Cytogenetics of benign breast lesions

This review summarizes the cytogenetic information on benign breast lesions of various histologies, i.e., fibrocystic lesions from women with and without a known hereditary predisposition to breast cancer, fibroadenomas, phyllodes tumors, and papillomas, and relate the chromosomal features with those in breast carcinoma. In general, the frequency of chromosome abnormalities is lower in benign lesions than in breast cancer, and seems to correlate with the histologic features of the tissue, and the corresponding risk of developing invasive mammary carcinoma; aberrations are more common in proliferative than in nonproliferative lesions. The karyotypes are generally less complex than those detected in invasive carcinoma, and more often involve balanced rearrangements. No lesion-specific aberration has so far been detected; on the contrary, changes repeatedly encountered in breast cancer samples can be found in benign lesions as well, e.g., gain of 1q, interstitial deletion of 3p, and trisomies 7, 18, and 20. Especially intriguing is the prevalence of rearrangements of the short arm of chromosome 3, with the minimally deleted bands 3p13–14, in proliferative lesions from prophylactic mastectomies in breast cancer families. The potential tumor suppressor gene(s) in this region remains, however, to be identified.     

A European validation study of smoking and environmental tobacco smoke exposure in nonsmoking lung cancer cases and controls

Objectives: The purpose of this study was to validate, in a case-control study, the reporting by lung cancer cases and controls of their own lifetime smoking habits and of the smoking habit of the spouse. Methods: In a multicenter (Sweden, Spain, Italy) case-control study of environmental tobacco smoke (ETS) and lung cancer, subjects were screened by repeated probing to exclude regular smokers of one cigarette/day or more for one year or more, and to quantify any occasional smoking. We then performed a short validation interview with next-of-kin in three centers. Results: Only five of 408 index subjects who had never smoked regularly (1.7 percent) were reported by next-of-kin to be former regular smokers. These subjects had a cumulative lifetime consumption of cigarettes below 1.1 pack years. Among 351 subjects with quantitative smoking information from both sources who reported ever smoking 400 cigarettes or less (the definition of never-smoker used in the multicenter ETS study), nine subjects (2.6 percent) had smoked more than this amount occasionally according to next-of-kin. Misclassification was not higher for cases than controls. Relative risks for lung cancer associated with indicators of ETS exposure were not substantially altered by excluding the nine possibly misclassified subjects. The reports from 223 pairs of index subjects and next-of kin regarding the cumulative amount smoked by the spouse agreed quite well (Spearman's rank correlation 0.75 for reported smokers, 0.92 for all subjects). Only one index subject failed to report a spouse who had smoked regularly (99 percent sensitivity). Conclusions: Smoking status and exposure to spousal ETS as reported by lung cancer cases and controls agreed strongly with reports by next-of-kin. Overall, our results suggest that bias from smoker misclassification is likely to be insignificant, and they contribute to the evidence linking exposure to ETS with an increased risk of lung cancer.     

Addition of histamine to interleukin 2 treatment augments type 1 T-cell responses in patients with melanoma in vivo: immunologic results from a randomized clinical trial of interleukin 2 with or without histamine (MP 104).

PURPOSE: Preclinical investigations suggest that histamine dihydrochloride (HDC) protects T cells and natural killer cells from inhibition by monocyte-derived reactive oxygen metabolites and synergizes with interleukin (IL) 2 in inducing T-cell activation. Here, we investigate whether this mechanism is operational in patients with melanoma treated with HDC as an adjunct to IL-2. EXPERIMENTAL DESIGN: Melanoma patients having liver metastases were treated with IL-2 with or without HDC within a randomized, multicenter, phase III trial. The effect of HDC on type 1 and type 2 T-cell cytokine production was investigated in peripheral blood samples from 19 patients with the use of intracellular cytokine flow cytometry. Melanoma-specific T-cell responses were analyzed in eight HLA-A2-positive patients. RESULTS: Frequencies of CD3+ T cells producing IFN-gamma (type 1 T cells) in response to phorbol myristate acetate/ionomycin increased (median, 1.8-fold) in patients receiving IL-2 plus HDC but not in those receiving IL-2 alone (P < 0.01 for comparison between arms). In contrast, the number of IL-13-producing type 2 T cells that increased in patients after treatment with IL-2 was not modulated by HDC. Melanoma- and tyrosinase-specific IFN-gamma and IL-13-producing T cells were detected in two of four HLA-A2-positive patients with melanoma following treatment with HDC + IL-2. CONCLUSIONS: Treatment of patients with stage IV melanoma with HDC in combination with IL-2 increases type 1 T-cell responses and may promote induction of melanoma-specific T cells. These effects are of relevance for tumor immunotherapy and provide a potential mechanism for the clinical efficacy of HDC added to IL-2.     

