The fetal membranes of the otter shrews and a synapomorphy for afrotheria.

The otter shrews of mainland Africa are the closest relatives of the Madagascar tenrecs. We sought for similarities in placentation between the two groups and, in a wider context, with other mammals of the Afrotheria clade. Specimens of the Nimba otter shrew (Micropotamogale lamottei) were obtained from the Ivory Coast and examples of the giant otter shrew (Potamogale velox) from the Hill Collection. The Nimba otter shrew has a central haemophagous organ similar to that in tenrecs. The labyrinth of the Nimba otter shrew, however, is endotheliochorial with syncytial trophoblast enclosing the maternal vessels. On the other hand tenrecs have cellular haemomonochorial placentae and an associated spongy zone, which is not present in the Nimba otter shrew. The placenta of the giant otter shrew is also endotheliochorial. The central region of its placenta is particularly interesting, since the juxtafetal portion is clearly a haemophagous region whereas the labyrinth feeding this region is endotheliochorial. Thus there is considerable variation in placental morphology within Tenrecidae. Importantly, however, both otter shrews have a large allantoic sac divided into four intercommunicating lobes by two pairs of septal folds. A similar arrangement has been described for representatives of each of the remaining five orders within Afrotheria. This is significant because previous anatomical studies have failed to establish a single synapomorphy in support of Afrotheria.

Outcome and Prognostic Factors in Adenosquamous Carcinoma of the Head and Neck - a Multicenter Rare Cancer Network Study

Background: Adenosquamous carcinoma (AC) of the head and neck is a distinct entity first described in 1968. Its natural history is more aggressive than squamous-cell carcinoma. The aim of this study was to assess the clinical profile, patterns of failure, and prognostic factors in patients with AC of the head and neck treated by radiation therapy (RT) with or without chemotherapy (CT).Materials and Methods: Data from 19 patients with stage I (n = 3), II (n = 1), III (n = 4), or IVa (n = 11) AC, treated between 1989 and 2009, were collected in a retrospective multicenter Rare Cancer Network study. Median age was 60 years (range, 48−73). Fifteen patients were male, and 4 female. Risk factors, including perineural invasion, lymphangitis, vascular invasion, positive margins were present in the majority (83%) of the patients. Tumour sites included oral cavity in 4, oropharynx in 4, hypopharynx in 2, larynx in 2, salivary glands in 2, nasal vestibule in 2, maxillary sinus in 2, and nasopharynx in 1 patient. Surgery (S) was performed in all but 5 patients. S alone was performed in only 1 patient, and definitive RT alone in 3 patients. Fifteen patients received combined modality treatment (S+RT in 11, RT+CT in 2, and all of the three modalities in 2 patients). Median RT dose to the primary and to the nodes was 66 Gy (range, 50−72) and 53 Gy (range, 44−66), respectively (1.8−2.0 Gy/fr., 5 fr./week). In 4 patients, the planning treatment volume included the primary tumour site only. Eight patients were treated with 2D RT, 7 with 3D conformal RT, and 2 with intensity-modulated RT.Results: After a median follow-up period of 39 months (range, 9−62), 9 patients developed distant metastases (lung, bone, mediastinum, and liver), 7 presented nodal recurrences, and only 4 had a local relapse at the primary site (all in-field recurrences). At last follow-up, 7 patients were alive without disease, 1 alive with disease, 9 died from progressive disease, and 2 died from intercurrent disease. The 3-year and median overall survival, disease-free survival (DFS), and locoregional control rates were 55% (95% confidence interval [CI]: 32−78%) and 39 months, 34% (95% CI: 12−56%) and 22 months, and 50% (95% CI: 22−78%) and 33 months, respectively. In multivariate analysis (Cox model), DFS was negatively influenced by the presence of extracapsular extension (p = 0.01) and advanced stage (IV versus I−III, p = 0.002).Conclusions: Overall prognosis of locoregionally advanced AC remains poor, and distant metastases and nodal relapse occur in almost half of the cases. However, local control is relatively better, and early stage AC patients had prolonged DFS when treated with combined-modality treatment.

Characterization of an interaction between fetal hemoglobin and lipid A of LPS resulting in augmented induction of cytokine production in vivo and in vitro.

