Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms

Neuropathy is common in patients receiving vinca alkaloids, platinum derivatives, or taxanes. This double-blind, randomized, placebo-controlled study assessed the efficacy of low-dose amitriptyline to relieve chemotherapy-induced symptoms in 44 patients (age 20-65 years) who had neuropathic symptoms (numbness, tingling, pain) with a severity of > or =3/10. They were treated with amitriptyline for eight weeks (10mg/day to start, then dose elevation of 10mg/week up to 50mg/day if tolerated, followed by a stable dose > or =4 weeks). The patients completed a diary twice weekly, noting the intensity of pain, numbness and tingling, global improvement, and adverse effects. Neurological examination was performed at each visit (baseline, four, and eight weeks). The patients assessed both intensity and relief of pain, and overall discomfort. They also completed the Neuropathic Pain Scale and validated measures of anxiety and depression, and quality of life (QoL). The results demonstrated that amitriptyline did not improve sensory neuropathic symptoms, although there was a trend toward global improvement and improved QoL in favor of the amitriptyline group. No statistical significance was reached, probably due to the small number of patients and too low dose of amitriptyline. Amitriptyline was well tolerated.     

A new triphenylethylene compound,Fc-1157a

Summary The antitumor effects of a new antiestrogen, Fc-1157a¹ have been studied in vitro and in vivo. In vitro the effect of Fc-1157a was comparable to that of tamoxifen. The effect was dose-dependent, and at concentrations higher than 10^-6 mol/l Fc-1157a induced real cell death of the MCF-7 cells. In DMBA-induced mammary cancer in rats Fc-1157a decreased the number of new tumors and inhibited the growth of existing tumors, these effects being statistically highly significant. The ratio of growing tumors to stable and regressing tumors was significantly decreased. Although these effects were slightly stronger with Fc-1157a than with tamoxifen, the difference between these two compounds was not statistically significant.Murine uterine sarcoma, an estrogen receptor-negative tumor, was resistant to tamoxifen, but was statistically significantly inhibited by high doses (100 and 200 mg/kg^-1 day^-1 for 5 days) of Fc-1157a.The antitumor effects of Fc-1157a are due mainly to the antiestrogenic activity. At high concentrations in vitro and at high doses in vivo Fc-1157a exerts antitumor effects some of which are different from those of tamoxifen and are directed even against estrogen receptor-negative tumors. The exact mechanism of the observed cytolytic effect at high doses is unknown.     

Analyzing atopic and non-atopic asthma

There is a need to better define phenotypes of asthma. However, many studies have data available only on asthma and atopy, so they are often used to define ‘atopic’ and ‘non-atopic’ asthma. We discuss and illustrate the problems of analyzing such outcomes. We used the 31 year follow-up of the Northern Finland Birth Cohort 1966 (n=5,429). ‘Atopic asthma’ and ‘non-atopic asthma’ were defined based on presence or absence of atopy (any skin prick test ≥3 mm) at age 31. Gender and ownership of cat in childhood were used as risk factors. Simple calculations on hypothetical datasets were used to support the conclusions. ‘Atopic asthma’ and ‘non-atopic asthma’, are not well separated disease entities. The association of a risk factor with ‘atopic asthma’ and ‘non-atopic asthma’ is determined both by its association with asthma and with atopy. E.g. if a risk factor is not associated with asthma, but is protective for atopy, this will produce a protective association with ‘atopic asthma’, but an opposite association with ‘non-atopic asthma’. This is the result from the typical analysis, which uses all non-asthmatics as the comparison group. Valid results, unconfounded by atopy, can be gained by comparing asthmatics to nonasthmatics separately among atopics and non-atopics, i.e. by doing the analysis stratified by atopy. If data only on asthma and atopy are available, asthma and atopy should be analyzed at first as separate outcomes. If atopic and nonatopic asthma are used as additional outcomes, valid results can be gained by stratifying the analysis by atopy.     

Self-reported temporomandibular disorder symptoms and severity of malocclusion in prospective orthognathic-surgical patients

Objective: The objective of this study is to analyze the association between self-reported symptoms of temporomandibular joint disorder (TMD) and the severity of malocclusion in prospective orthognathic-surgical patients.

