The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis.

Autosomal recessive malignant infantile osteopetrosis is a congenital disease characterized by pathologically increased bone density. Recently, the use of whole exome sequencing has been utilized as a clinical diagnostic tool in a number of Mendelian disorders. In this study, whole exome sequencing (WES) was successfully used in six patients with malignant infantile osteopetrosis (MIOP) and identified mutations in four MIOP-related genes (CLCN7, TCIRG1, SNX10, and TNFRSF11A). We report these patients, describe the mutations and review the current literature.

Non-fermentative Gram-negative rods bacteremia in children with cancer: a 14-year single-center experience.

PURPOSE: Data on non-fermentative Gram-negative rods (NFGNR) bacteremia in children with malignancies are limited. The aim of this study was to present clinical picture, antimicrobial susceptibility pattern, risk factors for resistance and outcome in NFGNR bacteremia in children with cancer. METHODS: All episodes of NFGNR bacteremia occurring during 2001-2014 in children with cancer in a tertiary-care hospital were retrospectively analyzed. Pseudomonas and Acinetobacter spp. resistant to three or more antibiotic classes and all Stenotrophomonas maltophilia (SM) were defined as multidrug-resistant bacteria (MDR). RESULTS: A total of 80 children (44 males, 0.8-18 years, median 5 years) developed 107 episodes (116 pathogens) of NFGNR bacteremia; Pseudomonas aeruginosa (PA) (51; 43.9%), Acinetobacter baumannii (AB) (21, 18.1%), SM (18, 15.5%); and others (27, 25.2%). The rate of NFGNR bacteremia in children with certain solid tumors (e.g. sarcoma, 12/134 (9.0%)) was comparable to that of hematological malignancies (52/429 (12.2%). Focal infection and septic shock occurred in 16 (14.9%) and four (3.7%) episodes, respectively. Thirty (25.8%) of 116 NFGNR were MDR. The most significant predictors of bacteremia with MDR PA or AB were severe neutropenia (<100 cells/mm3; OR 7.8, p = 0.002), hospital-acquired (OR 16.9, p < 0.0001) and breakthrough (OR 11.2, p < 0.0001) infection. Infection with MDR bacteria was associated with inappropriate empirical therapy. The 30-day mortality was 3/107 (2.8%), all in neutropenic patients with hematological malignancies. CONCLUSIONS: NFGNR bacteremia can present with nonspecific signs or symptoms. MDR NFGNRs are common and compromise treatment options, but mortality is relatively low. Knowledge of local epidemiology, pattern and risk factors for resistance is important to guide empirical therapy.

Post-thrombotic syndrome after central venous catheter removal in childhood cancer survivors: A prospective cohort study.

BACKGROUND: Although the use of central venous catheters (CVCs) has greatly improved the quality of care of children with cancer, these catheters increase the risk of deep vein thrombosis (DVT) and the potential long-term complication of post-thrombotic syndrome (PTS). We aimed to study PTS post-CVC removal using physical, functional and health related quality of life (HRQoL) domains in childhood cancer and bone marrow transplantation (BMT) survivors. PROCEDURE: We conducted a prospective study in a cohort of childhood cancer and BMT survivors post-CVC use. Participants were evaluated for PTS with the Modified Villalta Score (MVS) and the Manco-Johnson Instrument (MJI). HRQoL was assessed using the PedsQL™ questionnaire. RESULTS: A total of 158 children were enrolled at a median of 41 (4-149) months from CVC removal. Signs and symptoms of PTS were present in 34% (95% confidence interval [CI] 27-43%) (MVS criteria) and 30.5% (95% CI 23.1-37.8%) (MJI criteria). Diagnosis of PTS was associated with history of CVC occlusion, history of CVC-related DVT and the use of ≥2 CVCs. The presence of signs and symptoms of PTS was a predictor for low HRQoL tested by the PedsQL™ Total Scale scores and Physical Health Summary scores. CONCLUSIONS: PTS post-CVC removal in pediatric cancer survivors is not a rare event. The association between PTS and the history of CVC occlusion confirms earlier findings, and suggests that CVC occlusion may indicate asymptomatic DVT. PTS is also associated with lower HRQoL scores highlighting the need to study preventive measures, especially for high risk groups. Pediatr Blood Cancer 2015;62:285-290. © 2014 Wiley Periodicals, Inc.

