Liver Perfusion Changes Occurring During Pancreatic Islet Engraftment: A Dynamic Contrast‐Enhanced Magnetic Resonance Study

The aim of this study was to investigate liver microvascular adaptation following the intraportal infusion of pancreatic islets (pancreatic islet transplantation [islet‐tx]) in diabetic patients using dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI). DCE‐MRI was performed before and 7 days after islet‐tx in six diabetic patients. Initial area under curve (AUC60) and volume transfer coefficient (Ktrans) were assessed as markers of liver perfusion. Clinical and metabolic monthly follow‐up was performed in all patients, considering fasting C‐peptide and β‐score as main indices of graft function. High variability in the response of liver microvasculature to islet infusion was observed: two patients showed a significant reduction in liver perfusion after transplantation (pt.2: AUC60 = ?23.4%, Ktrans = ?31.7%; pt.4: AUC60 = ?23.7%, Ktrans = ?27.9%); three patients did not show any significant variation of liver perfusion and one patient showed a significant increase (pt.3: AUC60 = +31%, Ktrans = +42.8%). Interestingly, a correlation between DCE‐MRI parameters and indices of graft function was observed and, in particular, both patients with DCE‐MRI evidence of posttransplantation liver perfusion reduction experienced premature graft failure. Our preliminary study demonstrated that DCE‐MRI may identify different adaptive responses of liver microvasculature in patients submitted to islet‐tx. These different responses could have an impact on islet engraftment, although reported findings need confirmation from larger studies.

     

Drug-induced adverse reactions via breastfeeding: a descriptive study in the French Pharmacovigilance Database

Purpose

Most drugs are excreted in maternal milk and may therefore be ingested by children during breastfeeding. Data concerning the safety of the use of drugs by breastfeeding women are patchy, and almost nothing is known about this issue for many drugs.

Methods

The aim of this study was to describe the adverse drug reactions of drugs transmitted in breast milk on the basis of the data collected in the French Pharmacovigilance Database. All spontaneous reports of adverse drug reactions (ADRs) in breastfed infants recorded in the National Pharmacovigilance Database by the 31 French regional pharmacovigilance centres between 1984 and June 2011 were investigated.

Results

Between January 1985 and June 2011, 276 adverse drug reactions in 174 breastfed children were notified to the French Pharmacovigilance Network. The most frequently reported adverse drug reactions were neurological (28.6 %) and gastrointestinal (20.3 %). Sixty-five of the adverse drug reactions recorded were considered to be serious (37.4 %). The results of our study confirm that certain drugs were frequently implicated in serious adverse drug reactions. Two cases of ADRs (1.1 %) had a ‘certain’ causality score (I4) and 13 (7.5 %) a ‘likely’ score (I3). The suspected drugs include antiepileptic drugs, opiate analgesics and benzodiazepines. These results also demonstrate that some drugs that were thought to be anodyne or for which no data were available, such as ketoprofen and hydroxyzine, may be implicated in adverse effects. Finally, these data show that certain drugs, like pseudoephedrine, which should not be used during breastfeeding, were nevertheless implicated in several of the adverse drug reactions recorded.

Conclusion

This study shows that ADR via breastfeeding are rarely reported due to low awareness or low occurrence of ADR via breast milk. These results highlight the need for additional pharmacokinetic, clinical and epidemiological studies, given the paucity of published data. They also demonstrate the need to improve information for the general public about drugs and self-medication during breastfeeding.     

Manganese in exhaled breath condensate: A new marker of exposure to welding fumes

Objective

To evaluate manganese in exhaled breath condensate (Mn–EBC) as an indicator of exposure to fumes from metal inert gas welding process.

Methods

We collected EBC and urine from 17 welders and 16 unexposed control subjects after 5 days exposure. Concentrations of manganese (Mn), nickel (Ni), iron (Fe) and chromium (Cr) were measured in EBC and urine samples and correlated with cumulative exposure indices for the working week (CIW) and for the total welding years (WY), based on duration of welding activity and atmospheric metal measurements.

Results

Concentrations of Mn and Ni in EBC were significantly higher among welders than controls whereas this difference was not significant for Mn in urine. Levels of Mn and Ni in EBC were not correlated with their respective levels in urine. The linear regressions found significant positive coefficients between Mn–EBC, Ni–EBC, Ni–U and Cr–U concentrations and the cumulative exposure indices. Taking into account tobacco use, statistical analysis showed the same trends except for the relationship between Mn–U and CIW.

Conclusion

This pilot study showed that Mn–EBC, as well as Ni–EBC, can serve as reliable indices of occupational exposure to welding fumes and provide complimentary toxicokinetic information to that provided by urine analyses.     

