Development and Testing of an Addiction Treatment Level of Care Determination Tool

Two studies examined inter-rater reliability and content-related validity of an addiction treatment level of care determination tool currently in use in New York, the LOCADTR 3.0. The studies occurred after tool implementation. In study 1, 139 providers used the LOCADTR 3.0 to determine level of care for four case vignettes. Inter-rater reliability coefficients were calculated. In study 2, 387,338 state records from existing data were analyzed to determine how often providers opted to override the LOCADTR 3.0 level of care determination by choosing an alternative level of care. In study 1, an acceptable inter-rater reliability (IRR?=?.57–.59) was found. Good indication of content-related validity was also found; participants chose the same level of care the study team chose for each vignette 80% of the time. In study 2, the override option was selected only 10% of the time, further establishing the content validity of the tool. These studies provide evidence for acceptable preliminary reliability and validity of the LOCADTR 3.0.

     

Reversal of normal cerebral sexual dimorphism in schizophrenia: evidence and speculations

Sex differences in epidemiology, clinical course and symptomatology of schizophrenia have been widely documented, but still relatively little is known about the brain sexual dimorphism in this psychiatric disorder. While some neuroanatomical and neuropsychological studies have reported existence of differences between male and female patients in a direction of normal sexual dimorphism, others did not find any effect. A few recent reports point to a peculiar disturbance of normal sexual dimorphism in brain regions implicated in the processing of emotions, including amygdala, orbitofrontal cortex and anterior cingulate. Prompted by these findings we compared cerebral activations between the sexes during performance of two emotion processing tasks and found overall much more extensive and intense cerebral activations in men than in women with schizophrenia. Moreover, the pattern of obtained sex differences in cerebral activation in patients differed significantly from what has been observed in the general population. Based on these preliminary structural and functional neuroimaging data, as well as some clinical reports, it is hypothesized in the present paper that schizophrenia is characterized by a reversed (or at least seriously disturbed) cerebral sexual dimorphism. It is further argued that this phenomenon stems from masculinization and/or un-feminization of females and feminizations and/or un-masculinization of males by sex steroid hormones, such as estrogen and testosterone, during both organizational and activational stages of neurodevelopment.     

Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division

Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition—G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.

Early observations of cancer noted that cancer cells often possess an abnormal number of chromosomes. About 90% of solid tumors are aneuploid, meaning they harbor a chromosome count that is not a multiple of the haploid complement. Thus, aneuploidy is more common than any individual gene mutations in cancer (1). This abnormal DNA content leads to changes in RNA and protein expression and many phenotypic changes (2–5). Notably, aneuploidy is significantly associated with poor patient prognoses, both in pan-cancer analyses and cancer-type-specific studies (6–13).Despite its prevalence in cancer, recent studies have revealed that aneuploidy causes a wide variety of cellular stresses. As changes in gene copy number generally result in changes in gene expression, stoichiometric imbalances in protein complexes lead to increased protein misfolding and proteotoxic stress due to an increased demand for protein quality-control machinery (14–16). Aneuploidy also alters the metabolic landscape of cells and causes genome instability (5, 17–20). These aneuploidy-associated stresses lead to cell cycle changes and slow proliferation (4, 21). Specifically, aneuploidy causes G1 delays in the yeast, Saccharomyces cerevisiae, and lengthens G1 and S phase in mammalian cells under most circumstances (20, 22, 23).How can a feature of cancer be associated with poor patient prognosis if it slows cancer’s growth? One possibility is that aneuploidy increases a tumor’s resistance to treatment. In cancer, drug resistance has, among other parameters, been associated with cells missegregating chromosomes at a higher rate, a phenomenon known as chromosomal instability (CIN). CIN and aneuploidy exhibit positive feedback, with each driving the other. Colon cancer cell lines with CIN have increased multidrug resistance, and patients with high CIN tumors have a worse prognosis than those with chromosomally stable cancers (24). The connection between CIN and drug resistance has been attributed to increased heterogeneity and, hence, subclones within the tumor that are drug resistant. However, other studies have found that extremely high levels of CIN increase patient survival (25–27). Extreme aneuploidy stress could synergize with the antiproliferative effects of cancer drugs and may prevent cells from “holding onto” a drug-resistant karyotype.Specific aneuploidies also drive drug resistance in human cancer cells. In DLD1, a colon cancer cell line, two trisomic derivatives (trisomy 7 and trisomy 13) grew better than their euploid counterpart when treated with 5-fluorouracil (28). Whether aneuploidy-induced copy number changes of specific genes or some general feature of the aneuploid state drive chemotherapy resistance is currently unknown. Here we investigate this question, focusing on cis-diamminedichloroplatinum(II) (cisplatin) and paclitaxel, two front line chemotherapeutics that are used to treat highly aneuploid cancers such as bladder, ovarian, testicular, breast, and nonsmall cell lung cancer. We show that aneuploidy causes resistance to these chemotherapeutics through a general feature of the aneuploid condition: slowed proliferation. Equalizing growth of aneuploid and euploid control cells eliminates differences in drug resistance between them. Finally, we provide evidence that our findings are clinically relevant. Aneuploidy and chromosomal instability correlate with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that proliferative index is a major determinant of chemotherapy efficacy and that aneuploidy’s role in causing chemotherapy resistance is mediated at least in part by its adverse effects on cell proliferation.     

