Risk factors and outcomes associated with type of uterine rupture.

PURPOSE: To identify risk factors associated with the occurrence of complete uterine rupture (CUR) in comparison to partial uterine rupture (PUR) to further investigate to what extent a standardized definition is needed and what clinical implications can be drawn. METHODS: Between 2005 and 2017 cases with CUR and PUR at Charité University Berlin, Germany were retrospectively identified. Demographic, obstetric and outcome variables were analyzed regarding the type of rupture. Binary multivariate regression analysis was conducted to identify risk factors associated with CUR. In addition, the intended route of delivery (trial of labor after cesarean delivery (TOLAC) and elective repeat cesarean delivery (ERCD)), divided according to the type of rupture, was compared. RESULTS: 92 cases with uterine rupture were identified out of a total of 64.063 births (0.14%). Puerperal complications were more frequent in CUR (67.9 versus 41.1%, p = 0.021). Multiparity ≥ 3 was more frequent in CUR (31 versus 10.7%, p = 0.020). Factors increasing the risk for CUR were parity ≥ 3 (OR = 3.8, p = 0.025), previous vaginal birth (OR = 4.4, p = 0.011), TOLAC (OR = 6.5, p < 0.001) and the use of oxytocin (OR = 2.9, p = 0.036). After multivariate analysis, the only independent risk factor associated with CUR was TOLAC (OR = 7.4, p = 0.017). CONCLUSION: TOLAC is the only independent risk factor for CUR. After optimized antenatal counselling TOLAC and ERCD had comparable short-term maternal and fetal outcomes in a high resource setting. A high number of previous vaginal births does not eliminate the risk of uterine rupture. A clear distinction between CUR and PUR is essential to ensure comparability among studies.

A propensity-matched study of full laparoscopic versus hand-assisted minimal-invasive liver surgery.

BACKGROUND AND AIM: The implications of multi-incision (MILS) and hand-assisted (HALS) laparoscopic techniques for minimally invasive liver surgery with regard to perioperative outcomes are not well defined. The purpose of this study was to compare MILS and HALS using propensity score matching. METHODS: 309 patients underwent laparoscopic liver resections (LLR) between January 2013 and June 2018. Perioperative outcomes were analyzed after a 1:1 propensity score match. Subgroup analyses of matched groups, i.e., radical lymphadenectomy (LAD) as well as resections of posterosuperior segments (VII and/or VIII), were performed. RESULTS: MILS was used in 187 (65.2%) and HALS in 100 (34.8%) cases, with a significant decrease of HALS resections over time (p = 0.001). There were no significant differences with regard to age, sex, body mass index (BMI), American Society of Anesthesiologists (ASA) Score, previous abdominal surgery and cirrhosis between both groups. Patients scheduled for HALS were characterized by a significantly higher rate of malignant tumors (p < 0.001) and major resections (p < 0.001). After propensity score matching (PMS), 70 cases remained in each group and all preoperative variables as well as resection extend were well balanced. A significantly higher rate of radical LAD (p = 0.039) and posterosuperior resections was found in the HALS group (p = 0.021). No significant differences between the matched groups were observed regarding operation time, conversion rate, frequency of major complications, length of intensive care unit (ICU) stay, overall hospital stay and R1 rate. CONCLUSION: Our analysis suggests MILS and HALS to be equivalent regarding postoperative outcomes. HALS might be particularly helpful to accomplish complex surgical procedures during earlier stages of the learning curve.

Incidence of incisional hernia after laparoscopic liver resection.

BACKGROUND: Minimally invasive techniques have been broadly introduced to liver surgery during the last couple of years. In this study, we aimed to report the incidence and potential risk factors for incisional hernia (IH) as well as health-related quality of life (HRQoL) after laparoscopic liver resections (LLR). METHODS: All patients undergoing LLR between January 2014 and June 2017 were contacted for an outpatient hernia examination. In all eligible patients, photo documentation of the scar was performed and IH was evaluated by clinical examination and by ultrasound. Patients also completed a questionnaire to evaluate IH-specific symptoms and HRQoL. Obtained results were retrospectively analyzed with regard to patients' characteristics, perioperative outcomes and applied minimally invasive techniques, such as multi-incision laparoscopic liver surgery or hand-assisted/single-incision laparoscopic surgery (HALS/SILS). RESULTS: Of 184 patients undergoing surgery, 161 (87.5%) met the inclusion criteria and 49 patients (26.6%) participated in this study. After a median time of 26 months (range 19-50 months) after surgery, we observed an overall incidence of IH of 12%. Five of 6 patients were overweight or obese (BMI ≥ 25) and 5 of 6 hernias were located at the umbilical site. Univariate analysis suggested the performance status at time of operation (ASA score ≥ 3; HR 5.616, 95% CI 1.012-31.157, p = 0.048) and the approach (HALS/SILS, HR 6.571, 95% CI 1.097-39.379, p = 0.039) as potential risk factors for IH. A higher frequency of hernia-related physical restrictions (HRR; p = 0.058) and a decreased physical functioning (p = 0.17) were noted in patients with IH; however, both being short of statistical significance. CONCLUSION: Advantages of laparoscopic surgery with regard to low rates of IH can be translated to minimally invasive liver surgery. Even though there are low rates of IH, patients with poor performance status at the time of operation should be monitored closely. While patients' characteristics are hard to influence, it might be worth focusing on surgical factors such as the approach and the closure of the umbilical site to further minimize the rate of IH.