Investigations of the cerebrospinal fluid in cases of rheumatoid arthritis

The spinal fluid was examined in 141 cases of rheumatoid arthritis, thirty-eight men and 103 women, of whom fifty-eight (41 per cent) exhibited a protein content that was pathological in one way or other, fifteen (14 per cent) gave a pathological gold-sol reaction and seven showed an increased spinal fluid cell count. Altogether sixty-six cases (46.8 per cent) were found to have spinal fluids which were pathologically altered in some way.Statistical examination of the results shows, inter alia, that in cases of rheumatoid arthritis the average spinal fluid globulin value is increased and the average spinal fluid albumin value lowered, resulting in a raised average globulin-albumin quotient. Further, it was shown that the abnormal increases in spinal fluid protein values are not dependent on the degree of severity of the arthritic disease process and are little affected by the duration of the disease.The frequency of increased cell counts in the spinal fluid appears to be somewhat greater in cases with elevated protein contents.     

Two statins and cromolyn as possible drugs against the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides: a comparative study by advanced computer simulation methods

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET₃₅, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood–brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood–brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations.     

Combined effects of brachial pulse pressure and sialic acid for risk of cardiovascular events during 40 years of follow-up in 37 843 individuals

OBJECTIVE:: Pulse pressure (PP) is a risk marker for cardiovascular disease (CVD) in individuals 50 years and older. Inflammation is suggested to influence atherosclerosis, but could also increase PP. We aimed to examine the combined effects of PP and the inflammatory marker sialic acid, and their independent roles on CVD risk. METHODS:: From a population-based study in Sweden between 1962 and 1965, 18?429 men and 19?414 women at the age of 50 or older were selected and followed for first CVD event until 2005. We investigated the biological interactions between sialic acid and PP. The associations of PP and sialic acid with risk of CVD were calculated by using Cox proportional hazards model. Adjustments were made for conventional risk factors, mean arterial pressure (MAP) and socioeconomic status. RESULTS:: The mean age was 59.5 (SD 6.5) years and the number of incident CVD events in men and women were 3641 and 3227, respectively. No biological interaction was seen between PP and sialic acid. In men, the adjusted hazard ratio for PP was 0.92 [95% confidence interval (CI) 0.88-0.96, P?相似文献   

Antibiotic resistance in hospitals: a ward‐specific random effect model in a low antibiotic consumption environment

Association between previous antibiotic use and emergence of antibiotic resistance has been reported for several microorganisms. The relationship has been extensively studied, and although the causes of antibiotic resistance are multi‐factorial, clear evidence of antibiotic use as a major risk factor exists. Most studies are carried out in countries with high consumption of antibiotics and corresponding high levels of antibiotic resistance, and currently, little is known whether and at what level the associations are detectable in a low antibiotic consumption environment. We conduct an ecological, retrospective study aimed at determining the impact of antibiotic consumption on antibiotic‐resistant Pseudomonas aeruginosa in three hospitals in Norway, a country with low levels of antibiotic use. We construct a sophisticated statistical model to capture such low signals. To reduce noise, we conduct our study at hospital ward level. We propose a random effect Poisson or binomial regression model, with a reparametrisation that allows us to reduce the number of parameters. Inference is likelihood based. Through scenario simulation, we study the potential effects of reduced or increased antibiotic use. Results clearly indicate that the effects of consumption on resistance are present under conditions with relatively low use of antibiotic agents. This strengthens the recommendation on prudent use of antibiotics, even when consumption is relatively low. Copyright © 2012 John Wiley & Sons, Ltd.     

