X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

Cytomegalovirus-specific CD4 and CD8 T cell responses in infants and children.

Congenital cytomegalovirus (CMV) infection is the most common congenital infection causing childhood morbidity. The pathogenetic mechanisms behind long-term sequelae are unclear, but long-standing viremia as a consequence of the inability to convert the virus to a latent state has been suggested to be involved. Whereas primary CMV infection in adults is typically rapidly controlled by the immune system, children have been shown to excrete virus for years. Here, we compare T cell responses in children with congenital CMV infection, children with postnatal CMV infection and adults with symptomatic primary CMV infection. The study groups included 24 children with congenital CMV infection, 19 children with postnatal CMV infection and eight adults with primary CMV infection. Among the infants with congenital CMV infection, 13 were symptomatic. T cell responses were determined by analysis of interferon gamma production after stimulation with CMV antigen. Our results show that whereas adults display high CMV-specific CD4 T cell responses in the initial phase of the infection, children younger than 2 years have low or undetectable responses that appear to increase with time. There were no differences between groups with regard to CD8 T cell function. In conclusion, inadequate CD 4 T cell function seems to be involved in the failure to get immune control of the CMV infection in children younger than 2 years of age with congenital as well as postnatal CMV infection.

Intrapartum translabial three-dimensional ultrasound visualization of levator trauma.

OBJECTIVES: The aim of this study was to visualize levator trauma by three-dimensional (3D) ultrasound performed during labor and soon after the crowning of the fetal head and to determine how often levator trauma occurs. METHODS: This was a prospective, observational study of 66 women enrolled during the first stage of labor. The women underwent intrapartum 3D transperineal ultrasound examination during the first and second stages of labor and within 12 h after delivery. Volume datasets were acquired and analyzed to determine the presence of levator trauma. RESULTS: Data from 10 of the 66 women were excluded from analysis-nine because they underwent Cesarean section in the first or second stage of labor and one because she underwent hysterectomy and no postpartum volumes were collected. Thus our study group comprised 56 women-35 nulliparous and 21 parous. A total of 504 volumes were collected in the 56 women (three volumes for each stage of labor). One hundred and twenty levator volumes were excluded from analysis, but volumes of acceptable quality were available for all three stages of labor in all women. Eleven (31.4%) of the 35 nulliparae had levator lesions detected postpartum and none of them had levator lesions before delivery. Five (23.8%) of the 21 parous women had a levator tear detected in their postpartum volumes. In two of these five women the levator tear was also present in both volumes taken during labor. CONCLUSIONS: Visualization of the levator ani during labor by 3D ultrasound examination is feasible. Comparison of volumes obtained during labor and within the first 2 h after delivery supports the theory that crowning of the head is the immediate cause of avulsion of the levator ani muscle.

Poor outcome of adenovirus infections in adult hematopoietic stem cell transplant patients with sustained adenovirus viremia.

The outcome of adenovirus (ADV) infections in adult hematopoietic stem cell transplant (HSCT) patients remains poorly characterized. We studied 14 adults and 3 children, who had undergone HSCT and had developed ADV viremia. Peak ADV DNA levels were significantly higher in patients with ADV diseases than in those without (P=0.03). All children survived the ADV infections. Among the 14 adult HSCT patients, 11 were treated with cidofovir, 2 with ribavirin, and 1 did not receive antiviral treatment. Six of the 13 (46%) treated patients developed ADV diseases and 3 of them (23%) died of ADV infections. Sustained viremia (≥3 positive polymerase chain reaction assays during follow-up) was detected in all patients who finally died of ADV infections. However, 2 adults having had transient ADV viremia either survived or died of diseases other than ADV infections. Our study indicates that the outcome of adult HSCT patients with sustained ADV viremia may be poor, even for those who have received anti-ADV treatment.

Sonographic assessment of fetal spine and head position during the first and second stages of labor for the diagnosis of persistent occiput posterior position: a pilot study.

