Is acetaminophen, and its combination with pamabrom, an effective therapeutic option in primary dysmenorrhoea?

Primary dysmenorrhoea is the most frequent gynaecological condition, with a prevalence of 40 - 90% in women within the reproductive age. It is characterised by cyclic pelvic pain related to menstrual period, vomiting and headache. As prostaglandins and leukotrienes appear to be a major causative factor in this condition, NSAIDs are the first choice for treatment. Acetaminophen is an over-the-counter analgesic/antipyretic agent widely used in primary dysmenorrhoea as monotherapy or in combination. It has a weak inhibitory action on peripheral prostaglandin synthesis. Acetaminophen displays good gastrointestinal tolerance without any effect on haemostasis. Its combination with pamabrom, a mild diuretic agent, (Women s Tylenol Menstrual Relief Caplets, Midol Teen) was approved by the FDA for use in this indication. Nevertheless, the available information concerning the efficacy of acetaminophen in primary dysmenorrhoea is limited and not conclusive with respect to other NSAIDs or even placebo. The clinical evidence regarding the association with pamabrom is even more scarce. Well-designed, randomised, controlled trials are required to demonstrate the efficacy of the combination of acetaminophen plus pamabrom in the treatment of primary dysmenorrhoea.     

Comparative genomic hybridization in primary sinonasal adenocarcinomas

BACKGROUND: Little is known about the genetic alterations that occur in sinonasal adenocarcinomas. The goal of the current study was to detect recurrent chromosomal gains and losses in a series of 21 primary sinonasal adenocarcinomas using comparative genomic hybridization (CGH). METHODS: The authors examined ethmoid sinus adenocarcinoma samples from 21 patients. All 21 adenocarcinomas were associated with work-related exposure to wood dust. CGH was used to detect chromosomal abnormalities, and the results of CGH analysis were evaluated for correlations with clinicopathologic characteristics. RESULTS: Chromosomal gains and losses were detected in all 21 adenocarcinomas. Gains were detected at high frequencies at 7q11-21 (n = 15 [71%]), 18p11 (n = 14 [66%]), 8q11-22 (n = 13 [62%]), 5p11-13 (n = 12 [57%]), 12q11-13 and 19p (n = 11 [52%]), 20q (n = 10 [47%]), X and 5p (n = 9 [43%]), and 3q26-27 (n = 8 [38%]); and losses were detected at 8p22-23 (n = 18 [86%]), 18q22-23 (n = 17 [80%]), 17p13 (n = 12 [57%]), and 5q31-qter (n = 11 [52%]). Aside from low-level gains, 43 high-level amplifications were observed in the current series of 21 tumors, most commonly at Xq13 (n = 7 [33%]). CONCLUSIONS: CGH revealed that ethmoid sinus adenocarcinomas carry a large number of chromosomal losses and gains, including high-level amplifications. To the authors' knowledge, the current study represents the first attempt to investigate sinonasal adenocarcinomas on a genetic level by using CGH. The pattern of chromosomal abnormalities in these tumors was different from the pattern in other tumors within the same anatomic region (e.g., squamous cell carcinomas and salivary gland tumors); this finding may be explained by differences in etiology. Nonetheless, sinonasal adenocarcinomas appear to be genetically similar to adenocarcinomas of the stomach and colon, which also have an etiology that differs from that of sinonasal adenocarcinomas. Further study is necessary to better understand the molecular genetic basis underlying the development of sinonasal adenocarcinomas. In the near future, this type of understanding may present new possibilities for prevention and treatment of malignant disease.     

Cathepsin B mediates caspase-independent cell death induced by microtubule stabilizing agents in non-small cell lung cancer cells

We have previously reported that the microtubule stabilizing agents (MSAs) paclitaxel, epothilone B and discodermolide induce caspase-independent cell death in non-small cell lung cancer (NSCLC) cells. Here we present two lines of evidence indicating a central role for the lysosomal protease cathepsin B in mediating cell death. First, inhibition of cathepsin B, and not of caspases or other proteases, such as cathepsin D or calpains, results in a strong protection against drug-induced cell death in several NSCLC cells. Second, MSAs trigger disruption of lysosomes and release and activation of cathepsin B. Interestingly, inhibition of cathepsin B prevents the appearance of multinucleated cells, an early characteristic of MSA-induced cell death, pointing to a central, proximal role for cathepsin B in this novel cell death pathway.     

Second malignancies after chemotherapy and radiotherapy for Hodgkin disease

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.     

