Antipsychotic drug-induced neutropenia: results from the AMSP drug surveillance program between 1993 and 2016.

Neutropenia and agranulocytosis (N&A) are relatively rare, but potentially fatal adverse drug reactions (ADR). This study presents cases of N&A related to one or more antipsychotic drugs (APDs) in psychiatric inpatients. Data on APD utilization and reports of N&A caused by APDs were analyzed by using data from an observational pharmacovigilance program in German-speaking countries-Arzneimittelsicherheit in der Psychiatrie (AMSP)-from 1993 to 2016. 333,175 psychiatric inpatients were treated with APDs for schizophrenia and other indications during the observation period. A total of 124 cases of APD-induced N&A were documented, 48 of which fulfilled the criteria for agranulocytosis, corresponding to a rate of 0.37, respectively, 0.14 in 1000 inpatients treated with APDs. Neutropenia was more often detected in women, whereas there was no difference regarding sex in cases of agranulocytosis. Clozapine had the highest relative risk for inducing N&A and was imputed alone as a probable cause of N&A in 60 cases (1.57‰ of all patients exposed). Perazine showed the second highest relative risk with 8 cases and an incidence 0.52‰, followed by quetiapine (15 cases resp. 0.23‰ of all patients exposed) and olanzapine (7 cases; 0.13‰ of all patients exposed). N&A most often occurred during the first 3 months of treatment. Overall N&A are severe and potentially fatal complications that can occur during treatment with APDs. The results from this study largely agree with the currently available literature, highlighting the positive effects of alertness and established appropriate monitoring.

The effectiveness and safety of introducing condom-catheter uterine balloon tamponade for postpartum haemorrhage at secondary level hospitals in Uganda, Egypt and Senegal: a stepped wedge, cluster-randomised trial.

OBJECTIVE: To assess the effectiveness of introducing condom-catheter uterine balloon tamponade (UBT) for postpartum haemorrhage (PPH) management in low- and middle-income settings. DESIGN: Stepped wedge, cluster-randomised trial. SETTING: Eighteen secondary-level hospitals in Uganda, Egypt and Senegal. POPULATION: Women with vaginal delivery from October 2016 to March 2018. METHODS: Use of condom-catheter UBT for PPH management was introduced using a half-day training and provision of pre-packaged UBT kits. Hospitals were randomised to when UBT was introduced. The incident rate (IR) of study outcomes was compared in the control (i.e. before UBT) and intervention (i.e. after UBT) periods. Mixed effects regression models accounted for clustering (random effect) and time period (fixed effect). MAIN OUTCOME MEASURES: Combined IR of PPH-related invasive surgery and/or maternal death. RESULTS: There were 28 183 and 31 928 deliveries in the control and intervention periods, respectively. UBT was used for 9/1357 and 55/1037 women diagnosed with PPH in control and intervention periods, respectively. PPH-related surgery or maternal death occurred in 19 women in the control period (IR = 6.7/10 000 deliveries) and 37 in the intervention period (IR = 11.6/10 000 deliveries). The adjusted IR ratio was 4.08 (95% confidence interval 1.07-15.58). Secondary outcomes, including rates of transfer and blood transfusion, were similar in the trial periods. CONCLUSIONS: Introduction of condom-catheter UBT in these settings did not improve maternal outcomes and was associated with an increase in the combined incidence of PPH-related surgery and maternal death. The lack of demonstrated benefit of UBT introduction with respect to severe outcomes warrants reflection on its role. TWEETABLE ABSTRACT: Stepped wedge trial shows UBT introduction does not reduce the combined incidence of PPH-related surgery or death.

[Effect of DNA local conformation on the affinity and binding specificity of bis-netropsins to DNA]. / Vliianie lokal'noi konformatsii DNK na srodstvo i spetsifichnost' sviazyvaniia bis-netropsinov s DNK.

The interaction of short nucleotide duplexes with bis-netropsins, in which netropsin fragments are linked in the tail-to-tail orientation via cis-diammineplatinum group (<--Nt-Pt(NH3)-Nt-->) or aliphatic pentamethylene chain (<--Nt-(CH2)5-Nt-->), has been studied. Both the bis-netropsins have been shown to bind to DNA oligomer 5'-CCTATATCC-3' (I) as a hairpin with parallel orientation of netropsin fragments in 1:1 stoichiometry. Monodentate binding has been detected upon binding of bis-netropsins to other duplexes of sequences 5'-CCXCC-3'--where X = TTATT (II), TTAAT (III), TTTTT (IV), and AATTT (V)--along with the binding of bis-netropsins as a hairpin. The formation of dimeric antiparallel motif between the halves of two bound bis-netropsin molecules has been observed in the complexes of <--Nt-(CH2)5-Nt--> with DNA oligomers IV and V. The ratio of binding constant of bis-netropsin as a hairpin (K2) to monodentate binding constant (K1) has been shown to correlate with the width and/or conformational lability of DNA in the binding site. The share of bis-netropsin bound as a hairpin decreases in the order: TATAT > TTATT > TTAAT > TTTTT > AATTT, whereas the contribution of monodentate binding rises. The minimal strong binding site for <--Nt-Pt(NH3)-Nt--> and <--Nt-(CH2)5-Nt--> binding as a hairpin has been found to be DNA duplex 5'-CGTATACG-3'.