A previously described extract of sheep fetal liver was reported to reverse many of the cytokine changes associated with aging in mice, including an augmented spleen cell ConA-stimulated production of IL-4 and decreased production of IL-2. Similar effects were not seen with adult liver preparations. These changes were observed in various strains of mice, including BALB/c, DBA/2 and C57BL/6, using mice with ages ranging from 8 to 110 weeks. Preliminary characterization of this crude extract showed evidence for the presence of Hb gamma chain, as well as of lipid A of LPS. We show below that purified preparations of sheep fetal Hb, but not adult Hb, in concert with suboptimally stimulating doses of LPS (lipid A), cooperate in the regulation of production of a number of cytokines, including TNFalpha and IL-6, in vitro. Furthermore, isolated fresh spleen or peritoneal cells from animals treated in vivo with the same combination of Hb and LPS, showed an augmented capacity to produce these cytokines on further culture in vitro. Evidence was also obtained for a further interaction between CLP, LPS and fetal Hb itself in this augmented cytokine production. These data suggest that some of the functional activities in the fetal liver extract reported earlier can be explained in terms of a novel immunomodulatory role of a mixture of LPS (lipid A) and fetal Hb.

Blood pressure changes in acute ischemic stroke and outcome with respect to stroke etiology.

OBJECTIVE: Previous research suggested that proper blood pressure (BP) management in acute stroke may need to take into account the underlying etiology. METHODS: All patients with acute ischemic stroke registered in the ASTRAL registry between 2003 and 2009 were analyzed. Unfavorable outcome was defined as modified Rankin Scale score >2. A local polynomial surface algorithm was used to assess the effect of baseline and 24- to 48-hour systolic BP (SBP) and mean arterial pressure (MAP) on outcome in patients with lacunar, atherosclerotic, and cardioembolic stroke. RESULTS: A total of 791 patients were included in the analysis. For lacunar and atherosclerotic strokes, there was no difference in the predicted probability of unfavorable outcome between patients with an admission BP of <140 mm Hg, 140-160 mm Hg, or >160 mm Hg (15.3 vs 12.1% vs 20.8%, respectively, for lacunar, p = 015; 41.0% vs 41.5% vs 45.5%, respectively, for atherosclerotic, p = 075), or between patients with BP increase vs decrease at 24-48 hours (18.7% vs 18.0%, respectively, for lacunar, p = 0.84; 43.4% vs 43.6%, respectively, for atherosclerotic, p = 0.88). For cardioembolic strokes, increase of BP at 24-48 hours was associated with higher probability of unfavorable outcome compared to BP reduction (53.4% vs 42.2%, respectively, p = 0.037). Also, the predicted probability of unfavorable outcome was significantly different between patients with an admission BP of <140 mm Hg, 140-160 mm Hg, and >160 mm Hg (34.8% vs 42.3% vs 52.4%, respectively, p < 0.01). CONCLUSIONS: This study provides evidence to support that BP management in acute stroke may have to be tailored with respect to the underlying etiopathogenetic mechanism.

Gender differences in premorbid, entry, treatment, and outcome characteristics in a treated epidemiological sample of 661 patients with first episode psychosis.

OBJECTIVES: Gender differences in psychotic disorder have been observed in terms of illness onset and course; however, past research has been limited by inconsistencies between studies and the lack of epidemiological representative of samples assessed. Thus, the aim of this study was to elucidate gender differences in a treated epidemiological sample of patients with first episode psychosis (FEP). METHODS: A medical file audit was used to collect data on premorbid, entry, treatment and 18-month outcome characteristics of 661 FEP consecutive patients treated at the Early Psychosis Prevention and Intervention Centre (EPPIC), Melbourne, Australia. RESULTS: Prior to onset of psychosis, females were more likely to have a history of suicide attempts (p=.011) and depression (p=.001). At service entry, females were more likely to have depressive symptoms (p=.007). Conversely, males had marked substance use problems that were evident prior to admission (p<.001) and persisted through treatment (p<.001). At service entry, males also experienced more severe psychopathology (p<.001) and lower levels of functioning (GAF, p=.008; unemployment/not studying p=.004; living with family, p=.003). Treatment non-compliance (p<.001) and frequent hospitalisations (p=.047) were also common for males with FEP. At service discharge males had significantly lower levels of functioning (GAF, p=.008; unemployment/not studying p=.040; living with family, p=.001) compared to females with FEP. CONCLUSIONS: Gender differences are evident in illness course of patients with FEP, particularly with respect to past history of psychopathology and functioning at presentation and at service discharge. Strategies to deal with these gender differences need to be considered in early intervention programs.