Intracellular characterization of bean yellow mosaic virus-induced inclusions by differential enzyme digestion.

The composition of crystalline inclusions and dense bands in cells of broad bean leaves infected with bean yellow mosaic virus was studied by differential enzymatic digestion. Frozen thick sections were prefixed in glutaraldehyde and exposed to proteinases and nucleases, after which ultrathin sections were prepared for electron microscopy. Examination revealed that the crystals were completely digested by pepsin in 30 min, whereas the dense bands remained intact for the first 20 min, and could not be found after longer periods of digestion. When ultrathin sections of tissues embedded in glycol methacrylate were incubated with the enzymes, pepsin digested the crystals; this left only a filamentous residue which did not disappear after further exposure to pepsin or to RNase. Trypsin had the same effect, but was slower and less consistent. The dense bands were entirely digested in thin sections by pepsin and trypsin. Neither inclusion was affected by RNase or DNase in thick or thin sections. These results demonstrate that the crystals and dense bands are composed entirely or primarily of protein, but there is no evidence that they contain nucleic acid.

Some conditions affecting the intracellular arrangement and concentration of tobacco mosaic virus particles in local lesions.

Tobacco mosaic virus particles were found in small packets and in small numbers, with the electron microscope, in necrotic leaf cells of Nicotiana glutinosa when the samples were fixed in glutaraldehyde and postfixed in OsO(4), and the sections were stained with heavy metals. The numbers and size of the virus packets were increased greatly when the leaves were detached from the plant after inoculation Assay of concentration showed that detachment resulted in a 30-fold increase of virus. A similar increase in the number of virus particles detected by electron microscopy was produced by keeping inoculated plants at an air temperature of 26 degrees C. A still greater increase in concentration was effected by incubating detached inoculated leaves at 26 degrees C. Moreover the arrangement of virus particles in these cells resembled that of a systemic virus infection. Cells in local lesions of Chenopodium amaranticolor contained large numbers of virus particles both as packets and in the loose arrangement characteristic of systemic infection. Neither the number of particles nor their arrangement was affected in this host by detaching the leaf or by changing the air temperature. It is suggested that there may be two types of localized virus infections, one of which produces virus in low concentration and is amenable to changes in virus concentration and arrangement as a result of environmental manipulation.

BRAF V600E mutation in Juvenile Xanthogranuloma family neoplasms of the central nervous system (CNS-JXG): a revised diagnostic algorithm to include pediatric Erdheim-Chester disease.

The family of juvenile xanthogranuloma family neoplasms (JXG) with ERK-pathway mutations are now classified within the "L" (Langerhans) group, which includes Langerhans cell histiocytosis (LCH) and Erdheim Chester disease (ECD). Although the BRAF V600E mutation constitutes the majority of molecular alterations in ECD and LCH, only three reported JXG neoplasms, all in male pediatric patients with localized central nervous system (CNS) involvement, are known to harbor the BRAF mutation. This retrospective case series seeks to redefine the clinicopathologic spectrum of pediatric CNS-JXG family neoplasms in the post-BRAF era, with a revised diagnostic algorithm to include pediatric ECD. Twenty-two CNS-JXG family lesions were retrieved from consult files with 64% (n = 14) having informative BRAF V600E mutational testing (molecular and/or VE1 immunohistochemistry). Of these, 71% (n = 10) were pediatric cases (≤18 years) and half (n = 5) harbored the BRAF V600E mutation. As compared to the BRAF wild-type cohort (WT), the BRAF V600E cohort had a similar mean age at diagnosis [BRAF V600E: 7 years (3-12 y), vs. WT: 7.6 years (1-18 y)] but demonstrated a stronger male/female ratio (BRAF V600E: 4 vs WT: 0.67), and had both more multifocal CNS disease ( BRAFV600E: 80% vs WT: 20%) and systemic disease (BRAF V600E: 40% vs WT: none). Radiographic features of CNS-JXG varied but typically included enhancing CNS mass lesion(s) with associated white matter changes in a subset of BRAF V600E neoplasms. After clinical-radiographic correlation, pediatric ECD was diagnosed in the BRAF V600E cohort. Treatment options varied, including surgical resection, chemotherapy, and targeted therapy with BRAF-inhibitor dabrafenib in one mutated case. BRAF V600E CNS-JXG neoplasms appear associated with male gender and aggressive disease presentation including pediatric ECD. We propose a revised diagnostic algorithm for CNS-JXG that includes an initial morphologic diagnosis with a final integrated diagnosis after clinical-radiographic and molecular correlation, in order to identify cases of pediatric ECD. Future studies with long-term follow-up are required to determine if pediatric BRAF V600E positive CNS-JXG neoplasms are a distinct entity in the L-group histiocytosis category or represent an expanded pediatric spectrum of ECD.