New diketopiperazine alkaloids from Penicillium fellutanum.

Four new diketopiperazine alkaloids (1-4) were isolated from cultures of Penicillium fellutanum, and their structures were determined by MS and NMR measurements.

Reduction of cisplatin toxicity in cultured renal tubular cells by the bioflavonoid quercetin.

Quercetin (QC), a polyphenolic compound widely distributed in fruits and vegetables has recently gained interest due to its cisplatin (CP) sensitizing properties in cancer cells. It is currently unknown, whether quercetin also increases the susceptibility of the kidneys to cisplatin toxicity. We studied the effects of various bioflavonoids on CP toxicity in an in vitro model of cultured tubular epithelial cells (LLC-PK1). Viability of LLC-PK1 cells, as assessed by lactate dehydrogenase (LDH) release and MTT-test, was affected by CP (100-400 microM) in a time and dose dependent fashion. Pretreatment of cells with QC for 3 h significantly reduced the extent of cell damage. The protective activity of QC was concentration dependent, starting at 10-25 microM and reaching a plateau between 50 and 100 microM. Other bioflavonoids (catechin, silibinin, rutin) did not diminish cellular injury, even at higher concentrations (100-500 microM). Quercetin itself showed some intrinsic cytotoxicity at concentrations exceeding 75 microM. Our data indicate that quercetin reduces cisplatin toxicity in cultured tubular epithelial cells. The exact mechanism of protection is unclear, though scavenging of free oxygen radicals may play an important role.

Inhibition of oxidant-induced lipid peroxidation in cultured renal tubular epithelial cells (LLC-PK1) by quercetin.

The protective effect of quercetin against oxidant-induced cell injury (hypoxanthine/xanthine oxidase system) was studied in the renal tubular epithelial cell line LLC-PK1. Pretreatment with quercetin provided protection from structural and functional cell damage in a concentration-dependent manner (10-100 microM). Comparison with structural variants revealed that the protective property of quercetin depends on the number of hydroxyl substituents in the B-ring, the presence of an extended C-ring chromophore, 3-D-planarity and lipophilicity, indicating that membrane affinity is essential for protection. The hypothesis that quercetin exerts its protective effects via inhibition of lipid peroxidation was further examined. Protection by quercetin was found when lipid peroxidation, assessed by the release of malondialdehyde, was initiated by H2O2 or by the combination of 1-chloro-2,4-dinitrobenzene and aminotriazole. In contrast, the bioflavonoid was not protective when oxidative cell damage was induced by menadione and occurred in the absence of lipid peroxidation. These data suggest that cytoprotective effects of quercetin are related to membrane affinity and may be explained by interruption of membrane lipid peroxidation rather than by intracellular scavenging of oxygen free radicals.

Insights into potential cellular mechanisms of cisplatin nephrotoxicity and their clinical application.

Cisplatin preferentially accumulates in cells of the S3 segment of the renal proximal tubule and is toxified intracellularly by hydration. The earliest manifestation of toxicity is inhibition of protein synthesis. GSH depletion is another important mechanism causing CP toxicity. Intracellular binding to SH groups leads to GSH depletion, resulting in lipid peroxidation and eventually mitochondrial damage. New measures to prevent GSH depletion and scavenge intracellular free oxygen radicals have been tried in clinical studies. Promising results indicate that cisplatin nephrotoxicity can be further reduced in the future.

Community based dengue control in Columbia: people's knowledge and practice and the potential contribution of the biological larvicide Bti (Bacillus thuringiensis israelensis).

A study on dengue control was undertaken in a poor urban area in Cúcuta, Colombia. The first objective was to describe people's knowledge, attitudes and practices regarding dengue fever, the transmission of the disease and possible preventive measures. The second objective was to analyse the infestation of the community with Aedes aegypti larvae, and the third objective to test the efficacy of Bti (Bacillus thuringiensis israelensis) with respect to the level and duration of reduction of Ae. aegypti larvae in water tanks. It was found that people had a very fragmentary knowledge about dengue and about the necessary protective measures which did not lead them to any action. The infestation of water containers, particularly the larger tanks, was very high (house index = 61; Breteau index = 96). The application of Bti in water tanks led to satisfactory results: For one month and longer, the water tanks treated with Bti were free of mosquito larvae. The effect was reduced by a lower dose, washing the tanks and a less potent formulation. People's acceptance of Bti was higher than that of temephos. Further studies are necessary to confirm the utility of Bti in dengue control.

Proportionate mortality among construction laborers.

