Short-course High-dose Liposomal Amphotericin B for Human Immunodeficiency Virus-associated Cryptococcal Meningitis: A Phase 2 Randomized Controlled Trial.

Background: We performed a phase 2 noninferiority trial examining the early fungicidal activity (EFA) of 3 short-course, high-dose liposomal amphotericin B (L-AmB) regimens for cryptococcal meningitis (CM) in Tanzania and Botswana. Methods: Human immunodeficiency virus (HIV)-infected adults with CM were randomized to (i) L-AmB 10 mg/kg on day 1 (single dose); (ii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3 (2 doses); (iii) L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7 (3 doses); or (iv) L-AmB 3 mg/kg/day for 14 days (control). All patients also received oral fluconazole 1200 mg/day for 14 days. Primary endpoint was mean rate of clearance of cerebrospinal fluid cryptococcal infection (EFA). Noninferiority was defined as an upper limit of the 2-sided 95% confidence interval (CI) of difference in EFA between intervention and control <0.2 log10 colony-forming units (CFU)/mL/day. Results: Eighty participants were enrolled. EFA for daily L-AmB was -0.41 log10 CFU/mL/day (standard deviation, 0.11; n = 17). Difference in mean EFA from control was -0.11 (95% CI, -.29 to .07) log10 CFU/mL/day faster with single dose (n = 16); -0.05 (95% CI, -.20 to .10) log10 CFU/mL/day faster with 2 doses (n = 18); and -0.13 (95% CI, -.35 to .09) log10 CFU/mL/day faster with 3 doses (n = 18). EFA in all short-course arms was noninferior to control. Ten-week mortality was 29% (n = 23) with no statistical difference between arms. All arms were well tolerated. Conclusions: Single-dose 10 mg/kg L-AmB was well tolerated and led to noninferior EFA compared to 14 days of 3 mg/kg/day L-AmB in HIV-associated CM. Induction based on a single 10 mg/kg L-AmB dose is being taken forward to a phase 3 clinical endpoint trial. Clinical Trials Registration: ISRCTN 10248064.

An absorbed dose map of bone tissue treated with a radiopharmaceutical in vivo.

A beagle humerus treated with Ho-chelate radiopharmaceutical in vivo was examined by electron paramagnetic resonance (EPR) dosimetry. The bone was sectioned and the absorbed dose to each bone fragment was determined by additive re-irradiation of the bone tissue with calibrated doses of gamma radiation. The measured doses ranged from 4.3 Gy to 62 Gy. The highest doses were recorded in the predominately trabecular bone tissue and the lowest doses in the predominately cortical bone tissue. The mean absorbed dose for the entire bone was 17 Gy. The data from 50 bone fragments were combined to create an absorbed dose map of the interior bone surface.

MiR-181a promotes growth of thyroid cancer cells by targeting tumor suppressor RB1.

OBJECTIVE: MicroRNAs (miRs) are critical regulators in cancer development and progression. The current study aimed to investigate the expression and potential function of miR-181a in thyroid cancer. PATIENTS AND METHODS: A total of 15 paired thyroid cancer tissues and adjacent normal tissues were subjected to Real-time Polymerase Chain Reaction (PCR) to evaluate miR-181a expression. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, enzyme linked immunosorbent assay (ELISA) or flow cytometry was employed to assess the growth activity, apoptosis and cell cycle, respectively, upon modulation of the miR-181a expression in TPC-1 cells. Western blot was used to assess protein expression. The interaction between miR-181a and RB1 was tested by luciferase activity assay. RESULTS: The expression of miR-181a was significantly upregulated in thyroid cancer tissues compared with the adjacent tissues. Inhibition of miR-181a attenuated cell growth, which could be abrogated by miR-181a co-transfection. MiR-181a overexpression reduced apoptosis and promoted cell cycle progression; inhibition of miR-181a exerted opposite effects on both cell cycle and apoptosis. MiR-181a directly suppressed RB1 expression. RB1 expression in tumor tissues was downregulated and negatively correlated with miR-181a expression. CONCLUSIONS: miR-181a plays an oncogenic role in thyroid cancer; by targeting RB1, it promotes cell cycle progression and inhibits apoptosis.

Inter-generational effects of the in vitro maturation technique on pregnancy outcomes, early development, and cognition of offspring in mouse model.

In vitro maturation (IVM) of oocytes has been a highly successful method for avoiding the occurrence of severe ovarian hyperstimulation syndrome in some patients during in vitro fertilization. However, the safety of the protocol, especially the long-term effects, is still an issue of debate. The current study is to investigate the long-term effects of IVM on mice through two generations and reveal its inter-generational effects as well. The data indicate that the rates of embryo resorption and fetal death in the F1 generation were significantly increased while the newborn survival rate in the F1 and F2 generations were significantly decreased in the IVM group. Increased body weights in the F1 generation and mouse number per litter in the F2 generation were observed in both the IVM and VVM groups; however, no insulin resistance was detected. No significant differences were detected in birth defects, organ weights, testis histology and sperm motility, estrous cycle, and cognition among the IVM, VVM and N mice in either the F1 or F2 generations. Our results suggest that mouse IVM can affect pregnancy outcomes throughout two generations. IVM does not appear to influence the development and cognition of the offspring throughout two generations.