OBJECTIVES: The aim of this pilot study was to perform a preliminary investigation into the predictive values of the position of the fetal spine and of the occiput measured during the first and second stages of labor by intrapartum ultrasound for persistent occiput posterior (OP) position. METHODS: This was a prospective, cohort study, in which 100 women with singleton pregnancies were enrolled during the first or second stage of labor. The women underwent intrapartum transabdominal sonography and the positions of the fetal head and spine were recorded. The women were followed up until delivery and occiput position at birth was assessed. RESULTS: Eighty-four pregnancies were evaluated in the second stage of labor, with 74 of these also evaluated in the first stage. Fifty-one percent of fetuses were found to be in an OP position during the first stage of labor, but the majority of these rotated to an anterior position before delivery. There were six cases of OP at delivery, and all of these were among the 23 fetuses that were found to be in an OP position on ultrasound evaluation during the second stage of labor. All six were also found to have a posterior spine position during the second stage of labor, with this finding observed in only one fetus with occiput anterior position at delivery. CONCLUSIONS: The results of this study suggest that the position of the head and spine during the second stage of labor could be useful indicators for predicting the OP position at delivery. The results also suggest that the OP position at delivery results from a failure of rotation from the OP position, rather than a malrotation from the anterior position. Studies with larger sample sizes are needed to confirm these results.

Congenital cytomegalovirus infection: the impact of cerebral cortical malformations.

AIM: Cytomegalovirus has been suggested to have a teratogenous influence during the migration of neural cells from the ventricular zones to the cortex during the gestational period. The aim of this study was to investigate the prevalence of congenital cytomegalovirus infections in a cohort of children with neurological disability and cerebral cortical malformations recognized by neuroimaging. METHODS: Twenty-six children with neurological disability and cerebral cortical malformations were investigated retrospectively for congenital cytomegalovirus infection by analysing the dried blood spot samples for cytomegalovirus deoxynucleic acid using qualitative polymerase chain reaction. RESULTS: CMV DNA in the dried blood spot samples was found in four out of 26 children. Two of these four had severe disabilities with mental retardation, autism, spastic cerebral palsy, epilepsy and deafness. A third child had epilepsy and unilateral cerebral palsy, while the fourth had a mild motor coordination dysfunction and hearing deficit. CONCLUSION: In our study, the number of congenital cytomegalovirus infections in children with cerebral cortical malformations was higher (4/26) than expected with reference to the birth prevalence (0.2-0.5%) of congenital cytomegalovirus infection in Sweden. We thus conclude that congenital cytomegalovirus infection should be considered in children with cortical malformations of unknown origin.

Computer networking for scientists.

Scientific research has always relied on communication for gathering and providing access to data; for exchanging information; for holding discussions, meetings, and seminars; for collaborating with widely dispersed researchers; and for disseminating results. The pace and complexity of modern research, especially collaborations of researchers in different institutions, has dramatically increased scientists' communications needs. Scientists now need immediate access to data and information, to colleagues and collaborators, and to advanced computing and information services. Furthermore, to be really useful, communication facilities must be integrated with the scientist's normal day-to-day working environment. Scientists depend on computing and communications tools and are handicapped without them.

Quantification of adenovirus DNA in unrelated donor hematopoietic stem cell transplant recipients.

BACKGROUND: Adenovirus (AdV) infection is a life threatening condition in immunosuppressed patients. Quantitative AdV assays can improve the clinical management of these patients. OBJECTIVES: To evaluate quantitative measurement of AdV DNA with PCR in blood from hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN: Quantitative PCR was used to measure viral DNA levels of AdV in consecutive blood samples from 40 HSCT recipients (27 adults and 13 children) during a 1-year post-engraftment period. All patients received grafts from unrelated donors and were given anti-T-cell antibodies in the conditioning regimen. RESULTS: In the group of 40 patients, six (15%) had detectable AdV DNA in blood for different lengths of time. None of these six patients suffered from severe graft-versus-host disease. In three of the patients a high AdV viral load (>10,000 copies/mL) was detected, one of whom also had high viral load of EBV and CMV and one of EBV only. These three patients died within 2 months after detection of ADV viremia. A low AdV viral load (<500 copies/mL) was detected in three surviving patients and they did not have concomitant high viral load of neither CMV nor EBV. CONCLUSIONS: AdV viremia was present in 15% of the HSCT recipients and a high AdV viral load was associated with fatal outcome. Screening for AdV DNA with quantitative PCR in blood may be of clinical importance in allogeneic HSCT recipients in order to prevent severe clinical virological complications.

Interrelationship between plasma membrane integrity, mitochondrial membrane potential and DNA fragmentation in cryopreserved bovine spermatozoa.