Chemoembolization in hepatocellular carcinoma: multivariate analysis of survival prognostic factors after the first session

AIM: The aim of the study was to determine whether simple routine parameters evaluating the first session of transarterial chemoembolization (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, and post-embolization syndrome) can predict survival of patients treated for hepatocellular carcinoma. METHODS: Seventy-two patients treated with transarterial chemoembolization and evaluated one month after the first sessions with CT scan were included. Transarterial chemoembolization session included hepatic arteriography, lipiodol and doxorubicin (50 mg) emulsion injection, followed by gelatin sponge embolization. The following variables were studied in univariate and multivariate analysis: 6 recorded at the first session (age, cirrhosis etiology, Child-Pugh class, tumor number, largest lesion size, and alpha-fetoprotein concentration), and 5 recorded after the first session (variation in alfa-fetoprotein concentration, tumor lipiodol uptake, post-embolization syndrome, mean interval between each session, and associated treatment). RESULTS: Mean follow-up was 22.7 months (4-106). Mean survival was 30.4 months (95% CI: 23. 3-37.5). Actuarial survival at 1, 2, 3 and 5 years was respectively 65.5%, 44%, 29.5%, and 18%. The only independent prognostic factors in multivariate analysis were the Child Pugh class and the mean interval between sessions (P<0.001 and<0.01 respectively). None of our criteria evaluating the first TACE session significantly influenced survival. CONCLUSION: The 3 parameters (variation in alpha-fetoprotein concentration, tumor lipiodol uptake and post-embolization syndrome) after the first transarterial chemoembolization did not predict survival. They could not be used to determine which patient could benefit from repeated transarterial chemoembolization sessions.     

Subclavian angioplasty: Immediate and late results in 50 patients

In order to assess the therapeutic outcome of percutaneous transluminal angioplasty for subclavian stenosis, 50 patients were followed up clinically as well as with a velocimetric Doppler after attempted angioplasty. A minimal clinical follow-up of 9 months was expected. Subclavian stenoses were due to atheroma in 49 patients and to Takayasu's disease in 1 case. Indication of angioplasty was curative in 34 (68%) symptomatic patients (posterior fossa ischemia and/or upper limb ischemia) and preventive in 16 (32%) asymptomatic patients (severe difference of blood pressure between the 2 arms and/or association with carotid stenosis or axillo-femoral bypass). Angioplasty was successful in 45 patients (primary success rate = 90%). Three (6%) thrombosis occurred due to the percutaneous approach, one of the axillary and one of the brachial artery without any significant sequelae, and one of the aorta requiring an aorto-bifemoral bypass. A complication occurred in 2 unsuccessful angioplasties (4%): an ischemic stroke occurred in 1 case and a thrombosis of the dilated site requiring a surgical bypass. Clinical follow-up over a period of 9–101 months (mean = 41) was performed in 43 out of the 45 patients who had undergone angioplasty successfully. Two patients had a follow-up shorter than 9 months: one died after 5 months, the other was lost to follow-up. By the end of the clinical follow-up, 37 (84%) out of the 44 followed-up patients had benefitted from the procedure. Doppler study performed in 35 out of the 44 followed-up patients (80%) over a period of 2–90 months (mean = 39) showed 5 restenosis (14%). This study demonstrates the good long-term results of angioplasty in case of subclavian artery stenosis. Though there are complications, angioplasty could be proposed as a first choice treatment for subclavian stenosis as compared to surgery. Indications in asymptomatic patients should be carefully weighed as complications may occur. © 1993 Wiley-Liss, Inc.     

Homocysteine is the only plasma thiol associated with carotid artery remodeling

Several authors have reported that moderate hyperhomocysteinemia is related to asymptomatic carotid arterial wall remodeling, but few data are available on other thiol compounds with potential vascular toxicity. We, therefore, investigated the relationships between major plasma thiol compounds (homocysteine, cysteine and glutathione) and the structural phenotype of the common carotid artery in a cohort of 123 subjects with no evidence of cardiovascular disease. Fasting levels of thiol compounds were measured by high-performance liquid chromatography, and arterial geometry was evaluated using high-resolution echotracking devices. In univariate regression analysis, plasma homocysteine and plasma cysteine concentrations were positively associated with carotid artery internal diameter (P=0.0001 and 0.002, respectively) and intima media thickness (P=0.003 and 0.004), but the plasma glutathione concentration was not. In multivariate analysis, plasma homocysteine was independently and positively associated with carotid artery internal diameter (P<0.005) and intima media thickness (P<0.05), but plasma cysteine was not. These data suggest that homocysteine is the only plasma thiol compound that may be considered as a risk factor for preclinical cardiovascular disease.     

Colorectal Anastomotic Stenosis After Elective Laparoscopic Sigmoidectomy for Diverticular Disease: A Prospective Evaluation of 68 Patients

Purpose  This prospective study was designed to find the incidence of symptomatic anastomotic stenosis after elective laparoscopic sigmoidectomy for diverticular disease. Methods  Sixty-eight patients who underwent elective laparoscopic sigmoidectomy with double-stapling colorectal anastomosis between November 1998 and June 2007 were included. Follow-up after hospitalization was performed by using sequential rectoscopy for all patients. Symptomatic patients with anastomotic stricture were treated. Results  No patient died postoperatively and no patient had anastomotic leak or abdominal septic complication. Twenty-two patients (32 percent) had postoperative symptoms that suggested anastomotic stenosis; 12 of them (17.6 percent) eventually needed dilatation of their anastomosis (median diameter of the stenosis: 7 mm) a mean time of 176 days postoperatively. Eight patients had only one session, three patients had two sessions, and one patient had three sessions. There were no complications and all patients were symptom-free after dilatation. Age, sex, obesity, hypertension, diabetes, and vascular preservation had no influence on the risk of anastomotic stenosis. Conclusions  Incidence of symptomatic anastomotic stenosis after elective laparoscopic sigmoidectomy is high (17.6 percent). No risk factor could be identified. Endoscopic dilatations were successful without complication in all cases. Regular rigid rectoscopy definitely should be part of the postoperative follow-up in symptomatic patients.     

