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Objectives: To evaluate the impact of early (at first-line) vs delayed (3-year delay) ofatumumab initiation and long-term clinical, societal, and economic outcomes of ofatumumab vs teriflunomide in relapsing multiple sclerosis (RMS) patients from a Spanish societal perspective., Methods: A cost-consequence analysis was conducted using an Expanded Disability Status Scale (EDSS)-based Markov model. Inputs were sourced from ASCLEPIOS I and II trials and published literature., Results: At the end of 10 years, compared with first-line teriflunomide treatment, early first-line ofatumumab initiation was projected to result in 35.6% fewer patients progressing to EDSS ≥ 7 and 27.8% fewer relapses. The ofatumumab cohort required 7.3% reduced informal care time and had 19% fewer disability-adjusted life years (DALYs) than the teriflunomide cohort. A 3-year delay in ofatumumab treatment (3-year teriflunomide + 7-year ofatumumab) was projected to result in 32.2% more patients progressing to EDSS ≥ 7, 20.2% more relapses, 5.4% increased informal care time, and 16.6% more DALYs compared with early ofatumumab initiation. Early ofatumumab initiation was associated with total annual cost savings (excluding disease-modifying-therapies' acquisition costs) of €35,328 ($34,549; conversion factor 1€= $1.02255) and €24,373 ($23,836) per patient vs teriflunomide and 3-year delayed ofatumumab initiation, respectively., Conclusions: This study highlights the benefits of early initiation of high-efficacy therapy such as ofatumumab vs its delayed initiation for improving the outcomes in RMS patients (having characteristics similar to those of patients included in the ASCLEPIOS trials). Ofatumumab treatment was projected to provide improved long-term clinical, societal, and economic outcomes vs teriflunomide treatment in RMS patients from a Spanish societal perspective.

Objective: To evaluate the cost-utility of an integrated care program (ASMAIRE Infantil Program [PAI]) for children with asthma compared with standard of care., Methods: A decision-analytic model was used to compare an integrated care program compared to the standard of care in children with asthma in Bogota, Colombia. Baseline characteristics of the patients were established according to the distribution of patients in the PAI database. Other inputs were obtained from published meta-analysis, local registries, medical bills, general mortality data, and expert opinion. Costs were presented in 2017 Colombian pesos. Outcomes included quality-adjusted life-years (QALYs). Costs and outcomes were discounted by 5% per year. Incremental cost-utility ratios were presented for PAI compared with standard of care. Univariate and multivariate probabilistic sensitivity analyses were conducted to assess model robustness to parameter uncertainty., Results: The model predicted that patients that are part of the PAI would accrue more QALYs than patients on standard of care. The incremental results suggest that the PAI is a cost-effective treatment (incremental cost-utility ratio of Colombian pesos $33 753 817/QALY) compared with standard of care. Sensitivity analyses suggest that results are most sensitive to cost of care (with and without PAI) and costs of severe exacerbation. However, the PAI is cost-effective irrespective of variation in any of the input parameters., Conclusion: Our model predicted that an integrated intervention for the management of asthma in pediatric patients improves QALYs, reduces number of disease related exacerbations compared to standard therapy and is cost-effective for the long-term control of the disease in Colombia., (© 2020 Wiley Periodicals LLC.)

Introduction: Exacerbations of chronic obstructive pulmonary disease (COPD) have a huge impact on lung function, quality of life and mortality of patients. Emergency Department visits and hospitalizations due to exacerbations cause a significant economic burden on the health system., Objective: To describe the differences in the number of emergency visits and hospitalizations due to exacerbations of COPD among patients included in two models of care of the same institution., Materials and Methods: A historical cohort study in which COPD patients who are users of two models of care were included: COPD integrated care program (CICP) and general consultation of pulmonology (GCP). The first model, unlike the second one, offers additional educational activities, 24/7 telephone service, and priority consultations. The number of emergency visits and hospitalizations due to COPD exacerbations in patients who had completed at least one year of follow-up was evaluated. The multivariable Poisson regression model was used for calculating the incidence rate (IR) and the incidence rate ratio (IRR) with an adjustment for confounding factors., Results: We included 316 COPD patients (166 from the CICP and 150 from the GCP). During the year of follow-up, the CICP patients had 50% fewer emergency visits and hospitalizations than patients from the GCP (IRR=0.50, 95%CI: 0.29-0.87, p=0.014)., Conclusions: COPD patients in the CICP had fewer emergency visits and hospitalizations due to exacerbations. Prospective clinical studies are required to confirm the results and to evaluate the factors that contribute to the differences.