[Management of patients with chronic pain in acute and perioperative medicine : An interdisciplinary challenge]. / Management von Patienten mit chronischen Schmerzen in der Akut- und perioperativen Medizin : Eine interdisziplinäre Herausforderung.

Chronic pain is a frequent comorbidity of patients in hospitals and has an influence on the clinical course and the duration of hospitalization. There is a need to have a better understanding of chronic pain as a comorbidity and it should be considered to a greater extent in understanding diseases, in treatment concepts and hospital structures to ensure a resource-oriented and high-quality care. This begins on admission by identifying pre-existing pain and related risk factors with the medical history and taking these into account in the treatment regimen. A multimodal treatment approach that involves medicinal, educational, psychological and physiotherapeutic expertise is required in these patients. A unimodal approach in the treatment is not effective. A pain physician should be involved in the treatment team as early as possible. Furthermore, psychological joint supervision should be available for these patients as several studies have demonstrated positive perioperative effects of psychological approaches on the treatment in this patient group.

Laparoscopic versus open hemihepatectomy-a cost analysis after propensity score matching.

INTRODUCTION: Cost efficiency is important for hospitals in order to provide high-quality health care for all patients. As hemihepatectomies are increasingly being performed laparoscopically, the aims of this study were to evaluate the costs of laparoscopic hemihepatectomy and to compare them to conventional open techniques. PATIENTS AND METHODS: This is a retrospective analysis of clinical outcomes and financial calculations of all patients who underwent hemihepatectomy between January 2015 and December 2016 at the Department of Surgery, Campus Charité Mitte and Campus Charité Virchow-Klinikum, Berlin, Germany, being allocated to the DRG (diagnosis-related group) H01A (complex operations of the liver and pancreas with complex intensive care treatment) or H01B (operations of the liver and pancreas without complex intensive care treatment). To overcome selection bias, a 1:1 propensity score matching (PSM) analysis was performed. RESULTS: After PSM, a total of 64 patients were identified; 32 patients underwent laparoscopic hemihepatectomy (LH); and 32 patients received open hemihepatectomy (OH). After PSM, no significant differences were observed in clinical baseline characteristics. The duration of surgery was significantly longer for patients undergoing LH compared to OH (LH, 334 min, 186-655 min; OH, 274 min, 176-454 min; p = 0.005). Patients in the LH group had a significantly shortened median hospital stay of 5 d, when compared to OH (LH, 9.5 d, 3-35 d; OH, 14.5 d, 7-37d; p = 0.005). We observed a significant higher rate of postoperative complication in the OH group (p = 0.022). Cost analysis showed median overall costs of 17,369.85€ in the LH group and 16,103.64€ in the OH group (p = 0.390). CONCLUSION: Our data suggest that higher intraoperative costs of laparoscopic liver surgery, e.g., for surgical devices and due to longer operation times, are compensated by fewer postoperative complications and consecutive shorter length of stay when compared with OH.

Activation of Akt/FKHR in the medulla oblongata contributes to spontaneous respiratory recovery after incomplete spinal cord injury in adult rats.

After incomplete spinal cord injury (SCI), patients and animals may exhibit some spontaneous functional recovery which can be partly attributed to remodeling of injured neural circuitry. This post-lesion plasticity implies spinal remodeling but increasing evidences suggest that supraspinal structures contribute also to the functional recovery. Here we tested the hypothesis that partial SCI may activate cell-signaling pathway(s) at the supraspinal level and that this molecular response may contribute to spontaneous recovery. With this aim, we used a rat model of partial cervical hemisection which injures the bulbospinal respiratory tract originating from the medulla oblongata of the brainstem but leads to a time-dependent spontaneous functional recovery of the paralyzed hemidiaphragm. We first demonstrate that after SCI the PI3K/Akt signaling pathway is activated in the medulla oblongata of the brainstem, resulting in an inactivation of its pro-apoptotic downstream target, forkhead transcription factor (FKHR/FOXO1A). Retrograde labeling of medullary premotoneurons including respiratory ones which project to phrenic motoneurons reveals an increased FKHR phosphorylation in their cell bodies together with an unchanged cell number. Medulla infusion of the PI3K inhibitor, LY294002, prevents the SCI-induced Akt and FKHR phosphorylations and activates one of its death-promoting downstream targets, Fas ligand. Quantitative EMG analyses of diaphragmatic contractility demonstrate that the inhibition of medulla PI3K/Akt signaling prevents spontaneous respiratory recovery normally observed after partial cervical SCI. Such inhibition does not however affect either baseline contractile frequency or the ventilatory reactivity under acute respiratory challenge. Together, these findings provide novel evidence of supraspinal cellular contribution to the spontaneous respiratory recovery after partial SCI.

