Mitral valve reserve in double-orifice technique: an exercise echocardiographic study

BACKGROUND AND AIM OF THE STUDY: The edge-to-edge technique is used to restore valvular competence in mitral insufficiency. The efficacy of the method is under debate due to the potential for creating functional mitral stenosis. An exercise echocardiographic study was carried out to investigate valve function and hemodynamics in patients who had undergone double-orifice mitral valve repair. METHODS: Thirty patients (mean age 49.1 +/- 12.7 years) with previous double-orifice mitral valve repair underwent exercise echocardiography (10 W/min). An annular prosthesis was present in 28 patients (93%). The mean and maximum mitral valve gradient, planimetric valve area, stroke volume, systolic pulmonary artery pressure, heart rate and systolic blood pressure were measured at baseline and at peak stress. RESULTS: At peak stress, heart rate (77.7 +/- 12.2 versus 118.6 +/- 26.0 beats/min, p < 0.00001), systolic blood pressure (124.1 +/- 10.9 versus 146.6 +/- 22.8 mmHg, p < 0.00001) and stroke volume (78.0 +/- 10.2 versus 97.0 +/- 15.1 ml, p < 0.00001) were significantly increased, showing a physiological behavior of the mitral valve. The mean mitral valve gradient (2.8 +/- 1.3 versus 4.6 +/- 1.9 mmHg, p < 0.00001), maximum mitral valve gradient (6.4 +/- 2.8 versus 10.5 +/- 4.6 mmHg, p < 0.00002) and systolic pulmonary artery pressure (22.8 +/- 6.1 versus 28.2 +/- 9.9 mmHg, p < 0.001) were increased, but not to pathologic levels. Planimetric valve area increased significantly (3.2 +/- 0.6 versus 4.3 +/- 0.7 cm2, p < 0.00001). A significant negative linear correlation was found between the relative change in mitral valve area and planimetric valve area at rest (r = -0.51, p < 0.05). CONCLUSION: The double-orifice repair, even with concomitant ring annuloplasty, does not cause mitral valve obstruction, either at baseline or during physical exercise, and does not affect valve hemodynamic and valve reserve.     

<Emphasis Type="Italic">In vitro</Emphasis> evaluation of antibiotics' combinations for empirical therapy of suspected methicillin resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis>severe respiratory infections

Background  

Methicillin resistant Staphylococcus aureus (MRSA) is an increasingly common cause of nosocomial infections, causing severe morbidity and mortality worldwide, and accounting in some hospitals for more than 50% of all S. aureus diseases. Treatment of infections caused by resistant bacterial pathogens mainly relies on two therapeutic modalities: development of new antimicrobials and use of combinations of available antibiotics.     

Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico

Methylenetetrahydrofolate reductase (MTHFR) has two common variants with reduced activity due to polymorphisms at nucleotides 677 and 1298. Both affect folate metabolism and thus remethylation of homocysteine, but are also thought to affect nucleotide synthesis and DNA methylation. Methotrexate (MTX), which interrupts folate metabolism, is used in the treatment of a variety of diseases including acute lymphoblastic leukemia (ALL), but exerts in some patients toxic effects on fast dividing tissues such as mucosal epithelia. The enhanced toxicity may be due to cooperative effects between MTX and MTHFR variants. Accordingly, it has been reported that carrying the 677T allele of the MTHFR is a risk factor for MTX-associated mucositis. As in the Mexican population, which is characterized by a high prevalence of the 677T MTHFR variant, several of its commonly associated defects have not been observed, we investigated the relationship between MTX toxicity and the 677T allele. Out of 28 patients with ALL (CC: 2, CT: 10, TT: 16), 16 had episodes of MTX-associated mucositis (CC: 0, CT: 6, TT: 10). Neither at the gene level nor at the genotype level was a significant association with mucositis found. It may be postulated that the risk of higher MTX toxicity in patients with decreased MTHFR activity could be neutralized by the normally folate rich diet in Mexico.     