Influence of comorbidity on outcome after pulmonary resection in the elderly

The aim of this study was to determine the influence of comorbidity on outcome after pulmonary resection in patients over 75 years old. Three hundred and thirty-three patients with non-small-cell lung cancer operated on between 1998 and 2002 were divided into 3 age groups: < 60 years (group 1), 60-75 years (group 2), > 75 years (group 3). Overall operative mortality was 0.3%; 30-day mortality was 1%. There were more major complications with re-operation in groups 1 and 2, but minor complications occurred significantly more frequently in group 3 (36% vs 16%). Overall mean hospital stay was 12 days, with no significant difference among groups. Three-year survival rates were: 80%, 70%, and 65% in groups 1, 2, and 3, respectively, with no significant difference among groups. Age or the presence of comorbidity should not be considered contraindications for lung resection. With proper patient selection and careful preoperative evaluation, many major complications after pneumonectomy are avoidable.

Early major worsening in ischemic stroke: predictors and outcome.

INTRODUCTION: We aimed to investigate the characteristics and outcome of patients suffering early major worsening (EMW) after acute ischemic stroke (AIS) and assess the parameters associated with it. METHODS: All consecutive patients with AIS in the ASTRAL registry until 10/2010 were included. EMW was defined as an NIHSS increase of ≥8 points within the first 24 h after admission. The Bootstrap version of the Kolmogorov-Smirnov test and the χ(2)-test were used for the comparison of continuous and categorical covariates, respectively, between patients with and without EMW. Multiple logistic regression analysis was performed to identify independent predictors of EMW. RESULTS: Among 2155 patients, 43 (2.0 %) had an EMW. EMW was independently associated with hemorrhagic transformation (OR 22.6, 95 % CI 9.4-54.2), cervical artery dissection (OR 9.5, 95 % CI 4.4-20.6), initial dysarthria (OR 3.7, 95 % CI 1.7-8.0), and intravenous thrombolysis (OR 2.1, 95 % CI 1.1-4.3), whereas a negative association was identified with initial eye deviation (OR 0.4, 95 % CI 0.2-0.9). Favorable outcome at 3 and 12 months was less frequent in patients with EMW compared to patients without (11.6 vs. 55.3 % and 16.3 vs. 50.7 %, respectively), and case fatality was higher (53.5 vs. 12.9 % and 55.8 vs. 16.8 %, respectively). Stroke recurrence within 3 months in surviving patients was similar between patients with and without EMW (9.3 vs. 9.0 %, respectively). CONCLUSIONS: Worsening of ≥8 points in the NIHSS score during the first 24 h in AIS patients is related to cervical artery dissection and hemorrhagic transformation. It justifies urgent repeat parenchymal and arterial imaging. Both conditions may be influenced by targeted interventions in the acute phase of stroke.

Vascular dysfunction in children conceived by assisted reproductive technologies: underlying mechanisms and future implications.

Epidemiological studies in humans have demonstrated a relationship between pathological events during fetal development and increased cardiovascular risk later in life and have led to the so called "Fetal programming of cardiovascular disease hypothesis". The recent observation of generalised vascular dysfunction in young apparently healthy children conceived by assisted reproductive technologies (ART) provides a novel and potentially very important example of this hypothesis. This review summarises recent data in ART children demonstrating premature subclinical atherosclerosis in the systemic circulation and pulmonary vascular dysfunction predisposing to exaggerated hypoxia-induced pulmonary hypertension. These problems appear to be related to the ART procedure per se. Studies in ART mice demonstrating premature vascular aging and arterial hypertension further demonstrate the potential of ART to increase cardiovascular risk and have allowed to unravel epigenetic alterations of the eNOS gene as an underpinning mechanism. The roughly 25% shortening of the life span in ART mice challenged with a western style high-fat-diet demonstrates the potential importance of these alterations for the long-term outcome. Given the young age of the ART population, data on cardiovascular endpoints will not be available before 20 to 30 years from now. However, already now cohort studies of the ART population are needed to early detect cardiovascular alterations with the aim to prevent or at least optimally treat cardiovascular complications. Finally, a debate needs to be engaged on the future of ART and the consequences of its exponential growth for public health.

Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe.

