid discontinuation rates, overall and by prior anti-TNF use. Benefit/risk balance for the overall ITT population (regardless of week 8 responder status) was assessed using 'net efficacy adjusted for risk' (NEAR) odds ratios. Safety was assessed using adverse event rates. RESULTS:Of 248 adalimumab-treated patients, 123 (49.6%) achieved clinical response at week 8. Of these, 30.9%, 49.6%, and 43.1% achieved clinical remission, clinical response, and mucosal healing, respectively, at week 52. Of the week 8 responders using corticosteroids at baseline (N = 90), 21.1% achieved steroid-free remission and 37.8% were steroid-free at week 52. NEAR odds ratios indicated a positive benefit/risk balance for achievement of week 8 and week 52 response or remission without serious adverse events or serious infections. No safety concerns were identified. CONCLUSIONS:Adalimumab treatment was associated with a positive benefit/risk balance in the overall population of patients with moderately-to-severely active ulcerative colitis in ULTRA 2; early response was predictive of a positive outcome at 1 year (NCT00408629).

背景与目标：

BACKGROUND & AIMS: PURPOSE:To determine the vascularity of moderately and poorly differentiated hepatocellular carcinoma (mHCC and pHCC, respectively) as observed on and depicted by computed tomography during hepatic angiography and to perform pathological correlation. MATERIALS AND METHODS:Eighty-seven consecutive patients with 89 hepatocellular carcinomas (61 mHCCs and 28 pHCCs) were surgically resected in our hospital. The degree of contrast enhancement on computed tomography during hepatic angiography of the tumors was classified into high attenuation (H), isoattenuation (I), and low attenuation (L). We also examined hepatocellular carcinomas measuring less than 4 cm in diameter. Pathologically, the number of unpaired arteries in the tumors was determined (x200 magnification). RESULTS:The number of mHCC and pHCC in each degree of enhancement (H/I/L) was 59:1:1 and 19:6:3, respectively. The number of mHCC and pHCC measuring less than 4 cm without portal invasion was 48 and 15, respectively; the number of these tumors in each degree of enhancement (H/I/L) was 47:1:0 and 11:3:1, respectively. The mean number of unpaired arteries was 8.9 +/- 4.4 in mHCC and 5.2 +/- 4.3 in pHCC, respectively. All results were statistically significant (P < 0.01). CONCLUSIONS:Our results indicated that the arterial blood supply of pHCC was lower than that of mHCC.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Age, gender, and race are factors that influence atherosclerotic coronary heart disease (CHD) risk and may conceivably affect the efficacy of lipid-altering drugs. METHODS:Post hoc analysis of two multicenter, 6-week, double-blind, randomized, parallel-group trials assessed age (<65 and ≥ 65 years), gender, and race (white, black, and other) effects on atorvastatin plus ezetimibe versus up-titration of atorvastatin in hypercholesterolemic patients with CHD risk. High CHD risk subjects with low-density lipoprotein (LDL) cholesterol levels ≥ 70 mg/dL (~1.81 mmol/L) during stable atorvastatin 40 mg therapy were randomized to atorvastatin 40 mg plus ezetimibe 10mg, or up-titrated to atorvastatin 80 mg. Moderately high CHD risk subjects with LDL cholesterol levels ≥ 100 mg/dL (~2.59 mmol/L) with atorvastatin 20mg were randomized to atorvastatin 20mg plus ezetimibe 10mg, or atorvastatin 40 mg. RESULTS:Although some variability existed, age, gender, and race subgroups did not substantially differ from the entire patient population with regard to lipid-altering findings. Ezetimibe plus atorvastatin produced greater percent reductions in LDL cholesterol, total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B than up-titration of atorvastatin for all subgroups. HDL cholesterol and apolipoprotein AI changes were small and variable. CONCLUSION:Treatment efficacy in age, gender, and race subgroups did not substantially differ from the entire study population. Ezetimibe combined with atorvastatin generally produced greater incremental reductions in LDL cholesterol and several other key lipid parameters compared with doubling the atorvastatin dose in hypercholesterolemic patients with high or moderately high CHD risk. These results suggest that co-administration of ezetimibe with statins is a useful therapeutic option for treatment of dyslipidemia in differing patient populations.