The objective of this flow cytometric study was to examine plasma membrane integrity, mitochondrial membrane potential (MMP) and the degree of DNA fragmentation of cryopreserved bovine sperm immediately (0 h) and 3 h after thawing and to compare the results with each other and with the fertility of bulls. Cryopreserved spermatozoa from 4 consecutive ejaculates of 20 bulls were examined. Percentages of plasma membrane intact sperm (PMI) and sperm showing a high MMP (HMMP), respectively, were determined by the SYBR14/PI- and the JC-1 assays. DNA fragmentation was analysed by the standard deviation of the DNA fragmentation index (SD-DFI) and the percentage of sperm with a high degree of DNA fragmentation (%DFI) by using SCSA(TM). The mean non-return rate on day 56 (NRR 56) ranged from 63.7% to 78.0% (mean +/- SD: 71.8% +/- 3.7%). Mean values for PMI and HMMP decreased from 37.4% +/- 6.8% to 31.2% +/- 6.1% and from 38.8% +/- 7.1% to 23.8% +/- 7.7% respectively. SD-DFI increased from 56.9% +/- 8.0% to 69.0% +/- 12.9% and %DFI from 6.4% +/- 2.5% to 12.4% +/- 5.8%. The correlation between PMI 0 h and HMMP 0 h (r = 0.95; p < 0.0001) was higher (p < 0.05) than that between PMI 3 h and HMMP 3 h (r = 0.88; p < 0.0001). %DFI 0 h was neither related to PMI 0 h nor to HMMP 0 h (p > 0.05), nor was there a correlation (p > 0.05) between DFI 3 h and PMI 3 h; but %DFI 3 h and HMMP 3 h were significantly correlated (r = -0.31; p < 0.05). SD-DFI and %DFI 3 h were the only parameters related to NRR 56 (r = -0.58; p < 0.05). In conclusion, plasma membranes and mitochondria are similarly affected by the freezing and thawing process, but not during the incubation period after thawing.

The prognostic significance of human epidermal growth factor receptor correlations in squamous cell cervical carcinoma.

UNLABELLED: The aim of this study was to investigate the expression and prognostic influence of HER1 (EGFR), HER2 (c-erb-B2), HER3 (c-erb-B3) and HER4 (cerb-B4) in squamous cell cervical carcinomas (SCC) and the importance of receptor correlations. PATIENTS AND METHODS: 78 SCC were stained immunohistochemically for HER1-HER4. HER2 gene amplification was determined using fluorescence in situ hybridization (FISH). Parametric correlations were performed between the four receptors and tumor characteristics. Overall survival was evaluated by uni- and multivariate analyses. RESULTS: Overexpression was found in 63% of SCC for HER1, in 21.8% for HER2, in 74.4% for HER3 and in 79.5% for HER4. Correlations were observed between HER1 and HER4 (p = 0.019). Survival analyses revealed a significant association of HER1 overexpression with favorable outcome (p = 0.016), while overexpression of HER2 and HER3 was associated with poor prognosis (p = 0.006; p = 0.05, respectively). HER1 remained significant in multivariate analysis. CONCLUSION: These data suggest that the prognostic relevance of the different HER receptors is influenced by the balance between the various receptors, especially of HER4.

Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS.

BACKGROUND: Platelet hyperfunction contributes to acute coronary syndromes (ACS). Thus, we hypothesized that platelet function under high shear stress predicts recurrent ACS during long-term follow-up of ACS patients. PATIENTS AND METHODS: Consecutive ACS patients (n = 208) were prospectively followed-up for an average of 28 months. Platelet function was measured with the platelet function analyzer (PFA-100; Dade Behring, Marburg, Germany) at baseline for collagen/adenosine diphosphate closure times (CADP-CT) and for collagen/epinephrine closure times (CEPI-CT) after infusion of a uniform dose of 250 mg aspirin. RESULTS: Of the conventional risk factors, only the prevalence of diabetes was higher in ACS patients with re-events. However, use of clopidogrel and use of beta blockers were also slightly lower in patients with re-events (P < 0.05). The unadjusted risk hazard ratio (HR) for re-events was 3.3 [95% confidence interval (95% CI): 1.4-7.4; P = 0.005] in those patients with the shortest CADP-CT values (lowest quartile). Similarly, the risk was 2.0-fold higher (95% CI: 1.1-3.6; P = 0.02) in ACS patients with CEPI-CT < 300 s as compared with CEPI-CT >or = 300 s. Inclusion of diabetes, clopidogrel and beta blockers in a multivariate Cox regression model enhanced the predictive value of CEPI-CT (HR: 2.7). Inclusion of von Willebrand factor levels did not alter the HR for recurrent ACS (HR: 2.1; 95% CI: 1.1-5.2; P = 0.03) for CEPI-CT < 300 s, but reduced the HR for CADP-CT (HR: 2.8, 95% CI: 0.8-9.8; P = 0.11). CONCLUSION: Shortened CT values reflect biologically relevant platelet hyperfunction in patients with ACS because they predict recurrent ACS.