EPR dosimetry of cortical bone and tooth enamel irradiated with X and gamma rays: study of energy dependence.

Previous investigators have reported that the radiation-induced EPR signal intensity in compact or cortical bone increases up to a factor of two with decreasing photon energy for a given absorbed dose. If the EPR signal intensity was dependent on energy, it could limit the application of EPR spectrometry and the additive reirradiation method to obtain dose estimates. We have recently shown that errors in the assumptions governing conversion of measured exposure to absorbed dose can lead to similar "apparent" energy-dependence results. We hypothesized that these previous results were due to errors in the estimated dose in bone, rather than the effects of energy dependence per se. To test this hypothesis we studied human adult cortical bone from male and female donors ranging in age from 23 to 95 years, and bovine tooth enamel, using 34 and 138 keV average energy X-ray beams and 137Cs (662 keV) and 60Co (1250 keV) gamma rays. In a femur from a 47-year-old male (subject 1), there was a difference of borderline significance at the alpha = 0.05 level in the mean radiation-induced hydroxyapatite signal intensities as a function of photon energy. No other statistically significant differences in EPR signal intensity as a function of photon energy were observed in this subject, or in the tibia from a 23-year-old male (subject 2) and the femur from a 75-year-old female (subject 3). However, there was a trend toward a decrease (12-15%) in signal intensity at the lowest energy compared with the highest energy in subjects 1 and 3. Further analysis of the data from subject 1 revealed that this trend, which is in the opposite direction of previous reports but is consistent with theory, is statistically significant. There were no effects of energy dependence in the tooth samples.

Muscarinic m4 receptor activation by some atypical antipsychotic drugs.

To clarify the findings that clozapine is both a muscarinic receptor agonist and antagonist, we examined the effects of neuroleptics on forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing human muscarinic m4 receptors (CHO-hm4) and in rat striatum. With CHO-hm4 cells, clozapine induced a concentration-dependent and atropine-sensitive inhibition on cAMP formation, with EC50 = 60 nM and Emax = 74% of carbachol maximum. Other atypical neuroleptics, fluperlapine, tenilapine and olanzapine, were similar but less potent, while risperidone, rilapine, quetiapine (ICI 204,636), sertindole, and ziprasidone had almost no effect. Typical neuroleptics, haloperidol, chlorpromazine, fluphenazine, thiothixene, thioridazine, and molindone, showed either no effect or an atropine-resistant inhibition of cAMP formation. However, in rat striatal tissues, clozapine, up to 10 microM, did not show a significant inhibition of cAMP formation, probably due to a relatively low abundance of muscarinic m4 receptors and the presence of multiple types of muscarinic and other receptors, with which clozapine interacts. Nevertheless, muscarinic m4 receptor agonism, to some extent, may be a relevant mechanism for the therapeutic efficacy and side effects of clozapine and some atypical neuroleptics.

Acute administration of ethanol suppresses pentylenetetrazole-induced c-fos expression in rat brain.

The effect of acute ethanol administration on pentylenetetrazole-induced c-fos expression in rat brain was studied. Pentylenetetrazole induced the rapid and transient expression of c-fos mRNA in rat brain. Maximal induction at a dose of 30 mg/kg was detected within 30 min and persisted for 60 min. Thereafter c-fos gene expression decreased to control levels by 180 min. No increase in c-fos mRNA was evident at doses of pentylenetetrazole less than or equal to 20 mg/kg, whereas maximal elevation was seen at 30 to 40 mg/kg. This action was inhibited by acute ethanol treatment (blood alcohol level greater than or equal to 100 mg/dl). Acute ethanol treatment alone had no effect on c-fos gene expression.

Exclusion of close linkage of bipolar disorder to the dopamine D3 receptor gene in nine Australian pedigrees.

The recently cloned dopamine D3 receptor (DRD3) gene is of potential relevance to the aetiology of bipolar disorder because of an almost exclusive expression in limbic tissue, the region of the brain putatively responsible for control of emotion. We therefore aimed to determine whether bipolar disorder in nine pedigrees (with 171 members) was linked to this receptor gene, which has been mapped to chromosomal region 3q 13.3. Linkage of bipolar disorder and recurrent depression to the DRD3 gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective illness (ranging from bipolar I alone to all affective disorders). Close linkage to the DRD3 gene was strongly excluded using each model and definition, and these conclusions persisted when a wide range of rates of 'sporadic' (non-genetic) presentations of illness were incorporated in the analysis.

Exclusion of close linkage of bipolar disorder to the Gs-alpha subunit gene in nine Australian pedigrees.