Dietary fat clearance in normal subjects is regulated by genetic variation in apolipoprotein E.

Apolipoprotein E (apo E) plays an important role in receptor mediated clearance of lipoprotein particles from plasma. Common genetic variation in apo E exists with three alleles coding for proteins called E2, E3, and E4. In in vitro receptor binding assays, E2 binds poorly, whereas E3 and E4 function normally. Recently, the apo E phenotype has been shown to have an effect on low density lipoprotein (LDL) cholesterol levels with levels in subjects with E2 lower and E4 higher than E3. We have examined the effect of the apo E polymorphism on dietary fat clearance using the vitamin A-fat loading test, which specifically labels intestinally derived lipoproteins with retinyl palmitate (RP). 27 normal subjects were studied, 10 with E3/3, 9 with E3/2, 7 with E4/3, and 1 with E4/4. After a vitamin A-containing fatty meal, postprandial RP concentrations were measured in chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions for 14 h. Compared with E3/3 subjects, E3/2 subjects had a significantly higher nonchylomicron RP concentration (P less than 0.05) (peak heights and areas below the curves) indicating slower clearance and the E4/3, E4/4 group had a significantly lower nonchylomicron RP concentration (P less than 0.05) indicating faster clearance. The clearance in the latter group was twice that of E3/2 subjects (P less than 0.01). Thus, heterozygosity for the defective form of apo E, E2, delays, and the surprising presence of a functionally normal allele, E4, increases clearance. This apo E effect on exogenous fat clearance may explain the recently described effect of the apo E phenotypes on LDL cholesterol levels.

Different patterns of postprandial lipoprotein metabolism in normal, type IIa, type III, and type IV hyperlipoproteinemic individuals. Effects of treatment with cholestyramine and gemfibrozil.

To study exogenous fat metabolism, we used the vitamin A-fat loading test, which specifically labels intestinally derived lipoproteins with retinyl palmitate (RP). Postprandial RP concentrations were followed in total plasma, and chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions. In normal subjects postprandial lipoproteins were present for more than 14 h, and chylomicron levels correlated inversely with lipoprotein lipase activity and fasting high density lipoprotein (HDL) cholesterol levels and nonchylomicron levels correlated inversely with hepatic triglyceride lipase activity. The main abnormality in type IV patients was a 5.6-fold increase in the chylomicron fraction, whereas in type III patients it was a 6.4-fold increase in nonchylomicrons. Type IIa patients had abnormally low chylomicron fractions. In type IV patients gemfibrozil decreased, whereas in type IIa patients cholestyramine increased the chylomicron fraction 66 and 88%, respectively. This study demonstrates an unexpectedly large magnitude and long duration of postprandial lipemia in normal subjects and patients. These particles are potentially atherogenic, and their role in human atherosclerosis warrants further study.

Dietary polyunsaturated fats of the W-6 and W-3 series reduce postprandial lipoprotein levels. Chronic and acute effects of fat saturation on postprandial lipoprotein metabolism.

