Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation

Duchenne muscular dystrophy (DMD) is a severe progressive muscle-wasting disorder caused by mutations in the dystrophin gene. Studies have shown that bone marrow cells transplanted into lethally irradiated mdx mice, the mouse model of DMD, can become part of skeletal muscle myofibers. Whether human marrow cells also have this ability is unknown. Here we report the analysis of muscle biopsies from a DMD patient (DMD-BMT1) who received bone marrow transplantation at age 1 year for X-linked severe combined immune deficiency and who was diagnosed with DMD at age 12 years. Analysis of muscle biopsies from DMD-BMT1 revealed the presence of donor nuclei within a small number of muscle myofibers (0.5-0.9%). The majority of the myofibers produce a truncated, in-frame isoform of dystrophin lacking exons 44 and 45 (not wild-type). The presence of bone marrow-derived donor nuclei in the muscle of this patient documents the ability of exogenous human bone marrow cells to fuse into skeletal muscle and persist up to 13 years after transplantation.     

High-resolution impedance manometry findings in patients with nutcracker esophagus

Background and Aim: The objective of this study was to evaluate the association between high‐resolution manometry (HRM) and impedance findings and symptoms in patients with nutcracker esophagus (NE). Methods: After institutional review board approval retrospective review of a prospectively maintained database identified patients who were diagnosed with NE as per the Chicago classification (distal contractile integral [DCI] > 5000 mmHg‐s‐cm) at Creighton University between October 2008 and October 2010. Patients with achalasia or a history of previous foregut surgery were excluded. NE patients were sub‐divided into: (i) Segmental (mean distal esophageal amplitude [DEA] at 3 and 8 cm above lower esophageal sphincter [LES] < 180 mmHg) (ii) Diffuse (mean DEA at 3 and 8 cm above LES > 180 mmHg) and (iii) Spastic (DCI > 8000 mmHg‐s‐cm). Results: Forty‐one patients (segmental: 13, diffuse: 4, spastic: 24) satisfied study criteria. Patients with segmental NE would have been missed by conventional manometry criteria as their DEA < 180 mmHg. A higher percentage of patients with spastic NE (63%) had chest pain when compared to patients with segmental NE (23%) and diffuse NE (25%). There was a significant positive correlation between chest pain severity score and DCI while there was no significant correlation between dysphagia severity and DCI. Conclusions: In patients diagnosed with NE using the Chicago classification presence and intensity of chest pain increases with increasing DCI. The present criteria (> 5000 mmHg‐s‐cm) seems to be too sensitive and has poor symptom correlation. Adjusting the criteria to 8000 mmHg‐s‐cm is more relevant clinically.     

Dasatinib inhibits coated-platelet generation in patients with chronic myeloid leukemia

Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.     

Three years' experience with the sorin pericarbon stentless prosthesis: mid-term results with three different implantation techniques

BACKGROUND AND AIM OF THE STUDY: Sorin Pericarbon stentless pericardial valves were implanted using three different surgical techniques, and early and mid-term clinical and hemodynamic results were analyzed according to the method used. METHODS: Between January 2000 and December 2002, 102 Pericarbon stentless valves were implanted in 101 patients (55 females, 46 males; mean age 67.6+/-7.1 years). Among these patients, 63 had isolated aortic valve replacement and 39 underwent a combined procedure. The inflow portion of a matching-size prosthesis was fixed to the aortic annulus either by semi-continuous Prolene suture (n = 48), interrupted simple Ethibond (n = 29) or interrupted Ethibond mattress stitches (n = 25). Valve sizes were not significantly different in the three subgroups. The aortic cross-clamp and cardiopulmonary bypass times were 145+/-31 min and 171+/-39 min, respectively, with interrupted stitches; these times were significantly longer than in the continuous suture group (115+/-27 min and 143+/-45 min) or with interrupted mattress stitches (111+/-28 min and 137+/-34 min). RESULTS: Early mortality was 6.8% (n = 7) for the entire patient group. None of the deaths was valve-related. Postoperatively, all patients were followed up (mean 26.6+/-9.4 months). There were two late deaths (both non-valve-related). One patient developed early endocarditis, and the infected valve was re-replaced with another Pericarbon stentless valve. During the follow up period the mean and peak transvalvular gradient was decreased from 12.8+/-8.5 mmHg to 9.1+/-2.3 mmHg and from 22.5+/-13.9 mmHg to 16.1+/-4.3 mmHg respectively, and left ventricular wall thickness from 15.5+/-2.1 mm to 12.8+/-1.4 mm. Regurgitation was not more than trivial for any of the implanted valves. The implantation technique did not significantly affect the hemodynamic performance of the Pericarbon stentless valve. CONCLUSION: The Sorin Pericarbon stentless pericardial prosthesis showed excellent hemodynamic performance, even if implanted in a matching-size aortic root. The implantation technique used had no significant influence on valve performance.     

