Contrasting dynamics in the same plant-herbivore interaction

Long-term studies of two-species interactions under field conditions are unusual; most long-term field studies are of single species dynamics (1-6). Concurrent long-term studies on the dynamics of the same two interacting species in different locations are very rare. This result has led to the tacit assumption that different cases of the same two-species interaction would involve essentially quantitative differences (e.g., context-specific differences in the numeric values of demographic parameters like fecundity or death rates). Here, we show that for one of the best-known two-species systems (ragwort and cinnabar moth), this finding does not hold. The interaction between the plant and its herbivore is fundamentally different in coastal dunes in The Netherlands and in grasslands in Southeast England. In the first case, the dynamics are cyclic and the interaction involves both direct and delayed density dependence; in the second case, the insect has little impact on plant dynamics and there are no time lags in density dependence. The difference is caused by differences in the importance of seed-limitation in plant recruitment in the two locations.     

Effect of phenobarbital on seizure frequency and mortality in childhood cerebral malaria: a randomised, controlled intervention study

This randomized, placebo-controlled study assesses whether a single intramuscular dose of phenobarbital (20 mg/kg) given on admission to Kenyan children with cerebral malaria could lower the frequency of seizures, which complicate cerebral malaria by increasing the risk of death and neurological sequelae. A total of 340 children with cerebral malaria were admitted to the hospital; 170 received phenobarbital and 170 received placebo. The drug was adequately absorbed and well tolerated. Findings revealed a significantly lower frequency of seizures in the phenobarbital group than in the placebo group (18 [11%] vs. 46 [27%] children had 3 or more seizures of any duration; odds ratio (OR), 0.32; 95% confidence interval (CI), 0.18-0.58). However, mortality was doubled (30 [18%] vs. 14 [8%] deaths; OR, 2.39; 95% CI, 1.28-4.64) in the phenobarbital group. In addition, the frequency of respiratory arrest was higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus 3 or more doses of diazepam. In conclusion, although the phenobarbital dose of 20 mg/kg given to children with cerebral malaria provides highly effective seizure prophylaxis, an unacceptable increase in mortality is noted; hence, use of this dosage is not recommended.     

Efficient detection of hereditary nonpolyposis colorectal cancer gene carriers by screening for tumor microsatellite instability before germline genetic testing

BACKGROUND & AIMS: The optimal strategy for the detection of hereditary nonpolyposis colorectal cancer (HNPCC) gene carriers remains uncertain. We evaluated whether microsatellite instability (MSI) analysis or MSH2 and MLH1 protein immunostaining of tumors will screen individuals efficiently for germline MSH2 and MLH1 testing. METHODS: We performed a case-series study of 114 eligible families enrolled in our high-risk colorectal cancer (CRC) registry. Medical history data were collected on probands and relatives. MSI analysis was performed on proband tumors, and MSH2 and MLH1 protein immunostaining was assessed. Denaturing gradient gel electrophoresis was used to identify germline MSH2 or MLH1 mutations in probands found to have tumors with high-frequency MSI. RESULTS: Tumor tissue and adequate clinical data were available in 109 of the 114 families. Amsterdam criteria and Bethesda guidelines were met by 23% and 70% of the families, respectively. High-frequency MSI was identified in the proband tumors in 47 of the 109 families (43%). Germline MSH2 and MLH1 gene testing was carried out in the probands of 32 of 47 families with MSI-H tumors. Mutations were detected in 16 families (9 in MSH2 and 7 in MLH1) and sequence variants of uncertain significance in 5 families (1 in MSH2 and 4 in MLH1). Germline mutations or sequence variants of uncertain significance were detected in 15 of 19 (79%) of our Amsterdam families and in 6 of 13 (46%) of our non-Amsterdam families with MSI-H tumors. MSH2 and MLH1 protein immunostaining was assessed in 38 of the 47 MSI-H tumors. Unequivocal loss of hMLH1 expression was found in 20 tumors and loss of MSH2 expression in 9 tumors. Corresponding loss of protein expression was seen in 17 of 18 (94%) of tumors from probands with germline mutations or variants. CONCLUSIONS: The detection of high-frequency MSI or the loss of MSH2 or MLH1 immunostaining in CRCs are both useful criteria for selecting high-risk patients who should be tested for germline mutations in MSH2 or MLH1.     