Growing evidence suggests that guanine nucleotide binding proteins (G proteins) may be involved in both the pathogenesis and treatment of bipolar affective disorder. Both overactive G proteins and increased levels of the alpha subunit of the stimulatory form (Gs-alpha) have been demonstrated in peripheral leucocytes of manic patients while an increase of Gs-alpha subunit levels has also been found in a postmortem study of bipolar disorder. The function of Gs and Gi alpha subunits has now been shown to be affected by lithium. The present study aimed to determine whether bipolar affective disorder was linked to the Gs-alpha subunit gene which has been mapped to chromosomal region 20q13.2. Linkage analysis utilized the PCR amplification of a portion of the Gs-alpha gene that contains a dinucleotide repeat (CA repeat) polymorphism. Linkage of bipolar disorder and recurrent depression to the Gs-alpha subunit gene was tested using a series of autosomal dominant and recessive models with varying penetrance levels. Additionally, linkage was examined using a series of levels of definitions of affective illness. Close linkage to the Gs-alpha subunit gene was strongly excluded using each model and definition. Thus, our study indicates that a genetic defect in the Gs-alpha subunit gene is unlikely to be the cause of bipolar disorder.

Prognostic significance of some pathologic factors in breast carcinoma.

The prognostic significance of several pathologic factors was analysed in a series of 221 cases of breast carcinoma consecutively and primarily treated in a department of surgery. It was found that the outcome of patients could be fairly well outlined in routine practice using the axillary nodal involvement (absence or presence of metastases and number of "positive" nodes), tumor size as measured in surgical specimens and histopathologic evaluation. It was also found that the predictive value of tumor grading is clearly enhanced when it is used in combination with the histological classification. The histological pattern and sinus histiocytosis of regional lymph nodes, as well as the lymphoid infiltration of the tumors, were also found to have some prognostic importance. The presence of vascular invasion in primary tumors of patients with nodal metastases as well as the finding of extranodal extension did not provides additional prognostic information.

Estimation of the absorbed dose in radiation-processed food--3: The effect of time of evaluation on the accuracy of the estimate.

Electron paramagnetic resonance (EPR) spectrometry is evaluated as a method to retrospectively assess the absorbed dose to radiation-processed chicken (containing bone). Decay of the hydroxyapatite paramagnetic center EPR signal intensity was monitored at three different dose levels (0.5, 3.0, 7.0 kGy) up to 20 days, and the dose was assessed for each level at 1, 8, and 20 days after irradiation. It was determined that the time of evaluation (up to 20 days post-irradiation) did not adversely affect the estimate for 0.5 and 3.0 kGy bone, and only moderately affected the 7.0 kGy estimates.

[Isolated atrial fibrillation. The risk of embolism and its prevention]. / Fibrillation auriculaire isolée. Le risque embolique et sa prévention.

Whether or not atrial fibrillation is alone, if not idiopathic, is difficult to determine. The risk of embolization in lone atrial fibrillation is distinctly higher in healthy subjects over 60 years of age when the left atrium is dilated. In chronic atrial fibrillation this risk is higher than in paroxysmal fibrillation, especially within the year following the onset of the arrhythmia. In most patients anticoagulant therapy is effective in the primary or secondary prevention of embolic accidents. In subjects older than 75 aspirin given in daily doses of 325 mg seems to give similar results. The risk of antithrombosis therapy must not be underevaluated. The alternative is to maintain or restore the sinus rhythm, even at an advanced age, if the arrhythmia is recent and the left atrium is moderately dilated.

Assessment of treatment patterns and patient outcomes before vs after implementation of a severity-based Clostridium difficile infection treatment policy.

BACKGROUND: National guidelines recommend oral vancomycin for severe Clostridium difficile infection (CDI) based on results from recent clinical trials demonstrating improved clinical outcomes. However, real-world data to support these clinical trials are scant. AIM: To compare treatment patterns and patient outcomes of those treated for CDI before and after implementation of a severity-based CDI treatment policy at a tertiary teaching hospital. METHODS: This study evaluated adult patients with a positive C. difficile toxin before and after implementation of a policy where patients with severe CDI given metronidazole were switched to oral vancomycin unless contra-indicated. Patients were stratified according to disease severity using a modified published severity score. Treatment patterns based on CDI severity and rates of refractory CDI were assessed. FINDINGS: In total, 256 patients with CDI (mean age 66 years, standard deviation 17, 52% female) were evaluated (before implementation: N = 144; after implementation: N = 112). Use of oral vancomycin for severe CDI increased significantly from 14% (N = 8) to 91% (N = 48) following implementation of the policy (P < 0.0001). Refractory disease in patients with severe CDI decreased significantly from 37% to 15% following implementation of the policy (P = 0.035). No significant differences were noted among patients with mild to moderate CDI. CONCLUSION: A severity-based CDI treatment policy at a tertiary teaching hospital increased the use of oral vancomycin and was associated with decreased rates of refractory CDI.

Plasmons in the metallic nanoparticle-film system as a tunable impurity problem.

We show that the plasmon resonances of a metallic nanoparticle interacting with the surface plasmons of a metallic film is an electromagnetic analogue of the spinless Anderson-Fano model. This is the same model used to describe the interaction of a localized electronic state with a continuous band of electronic states. The three characteristic regimes of this model are realized here, where the energy of the nanoparticle plasmon resonance lies above, within, or below the energy band of surface plasmon states. These three interaction regimes are controlled by film thickness. The latter regime is experimentally observed and identified.