The chronic and acute effects of different types of dietary fat on postprandial lipoprotein metabolism were studied in eight normolipidemic subjects. Each person was placed for 25 d on each of three isocaloric diets: a saturated fat (SFA), a w-6 polyunsaturated fat (w-6 PUFA) and a w-3 polyunsaturated fat (w-3 PUFA) diet. Two vitamin A-fat loading tests were done on each diet. The concentrations in total plasma and chylomicron (Sf greater than 1,000) and nonchylomicron (Sf less than 1,000) fractions of retinyl palmitate (RP) were measured for 12 h postprandially. Compared with the SFA diet, the w-6 PUFA diet reduced chylomicron and nonchylomicron RP levels 56 and 38%, respectively, and the w-3 PUFA diet reduced these levels 67 and 53%, respectively. On further analysis, the main determinant of postprandial lipoprotein levels was the type of fat that was chronically fed, which appeared to mediate its effect by changing the concentration of the endogenous competitor for the system that catabolizes triglyeride-rich lipoproteins. However, there was a significant effect of the acute dietary fat load, which appeared to be due to a differential susceptibility to lipolysis of chylomicrons produced by SFA as opposed to PUFA fat loads. The levels of postprandial lipoproteins are determined by the interaction of these chronic and acute effects.

Biogeochemical consequences of rapid microbial turnover and seasonal succession in soil.

Soil microbial communities have the metabolic and genetic capability to adapt to changing environmental conditions on very short time scales. In this paper we combine biogeochemical and molecular approaches to reveal this potential, showing that microbial biomass can turn over on time scales of days to months in soil, resulting in a succession of microbial communities over the course of a year. This new understanding of the year-round turnover and succession of microbial communities allows us for the first time to propose a temporally explicit N cycle that provides mechanistic hypotheses to explain both the loss and retention of dissolved organic N (DON) and inorganic N (DIN) throughout the year in terrestrial ecosystems. In addition, our results strongly support the hypothesis that turnover of the microbial community is the largest source of DON and DIN for plant uptake during the plant growing season. While this model of microbial biogeochemistry is derived from observed dynamics in the alpine, we present several examples from other ecosystems to indicate that the general ideas of biogeochemical fluxes being linked to turnover and succession of microbial communities are applicable to a wide range of terrestrial ecosystems.

A mutant p21 cyclin-dependent kinase inhibitor isolated from a Burkitt's lymphoma.

The growth arrest mediated by p53 is caused at least in part by the p53 mediated expression of p21 (p21waf1/Cip1). Since only one-third of primary Burkitt's lymphomas (BL) demonstrate mutations in the p53 gene, we examined the structural integrity of the p21 coding region by single-strand conformational polymorphism and DNA sequence analysis to determine the extent to which this gene is mutated in BL. Of 34 BLs analyzed, a frequent change (38%) at codon 31 that replaced Ser with Arg was found in 13 samples, 10 of which were from Africa. This change at codon 31 is also detected in peripheral blood DNA from normal subjects and may thus represent a polymorphism. One BL cell line, DH978, carried a change at codon 63: Phe to Leu. This mutation was heterozygous, and both the wild-type and the mutated p21 mRNA were expressed in the tumor cell line. By transfection experiments, the mutant p21 was less efficient in suppressing clonogenicity than wild-type p21. To our knowledge, this is the only mutation described in p21. The availability of this mutant p21 should further help in functional studies of p21.

Free will perceptions and psychiatric symptoms in patients diagnosed with schizophrenia.

WHAT IS KNOWN ON THE SUBJECT?: Some research suggests that holding a free will perspective may offer mental health and physical health benefits. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This study is the first to examine links between free will perceptions and psychiatric symptoms in patients diagnosed with schizophrenia. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: Study results suggest that helping people with a diagnosis of schizophrenia to recognize situations where they do have some freedom of choice over their actions and emotional reactions (free will) may assist them in improving their experiences and better managing their symptoms. ABSTRACT: Introduction Some research indicates that having a strong sense that one possesses free will may be associated with better psychological and physical health. This study is the first to examine the relationship between free will perceptions and psychiatric symptoms in patients with a diagnosis of schizophrenia. Method Thirty-two participants were interviewed using the Brief Psychiatric Rating Scale to assess symptom severity and the Free Will Subscale of the Free Will and Determinism Scale to assess free will perceptions. Results As hypothesized, a negative association was found between free will perceptions and total symptom severity, though it appears that this was mainly accounted for by positive symptoms. A content analysis was also conducted to qualitatively examine how patients conceptualize the construct of free will and its role in coping with their own mental illness. Discussion Study results suggest that holding a free will perspective may mitigate psychiatric symptoms in patients with a diagnosis of schizophrenia. Thus, psychiatric nurses and other mental health clinicians may improve current treatments for schizophrenia by helping patients recognize situations where they do have some freedom of choice over their actions and emotional reactions (free will) to stressful life events.