Immune responses to major histocompatibility complex homozygous lymphoid cells in murine F1 hybrid recipients: implications for transfusion-associated graft-versus-host disease

Graft-versus-host disease (GVHD) is currently encountered after bone marrow transplantation and transfusion. GVHD associated with transfusion (TA-GVHD) in apparently immunocompetent recipients has been recently reported with increasing frequency. A consistent finding in many of these cases is that the recipient received blood from a donor homozygous for one of the recipient's HLA haplotypes. However, the observed frequency of TA-GVHD is much lower than the estimated probability of this donor/recipient combination. The potential role of recipient immune responses in controlling TA-GVHD was investigated using an analogous murine model in which GVHD is induced by the injection of parental lymphoid cells into unirradiated F1 hybrid recipients. The effect of various immune manipulations of the recipient of GVHD induction was assessed by determining the number of donor lymphoid cells required to induce GVHD responses. Whereas depletion of recipient CD4+ cells increased the number of donor cells needed to induce GVHD, depletion of recipient CD8+ and natural killer cells resulted in fewer donor cells being needed to induce a GVHD response. These studies suggest a central role for functioning recipient CD8 and natural killer cells in the down-regulation of TA-GVHD development in recipients.     

Impaired nicotinamide adenine dinucleotide synthesis in pyruvate kinase- deficient human erythrocytes: a mechanism for decreased total NAD content and a possible secondary cause of hemolysis

Erythrocytes from individuals with pyruvate kinase (PK) deficiency have approximately half the total (oxidized and reduced) nicotinamide adenine dinucleotide (NAD) of normal erythrocytes. In order to elucidate the mechanism(s) for the decrease in total NAD, we examined NAD synthesis in intact erythrocytes. It is demonstrated that NAD synthesis is impaired in PK-deficient erythrocytes to a degree that is dependent on the PK activity and adenosine 5'-triphosphate (ATP) concentration of these cells. After incubation in the presence of fluoride, which simulates the characteristics of PK deficiency by inhibiting enolase, normal erythrocytes had impaired NAD synthesis and decreased ATP concentrations. Fluoride did not inhibit NAD synthesis in a hemolysate system that is not dependent on glycolysis for ATP generation. These data suggest that fluoride does not inhibit the enzymes of NAD synthesis and that impairment of NAD synthesis by fluoride is mediated by decreased ATP formation. Thus, it is concluded that impaired NAD synthesis in PK-deficient erythrocytes is caused by decreased ATP formation due to the PK deficiency. Since the rate of glycolysis is limited by the availability of NAD+, it is suggested that impaired NAD synthesis causes further ATP depletion and thereby may enhance hemolysis in PK-deficient erythrocytes.     

急性和慢性呼吸道炎症疾病激肽形成机制探讨

目的探讨急性和慢性呼吸道炎症过程中激肽的生成途径和机制。方法测定支气管肺癌伴阻塞性肺炎,慢性支气管炎和健康对照组支气管肺泡灌洗液（ＢＡＬＦ）凝胶过滤前后激肽、激肽形成酶活性（ＴＡＭＥｅａ）,血浆血管舒缓素（ＰＫ）和α２巨球蛋白（α２Ｍ）,并进一步鉴定ＴＡＭＥｅａ性质。结果急、慢性组ＴＡＭＥｅａ和激肽水平与健康对照组比较差异有显著性（Ｐ＜０００１,Ｐ＜０．０１）,但两组间差异无显著性（Ｐ＞００５）;急性组ＰＫ和α２Ｍ与慢性组比较差异有显著性（Ｐ＜０００１）。凝胶过滤结果显示：急性组ＢＡＬＦ的ＴＡＭＥｅａ最高峰位于分子量约８０００００处,与第一个α２Ｍ峰重叠,而慢性组的最高峰位于４００００处。ＴＡＭＥｅａ抑制试验证实８０００００处的ＴＡＭＥｅａ来自于ＰＫ;而４００００处的ＴＡＭＥｅａ主要来源于组织血管舒缓素（ＴＫ）。结论急性呼吸道炎症的ＴＡＭＥｅａ主要来自血浆的ＰＫ;而慢性呼吸道炎症则以局部组织腺体分泌的ＴＫ为主。     

Loss to follow-up among youth accessing outpatient HIV care and treatment services in Kisumu,Kenya