Nuclear-cytoplasmic shuttling of BARD1 contributes to its proapoptotic activity and is regulated by dimerization with BRCA1

The breast cancer-associated protein, BARD1, colocalizes with BRCA1 in nuclear foci in the S phase and after DNA damage, and the two proteins form a stable heterodimer implicated in DNA repair, protein ubiquitination, and control of mRNA processing. BARD1 has a BRCA1-independent proapoptotic activity; however, little is known about its regulation. Here, we show that BARD1 localization and apoptotic activity are regulated by nuclear-cytoplasmic shuttling. We identified a functional CRM1-dependent nuclear export sequence (NES) near the N-terminal RING domain of BARD1. The NES forms part of the BRCA1 dimerization domain, and coexpression of BRCA1 resulted in masking of the NES and nuclear retention of BARD1. In transient expression assays, BARD1 apoptotic activity was stimulated by nuclear export, and both apoptotic function and nuclear export were markedly reduced by BRCA1. Similar findings were obtained for endogenous BARD1. Silencing BRCA1 expression by siRNA, or disrupting the endogenous BARD1/BRCA1 interaction by peptide competition caused a reduction in BARD1 nuclear localization and foci formation, and increased the level of cytoplasmic BARD1 correlating with increased apoptosis. Our findings suggest that BRCA1/BARD1 heterodimer formation is important for optimal nuclear targeting of BARD1 and its role in DNA repair and cell survival.     

Right hemispheric dysfunction in a case of pure progressive aphemia: fusion of multimodal neuroimaging

This article describes the unusual case of a 60-year-old woman suffering from pure progressive aphemia. The fusion of multimodal neuroimaging (MRI, perfusion SPECT) implicated the right frontal lobe, especially the inferior frontal gyrus. This area also showed the greatest functional MRI activation during the performance of a covert phonemic fluency task. Results are discussed in terms of bihemispheric language representation. The fusion of three sets of neuroimages has aided in the interpretation of the patient's cognitive brain dysfunction.     

Antioxidants are necessary for myelination of dorsal root ganglion neurons, in vitro

We have demonstrated that myelination of dorsal root ganglion (DRG) axons occurs in a fully defined, serum-free medium (B27). This implies that there may be components in B27 medium that support myelination. To determine which of the components in B27 were essential for myelination, we systematically removed components from B27 until myelination was lost. We added these components to a fully defined minimal medium (N2) that supports neuron survival but not myelination. When antioxidants were removed from B27, myelination was lost. However, the individual antioxidants did not induce myelination when added to N2 medium. Addition of ascorbic acid along with the B27 antioxidants was sufficient to induce myelination in N2 medium, which was enhanced by retinyl acetate. Removal of vitamin E from B27 caused a partial loss of myelination, and addition of vitamin E to N2 medium containing ascorbic acid induced partial myelination. Addition of serum to the B27 myelinating medium inhibited myelination completely. These results indicate that antioxidants are important for myelination, in vitro. Vitamin E may play an important role. Use of a serum-free medium may be beneficial for in vitro myelination studies because serum has unknown inhibitory effects.     

Interacting effects of genetic predisposition and depression on adolescent smoking progression

OBJECTIVE: The goal of the present study was to identify specific genetic associations with smoking progression in adolescents and to determine whether these genetic effects on smoking practices are potentiated by depression symptoms. METHOD: Effects of dopamine transporter (SLC6A3) and dopamine receptor (DRD2) genetic variants on smoking progression were evaluated in a cohort of 615 adolescents, including those who had never smoked, and in a subgroup including only adolescents who had been exposed to nicotine (i.e., smoked at least a puff of a cigarette) (N=292). These adolescents were followed from 9th to 11th grade. Depression symptoms were also assessed. RESULTS: In the model of adolescents with a previous smoking experience, the likelihood of progressing to a higher level of smoking by the 11th grade increased almost twofold with each additional DRD2 A1 allele. The likelihood of smoking progression with each additional A1 allele was more pronounced among adolescents with substantial depression symptoms. The model including never-smokers revealed no significant genetic effects. Neither model revealed effects of SLC6A3. CONCLUSIONS: These results provide the first evidence, to the authors' knowledge, for an association of the DRD2 A1 allele with smoking progression among adolescents. This effect is potentiated by depression symptoms. These effects appear to be specific to adolescents who have had at least some nicotine exposure (i.e., at least a puff of a cigarette).