Acoustic excitations and elastic heterogeneities in disordered solids

In the recent years, much attention has been devoted to the inhomogeneous nature of the mechanical response at the nanoscale in disordered solids. Clearly, the elastic heterogeneities that have been characterized in this context are expected to strongly affect the nature of the sound waves which, in contrast to the case of perfect crystals, cannot be completely rationalized in terms of phonons. Building on previous work on a toy model showing an amorphization transition, we investigate the relationship between sound waves and elastic heterogeneities in a unified framework by continuously interpolating from the perfect crystal, through increasingly defective phases, to fully developed glasses. We provide strong evidence of a direct correlation between sound wave features and the extent of the heterogeneous mechanical response at the nanoscale.In crystals, molecules thermally oscillate around the periodic lattice sites and vibrational excitations are well understood in terms of quantized plane waves, the phonons (1). The vibrational density of states (vDOS) in the low-frequency regime is well described by the Debye model, where the vibrational modes are the acoustic phonons. In contrast, disordered solids, including structural glasses and disordered crystals, exhibit specific vibrational properties compared with the corresponding pure crystalline phases. It is not possible here to give a fair review of the extensive theoretical and experimental work generated by these issues; we therefore mention below a few facts that we consider the most relevant in the present context. The origin of the vDOS modes in excess over the Debye prediction around ω ∼1 THz, the so-called Boson peak (BP), is still debated (see, among many others, refs. 2 and 3). At the BP frequency, Ω^BP, localized modes have also been observed (4). Acoustic plane waves, which are exact normal modes in crystals, can still propagate in disordered solids. Indeed, at low frequencies, Ω, and long wavelengths, Λ, acoustic sound waves do not interact with disorder and can propagate conforming to the expected macroscopic limit. However, as Ω is increased beyond the Ioffe–Regel (IR) limit, Ω^IR, acoustic excitations interact with the disorder and are significantly scattered (5–7). Interestingly, this strong scattering regime occurs around the BP position, Ω^IR ∼ Ω^BP (8, 9). The exact origin of this phenomenon and its connection to the BP remain elusive.A possible rationalization of the above issues is based on the existence of elastic heterogeneities (10), which can originate from structural disorder, as in structural glasses (2), or disordered interparticle potentials, even in lattice structures such as disordered colloidal crystals (11). In the heterogeneous-elasticity theory of refs. 7 and 12 this amounts to consider spatial statistical fluctuations of the shear modulus. Within the framework of jamming approaches and using effective medium theories, elastic heterogeneities are related to the proximity of local elastic instabilities (13). Recent simulation work (14–16) has clearly demonstrated their existence in disordered solids. This is at variance with the case of simple crystals, which are characterized by a fully affine response and homogeneous moduli distributions (17). More specifically, in the large length scale limit, macroscopic moduli are observed. In contrast, as the length scale is reduced, moduli heterogeneities are detected, at a typical length scale ξ ≃ 10−15σ (15), where σ is the typical atomic diameter. Breakdown of both continuum mechanics (18) and Debye approximation (5, 6) has been demonstrated at the same mesoscopic length-scale ξ, where they are still valid for crystals. Remarkably, the wave frequency corresponding to the wavelength Λ ∼ ξ is very close to Ω^IR ∼ Ω^BP (19). Altogether these results indicate that a close connection must exist between elastic heterogeneities and acoustic excitations. In this paper we precisely address this point.In ref. 20 we considered a numerical model featuring an amorphization transition (21). We showed how to systematically deform the local moduli distributions, evaluated by coarse-graining the system in small domains of linear length scale w. We characterized the degree of elastic heterogeneity in terms of SD of those distributions and studied the effect on normal modes (eigenvalues of the Hessian matrix) and thermal conductivity. Building on that work, we are now in the position to investigate the relation between elastic heterogeneities and acoustic excitations, unifying in a single framework ordered and disordered solid states and considering quantities directly probed by experiments. By interpolating in a controlled way from perfect crystals, through increasingly defective phases, to fully developed amorphous structures, we (i) calculate the dynamical structure factors, extracting the relevant spectroscopic parameters; (ii) characterize the wave vector dependence of sound velocity and broadening of the acoustic excitations and clarify their nature in terms of the IR limit; and (iii) provide, for the first time to our knowledge, direct evidence of the correlation of the excitations lifetimes and Ω^IR with the magnitude of the elastic heterogeneities.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.