Youth are particularly vulnerable to acquiring HIV, yet reaching them with HIV prevention interventions and engaging and retaining those infected in care and treatment remains a challenge. We sought to determine the incidence rate of loss to follow-up (LTFU) and explore socio-demographic and clinical characteristics associated with LTFU among HIV-positive youth aged 15–21 years accessing outpatient care and treatment clinics in Kisumu, Kenya. Between July 2007 and September 2010, youth were enrolled into two different HIV care and treatment clinics, one youth specific and the other family oriented. An individual was defined as LTFU when absent from the HIV treatment clinic for ≥?4 months regardless of their antiretroviral treatment status. The incidence rate of LTFU was calculated and Cox regression analysis used to identify factors associated with LTFU. A total of 924 youth (79% female) were enrolled, with a median age of 20 years (IQR 18–21). Over half, (529 (57%)), were documented as LTFU, of whom 139 (26%) were LTFU immediately after enrolment. The overall incidence rate of LTFU was 52.9 per 100 person-years (p-y). Factors associated with LTFU were pregnancy during the study period (crude HR 0.68, 95% CI 0.53–0.89); CD4 cell count >350 (adjusted hazard ratios (AHR) 0.59, 95% CI 0.39–0.90); not being on antiretroviral therapy (AHR 4.0, 95% CI 2.70–5.88); and non-disclosure of HIV infection status (AHR 1.43, 95% CI 1.10–1.89). The clinic of enrolment, age, marital status, employment status, WHO clinical disease stage and education level were not associated with LTFU. Interventions to identify and enrol youth into care earlier, support disclosure, and initiate ART earlier may improve retention of youth and need further investigation. Further research is also needed to explore the reasons for LTFU from care among HIV-infected youth and the true outcomes of these patients.     

High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women

VWF and ADAMTS13 are major determinants of platelet adhesion after vessel injury. In the present study, we aimed to determine whether VWF or ADAMTS13 plasma antigen levels influence the risks of ischemic stroke (IS) or myocardial infarction (MI) in young women and how these risks are affected by oral contraceptive (OC) use. VWF and ADAMTS13 plasma antigen levels were measured in a frequency-matched case-control study of 1018 young (18-49 years) women including 175 IS patients and 205 MI patients. Increasing levels of VWF and decreasing levels of ADAMTS13 were associated with the risk of IS and MI in a dose-dependent manner. Having both high VWF and low ADAMTS13 resulted in an odds ratio (OR) of 6.9 (95% confidence interval [95% CI], 2.0-23.0) for IS and 11.3 (95% CI, 3.6-35.2) for MI. Use of OCs increased the risk of IS and MI associated with high VWF (OR = 12; 95% CI, 5.5-26.2 and OR = 7.5, 95% CI, 3.6-15.7, respectively) and the risk of IS associated with low ADAMTS13 (OR = 5.8, 95% CI, 2.7-12.4). We conclude that high VWF and low ADAMTS13 plasma levels both increase the risk of IS and MI. The risks associated with high VWF or low ADAMTS13 levels are further increased by the use of OCs.     

Analysis of p53 mutations in a large series of lymphoid hematologic malignancies of childhood

p53 mutations are found in a wide variety of cancers, including hematologic malignancies. These alterations apparently contribute to development of the malignant phenotype. We analyzed a large series of lymphoid (330 cases) and a smaller series of myeloid (29 cases) malignancies of childhood for p53 mutations by single-strand conformational polymorphism (SSCP) following polymerase chain reaction. Samples with abnormal SSCP were reamplified and analyzed by direct sequencing method. p53 mutations were detected within the known mutational hotspots (exons 5 to 8) in 8 of 330 lymphoid malignancies, and in none of 29 myeloid malignancies, showing that the frequency of p53 mutations in childhood lymphoid malignancies was very low (8 of 330 cases [2%]). Four of these patients had very aggressive, fatal acute lymphocytic leukemia (ALL). None of 13 infants and none of 48 patients with T-lineage leukemia had detectable p53 mutations in their ALL cells. Exceptionally, p53 mutations were comparatively frequent in a small sample of B-cell non-Hodgkin's lymphomas (2 of 8 cases). Mutations were detected in samples from two patients with ALL at relapse; these were not detected in samples at initial diagnosis from the same patients, suggesting that p53 mutations may be associated with progression to a more malignant phenotype. Seven of eight alterations of p53 were missense mutations, and seven of eight samples may be heterozygous for the mutant p53, indicating that p53 protein may act in a dominant negative fashion.