Quality assessment of the mammographic screening programme in the Azienda Sanitaria locale Provincia Milano 1 -- analysis of interval cancers and discussion of possible causes of diagnostic error

PURPOSE: To evaluate the sensitivity of the mammographic screening programme and the causes of diagnostic fault in cases surfacing as interval cancers. MATERIALS AND METHODS: Interval cancers (CI) were identified by linkage of the screening database for the years 2000-2002 to the database of hospital discharge records (HDR) for breast cancer during 2000-2002. Linkage between screening attenders during 2000-2001 and HDR (biennial follow-up for year 2000, one year follow-up for year 2001) was used to calculate the proportional rate of observed/expected IC. The observed/ expected rate was compared with international standards and literature data. Screening mammograms followed by IC, randomly admixtured with negative controls, underwent blind review by an independent radiologist, using the recommended classification criteria to evaluate causes of error (occult, minimal signs, screening error). RESULTS: The analysis of HDR during 2000-2002 allowed us to identify 31 out of 89 expected IC. Proportional observed/expected IC rate in the first or second year of screening interval was 26 or 67%, respectively. Screening mammograms for radiological review were available in 38 of 61 total IC: 20 cases (52.6%) were classified as occult, whereas minimal signs or screening errors were 2 (5.2%) or 16 (42.1%), respectively. Diagnostic suspicion had been reported at screening in 7 of 16 cases classified as screening error, but were not diagnosed at the subsequent diagnostic assessment. CONCLUSIONS: Proportional IC rate was higher than reported in the literature or currently recommended (<30% in the 1st, <50% in the 2nd year). The analysis of error causes shows an excess of screening errors with respect to current recommendations (<20% of IC should be classified as screening error at review), but also an excess of IC suspected at screening but misdiagnosed at assessment (7/38=18.4 %). Overall the analysis revealed a reduced sensitivity of the screening programme, as often observed in service screening as compared to excellence centres, and suggests proper action to improve diagnostic accuracy. Analysis and critical review of IC is an early indicator of screening efficacy which is not currently used in Italian screening programmes. Using HDR for this purpose may have limited drawbacks, but gives the advantage of earlier identification of IC as compared to cancer registries and is the most reliable source of information in areas lacking a cancer registry. The present study methodology might be currently applied in screening programmes.     

Risk factors for low birth weight: a review

Low birth weight (LBW) is one of the main predictors of infant mortality. The global incidence of LBW is around 17%, although estimates vary from 19% in the developing countries (countries where it is an important public health problem) to 5-7% in the developed countries. The incidence in Spain in the decade 1980-1989 was about 5.7%. LBW is generally associated with situations in which uterine malnutrition is produced due to alterations in placental circulation. There are many known risk factors, the most important of which are socio-economic factors, medical risks before or during gestation and maternal lifestyles. However, although interventions exist to prevent many of these factors before and during pregnancy, the incidence of LBW has not decreased.     

Differential regulation of basolateral Cl-/HCO3- exchangers SLC26A7 and AE1 in kidney outer medullary collecting duct

SLC26A7 is a recently identified Cl(-)/HCO(3)(-) exchanger that co-localizes with AE1 on the basolateral membrane of Alpha intercalated cells (A-IC) in outer medullary collecting duct (OMCD). The purpose of these studies was to determine whether AE1 and SLC26A7 are differentially regulated in OMCD in pathophysiologic states. Toward this end, the expression and regulation of AE1 and SLC26A7 was examined in water deprivation, a condition known to increase the osmolality of the medulla. Rats were subjected to 3 d of water deprivation while having free access to food. Northern hybridizations demonstrated that in the outer medulla, the mRNA expression of SLC26A7 increased by approximately 300% (P < 0.01 versus control; n = 3), whereas the expression of AE1 decreased by approximately 50% (P < 0.05 versus control, n = 3) in water-deprived rats. Immunoblot analysis studies demonstrated that in the outer medulla, SLC26A7 abundance increased by approximately 3.5-fold (P < 0.02 versus control; n = 3), whereas the AE1 abundance decreased by approximately 55% (P < 0.05 versus control) in water deprivation. The expression of SLC26A7 remained unchanged in the kidney cortex and stomach in water deprivation, indicating the specificity of SLC26A7 upregulation in outer medulla. In situ hybridization indicated the exclusive expression of SLC26A7 in the outer medulla and double immunofluorescence labeling confirmed the co-localization of AE1 and SLC26A7 on the basolateral membrane of A-IC cells in OMCD. It is concluded that AE1 and SLC26A7 are differentially regulated in OMCD in water deprivation. On the basis of these results and previous functional studies indicating the activation of SLC26A7 activity by high osmolality, it is proposed that SLC26A7 may play an important role in bicarbonate reabsorption and or cell volume regulation in OMCD (specifically under hypertonic conditions).     