Reinke's edema is a smoking-associated, benign, mostly bilateral lesion of the vocal folds leading to difficulties in breathing and voice problems. Pronounced histological changes such as damaged microvessels or immune cell infiltration have been described in the vocal fold connective tissue, the lamina propria Thus, vocal fold fibroblasts, the main cell type of the lamina propria , have been postulated to play a critical role in disease mediation. Yet information about the pathophysiology is still scarce and treatment is only surgical, i.e. symptomatic. To explore the pathophysiology of Reinke's edema, we exposed near-primary human vocal fold fibroblasts to medium conditioned with cigarette smoke extract for 24 h as well as 4 days followed by quantitative mass spectrometry.Proteomic analyses after 24 h revealed that cigarette smoke increased proteins previously described to be involved in oxidative stress responses in other contexts. Correspondingly, gene sets linked to metabolism of xenobiotics and reactive oxygen species were significantly enriched among cigarette smoke-induced proteins. Among the proteins most downregulated by cigarette smoke, we identified fibrillar collagens COL1A1 and COL1A2; this reduction was validated by complementary methods. Further, we found a significant increase of UDP-glucose 6-dehydrogenase, generating a building block for biosynthesis of hyaluronan, another crucial component of the vocal fold lamina propria In line with this result, hyaluronan levels were significantly increased because of cigarette smoke exposure. Long term treatment of 4 days did not lead to significant changes.The current findings corroborate previous studies but also reveal new insights in possible disease mechanisms of Reinke's edema. We postulate that changes in the composition of the vocal folds' extracellular matrix -reduction of collagen fibrils, increase of hyaluronan- may lead to the clinical findings. This might ease the identification of better, disease-specific treatment options., (© 2019 Gugatschka et al.)

Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L-Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre-constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE.

Objective: The objective of the study was to evaluate perinatal and long-term complications of fetuses with intrauterine growth restriction (IUGR) compared with constitutionally small for gestational age (SGA) ones., Study Design: The outcome of infants with IUGR and SGA born at the Medical University Graz (Austria) between 2003 and 2009 was retrospectively analyzed. Group assignment was based on birthweight, Doppler ultrasound, and placental morphology. The primary outcome was neurodevelopmental delay at 2 years corrected age. The secondary outcomes were perinatal complications., Results: We included 219 IUGR and 299 SGA infants for perinatal and 146 and 215 for long-term analysis. Fetuses with IUGR were delivered earlier (35 vs 38 weeks) and had higher rates of mortality (8% vs 1%; odds ratio [OR], 8.3) as well as perinatal complications (24.4% vs 1.0%; OR, 31.6). The long-term outcome was affected by increased risk for neurodevelopmental impairment (24.7% vs 5.6%; OR, 5.5) and growth delay (21.2% vs 7.4%; OR, 3.4)., Conclusion: IUGR infants are subject to an increased risk for adverse short- and long-term outcome compared with SGA children., (Copyright © 2013 Mosby, Inc. All rights reserved.)

We describe the distribution of indoleamine 2,3-dioxygenase 1 (IDO1) in vascular endothelium of human first-trimester and term placenta. Expression of IDO1 protein on the fetal side of the interface extended from almost exclusively sub-trophoblastic capillaries in first-trimester placenta to a nearly general presence on villous vascular endothelia at term, including also most bigger vessels such as villous arteries and veins of stem villi and vessels of the chorionic plate. Umbilical cord vessels were generally negative for IDO1 protein. In the fetal part of the placenta positivity for IDO1 was restricted to vascular endothelium, which did not co-express HLA-DR. This finding paralleled detectability of IDO1 mRNA in first trimester and term tissue and a high increase in the kynurenine to tryptophan ratio in chorionic villous tissue from first trimester to term placenta. Endothelial cells isolated from the chorionic plate of term placenta expressed IDO1 mRNA in contrast to endothelial cells originating from human umbilical vein, iliac vein or aorta. In first trimester decidua we found endothelium of arteries rather than veins expressing IDO1, which was complementory to expression of HLA-DR. An estimation of IDO activity on the basis of the ratio of kynurenine and tryptophan in blood taken from vessels of the chorionic plate of term placenta indicated far higher values than those found in the peripheral blood of adults. Thus, a gradient of vascular endothelial IDO1 expression is present at both sides of the feto-maternal interface.