Ion channels meet auxin action.

The regulation of cell division and elongation in plants is accomplished by the action of different phytohormones. Auxin as one of these growth regulators is known to stimulate cell elongation growth in the aerial parts of the plant. Here, auxin enhances cell enlargement by increasing the extensibility of the cell wall and by facilitating the uptake of osmolytes such as potassium ions into the cell. Starting in the late 1990s, the auxin regulation of ion channels mediating K+ import into the cell has been studied in great detail. In this article we will focus on the molecular mechanisms underlying the modulation of K+ transport by auxin and present a model to explain how the regulation of K+ channels is involved in auxin-induced cell elongation growth.

Elevated keratin 18 protein expression indicates a favorable prognosis in patients with breast cancer.

This study was performed to determine if keratin 18 (K18) has prognostic significance in breast cancer cell lines and patients with breast carcinoma. Paraffin sections of primary breast carcinoma tumors and human breast carcinoma cell lines were examined for K18 expression by immunohistochemical staining with the monoclonal antibody CK2. K18 protein expression was low in highly metastatic cell lines and, conversely, high in weakly metastatic cell lines, suggesting that it may function as a prognostic indicator. K18 expression was consequently examined in 134 patients with breast cancer. The staining intensity was compared with clinicopathological variables and follow-up data spanning 8 years. A definitive positive staining was observed in 22 (16.4%) women. The mortality rate was 4. 5% in the K18-positive group and 44.6% in the K18-negative group. Multivariate analysis found K18 expression to be an independent and significant predictor for overall survival.

Eating behavior and plasma beta-endorphin in bulimia.

To study the possible role of plasma beta-endorphin in bulimia, we measured plasma beta-endorphin immunoreactivity in 34 female patients with normal-weight bulimia and 34 normal female controls matched for weight as percent of ideal. Plasma beta-endorphin immunoreactivity in bulimics (mean 59.6 pg/ml; SEM 5.6) was significantly lower (p less than 0.05) than in controls (mean 79.5 pg/ml; SEM 8.5). Within the bulimic group, plasma beta-endorphin immunoreactivity correlated inversely with severity of bulimic symptomatology as measured by the Eating Attitudes Test Bulimia Subscale (p less than 0.05). Endorphin level did not correlate with severity of depression or with percent ideal body weight. Abnormalities in opioid metabolism may be implicated in eating disorders and account for the addictive properties of these disorders.

Real-time monitoring of cytomegalovirus infections after stem cell transplantation using the TaqMan polymerase chain reaction assays.

BACKGROUND: Real-time monitoring of cytomegalovirus (CMV) infections in transplant patients demands a rapid and high-throughput CMV DNA quantification method. METHODS: TaqMan polymerase chain reaction assays based on CMV immediate early protein exon 4 and glycoprotein B were developed and were compared with a COBAS AMPLICOR CMV MONITOR (CMM) test for quantifying CMV DNA in peripheral blood leukocytes from seven stem cell transplant patients having received antiviral treatment. RESULTS: There was a good correlation between the TaqMan assays and the CMM test for CMV DNA quantification. The throughput of the TaqMan assays was, however, about 3 times higher than that of the CMM test. The CMV DNA dynamics patterns determined by the TaqMan polymerase chain reaction were well in line with the outcome of the antiviral therapy. CONCLUSIONS: The TaqMan assays may potentially serve as a useful tool for rapid quantification of CMV infections in stem cell transplant patients.

Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients.

BACKGROUND: Several preventive strategies against cytomegalovirus (CMV) disease have been developed during the last decade. These have frequently been used in combination, and it has been difficult to identify each strategy's contribution. METHODS: Risk factors for CMV disease, death in CMV disease and transplant-related mortality were analyzed in 584 patients, who underwent a total of 594 allogeneic bone marrow transplants. RESULTS: The overall probability of CMV disease was 8.9%. No seronegative patient who had a seronegative marrow donor developed CMV disease. The corresponding probabilities for seronegative patients with seropositive donors, seropositive patients with seronegative donors, and seropositive patients with seropositive donors were 5.4%, 13.7%, and 11.7%, respectively. In multivariate Cox models, the use of preemptive antiviral therapy and being CMV-seronegative reduced the risk for CMV disease, CMV-associated death, and transplant-related mortality (TRM). Patients who received unrelated or mismatched family donor transplants had increased risks for CMV disease, CMV-associated death, and TRM. Older age was a significant risk factor for CMV disease and TRM. A total of 258 patients who were monitored by polymerase chain reaction for CMV DNA were analyzed separately to assess whether addition of another CMV preventive strategy could give benefit. Patients who received mismatched or unrelated donor transplants had increased risk for CMV disease, death in CMV disease, and TRM. High-dose acyclovir prophylaxis or addition of intravenous immune globulin had no influence. CONCLUSIONS: Preemptive therapy based on polymerase chain reaction for CMV DNA was associated with reduced risks for CMV disease, CMV-associated death, and TRM, whereas other prophylactic modalities did not give additional benefit.