OBJECTIVES: Ultrasound scan in the mid-trimester of pregnancy is now a routine part of prenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of dysmorphic syndromes by fetal ultrasound examination. METHODS: Data from 20 registries of congenital malformations in 12 European countries were included in the study. RESULTS: There were 2454 cases with congenital heart diseases, 479 of which were recognized syndromes, including 375 chromosomal anomalies and 104 syndromes without chromosomal anomalies. Fifty-one of the 104 were detected prenatally (49.0%). One hundred and ninety-two of 1130 cases with renal anomalies were recognized syndromes, including 128 chromosomal anomalies and 64 syndromes without chromosomal anomalies; 162 of them (84.4%) were diagnosed prenatally, including 109 chromosomal anomalies and 53 non-chromosomal syndromes. Fifty-four of the 250 cases with limb defects were recognized syndromes, including 16 chromosomal syndromes and 38 syndromes without chromosomal anomalies; 21 of these 54 syndromes were diagnosed prenatally (38.9%), including 9 chromosomal syndromes. There were 243 cases of abdominal wall defects including 57 recognizable syndromes, 48 with omphalocele and 9 with gastroschisis; 48 were diagnosed prenatally (84.2%). Twenty-six of the 187 cases with diaphragmatic hernia had recognized syndromes, including 20 chromosomal aberrations and 6 syndromes without chromosomal anomalies. Twenty-two of them (84.6%) were detected prenatally. Sixty-four of 349 cases with intestinal anomalies were recognized syndromes; 24 were diagnosed prenatally (37.5%). There were 553 cases of cleft lip and palate (CL(P)) and 198 of cleft palate (CP) including 74 chromosomal anomalies and 73 recognized non-chromosomal syndromes. Prenatal diagnosis was made in 51 cases of CL(P) (53.7%) and 7 of CP (13.7%). Twenty-two of 188 anencephalic cases were syndromic and all were diagnosed prenatally. Of 290 cases with spina bifida, 18 were recognized syndromes, and of them 17 were diagnosed prenatally. All 11 syndromic encephaloceles were diagnosed prenatally. CONCLUSIONS: Around 50% of the recognized syndromes which are associated with major congenital anomalies (cardiac, renal, intestinal, limb defects, abdominal wall defects and oral clefts) can be detected prenatally by the anomaly scan. However the detection rate varies with the type of syndrome and with the different countries' policies of prenatal screening.

Autologous adult cortical cell transplantation enhances functional recovery following unilateral lesion of motor cortex in primates: a pilot study.

BACKGROUND:: Although cell therapy is a promising approach after cerebral cortex lesion, few studies assess quantitatively its behavioral gain in non-human primates. Furthermore, implantations of fetal grafts of exogenous stem cells are limited by safety and ethical issues. OBJECTIVE:: To test in non-human primates the transplantation of autologous adult neural progenitor cortical cells with assessment of functional outcome. METHODS:: Seven adult macaque monkeys were trained to perform a manual dexterity task, before the hand representation in motor cortex was chemically lesioned unilaterally. Five monkeys were used as control, compared to two monkeys subjected to different autologous cells transplantation protocols performed at different time intervals. RESULTS:: After lesion, there was a complete loss of manual dexterity in the contralesional hand. The five "control" monkeys recovered progressively and spontaneously part of their manual dexterity, reaching a unique and definitive plateau of recovery, ranging from 38% to 98% of pre-lesion score after 10 to 120 days. The two "treated" monkeys reached a first spontaneous recovery plateau at about 25 and 40 days post-lesion, representing 35% and 61% of the pre-lesion performance, respectively. In contrast to the controls, a second recovery plateau took place 2-3 months after cell transplantation, corresponding to an additional enhancement of functional recovery, representing 24 and 37% improvement, respectively. CONCLUSIONS:: These pilot data, derived from two monkeys treated differently, suggest that, in the present experimental conditions, autologous adult brain progenitor cell transplantation in non-human primate is safe and promotes enhancement of functional recovery.

Evaluation of a modified Broström-Gould procedure for treatment of chronic lateral ankle instability: A retrospective study with critical analysis of outcome scoring.

BACKGROUND: Chronic lateral ankle instability accounts for 20% of the ankle injuries. This study evaluates functional outcome of the modified Broström-Gould technique using suture anchors, with 4 different clinical scores. METHODS: A consecutive series of 41 patients were included with a minimum follow-up of one year. The function was assessed using 4 clinical scores including: the AOFAS for hind foot; the FAAM; the CAIT and the CAIS. RESULTS: Out of 41 patients; 27 patients were very satisfied, 11 satisfied and 3 were not satisfied. Ankle mobility returned to normal in 93% of patients. At follow-up the AOFAS was 89/100 (37-100), the FAAM 85/100% (35-100%), the CAIT 20/30 (5-30), and the CAIS 74/100% (27-100%). CONCLUSION: Outcome of modified Broström-Gould procedure is good with high satisfaction rate in terms of ankle mobility. The disparity in outcome of scores, signals towards the need of a standard evaluation system.