A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study

Patients with thrombophilia and/or a history of venous thromboembolism (VTE) exhibit a high risk of thrombosis during pregnancy. The present multicentre study prospectively assessed a prophylaxis strategy, based on a risk score, in pregnancies with increased risk of VTE. Among 286 patients included in the study, 183 had a personal history of VTE (63·98%) and 191 patients (66·8%) had a thrombophilia marker. Eighty nine (46·6%) thrombophilic women had a personal history of VTE. Patients were assigned to one of three prophylaxis strategies according to the risk scoring system. In postpartum, all patients received low molecular weight heparin (LMWH) prophylaxis for at least 6 weeks. In antepartum, LMWH prophylaxis was prescribed to 61·8% of patients with high risk of VTE. Among them, 37·7% were treated in the third trimester only and 24·1% were treated throughout pregnancy. In this cohort, one antepartum-related VTE (0·35%) and two postpartum-related VTE (0·7%) occurred. No case of pulmonary embolism was observed during the study period. The rate of serious bleeding was 0·35%. There was no evidence of heparin-induced thrombocytopenia or osteoporosis. The use of a risk score may provide a rational decision process to implement safe and effective antepartum thromboprophylaxis in pregnant women at high risk of VTE.     

Detection of Neuroendocrine Tumors of the Small Bowel by Double Balloon Enteroscopy

Background Neuroendocrine tumors (NET) account for one-third of all small bowel neoplasms. The search for the primary tumor in NET is important, even though it is difficult to localize, as its surgical excision leads to a better prognosis, even in metastasized stages of the disease. The objective of this study was to evaluate the use of double balloon enteroscopy (DBE) for the detection of the primary tumor in patients with NET. Methods Twelve consecutive patients (eight women, four men) with suspected carcinoid syndrome, either metastatic to the liver (n = 5), symptoms of a neuroendocrine tumor with elevated tumor markers (n = 5), or obscure gastrointestinal bleeding (n = 2) underwent DBE for the search of the primary tumor or the source of bleeding. All patients underwent abdominal sonography and a computed tomography (CT) scan, esophagogastroduodenoscopy (EGD), ileocolonoscopy, and octreotide scintigraphy prior to DBE. Capsule endoscopy was performed in four patients. Results A total of 17 DBE were performed in the 12 patients. The CT scan and sonography of the abdomen as well as EGD and ileocolonoscopy were unable to detect the primary tumor in any patient. A submucosal tumor of the ileum or the jejunum could be detected by DBE was detected in seven patients (58%) (anal route, n = 4; oral route, n = 3). In four of these patients (33%) this finding could be confirmed by the surgical resection of a NET. In two patients (17%) with a submucosal ileum protrusion suspicious for NET, laparotomy and intraoperative endoscopy did not confirm the tumor. Conclusions In this study, the diagnostic yield of DBE for primary tumor search in patients with metastatic or suspected NET was 33%. Although endoscopic small bowel investigation by DBE seems to enrich the diagnostic possibilities for the diagnosis of small bowel-NET, at the present time DBE should only be performed in selected cases, possibly based on a positive previous work-up. Michael Bellutti and Lucia C. Fry contributed equally to this paper.     

Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study

Objective  Data on trabecular bone mass in acromegaly are controversial. All the studies are cross-sectional and bone mineral density (BMD) has been evaluated largely by dual X-ray absorptiometry (DXA), which is influenced by bone enlargement. In this study we assessed in acromegalic patients the effects overtime of GH excess on trabecular bone mass measured by single-energy quantitative computed tomography (QCT) which is not influenced by bone size.
Design  Longitudinal retrospective study.
Patients  A total of 46 acromegalic patients followed-up for 48 months (median), subdivided into four groups: group A (eugonadal patients with active disease: n  = 13), group B (hypogonadal patients with active disease; n  = 9), group C (eugonadal patients with controlled disease; n  = 10), group D (hypogonadal patients with controlled disease; n  = 14).
Measurements  Serum GH and IGF-I levels, spinal trabecular BMD, and vertebral fractures were evaluated in all patients. BMD variations were reported as change (Δ) in Z -values (Z-QCT) measured at baseline and end of follow-up per year (Δ Z-QCT).
Results  Δ Z-QCT was greater in group A vs. group B and D ( P = 0·002 and P  = 0·0001, respectively) and in group C vs. group D ( P = 0·009). Multivariate regression analysis showed that hypogonadal status (β = –0·69; P  = 0·001) and baseline duration of hypogonadism (β = 0·44; P  = 0·02) but not baseline duration of acromegaly, length of follow-up and disease activity, were significantly associated with Δ Z-QCT.
Conclusions  This longitudinal study suggests that the effect of chronic GH excess on spinal trabecular bone mass seems to be anabolic in active eugonadal patients but not in hypogonadal ones.     

Increased expression of renal cyclooxygenase-2 and neuronal nitric oxide synthase in hypertensive Cx40-deficient mice

Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.     

Peripheral myelin protein 22 is a constituent of intercellular junctions in epithelia

Alterations in peripheral myelin protein 22 (PMP22) gene expression are associated with a host of heritable demyelinating peripheral neuropathies, yet the function of the protein remains unknown. PMP22 expression is highest in myelinating Schwann cells of peripheral nerves; however, significant levels of PMP22 mRNAs can be detected in a variety of non-neural tissue, including epithelia. To date, PMP22 protein expression and localization in non-neural tissues have not been studied in detail. In adult rat liver and intestine, and cultured epithelial cells, we detected PMP22-like immunoreactivity associated with markers of the tight junctional complex, including zonula occludens 1 (ZO-1) and occludin. Upon disruption of intercellular contacts, PMP22 was internalized into vesicles that were immunoreactive for both anti-occludin and anti-PMP22 antibodies. Nonionic detergent extraction of cultured epithelial cells did not solubilize PMP22, as the majority of the protein remained in the detergent insoluble fraction, as did ZO-1 and occludin. We also observed the targeting of exogenous myc-tagged PMP22 to apical cell junctions in polarized epithelia and to anti-ZO-1 antibody immunoreactive cell contacts of L fibroblasts. These studies support a role for PMP22 at intercellular junctions of epithelia and may indicate a similar function in myelinating Schwann cells. Furthermore, our findings could provide an explanation for certain phenotypes of PMP22 neuropathy mice that cannot be accounted for by dysmyelination.     

Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging

Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS–ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16–1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39–8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 –0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08–0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a “class” was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.     

Long-term outcome of neoadjuvant systemic therapy for locally advanced breast cancer in routine clinical practice

Purpose

The aim of this study is to evaluate the long-term outcome of patients with locally advanced breast cancer treated with neoadjuvant systemic chemotherapy (NST) in routine clinical practice.

Methods

Four hundred and nine patients were identified between January 1999 and December 2011. All patients received NST followed by surgery, adjuvant treatments and radiotherapy, as appropriate.

Results

At Kaplan–Meier analysis, patients with surgical stage III disease were more likely to develop distant metastasis and die from breast cancer (p < 0.001). Luminal A and luminal B/HER2-negative patients had better prognosis; moreover, patients with hormone receptor (HR)-positive tumors had a significantly longer DRFS (p < 0.0049) and OS (p < 0.0001) compared with patients with HR-negative tumors as well as patients who underwent breast-conserving surgery (DRFS and OS: p < 0.001). In multivariate analysis, HR negativity (p < 0.001 for both DRFS and OS), mastectomy (DRFS: p = 0.009; OS: p = 0.05) and stage III disease (DRFS: p < 0.001; OS: p = 0.003) were associated with shorter DRFS and OS.

Conclusions

HR negativity, mastectomy and pathological stage III disease are the variables independently associated with a worse outcome in our cohort of patients. These data are of high interest since they derive from a very heterogeneous group of patients, treated with different neoadjuvant/adjuvant regimens outside of clinical trials and with a long follow-up period.