Application of the modified vaccination technique for the prevention and cure of chronic ailments

Over the years vaccination has proven to be the most successful health protection program for large populations, to prevent them from acquiring serious infectious and contagious diseases caused by exogenous antigens (ags) such as bacteria and viruses. Protection is generally achieved by an active immunization program, though passive immunization has also been employed, especially in the past, to combat diseases caused by certain bacterial infections (e.g. tetanus, diphtheria, etc.).Most recently, encouraging research data suggests that therapeutic approaches employing vaccination techniques can also be used to correct or deal with mishaps induced by or involving endogenous ags. However, most attempts at employing conventional vaccination techniques to do so have proven less than successful. In the case of cancer, one of the reasons for this is that the presentation of cancer related ags in presently available immunization frameworks is unable to evoke a powerful, specific cancer killing response. Therefore, drug treatments have been required in order to achieve additional beneficial effects.Recently, the Barabas group has developed a new vaccination technique (the third vaccination method, after active and passive immunization) called Modified Vaccination Technique (MVT). In experiments the MVT has been able to prevent-and with equal effectiveness, terminate-mishaps induced by or involving endogenous ags, e.g. in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN).The MVT is safe, and is able to initiate a specific immune response in the injected host (provided the injected components are in pure form). The MVT promises to provide the next generation of vaccines for the prevention, treatment, and termination of chronic disorders in humans, such as autoimmune diseases, cancer, and chronic infections.     

The role of intense affective states in signaling a suicide crisis

We explore the extent to which intense affective states in depressed patients may signal a suicide crisis, i.e., an acute risk for suicide. Therapists for 36 patients who died by suicide while in treatment completed questionnaires and wrote detailed structured narratives. Nine affects--desperation, hopelessness, rage, anxiety, feelings of abandonment, loneliness, guilt, humiliation, and self-hatred were evaluated as to their intensity in the patient before the suicide. Comparable information was obtained on 26 depressed, nonsuicidal patients treated by the same therapists. The suicide patients had a significantly greater number of intense affects than did the comparison patients. The affect that most distinguished the 2 groups was desperation, which was intense in 30 (83%) of the suicide patients but in none of the comparison patients. Recognizing intense affective states and the interaction among them may help clinicians identify a suicide crisis in depressed patients.     

Respiratory syncytial virus infection in children admitted to hospital but ventilated mechanically for other reasons

One thousand five hundred sixty‐eight RSV infections were documented prospectively in 1,541 pediatric patients. Of these, 20 (1.3%) had acquired the RSV infection while treated by mechanical ventilation for reasons other than the actual RSV infection (group ventilated mechanically). The clinical characteristics of children who were infected with respiratory syncytial virus (RSV) infection while ventilated mechanically for other reasons are described and compared with a matched control group. Sixty percent of the group ventilated mechanically had at least one additional risk factor for a severe course of infection (prematurity 50%, chronic lung disease 20%, congenital heart disease 35%, immunodeficiency 20%). The median age at diagnosis in the group ventilated mechanically was 4.2 months. The matched pairs analysis (group ventilated mechanically vs. control group) revealed a higher proportion of patients with hypoxemia and apnoea in the group ventilated mechanically; more patients in the control group showed symptoms of airway obstruction (wheezing). At least one chest radiography was performed in 95% of the patients (n = 19) in the group ventilated mechanically versus 45% (n = 9) in the control group (P = 0.001). The frequency of pneumonia was 40% in the group ventilated mechanically and 20% in the control group. Despite existing consensus recommendations, only two patients (10%) of the group ventilated mechanically had received palivizumab previously. Significantly more patients in the group ventilated mechanically received antibiotic treatment (85% vs. 45%, P = 0.008), and attributable mortality was higher in the group ventilated mechanically (15% [n = 3] vs. 0% in the control group, P = 0.231). Children treated by long term mechanical ventilation may acquire RSV infection by transmission by droplets or caregivers and face an increased risk of a severe course of RSV infection. The low rate of immunoprophylaxis in this particular risk group should be improved. J. Med. Virol. 81:160–166, 2009. © 2008 Wiley‐Liss, Inc.