Severe isolated aortic stenosis with normal left ventricular systolic function and low transvalvular gradients: pathophysiologic and prognostic insights

BACKGROUND AND AIM OF THE STUDY: A significant proportion of patients with severe valvular aortic stenosis (AS) and preserved left ventricular (LV) systolic function have low transvalvular gradients. The study aim was to determine the mechanisms and outcome of patients with this hemodynamic profile of AS. METHODS: Among 1,679 patients who underwent transthoracic echocardiography for the evaluation of AS at the authors' institution, 215 (105 females, 110 males; mean age: 77 +/- 10 years) had isolated AS (mean aortic valve area index 0.39 +/- 0.1 cm2/m2), normal sinus rhythm and normal LV ejection fraction. The mean follow up was 23 +/- 12 months, and the end-points were mortality, aortic valve replacement (AVR), or mortality or AVR. RESULTS: Forty-seven patients had a transvalvular mean gradient (MG) <30 mmHg (MG(low)) and 168 had MG > or = 30 mmHg (MG(high)). Compared to MG(high), the MG(low) group had a higher prevalence of hypertension, lower LV end-diastolic volume index (47 +/- 9 versus 56 +/- 12 ml/m2, p <0.0001), lower LV stroke vol-ume index (37 +/- 12 versus 41 +/- 11 ml/beat, p <0.0002), a lesser severity of stenosis (aortic valve area index 0.37 +/- 0.09 versus 0.46 +/- 0.09 cm2/m2, p <0.0001) and a higher systemic vascular resistance (2163 +/- 754 versus 1879 +/- 528 dyne cm s(-5). The LV end-diastolic volume index, systemic vascular resistance and energy loss index were predictors of MG <30 mmHg (OR = 0.30, 95% CI, 0.12, 0.62; OR = 3.05, 95% CI, 1.71, 6.26; and OR = 6.76, 95% CI, 3.44,15.38, respectively). MG <30 mmHg (MGhigh) was associated with almost 50% lower referral to surgery and a two-fold increase in preoperative mortality. CONCLUSION: In severe AS with a normal LV ejection fraction, MG <30 mmHg is related to a lesser severity of stenosis, a smaller LV volume, a lower flow rate and a higher systemic vascular resistance. Compared to the MG(high) group, these patients were less frequently referred to surgery and had a higher mortality.     

Trends in drug misuse recorded in primary care in the UK from 1998 to 2005

BACKGROUND: A recent report by the UK Drugs Policy Commission has highlighted the high levels of drug use in Britain and this has been interpreted as indicative of ineffective drug polices. However, the interpretation was based on sporadic self-report data and indirect extrapolation. This paper assesses trends in the prevalence and incidence of drug misuse in the UK from 1998 to 2005 as recorded in general practice. METHODS: The study was a retrospective analysis of the General Practice Research Database. The study cohort comprised approximately 900,000 patients each year from 183 general practices. RESULTS: Among the Government's key target age group (16-24 years), there was a marked decrease in both prevalence and incidence of illicit drug misuse from 1998 to 2002 (P < 0.01). In older adults (25-59 years), the pattern was more variable during the first part of this period, but incidence remained stable from 2002 to 2005. CONCLUSIONS: These data indicate that the problematic drug use in the UK may be declining and that the policies may be more effective than has been previously thought. General Practice data are nonetheless only part of the picture in terms of understanding the prevalence of problematic drug use.     

Long-Term Safety of a Non-Chlorofluorocarbon- Containing Triamcinolone Acetonide Inhalation Aerosol in Patients with Asthma

In response to environmental concerns regarding chlorofluorocarbon (CFC), two new triamcinolone acetonide (TAA) inhalation aerosol (Azmacort Inhalation Aerosol) formulations have been developed using a more environmentally favorable propellant, HFA-134a (1,1,1,2-tetrafluoroethane). This multicenter, open-label study evaluated the safety of switching asthma patients from TAA-CFC to one of two TAA-HFA formulations. After a 2- or 4-week baseline period during which patients received only CFC-containing TAA Inhaler, 552 patients were randomized to receive TAA-HFA 75 or 225 μg for 6 or 12 months. A total of 493 patients completed treatment. Seven patients discontinued because of adverse events and two because of ineffective asthma control. The incidence of adverse events was similar in the two treatment groups, and most events were mild to moderate in severity and were not considered related to study medication. No clinically relevant suppression of the hypophyseal-pituitary-adrenal (HPA) axis was observed. Pulmonary function tests were not adversely affected by use of either study medication, and improvements were noted in forced expiratory volume in 1 sec (FEV₁) and forced expiratory flow between 25% and 75% of forced vital capacity (FEF_25%-75%) throughout the course of treatment. This study confirms that TAA-HFA provides effective, long-term asthma control and can safely be substituted for the currently marketed CFC-containing TAA product.     