Precision of scoring radiation-induced chromosomal aberrations and micronuclei by unexperienced scorers

Abstract

Purpose: Dose assessment plays an important role in case of radiological accidents and can be performed by scoring structural changes of chromosome morphology induced in cells by ionizing radiation. The results of such a test are biased by scorer experience, therefore, simple to learn assays are recommended to be used when fast analysis of a large amount of data is needed. The aim of this study was to compare the performance of two radiobiological assays – chromosomal aberrations and micronuclei – by unexperienced scorers with the reference values generated by an expert.

Materials and methods: Each participant of an EU-funded two-week radiobiology course was asked to score Chinese hamster ovary cells exposed to gamma radiation up to 4?Gy. The congruence of students’ and expert’s scores at each dose and the coherence of the dose-response curve parameters between the students were investigated.

Results: Micronucleus test tended to be faster and easier to learn than scoring chromosomal aberrations. However, both assays carried out by inexperienced students showed reasonable dose-response curves.

Conclusions: In the case of a large radiological accident involving many casualties, the unexperienced scorers would support the process of biodosimetric triage by cytogenetic biological dosimetry.     

Fabrication of Antibacterial Metal Surfaces Using Magnetron-Sputtering Method

One-hundred-nanometer films consisting of silver, copper, and gold nanocrystallites were prepared, and their antibacterial properties were quantitatively measured. The magnetron-sputtering method was used for the preparation of the metallic films over the glass plate. Single- and double-layer films were manufactured. The films were thoroughly characterized with the XRD, SEM, EDS, and XPS methods. The antibacterial activity of the samples was investigated. Gram-negative Escherichia coli, strain K12 ATCC 25922 (E. coli), and Gram-positive Staphylococcus epidermidis, ATCC 49461 (S. epidermidis), were used in the microbial tests. The crystallite size was about 30 nm in the cases of silver and gold and a few nanometers in the case of copper. Significant oxidation of the copper films was proven. The antibacterial efficacy of the tested samples followed the order: Ag/Cu > Au/Cu > Cu. It was concluded that such metallic surfaces may be applied as contact-killing materials for a more effective fight against bacteria and viruses.     