Intrauterine thrombosis of umbilical cord vessels is a rare event (2.5-4.5/10,000) and usually followed by poor fetal outcome. We present the rare case of spontaneous intrauterine thrombosis of an umbilical artery leading to severe intrauterine growth restriction (IUGR) and provide clinical and pathological findings. A 28-year-old nulliparous third gravida was referred to our institution because of IUGR at 32+4 weeks of gestation. Fetal growth had been appropriate until the 31st week of gestation and had stopped thereafter. There were no signs of abruption of the placenta and no structural abnormalities except an absent paravesical colour Doppler flow in the region of the right umbilical artery. Other Doppler measurements, karyotype and TORCH serology were normal. Intermittent non-reassuring fetal heart rate led to cesarean section at 34+3 weeks of gestation. A healthy girl with measurements on the 3rd centile was born (weight of 1,590 g, length of 41 cm and head circumference of 29 cm). Gross examination displayed an elongated, highly twisted umbilical cord with a length of 70 cm, central insertion and three umbilical vessels. Microscopic examination confirmed the diagnosis of umbilical artery thrombosis along the entire length of the umbilical cord. Calcification within the thrombus and microcalcification in occluded chorionic vessels were observed as well as hemorrhagic endovasculitis and endangiopathia obliterans in the stem villi arteries. This fetal thrombotic vasculopathy (FTV) comprised about 40% of the parenchyma. The coagulation parameters and blood counts of the mother and the infant were normal apart from transient neonatal thrombocytopenia. The reason for thrombosis remained unclear but could be attributed to the elongated and highly twisted umbilical cord. Intrauterine arterial thrombosis may cause severe IUGR. This condition might be detectable by ultrasound in the course of an IUGR workup, especially when no other reasons can be found.

We report a case of a benign neurilemmoma arising from the right mental nerve. Schwannomas are rare neurogenic tumours that originate from Schwann cells of the peripheral nervous system. Frequent locations are the head and neck region. Most of the tumours occur in the soft tissue whereas intraosseous schwannomas are rare. This case report deals with a young patient who was referred to our hospital with an unidentified fast-growing tumour located mainly in the premolar region of the right mandible. The tumour presented as an expansive, unilocular, well defined, radiolucent lesion on orthopantomography. No expansion of the mandibular canal could be seen. Computerized tomography scans of the mandible helped to identify the solid nature of the tumour. A biopsy was necessary to make the final diagnosis and the tumour was then excised surgically. Postoperative magnetic resonance imaging scans and a histological examination of the surgical specimen showed no signs of neurofibromatosis type 2.

Atherosclerotic lesions often harbor Chlamydophila pneumoniae (C. pneumoniae). The objective of the present study was to examine whether serological tests are able to predict individual endovascular infection. Endarterectomy specimens from 70 patients with severe carotid artery stenosis were stained immunohistochemically for C. pneumoniae. Antibody titers to C. pneumoniae were measured in serum with a recombinant ELISA recognizing chlamydial lipopolysaccharide (cLPS) and with microimmunofluorescence (MIF). C. pneumoniae antigens were detected in 64 (91%) carotid artery specimens. Serum IgG antibodies to C. pneumoniae were detected in 43% of patients by cLPS-ELISA and in 77% by MIF test. Detection of C. pneumoniae positive cells within atherectomy specimens was strongly correlated to seroprevalence (P = 0.002) and to titers (P = 0.003) of cLPS-IgG antibodies, but not to results of the MIF-test. We conclude that cLPS-IgG antibodies hold promise as a surrogate marker to identify individuals with high endovascular antigen load.

Expression of indoleamine 2,3-dioxygenase (IDO) in epithelium of the endometrium and the cervix is not restricted to normal but also present in carcinomatous tissue. The enzyme was found in the majority of cases studied, pioneer cells at the invasion front of the tumors being especially strongly reactive in immunohistology. In addition, also cells in the peritumoral infiltrate of the stroma expressed IDO. Taken together, these findings together with previous data on the immunosuppressive impact of tryptophan depletion suggest IDO-induced suppression of antitumoral immune response in both adenocarcinoma and squamous cell carcinoma of endometrium and cervix. On the other hand, IDO as also known to inhibit tumor cell proliferation by tryptophan depletion.