High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting,and of CPT1A and CPT1C that regulate fatty acid metabolism

The diagnosis of glioblastoma is still based on tumor histology, but emerging molecular diagnosis is becoming an important part of glioblastoma classification. Besides the well-known cell cycle-related circuitries that are associated with glioblastoma onset and development, new insights may be derived by looking at pathways involved in regulation of epigenetic phenomena and cellular metabolism, which may both be highly deregulated in cancer cells. We evaluated if in glioblastoma patients the high grade of malignancy could be associated with aberrant expression of some genes involved in regulation of epigenetic phenomena and lipid metabolism. We measured the mRNA levels of ZFP57, TRIM28, CPT1A, CPT1B, and CPT1C in a cohort of 80 patients divided in two groups: grade II and grade IV. We evidenced that high grade glioblastoma is associated with increased level of ZFP57, a protein involved in gene imprinting, and aberrant expression of CPT1A and CPT1C, regulators of fatty acid oxidation. Our study may pave the way to identify new markers that could be potentially useful for diagnosis and/or prognosis of glioblastoma.     

Serglycin is a theranostic target in nasopharyngeal carcinoma that promotes metastasis

Nasopharyngeal carcinoma (NPC) is known for its high-metastatic potential. Here we report the identification of the proteoglycan serglycin as a functionally significant regulator of metastasis in this setting. Comparative genomic expression profiling of NPC cell line clones with high- and low-metastatic potential revealed the serglycin gene (SRGN) as one of the most upregulated genes in highly metastatic cells. RNAi-mediated inhibition of serglycin expression blocked serglycin secretion and the invasive motility of highly metastatic cells, reducing metastatic capacity in vivo. Conversely, serglycin overexpression in poorly metastatic cells increased their motile behavior and metastatic capacity in vivo. Growth rate was not influenced by serglycin in either highly or poorly metastatic cells. Secreted but not bacterial recombinant serglycin promoted motile behavior, suggesting a critical role for glycosylation in serglycin activity. Serglycin inhibition was associated with reduced expression of vimentin but not other epithelial-mesenchymal transition proteins. In clinical specimens, serglycin expression was elevated significantly in liver metastases from NPC relative to primary NPC tumors. We evaluated the prognostic value of serglycin by immunohistochemical staining of tissue microarrays from 263 NPC patients followed by multivariate analyses. High serglycin expression in primary NPC was found to be an unfavorable independent indicator of distant metastasis-free and disease-free survival. Our findings establish that glycosylated serglycin regulates NPC metastasis via autocrine and paracrine routes, and that it serves as an independent prognostic indicator of metastasis-free survival and disease-free survival in NPC patients.     

Gender effect on onset,prevalence and surgical treatment of cataract in patients with Myotonic Dystrophy type 1

Myotonic Dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, affecting 1:8000 individuals. It is a multi-systemic disorder involving muscle, heart, endocrine and respiratory apparatus and eye. The eye symptoms can include ptosis, external ophthalmoplegia, epiphora, and early onset cataracts. Cataracts occur at a much earlier age (usually between 30 and 40) than the general population, where females are usually affected more than men. We studied gender differences in cataract prevalence and treatment age in 243 DM1 patients (134 M; 109 F), aged 18 to 70 years, who were subsequently screened at routine follow-up. For each patient, information was collected on age, sex, CTG expansion, age of cataract onset, and age at cataract surgery, when available.Seventy-three patients, 30 females and 43 males, had cataracts, at a mean age of onset of 41.14 ± 12.64 in females, and 40.36 ± 10.03 in males. Sixty-nine of them underwent cataract surgery, males at an earlier age than females (42.8 ± 9.8 years versus 47.3 ± 12.6 years) and in 52.5% of cases before the age of 40, compared to 17.2% of females. The difference was statistically significant. The assumption that females in general and those with DM1 in particular develop cataracts more frequently and earlier than males is not confirmed, at least in this study. A possible explanation for these results could be related to non-advanced age, the protective role of estrogen and the lower prevalence of smoking in the study population.Key words: Myotonic Dystrophy type 1, Steinert disease, gender, cataract, cataract surgery, prevalence