Loss of seroreactivity against human papillomavirus (HPV) in bone marrow transplant recipients.

Sera from 19 autologous and 35 allogeneic bone marrow transplant (BMT) patients at Huddinge University Hospital were analyzed by different ELISA assays before and 1 year after BMT for the presence of IgG antibodies towards human papillomavirus (HPV). One assay was a peptide-based enzyme-linked immunoadsorbent assay (ELISA). These peptides were derived from the amino acid sequences of the two major viral capsid proteins of HPV 16, p(31) L1 and (p49) L2. The other was an ELISA using HPV-type 16 virus-like particles (VLPs) as antigens. Before BMT 13/19 autologous and 14/35 allogeneic BMT patients were IgG positive towards p49 (L2). Reactivity to p31 (L1) was less frequent and was only observed in 7/19 autologous and 3/35 allogeneic BMT patients. One year after BMT 1/4 of the autologous and 2/3 of the allogeneic BMT patients who were IgG positive to p49 (L2) lost these antibodies as measured by the peptide ELISA assay. Regarding IgG reactivity to p31 (L1), one of the seven p31 (L1) positive autologous BMT patients and all three of the p31 (L1) positive allogeneic BMT patients lost this reactivity 1 year after BMT. Of all the 19 autologous and the 35 allogeneic BMT patients only two allogeneic BMT patients were weakly IgG reactive towards VLPs and 1 year after BMT this activity was lost in one of the two patients.

Long-term immunity to poliovirus after vaccination of allogeneic stem cell transplant recipients.

Revaccination with poliovirus after allogeneic stem cell transplant (SCT) is usually effective, but the longevity of this immunity is unknown. Therefore, poliovirus immunity was studied in 134 patients having survived at least 5 years after vaccination. The median follow-up from vaccination was 8 years (1-19 years). In all, 21 (15.6%) patients had become seronegative to at least one of the poliovirus serotypes during follow-up. The estimated probabilities of remaining immune to poliovirus at 5 and 10 years after vaccination were 94 and 94% for subtype 1, 98 and 94% for subtype 2, and 93 and 90% for subtype 3, respectively. In multivariate analysis, the only risk factor for loss of immunity was younger patient age (P < 0.01), and there was a strong trend for patients with chronic GVHD to lose immunity more rapidly (P = 0.07). A total of 14 patients received a booster dose of an inactivated poliovirus vaccine and all responded. We conclude that poliovirus immunity is retained long term after revaccination in most patients after allogeneic SCT.

Measles immunity after allogeneic stem cell transplantation; influence of donor type, graft type, intensity of conditioning, and graft-versus host disease.

During follow-up after allogeneic stem cell transplantation (SCT), patients frequently lose their immunity to infectious agents such as measles. The aim of this study was to analyze the influence of different factors on measles immunity. In total, 395 patients with a disease-free survival of at least 1 year were included. Measles vaccination was given at 2 years after SCT to children and young adults without chronic GVHD or ongoing immunosuppression. In all, 264 patients had matched sibling donors and 131 either mismatched family or unrelated donors. Totally, 318 patients received bone marrow and 77 peripheral blood stem cells. Overall, 375 patients had undergone myeloablative and 20 nonmyeloablative conditioning. Out of 395 patients, 133 (34%) were seronegative to measles. In multivariate models, younger age or being vaccinated to measles, rather than previous measles disease, before transplantation were risk factors both for becoming seronegative and to have doubtfully protective immunity to measles. Acute GVHD grade II-IV was a risk factor for seronegativity and blood stem cells a risk factor for doubtfully protective immunity. Children and young adults previously immunized to measles have a high risk for becoming vulnerable to a measles infection. Since measles is again circulating in many countries and measles is a serious infection after SCT, vaccination should be considered.