Objective: The aim of this study was to evaluate the effect of various ex vivo expansion conditions on the cell products and their ability to accelerate hematopoietic recovery in patients undergoing stem cell transplantation., Patients and Methods: Unselected peripheral blood progenitor cells (PBPCs) from 43 breast cancer patients were seeded into gas-permeable bags containing serum-free media, granulocyte colony-stimulating factor, stem cell factor, and pegylated megakaryocyte growth and development factor. Between 2 and 24 x 10(9) PBPCs were cultured at 1, 2, or 3 x 10(6) cells/mL for 9 to 14 days. The expanded PBPCs and cryopreserved PBPCs containing at least 5 x 10(6) CD34(+) cells/kg were infused following completion of high-dose chemotherapy., Results: Increasing culture duration from 9 to 11-14 days significantly improved the expanded cell yield and fold expansion, whereas increasing PBPC seeding density above 10(6) cells/mL had the opposite effect. The expanded cell dose was the only culture variable that correlated significantly with the time to neutrophil recovery (r = -0.66; p = 0.0001). Study patients had significantly faster neutrophil (p < 0.0001) and platelet (p = 0.001) recovery, reduced red cell transfusions (p = 0.01), and shorter hospital stays (p < 0.0001) than historical controls. The most clinically efficacious expanded cell product was seeded with 10(10) PBPCs at 10(6) cells/mL, then cultured for 11 days. The six patients in that cohort experienced 2.8 +/- 1 days of absolute neutropenia and had neutrophil recovery 5.7 +/- 0.8 days post-transplant; none had a neutropenic fever or required intravenous antibiotics., Conclusion: Unselected PBPCs expanded ex vivo significantly impact hematopoietic recovery following high-dose therapy. Optimization of the expansion conditions enhances the efficacy of this cell product.

The safety and efficacy of administering ex vivo expanded peripheral blood progenitor cells (PBPC) to patients with breast cancer who undergo high-dose chemotherapy and PBPC transplantation was investigated. Unselected PBPC were cultured in gas-permeable bags containing 1-L serum-free media, granulocyte colony-stimulating factor, stem cell factor, and pegylated megakaryocyte growth and development factor for 9 days. Cell dose cohorts were assigned to have between 2 and 24 x 10(9) PBPC cultured at 1, 2, or 3 x 10(6) cells/mL. Twenty-four patients received high-dose chemotherapy followed by infusion of the cultured PBPC and at least 5 x 10(6) CD34(+) uncultured cryopreserved PBPC per kilogram. No toxicities resulted from infusions of the ex vivo expanded PBPC. The study patients had shorter times to neutrophil (P =.0001) and platelet (P =.01) recovery and fewer red cell transfusions (P =.02) than 48 historical controls who received the same conditioning regimen and posttransplantation care and at least 5 x 10(6) CD34(+) PBPC per kilogram. Improvements in all these endpoints were significantly correlated with the expanded cell dose. Nine of 24 (38%) patients recovered neutrophil counts above 500/microL by day 5 or 6 after transplantation, whereas none of the controls had neutrophil recovery before the eighth day. Seven (29%) patients had neutropenia for 3 or fewer days, and 9 (38%) patients did not experience neutropenic fevers or require broad-spectrum antibiotics. Therefore, ex vivo expanded PBPC are capable of ameliorating posttransplantation neutropenia, thrombocytopenia, and anemia in patients receiving high-dose chemotherapy.

An unusual case of subaortic stenosis and aortic regurgitation caused by accessory mitral valve tissue in a 10 year old boy is reported. Two-dimensional and Doppler echocardiography revealed the characteristic feature of a mobile, parachute-like mass in the left ventricular outflow tract pro-lapsing into the aortic valve during systole and, thus, producing a systolic pressure gradient of 70 mm Hg between the left ventricle and aorta and causing mild aortic regurgitation. The accessory valve tissue was completely excised via an aortotomy without injury to the normal mitral and aortic valves. Two dimensional echocardiography provides excellent morphological information about the relationship between the accessory mitral valve tissue and the mitral and aortic valves, respectively. Accurate preoperative evaluation by two-dimensional echocardiography facilitates the successful surgical management of this rare condition.

Selenium and cadmium concentrations were investigated in 60 autopsy tissue samples obtained from fetal life up to adulthood (defined in this study as 25-87 y of age) in Styria, a moderately industrialized region in Austria that has a low selenium supply. During the first 2 y after birth, median liver selenium concentrations were slightly lower (i.e., 1.5 nmol/g wet weight) than concentrations found in fetal life (i.e., 2.9 nmol/g) and adulthood (2.1 nmol/g). Whereas in the fetal period median selenium content in the kidney cortex (2.1 nmol/g) and the thyroid gland (1.6 nmol/g) was lower than that found in the liver, the reverse was true for adults (i.e., kidney, 5.5 nmol/g; thyroid, 4.3 nmol/g). Tissue cadmium concentrations approached 0 during gestation. Accumulation in the kidney and liver commenced immediately after birth. In the thyroid gland of adults, significantly higher concentrations of cadmium were found. Median concentrations in adults showed no statistical significant age dependency (i.e., liver, 7.6 nmol/g; kidney, 59.8 nmol/g; thyroid, 11.2 nmol/g). In summary, the data revealed very low tissue selenium concentrations and low cadmium burdens for the Styrian population that was not exposed occupationally.