背景与目标：

BACKGROUND & AIMS: BACKGROUND:Chemotherapy-induced nausea and vomiting (CINV) belong among the most burdensome side effects in hemato-oncology. Mostly, a combination of ondansetron and dexamethasone is used as antiemetic prophylaxis in pediatric patients undergoing emetogenic chemotherapy. However, dexamethasone is prohibited in different pediatric chemotherapy protocols. Currently, data on the use of ondansetron with the new antiemetic agent fosaprepitant without dexamethasone is not available for pediatric patients. METHODS:In this non-interventional observation study, 79 pediatric patients with a median age of 8.0 years (range 0.5-17.9 years) who received a CINV prophylaxis regimen with either fosaprepitant (4 mg/kg; maximum 150 mg) and ondansetron (as 24-h continuous infusion) (n = 40; fosaprepitant group/FG) or ondansetron only (n = 39; control group/CG) during moderately or highly emetogenic chemotherapy were analyzed. The groups were analyzed and compared for frequency of vomiting, administered doses of on-demand antiemetic dimenhydrinate and adverse events during the acute (0-24 h after chemotherapy administration) and delayed (> 24 h-120 h) CINV phases. RESULTS:A total of 112 and 116 chemotherapy blocks were analyzed in the fosaprepitant and the control group, respectively. The emetogenic potential of the administered chemotherapy did not significantly differ (p = 0.8812) between the two cohorts. In the acute CINV phase, the percentage of patients experiencing vomiting (n = 26 patients) and the vomiting events were significantly higher (p = 0.0005 and p < 0.0001, respectively) in the CG (n = 26 patients (66.7%); 88 events) compared with the FG (n = 10 patients (25.0%); 37 events). In the delayed CINV phase, the percentage of patients experiencing vomiting and the vomiting events were also significantly higher (p = 0.0017 and p < 0.0001, respectively) in the CG (n = 31 patients (79.5%); 164 events) compared with the FG (n = 17 patients (42.5%); 103 events). Additionally, significantly more dimenhydrinate doses were administered in the CG compared with the FG patients (n = 322/n = 198; p < 0.0001). The occurrence of adverse events did not significantly differ between the two groups (p > 0.05). CONCLUSION:Fosaprepitant (4.0 mg/kg) in addition to ondansetron, without application of dexamethasone, was well tolerated, safe, effective and superior to ondansetron only as CINV prophylaxis in pediatric patients during moderately and highly emetogenic chemotherapy.

背景与目标：

BACKGROUND & AIMS: :We evaluated the immunoglobulin class responsible for the protective activity in serum obtained from humans and rabbits after immunization with the R595 (Re chemotype) mutant of Salmonella minnesota. Whole serum obtained before immunization and the IgG and IgM fractions failed to protect mice against lethal challenge with viable Klebsiella pneumoniae or Morganella morganii or with Salmonella typhi lipopolysaccharide (LPS). The protective activity of postimmunization serum resided solely in IgM antibody, whereas IgG antibody exhibited no protective activity. IgM antibody to the Re mutant was protective against bacterial challenge with both test strains of bacteria and S. typhi LPS. IgM antibody, at approximately the same concentration present in postimmunization serum, increased the LD50 of K. pneumoniae from less than 8.0 x 10(2) to greater than 2.0 x 10(4). These findings indicate that commercially prepared human IgG with high titers of antibody to antigens of the core portion of LPS would have little clinical utility.

背景与目标： : 我们评估了用明尼苏达州沙门氏菌的R595 (Re化学型) 突变体预防接种从人和兔子获得的血清中负责保护活性的免疫球蛋白类别。预防接种前获得的全血清以及IgG和IgM组分未能保护小鼠免受可行的肺炎克雷伯菌或摩根氏菌或伤寒沙门氏菌脂多糖 (LPS) 的致命攻击。免疫后血清的保护活性仅停留在IgM抗体中，而IgG抗体则没有保护活性。针对Re突变体的IgM抗体对细菌和伤寒链球菌LPS的测试菌株均具有抗细菌攻击的保护作用。在免疫后血清中存在的浓度大致相同的IgM抗体将肺炎克雷伯菌的LD50从小于8.0 × 10(2) 增加到大于2.0 × 10(4)。这些发现表明，商业制备的具有针对LPS核心部分抗原的高滴度抗体的人IgG几乎没有临床用途。