Pre-treatment of C57BL6/J mice with the TLR4 agonist monophosphoryl lipid A prevents LPS-induced sickness behaviors and elevations in dorsal hippocampus interleukin-1ß, independent of interleukin-4 expression.

Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1ß and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1ß compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1ß.

Absence of germline p53 mutations in familial lymphoma.

p53, a tumor suppressor gene, is frequently mutated in sporadic human cancer, and inherited mutations in p53 predispose to the early onset of cancer. p53 mutations occur frequently in sporadic lymphoma, and, in mice deficient for p53, lymphoma is the most common type of malignancy. Families with an increased incidence of lymphoma have been described, suggesting an inherited predisposition to lymphoma in these circumstances. To determine whether the predisposition to lymphoma in these families results from germline mutations in p53, we analysed exons 4-11 of the p53 gene in 35 individuals from 19 lymphoma-prone kindreds. We found no germline p53 mutations in any of the individuals tested. However, p53 expression assessed by immunohistochemistry, which suggests mutation, was observed in 35% of the tumor samples from the familial Hodgkin's disease cases and in 13% of the familial non-Hodgkin's lymphoma cases. These results suggest that p53 mutations do not play a critical role in heritable susceptibility to lymphoma. p53 may act by different, non-mutation related mechanisms in this setting, or be involved in late events in the pathogenesis of these tumors.

Severe atypical neuropathy associated with administration of hematopoietic colony-stimulating factors and vincristine.

PURPOSE: We have observed a severe atypical neuropathy (SAN) in patients with small non-cleaved-cell (SNCL) and large-cell lymphoma (LCL) treated with intensive chemotherapy and hematopoietic colony-stimulating factors (CSFs). The present analysis was undertaken in an attempt to identify factors associated with the development of this syndrome. PATIENTS AND METHODS: Fifty-four adult and pediatric patients consecutively treated according to the same chemotherapy protocol were included in the analysis. Low-risk patients received three cycles of cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate (CODOX-M) while in high-risk patients this drug combination was alternated with high-dose cytarabine (ara-C), etoposide, and ifosfamide (IVAC) for a total of four cycles. Twenty-eight patients received a CSF (granulocyte [G]- or granulocyte-macrophage [GM]-CSF), and 26 patients received no CSF. A statistical analysis, which included a logistic regression model, was undertaken to examine the importance of potential contributing factors to the development of SAN. RESULTS: SAN, which consisted of excruciating foot pain, usually associated with marked motor weakness, was observed in 12 patients. There was a highly significant association between the occurrence of this syndrome and the administration of CSFs, and an independent association with the cumulative dose of vincristine given in the first cycle of chemotherapy. Furthermore, the analysis suggested a synergistic effect between administration of the CSFs and vincristine in the genesis of this neuropathy. CONCLUSION: Our results indicate that CSFs can precipitate SAN when given in conjunction with vincristine. The development of SAN was associated most strongly with the cumulative dose of vincristine -- the size of individual doses and the number of doses given in cycle 1 were important to the extent that they influenced the cumulative dose.

A double-blind clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination.

We performed a double-blind, controlled clinical trial comparing phentermine resin (30 mg in the morning), fenfluramine hydrochloride (20 mg three times a day), and a combination of phentermine resin (15 mg in the morning) and fenfluramine hydrochloride (30 mg before the evening meal), and placebo. We combined low doses of the two drugs to maintain efficacy while diminishing adverse effects. Eighty-one people with simple obesity (130% to 180% of ideal body weight) participated. Individualized diets were prescribed and discussed again during the 24-week study period. Weight loss in those receiving the combination (8.4 +/- 1.1 kg; mean +/- SEM) was significantly greater than in those receiving placebo (4.4 +/- 0.9 kg; Scheff é's test) and equivalent to that of those receiving fenfluramine (7.5 +/- 1.2 kg) or phentermine (10.0 +/- 1.2 kg) alone. Adverse effects were less frequent with the combination regimen than with other active treatments. Thirty-seven participants dropped out of the study, 18 for reasons related to drug treatment. Combining fenfluramine and phentermine capitalized on their pharmacodynamic differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.