Back pain is also improved by lumbar disc herniation surgery

Background and purpose — Indication for lumbar disc herniation (LDH) surgery is usually to relieve sciatica. We evaluated whether back pain also decreases after LDH surgery.Patients and methods — In the Swedish register for spinal surgery (SweSpine) we identified 14,097 patients aged 20–64 years, with pre- and postoperative data, who in 2000–2016 had LDH surgery. We calculated 1-year improvement on numeric rating scale (rating 0–10) in back pain (N_back) and leg pain (N_leg) and by negative binomial regression relative risk (RR) for gaining improvement exceeding minimum clinically important difference (MCID).Results — N_leg was preoperatively (mean [SD]) 6.7 (2.5) and N_back was 4.7 (2.9) (p < 0.001). Surgery reduced N_leg by mean 4.5 (95% CI 4.5–4.6) and N_back by 2.2 (CI 2.1–2.2). Mean reduction in N_leg) was 67% and in N_back 47% (p < 0.001). Among patients with preoperative pain ≥ MCID (that is, patients with significant baseline pain and with a theoretical possibility to improve above MCID), the proportion who reached improvement ≥ MCID was 79% in N_leg and 60% in N_back. RR for gaining improvement ≥ MCID in smokers compared with non-smokers was for N_leg 0.9 (CI 0.8–0.9) and ­N_back 0.9 (CI 0.8–0.9), and in patients with preoperative duration of back pain 0–3 months compared with > 24 months for N_leg 1.3 (CI 1.2–1.5) and for N_back 1.4 (CI 1.2–1.5).Interpretation — LDH surgery improves leg pain more than back pain; nevertheless, 60% of the patients with significant back pain improved ≥ MCID. Smoking and long duration of pain is associated with inferior recovery in both N_leg and N_back.

The most common indication for lumbar disc herniation (LDH) surgery is persistent sciatica that does not respond to nonoperative treatment (Blamoutier 2013). However, most patients who undergo LDH surgery also suffer from back pain (Hakkinen et al. 2003, Stromqvist et al. 2017), on a national level reported in 93% of patients having LDH surgery (Stromqvist et al. 2017). Decades ago, Mixter (1937) therefore argued that LDH extirpation should be accompanied by fusion to minimize postoperative back pain. Recent studies have opposed this view, showing that LDH surgery is not followed by increased back pain when only removing the hernia (Pearson et al. 2008, Owens et al. 2018), and in many cases even improvement of back pain seems sustainable over time.Most studies that evaluate the outcome of LDH surgery focus on the relief from sciatica and improvement in patient-reported outcome measures (PROMs) (Weber 1983, Atlas et al. 2005, Peul et al. 2007, Weinstein et al. 2008, Lurie et al. 2014). A few studies have focused on back pain or included back pain in the evaluation (Kotilainen et al. 1993, Hakkinen et al. 2003, Toyone et al. 2004, Atlas et al. 2005, Pearson et al. 2008, Owens et al. 2018). While some of these infer that back pain is improved by the LDH surgery (Hakkinen et al. 2003, Toyone et al. 2004, Pearson et al. 2008, Owens et al. 2018) others report inconclusive results (Kotilainen et al. 1993, Atlas et al. 2005). There is a lack of consensus on the expected level of back pain reduction with LDH surgery.It would also be of clinical interest to identify preoperative factors that are associated with favorable reduction of back pain following LDH surgery such as age, sex, smoking, preoperative health, and duration of pain (Nygaard et al. 2000, Jansson et al. 2005, Stromqvist et al. 2016, Wilson et al. 2016, Hareni et al. 2019).We (i) evaluated whether back pain is reduced after LDH surgery and if so, to what extent compared with the reduction in leg pain and (ii) what proportion of patients gain improvement in back and leg pain exceeding minimum clinically important difference (MCID). The secondary aim was to identify factors associated with improvement in back pain exceeding MCID.