Stomal recurrence after primary total laryngectomy

Stomal recurrence after total laryngectomy is usually considered to be incurable. A total of 402 patients suffering from squamous cell carcinoma of the larynx treated by total laryngectomy during the period 1982-96 were analysed. In the group of patients studied, the significant risk factors for stomal recurrence were glottic-subglottic tumour localization and regional tumour spread. Postoperative radiotherapy can significantly reduce the risk of stomal recurrence.     

Suicide in the elderly 60 years of age and over in the south-east part of Serbia

Some previous investigations indicated that economic crisis (inflation in Serbia 1993/94) have great influence on increasing suicide rates in Serbia. After that suicide decreased, despite the war and bombing in 1999, specially among the elderly people. A total of 453 suicides were registered on the territory of south-eastern Serbia during 1995-2001 years. Of them 295 (65.1%) were aged over 60 years. Generally linear trends of suicide among both genders from 1995 to 2001 decreased, but the slope of decreasing was grater among males than among females. The highest rates among the both genders were registered in the years with the maximum number of suicides, but the linear trends of rates have statistically important correlation with time (r>0.5). Average annual suicide rate among males was 42.5, and among women it was 18.7. The highest average annual suicide rate among men was observed in the age group 75 years and over (93.3), and the lowest in the age group 65-69 (20.6). Among males, in the all age group linear trends of suicide rates decreased, with the highest slope among 75 years and over and the lowest among 65-69 years. The highest suicide rate among females was registered in age group 75 years and over (25.6), the lowest in the age group 65-69 (13.5). The linear trends are similar as among males: downward trend was observed among all aged groups, with the highest slope among women 75 years and over. The most common way of suicide among men was hanging up (63%), poisoning and by firearms. There were no statistical differences between way of suicide and age groups. The most frequent way of suicide among females was hanging up (55%), poisoning (25%) and drowning (12%). There were statistically significant differences in drowning between age groups, 70-74 and 75 and over (p<0.05), and between poisoning and age groups 60-64 years and 75 years and over. Poisoning and drowning are statistically more frequent among women than among men.     

Synthesis and biological evaluation of analogues of 7-chloro-4,5-dihydro-4- oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (TQX-173) as novel selective AMPA receptor antagonists

In recent papers (Catarzi, D.; et al. J. Med. Chem. 2000, 43, 3824-3826; 2001, 44, 3157-3165) we reported chemical and biological studies on 4,5-dihydro-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates (TQXs) bearing different nitrogen-containing heterocycles at position-8. In particular, from these studies it emerged that both the 7-chloro-4,5-dihydro-4-oxo-8-(1,2,4-triazol-4-yl)-1,2,4-triazolo[1,5-a] quinoxaline-2-carboxylic acid TQX-173 (compound B) and its corresponding ethyl ester (compound A) were the most active and selective compounds of this series. In pursuing our investigation on the structure-activity relationships of these TQX derivatives, different electron-withdrawing groups (CF(3), NO(2)) were introduced at position 7 on the TQX ring system, replacing the 7-chloro substituent of B and of other selected 8-heteroaryltriazoloquinoxaline-2-carboxylates previously described. All the newly synthesized compounds were biologically evaluated for their binding at the Gly/NMDA, AMPA, and KA high-affinity receptors. Gly/NMDA binding assays were performed to assess the selectivity of the reported compounds toward the AMPA receptor. Compounds endowed with micromolar binding affinity for the KA high-affinity binding site were also evaluated for their binding at the KA low-affinity receptor. Some selected compounds were also tested for their functional antagonist activity at the AMPA and NMDA receptor-ion channel complex. The results obtained in this study have pointed out that 4,5-dihydro-7-nitro-4-oxo-8-(3-carboxypyrrol-1-yl)-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylic acid (9b) and its corresponding ethyl ester (9a) are the most potent and selective AMPA receptor antagonists reported to date among the TQX series.     

1,2,4-triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand-receptor modeling studies

In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K(i) = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.