Activated Carbons Obtained from Orange Peels,Coffee Grounds,and Sunflower Husks—Comparison of Physicochemical Properties and Activity in the Alpha-Pinene Isomerization Process

This work presents studies on the preparation of porous carbon materials from waste biomass in the form of orange peels, coffee grounds, and sunflower seed husks. The preparation of activated carbons from these three waste materials involved activation with KOH followed by carbonization at 800 °C in an N₂ atmosphere. This way of obtaining the activated carbons is very simple and requires the application of only two reactants. Thus, this method is cheap, and it does not generate much chemical waste. The obtained activated carbons were characterized by XRD, SEM, XPS, and XRF methods. Moreover, the textural properties, acidity, and catalytic activity of these materials were descried. During catalytic tests carried out in the alpha-pinene isomerization process (the use of the activated carbons thus obtained in the process of alpha-pinene isomerization has not been described so far), the most active were activated carbons obtained from coffee grounds and orange peels. Generally, the catalytic activity of the obtained materials depended on the pore size, and the most active activated carbons had more pores with sizes of 0.7–1.0 and 1.1–1.4 nm. Moreover, the presence of potassium and chlorine ions in the pores may also be of key importance for the alpha-pinene isomerization process. On the other hand, the acidity of the surface of the tested active carbons did not affect their catalytic activity. The most favorable conditions for carrying out the alpha-pinene isomerization process were the same for the three tested activated carbons: temperature 160 °C, amount of the catalyst 5 wt.%, and reaction time 3 h. Kinetic studies were also carried out for the three tested catalysts. These studies showed that the isomerization over activated carbons from orange peels, coffee grounds, and sunflower seed husks is a first-order reaction.     

MK-801 (Dizocilpine): Synergist and conditioned stimulus in bromocriptine-induced psychomotor sensitization

Intraperitoneal injections of the D₂/D₃ dopamine agonist bromocriptine (5.0 mg/kg, IP) induced locomotion that became progressively stronger on successive days of testing. The sensitized response developed twice as rapidly when the non-competitive NMDA antagonist MK-801 (0.25 mg/kg, IP) was given 30 min after bromocriptine (so that the peak effects of the two drugs overlapped). In a second group of animals, MK-801 was given 30 min prior to bromocriptine (the pretreatment regimen typical of studies where MK-801 is reported to block cocaine, amphetamine or morphine sensitization) and locomotion was monitored during the pretreatment period; in this case sensitization to the locomotor-stimulating effects of MK-801 alone (in the pretreatment period) as well as sensitization to the locomotor-stimulating effects of the drug combination (following the second injection) were observed. No sensitization to the effects of MK-801 alone (pretreatment) were seen in animals that received saline rather than bromocriptine as their second injection in this experiment. Thus MK-801 does not block but rather enhances bromocriptine sensitization; it appears to do so by a synergism with the locomotor effects of bromocriptine and by becoming a conditioned stimulus for the sensitized response. These findings confirm the earlier report that NMDA receptor activation is not critical to bromocriptine-induced sensitization, and they illustrate the importance of controls for conditioning and state-dependency phenomena in studies of drug interactions in psychomotor sensitization. © 1996 Wiley-Liss, Inc.     

Page kidney: Rare cause of acute kidney injury after complicated renal artery angioplasty

The authors present a case of a patient who experienced a rare complication after attempted renal angioplasty and stenting, Page kidney. This patient presented with new onset hypertension secondary to bilateral renal artery stenosis and was referred for revascularization given hypertension refractory to medical management. The right renal artery underwent successful angioplasty and stenting; however, the left renal artery experienced recoil stenosis. Post‐procedure the patient developed acute kidney injury secondary to Page kidney from subcapsular and extracapsular hematoma. This was managed conservatively with transfusions and the hematoma and acute kidney injury self‐resolved over the next 4 months. This case highlights the importance of revascularization for refractory hypertension secondary to hemodynamically significant bilateral renal artery stenosis, the rare complication of Page kidney with attempted revascularization of renal artery stenosis and the involvement of a hypertension specialist in the decision of revascularization of renal artery stenosis.