"Adolescent-onset Still's disease": characteristics and outcome in comparison with adult-onset Still's disease.

OBJECTIVES: To determine if adolescent onset systemic juvenile idiopathic arthritis (JIA) and adult onset Still's disease (AOSD) represent the same clinical continuum of disease. METHODS: Retrospective review of available clinical data on all pediatric and adult patients diagnosed with Still's disease within the last 10 years at a university hospital. Assessment of functional outcomes at last visit by clinical evaluation and HAQ or c-HAQ. RESULTS: Nine patients were identified as adolescent onset systemic JIA and were compared with 10 patients with AOSD (onset > 18 years old). No statistically significant differences were found between the two groups in terms of clinical presentation at onset and outcome at follow up. CONCLUSION: Adolescent patients presenting with systemic JIA have a disease onset and course undistinguishable from that of AOSD patients, suggesting that they represent a continuum of a single disease entity.

Role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma.

L'utilisation de faisceaux de protons accélérés dans le traitement des mélanomes de l'uvée a été utilisée pour la première fois en Suisse (et par ailleurs en Europe) en 1984. Depuis, la protonthérapie a constamment évolué avec des logiciels toujours plus performants et précis pour devenir à l'heure actuelle le traitement de référence pour ce type de tumeurs. Ainsi, jusqu'à ce jour, l'Institut Paul Scherrer à Villigen a traité plus de 7000 cas de tumeurs oculaires. Mais la protonthérapie, aussi efficace soit-elle avec un taux de guérison de plus de 98%, comporte malheureusement un certain nom bre d'effets secondaires et indésirables pouvant parfois mener le patient jusqu'à l'énucléation secondai re. De la simple dermatite actinique à l'hémorragie intravitréenne massive, les complications induites sont pour la plupart bien connues et documentées mais leurs prises en charge, notamment sur un organe préalablement irradié diffèrent. Alors que nous avons beaucoup de recul sur la protonthérapie, la gestion de ses complications reste propre à chaque centre de soin et n'est que très peu documentée. Les complications majeures de la protonthérapie qui ont nécessité une prise en charge par le chirurgien vitrorétinien représentent souvent un défi majeur. Bien que rares, puisqu'elles ne représentent que 2% de notre collectif, celles-ci peuvent avoir de lourdes conséquences. Pa r exemple, une hémorragie intravitréenne massive, complication la plus fréquente dans notre série, compromet l'observation de la tumeur au fond d'oeil et empêche le bon suivi oncologique. La chirurgie vitrorétinienne a alors pour mission, de restaurer la transparence des milieux, élément indispensable à l'ophtalmologue pour le suivi clinique, iconographique et radiologique des mélanomes de l'uvée. Secondairement, cette chirurgie permet parfois d'augmenter l'acuité visuelle de l'oeil malade. La chirurgie vitrorétinienne est un précieux atout pour l'oncologue et permet d'éviter une énucléation secondaire. Elle participe ainsi à la prise en charge globale du patient atteint de mélanome de l'uvée.

Long-term ex vivo expansion of human fetal liver primitive haematopoietic progenitor cells in stroma-free cultures

Successful expansion of haematopoietic cells in ex vivo cultures will have important applications in transplantation, gene therapy, immunotherapy and potentially also in the production of non-haematopoietic cell types. Haematopoietic stem cells (HSC), with their capacity to both self-renew and differentiate into all blood lineages, represent the ideal target for expansion protocols. However, human HSC are rare, poorly characterized phenotypically and genotypically, and difficult to test functionally. Defining optimal culture parameters for ex vivo expansion has been a major challenge. We devised a simple and reproducible stroma-free liquid culture system enabling long-term expansion of putative haematopoietic progenitors contained within frozen human fetal liver (FL) crude cell suspensions. Starting from a small number of total nucleated cells, a massive haematopoietic cell expansion, reaching > 1013-fold the input cell number after approximately 300 d of culture, was consistently achieved. Cells with a primitive phenotype were present throughout the culture and also underwent a continuous expansion. Moreover, the capacity for multilineage lymphomyeloid differentiation, as well as the recloning capacity of primitive myeloid progenitors, was maintained in culture. With its better proliferative potential as compared with adult sources, FL represents a promising alternative source of HSC and the culture system described here should be useful for clinical applications.