This report presents the results of proportionate mortality ratio (PMR) analyses and proportionate cancer mortality ratio (PCMR) analyses among the 11,685 members of the Laborers' International Union of North America (LIUNA), who died between 1985-1988, using U.S. proportionate mortality rates as the comparison population. Statistically significant elevated mortality risks were observed for all malignant neoplasms (N = 3285, PMR = 1.13, CI = 1.09-1.17), as well as for site-specific neoplasms of the lung (N = 1208, PCMR = 1.06, CI = 1.00-1.12), stomach (N = 170, PCMR = 1.44, CI = 1.23-1.68), and thyroid gland (N = 10, PCMR = 2.24, CI = 1.07-4.12). The PCMRs for these malignant neoplasms were elevated among both white and non-white males, regardless of length of union membership, in most 10-year categories of age at death above 40 and for the three largest LIUNA regions examined. The study also observed 20 mesothelioma deaths, which indicated that some LIUNA members had been previously exposed to asbestos. Statistically significant elevated risks were also observed for deaths from transportation injuries (N = 448, PMR = 1.37, CI = 1.25-1.51), falls (N = 85, PMR = 1.34, CI = 1.07-1.66), and other types of injuries (N = 245, PMR = 1.61, CI = 1.42-1.83). The deaths due to injuries were most often observed among those members who had the shortest amount of time within the union, were younger, and first entered the union after 1955. This is the first study that has examined the general mortality experience limited to construction laborers only (Bureau of Census code 869).

Bioactive chromenes from Rhyncholacis penicillata.

Investigation of the aerial parts of Rhyncholacis penicillata afforded the new chromenes, 7-hydroxy-6-(3-methylbutyryl)-5-oxymethyl-chromene (rhynchonin A) and 7-hydroxy-6-(2-methylbutyryl)-6-oxymethylchromene (rhynchonin B). Structures were elucidated by spectroscopic methods and independent synthesis. Rhynchonin A showed broad insecticidal, acaricidal and nematicidal potency including strong biological activity against Heliothis zea.

Porcine reproductive and respiratory syndrome: temperature and pH stability of Lelystad virus and its survival in tissue specimens from viraemic pigs.

We investigated the growth of Lelystad virus (LV) in porcine alveolar macrophages, the thermal and pH stability of the virus in cell culture medium, and its survival in tissue specimens from viraemic pigs. Lelystad virus grew to titres of 10(6) TCID50/ml, which were found at 40 h after virus inoculation when the macrophage cultures showed a cytopathic effect of approximately 40%. In culture medium at pH 7.5, LV was stable for prolonged periods of storage at -70 degrees C and -20 degrees C. At higher temperatures the half-life of LV was 140 h at 4 degrees C, 20 h at 21 degrees C, 3 h at 37 degrees C and 6 min at 56 degrees C. The half-life of LV, both at 4 degrees C and 37 degrees C, changed considerably when the pH of the medium was varied. At 4 degrees C and pH 6.25 a maximum half-life of 50 h and at 37 degrees C and at pH 6.0 a maximum half-life of 6.5 h was observed. However, increasing or decreasing the pH of the medium rapidly decreased the half-life of LV at both temperatures. Although, LV proved to be more stable at pH 6.00 than at pH 7.5, it did not replicate at pH 6.0. We also tested various tissue specimens from viraemic pigs for the presence of LV. The virus was detected in tonsils, lymph nodes, lungs, serum, and sporadically, albeit at low titres, in muscle tissue. The titre of virus in muscle tissue and organs was only minimally affected by storage for up to 48 h at 4 degrees C.

Terpene hydrocarbons in Pimpinella anisum L.

The essential oil of anise (fruits and shoots) was investigated focusing on the composition of the hydrocarbon fraction. Several sesquiterpenes were identified by GC-MS and the relative composition of the fractions was established by GC analysis. gamma-Himachalene and the diterpene neophytadiene were isolated by TLC and column chromatography at low temperatures. Their structures were determined by MS and NMR including 1H-1H correlated COSY and NOE experiments.

Assessment of in situ host immunity to syngeneic tumors utilizing the multicellular spheroid model.

In situ host immunity to the EMT6/Ro mammary sarcoma tumor was evaluated by implanting multicellular spheroids of this tumor into the peritoneal cavity of syngeneic BALB/cKa mice and determining the kinetics of host cell infiltration and tumor cell killing. Spheroids grown in vitro and implanted into unsensitized mice continued to grow resulting in peritoneal tumor masses and eventual death of the animal. However, in mice previously sensitized with a single injection of heavily irradiated EMT6/Ro cells, spheroids implanted intraperitoneally were rapidly infiltrated by host immune cells (macrophages, lymphocytes, and granulocytes), tumor cell killing was detectable within 1 day and by Day 6 essentially no clonogenic tumor cells were recoverable. Despite this marked loss of both total and clonogenic tumor cells, there was little decrease in the diameter of the spheroids recovered during this time period. Physical size thus does not provide a reliable estimation of tumor cell killing. The tumor cell killing was immunologically specific in that little killing was observed when EMT6/Ro spheroids were implanted into mice sensitized with other allogeneic or syngeneic tumor cells. Host cells from within the spheroids were found to be cytotoxic for EMT6/Ro tumor cells in a 51Cr release assay. A major portion of these cytotoxic cells appear to be T lymphocytes. However, other host cell types may also be involved in the in vivo tumor cell killing.