A 45-year-old woman underwent a resection for a hepatic metastasis of the liver caused by a carcinoma of the colon. Shortly after the Pringle maneuver severe hemorrhage from the upper left quadrant of the abdomen was observed. Exploration revealed a spontaneous parenchymal laceration of the spleen.

Symmetric hypoplasia of the temporal cerebral lobes was demonstrated by magnetic resonance imaging of the brain in a macrocephalic male patient with glutaric aciduria type II within the first week of life. Psychomotor development was normal until the age of 11 months, when the patient died of sudden cardiac arrest. Autopsy revealed symmetric hypoplasia of the temporal cerebral lobes with loss of axons and hypomyelination in the temporal medullary layers.

A 7-month-old male infant with clinical symptoms of severe toxic shock syndrome died on day 9 of illness. At autopsy, demonstration of coronary vasculitis together with thrombosis of the left coronary artery revealed the true diagnosis of atypical Kawasaki disease. The marked similarity in many clinical features makes the distinction between these two diseases difficult when atypical clinical presentation of Kawasaki disease is present.

The iodine concentration was determined in 89 thyroid tissue samples of post-mortem examination material of thyroid healthy persons in dependency to the age. Before the 22nd week little iodine is stored in the fetal thyroid gland (median and range: 24 micrograms/g wet weight [0 to 27 micrograms/g]). From the 23rd week on the concentration is significantly higher (p = 0.004). There is a further increase of iodine concentration in the first 6 months of life, with a median concentration of 171 micrograms/g (75 to 808 micrograms/g). With a median of 599 micrograms/g (464 to 699 micrograms/g) the iodine concentration in the second year of life is comparable with that of adults (640 micrograms/g [218 to 2772 micrograms/g]). From the 60th year of life the median concentration is 462 micrograms/g (155 to 2100 micrograms/g), but this decrease is not statistically significant. Additionally the iodine concentration was determined in 7 topographically defined regions of 28 thyroid glands. The median iodine concentration did not differ in the 7 regions, but the iodine content in one and the same thyroid gland differed from region to region. Therefore in the healthy thyroid gland no regions exist, which have generally stored less iodine than others. However, no conclusion can be drawn from the iodine concentration of one biopsy to the whole iodine concentration of the organ.

We describe a previously unknown congenital abnormality of the lymphatic system, characterized by multiple cystic lesions of the lower extremities and thorax. Diagnosis was made by ultrasound in the second trimester. The ultrasound findings, pathology results, and differential diagnosis are presented.

The routine use of ultrasonics during pregnancy allows an early diagnosis of a sacrococcygeal teratoma (SCT) with a high degree of certainty. The perinatal management is shown in a four case example prenatally diagnosed. The assessment of N-Acetylcholinesterase in the amniotic fluid in cases of cystic teratomas does not allow a safe differentiation from a myelomeningocele. A puncture of the tumor can be helpful for the verification of the diagnosis. Cells of all three germ layers may be found in the cytological fluid. The sonomorphological differentiation into solid and cystic tumors may play a significant role for the intrauterine growth. Even when diagnosed very early, cystic tumors do not compromise the intrauterine growth. Large solid tumors may lead to hydrops fetalis and intrauterine death. Furthermore, the prognosis depends on concomitant malformation as well as on the intracorporal spreading of the tumor. Therefore, a careful ultrasonic examination allows a good prenatal prognosis as to the severity of the malformation. Delivery is done by caesarean section in cases of large cystic-solid tumors. Small teratomas as well as most cystic tumors allow vaginal delivery after having been punctured previously.

Toxoplasmosis is a special prenatal infection because it is susceptible to medication. Serologic screening and early diagnosis of a new infection is a prerequisite for successful treatment, which protects the fetus from infection. A case of a twenty-two year old gravida-II shows, that infection is possible despite negative initial screening. A new infection was diagnosed because of seroconversion at a routine screening at the end of the second trimester. An ultrasound scan showed severe hydrocephalus, hepatomegaly, and ascites. Labor was induced in the 33rd gestational week. Conatal toxoplasmosis was confirmed by histologic and microbiologic studies of the placenta and membranes. We discuss the difficulties resulting from negative primary serology.