BACKGROUND & AIMS: PURPOSE:To estimate the alpha/beta ratio for rectal cancer according to the outcome of three fractionation schedules of preoperative radiotherapy. METHODS AND MATERIALS:Between 1996 and 2002, 168 patients with locally advanced rectal cancer were treated as follows: 53 patients received 25 Gy in 5 Gy per fraction, 45 received 30 Gy in 3.0 Gy per fraction, and 70 were treated with accelerated hyperfractionation (42 Gy, 1.5 Gy per fraction, given twice daily). No patients received concurrent chemotherapy. The clinical characteristics of the groups were comparable. Surgery was performed shortly after radiotherapy. Crude data on locoregional tumor control were fitted directly using a linear-quadratic model, and the actuarial data were analyzed using Cox model. RESULTS:A linear-quadratic model provided an alpha estimate of 0.339 (SE 0.115) and beta estimate of 0.067 (SE 0.027), which resulted in an alpha/beta ratio of 5.06 Gy (95% confidence interval -0.1 to 10.3). In all three schemes the overall radiation treatment time was short, which limits the rationales for incorporating time effect into the model. If, however, time was incorporated the alpha/beta ratio was 11.1 Gy and the dose increment required to compensate for repopulation was 0.15 Gy/day. The actuarial analysis provided similar alpha/beta estimates. CONCLUSION:Although because of the retrospective character of the study, nonrandomized selection of fractionation schedule, and uncontrolled quality of surgery the present results can be regarded as hypothesis generating only, the control rates obtained in the pelvis are consistent with a moderately low alpha/beta ratio for rectal cancer.

背景与目标：

BACKGROUND & AIMS: :Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.

背景与目标： : 精神分裂症是一种严重的精神疾病，具有很强的遗传力，在症状，病程和治疗反应方面具有明显的异质性。人们对确定遗传危险因素非常感兴趣，这些因素可以帮助阐明病理生理学，并可能导致改进的治疗方法的发展。连锁和全基因组关联研究 (GWASs) 表明，精神分裂症的遗传基础是异质的。然而，尚不清楚潜在的遗传变异是否大多数是中度罕见的，并且可以通过在大型随访队列中的测序病例中观察到的变异的基因分型来鉴定，或者它们是否通常会更加罕见，因此通过寻求结合候选变异的基于基因的方法更有效地鉴定。在这里，我们考虑166患有精神分裂症或分裂情感障碍的人，他们的基因组或外显子测序到高覆盖率。从这些数据中，我们选择了在2,617例病例和1,800对照的独立队列中进一步评估的5,155变异。在初始或随访队列中，没有单一变异显示出研究范围内的显着关联。但是，我们确定了许多特定于病例的变异，其中一些可能是精神分裂症的真正危险因素，并且可以在其他数据集中容易地询问这些变异。我们的结果表明，精神分裂症的风险不太可能主要受到GWASs可检测范围之外的变异的影响。相反，多个较罕见的遗传变异必须对精神分裂症的易感性做出重大贡献，这表明需要非常大的样本量和基于基因的关联测试才能安全地识别遗传风险因素。

BACKGROUND & AIMS: BACKGROUND:Evidence for an increased prevalence of candidaemia and for high associated mortality in the 1990s led to a number of different recommendations concerning the management of at risk patients as well as an increase in the availability and prescription of new antifungal agents. The aim of this study was to parallel in our hospital candidemia incidence with the nature of prescribed antifungal drugs between 1993 and 2003. METHODS:During this 10-year period we reviewed all cases of candidemia, and collected all the data about annual consumption of prescribed antifungal drugs. RESULTS:Our centralised clinical mycology laboratory isolates and identifies all yeasts grown from blood cultures obtained from a 3300 bed teaching hospital. Between 1993 and 2003, 430 blood yeast isolates were identified. Examination of the trends in isolation revealed a clear decrease in number of yeast isolates recovered between 1995-2000, whereas the number of positive blood cultures in 2003 rose to 1993 levels. The relative prevalence of Candida albicans and C. glabrata was similar in 1993 and 2003 in contrast to the period 1995-2000 where an increased prevalence of C. glabrata was observed. When these quantitative and qualitative data were compared to the amount and type of antifungal agents prescribed during the same period (annual mean defined daily dose: 2662741; annual mean cost: 615,629 euros) a single correlation was found between the decrease in number of yeast isolates, the increased prevalence of C. glabrata and the high level of prescription of fluconazole at prophylactic doses between 1995-2000. CONCLUSION:Between 1993 and 2000, the number of cases of candidemia halved, with an increase of C. glabrata prevalence. These findings were probably linked to the use of Fluconazole prophylaxis. Although it is not possible to make any recommendations from this data the information is nevertheless interesting and may have considerable implications with the introduction of new antifungal drugs.

背景与目标：