Material and methods: The subjects consisted of 50 consecutive patients (13 males and 37 females) referred to two university clinics for assessment of orthodontic-surgical treatment need. Data considering self-reported TMD symptoms were gathered using a semi-structured diary. At the first appointment, all patients rated the importance of treatment (on a scale of 1–10) and assessed self-perceived dental appearance using a VAS scale. The scale was anchored with photographs 1 and 10 from the Aesthetic Component (AC) of the Index of Orthodontic Treatment Need (IOTN). Study models were assessed by an experienced orthodontic specialist using the Peer Assessment Rating (PAR) index and the Index of Complexity, Outcome and Need (ICON). Association between the PAR and ICON scores and the number of reported symptoms was analyzed statistically.

Results: Seventy-one percent of patients reported experiencing TMD symptoms. The most prevalent symptoms were pain in the head and/or neck region and fatigue in the TMJ region. The number of symptoms was highest in the morning. Ninety percent of males and 86% of females rated the importance of treatment as high; males experiencing TMD symptoms tended to rate surgery as more important compared with males with no symptoms (p?=?0.056).

Conclusions: In this sample, the results cannot unambiguously confirm an association between self-reported symptoms of TMD and objectively defined severity of malocclusion.     

Cellular redox state and its relationship to the inhibition of clonal cell growth and the induction of apoptosis during all-trans retinoic acid exposure in acute myeloblastic leukemia cells

BACKGROUND AND OBJECTIVE: All-trans retinoic acid (ATRA) induces growth arrest and apoptosis in acute myeloblastic leukemia (AML) cells. Since cellular redox state regulates these events, we were interested in studying whether it has any role in the responsiveness of AML cells to ATRA. DESIGN AND METHODS: Two human AML cell lines, the ATRA-sensitive OU-AML-3, and the ATRA-resistant OU-AML-7, were used as models. Clonogenic cell culture assay, annexin V method, and measurement of mitochondrial membrane potential were used for the determination of cell growth and apoptosis. Peroxide formation was analyzed by flow cytometry, glutathione and g-glutamylcysteine synthetase (g-GCS) activity was determined spectrophotometrically, and the expression of manganese superoxide dismutase (MnSOD) by Western blotting. RESULTS: ATRA inhibited clonogenic cell growth and induced apoptosis particularly in OU-AML-3 cells. The OU-AML-7 cells had a higher basal level of glutathione and g-GCS activity than the OU-AML-3 cells. ATRA enhanced the generation of peroxides after 24h exposure, which was more prominent in the sensitive than the resistant cell line and was not preventable by N-acetyl-L-cysteine. ATRA also increased the activity of g-GCS, which was associated with increased intracellular glutathione in the resistant cell line, while the glutathione level was maintained in the sensitive cell line. During ATRA exposure, MnSOD was induced in the sensitive cell line, but not until after 72 h. Buthionine sulfoximine significantly increased the inhibitory effect of ATRA on colony formation in both cell lines, but only marginally enhanced the effect of ATRA on the induction of apoptosis. INTERPRETATION AND CONCLUSIONS: The balance between oxidative and antioxidative actions of ATRA, as well as the basal redox state of the cells seem to have a definite influence on the responsiveness of AML cells to ATRA.     

N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.     

Evolution of gastritis in patients with gastric erosions

Objective. Gastric erosions are mainly associated with Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs), but there has been no information available on the long-term evolution of gastritis in subjects with erosions. Material and methods. A series of 117 patients with gastric erosions without peptic ulcer disease and matched controls without erosions or ulcers were studied. Available subjects underwent endoscopy and biopsy 17 years later. Parietal cell antibodies were analysed at the first visit. Results. Fifty-two patients and 67 controls were available for follow-up. Since H. pylori was a major determinant of gastritis, only subjects with unchanged H. pylori status were included in the evaluation of gastritis progression. At the follow-up visit, gastric erosions were present in 38% (16/42) of the patients and 11% (5/46) of the controls (p=0.005). In H. pylori-negative subjects, no evolution of histological changes was seen. In H. pylori-positive subjects, body gastritis was initially less active in the erosion group. With time, antral gastritis worsened only in the erosion group. Parietal cell antibodies were more common in the control group (23%; erosion patients 0%; p=0.01), which also showed worsening of gastritis (p=0.003) and aggravation of atrophy (p=0.002) in the body mucosa. Conclusions. Gastritis in H. pylori-positive subjects with gastric erosions shows evolution of antral predominance, body predominance including development of atrophic changes being rare. Accordingly, patients with erosions share the characteristics of gastritis of the duodenal ulcer phenotype. These findings support the importance of H. pylori and acid in the pathogenesis of gastric erosions in H. pylori-positive patients.