Histiocytic hemophagocytosis in miliary tuberculosis.

The signs, symptoms, and bone marrow findings of the recently described virus-associated hemophagocytic syndrome was seen in a patient we treated. The manifestations of this syndrome may not be specific to viral infections and may possibly occur in other infectious processes. Autopsy findings in the present case showed it to be associated with disseminated miliary tuberculosis. Concomitant viral infection was excluded. To our knowledge, only one similar patient has previously been described.

Fluctuations of lipid and lipoprotein levels in hyperlipidemic postmenopausal women receiving hormone replacement therapy.

BACKGROUND: Fluctuations in lipid and lipoprotein levels are encountered quite often in hyperlipidemic patients. We examined the possibility that lipid and lipoprotein levels fluctuate due to the different effects of estrogen and progestogen in postmenopausal hyperlipidemic women receiving combined hormonal replacement therapy. METHODS: In an open-label study conducted during 3 consecutive hormonal cycles (3 months), levels of fasting total cholesterol, triglycerides, and low (LDLC)- and high-density lipoprotein cholesterol (HDLC) were determined in 36 postmenopausal hyperlipidemic women on day 13 of conjugated equine estrogen (1.25 mg/d) therapy and on day 25 after 12 days of receiving estrogen plus medroxyprogesterone acetate (5 mg/d). RESULTS: While receiving estrogen and combined therapies, means +/- SD total cholesterol levels increased from 6.50 +/- 0.97 mmol/L (251 +/- 37 mg/dL) to 6.88 +/- 1.42 mmol/L (266 +/- 54 mg/dL) (P<.001); LDLC levels, from 4.05 +/- 1.14 mmol/L (156 +/- 44 mg/dL) to 4.62 +/- 1.36 mmol/L (178 +/- 52 mg/dL) (P<.001). Mean +/- SD HDLC cholesterol levels decreased from 1.44 +/- 0.32 mmol/L (55 +/- 12 mg/dL) to 1.29 +/- 0.28 mmol/L (50 +/- 10 mg/dL) (P<.001); triglyceride levels, from 2.23 +/- 1.03 mmol/L (197 +/- 91 mg/dL) to 2.06 +/- 1.04 mmol/L (182 +/- 92 mg/dL) (P<.001). CONCLUSIONS: Hyperlipidemic postmenopausal women receiving combined sequential estrogen and progestogen replacement therapy demonstrate very significant fluctuations in their lipid and lipoprotein levels. These fluctuations depend on the hormonal phase, ie, estrogen alone or combined with progestogen.

Metformin enhances clearance of chylomicrons and chylomicron remnants in nondiabetic mildly overweight glucose-intolerant subjects.

OBJECTIVE: To assess the effect of metformin on the metabolism of intestinally derived lipoproteins in nondiabetic individuals who were mildly overweight and glucose intolerant. RESEARCH DESIGN AND METHODS: A total of nine subjects with a BMI > or = 25 kg/m(2) and fasting serum glucose < or = 6.1 mmol/l and who were glucose intolerant were studied. The subjects underwent a vitamin A fat-loading test before and after a 3-month treatment with 850 mg metformin twice a day. The metabolic behavior of the postprandial lipoproteins was compared with that found in a group of 19 healthy normolipidemic individuals who participated in a previous study. RESULTS: Mean total plasma, chylomicron fraction, and nonchylomicron fraction retinyl palmitate (RP) pretreatment levels were 3.4-fold, 3.59-fold, and 3-fold higher, respectively, in the study group than in the normolipidemic group and were reduced by 50, 56, and 32%, respectively, after 3 months of metformin treatment. The decrease of chylomicron levels after treatment was positively correlated to the fasting triglyceride values before treatment (r = 0.73, P = 0.039) and to the serum insulin level at 120 min of standard glucose loading before treatment (r = 0.91, P = 0.002). CONCLUSIONS: Metformin was shown to be beneficial in the clearance of postprandial lipoproteins in nondiabetic individuals who were mildly overweight and glucose intolerant.

Administration of the inverse benzodiazepine agonist MRK-016 rescues acquisition and memory consolidation following peripheral administration of bacterial endotoxin.

Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.