Heterogeneous stock rats: a model to study the genetics of despair-like behavior in adolescence.

Major depressive disorder (MDD) is a complex illness caused by both genetic and environmental factors. Antidepressant resistance also has a genetic component. To date, however, very few genes have been identified for major depression or antidepressant resistance. In this study, we investigated whether outbred heterogeneous stock (HS) rats would be a suitable model to uncover the genetics of depression and its connection to antidepressant resistance. The Wistar Kyoto (WKY) rat, one of the eight founders of the HS, is a recognized animal model of juvenile depression and is resistant to fluoxetine antidepressant treatment. We therefore hypothesized that adolescent HS rats would exhibit variation in both despair-like behavior and response to fluoxetine treatment. We assessed heritability of despair-like behavior and response to sub-acute fluoxetine using a modified forced swim test (FST) in 4-week-old HS rats. We also tested whether blood transcript levels previously identified as depression biomarkers in adolescent human subjects are differentially expressed in HS rats with high vs. low FST immobility. We demonstrate heritability of despair-like behavior in 4-week-old HS rats and show that many HS rats are resistant to fluoxetine treatment. In addition, blood transcript levels of Amfr, Cdr2 and Kiaa1539, genes previously identified in human adolescents with MDD, are differentially expressed between HS rats with high vs. low immobility. These data demonstrate that FST despair-like behavior will be amenable to genetic fine-mapping in adolescent HS rats. The overlap between human and HS blood biomarkers suggest that these studies may translate to depression in humans.

p34(cdc2) and mitotic cyclin expression in the developing quail neuroretina.

After an initial proliferation phase, neurons of the central nervous system (CNS) of higher eukaryotes remain postmitotic during their entire lifespan. This requires that a very stringent control be exerted on the cell division apparatus, whose molecular mechanisms remain quite elusive. Here we have used quail neuroretina as a model to study the control of cell division in the developing CNS. In vertebrates, embryonic neuroretinal cells (NR cells) stop their proliferation at different times depending on the cell type. Most NR cells in the quail embryo become postmitotic between E7 and E8. To acquire a better understanding of the molecular events leading to quiescence in NR cells, we have analyzed the expression of cdc2 and of two activators of p34(cdc2): cyclin A and cyclin B2 in the developing neuroretina. We report that these three proteins are downregulated between E7 and E9, suggesting that a common mechanism could block their transcription in differentiating neurons. We also report, using an immunohistochemical approach, that p34(cdc2) downregulation is correlated with the appearance of the microtubule-associated protein tau. These results strongly suggest that inhibition of cdc2 gene expression is closely linked to the achievement of terminal differentiation in neurons. However, we also show that postmitotic ganglion cells precursors begin to synthesize the early neuronal differentiation marker beta3-tubulin while p34(cdc2) is still detectable in these cells, suggesting that p34(cdc2) or a closely related kinase could play a role in some "young" postmitotic neurons.

Does monoamine oxidase type B play a role in dopaminergic nerve cell death in Parkinson's disease?

Evidence supports the role of hyperoxidation phenomena in the mechanism of nerve cell death in Parkinson's disease (PD). The oxidative degradation of dopamine, catalyzed by monoamine oxidase type B (MAO-B), produces free radicals and thus could be implicated in the degenerative process. For this reason, we investigated by immunohistochemistry the distribution of MAO-B-containing cells in the midbrain of five patients with PD and five matched control subjects. MAO-B-like immunoreactivity was detected in glial cells, fibers, and neurons. Although most of the MAO-B-positive neurons probably belonged to the raphe dorsalis, we demonstrated by double-labeling immunohistochemistry that some of them were also dopaminergic. MAO-B-positive dopaminergic neurons were present in all dopaminergic groups of the control midbrain. Within the substantia nigra pars compacta, most dopaminergic neurons were located in the dorsal part of the structure. MAO-B-positive dopaminergic neurons were still detected in PD midbrains. Compared with control subjects, the loss of dopaminergic neurons containing MAO-B (-45%) was no higher than that of MAO-B-negative dopaminergic neurons (-59%). The density of MAO-B-positive glial cells varied in the control midbrains: high in the least affected dopaminergic group (the central gray substance) and low in the most affected region (the substantia nigra pars compacta). The density of MAO-B-positive glial cells within dopaminergic cell subgroups in control midbrains were negatively correlated (r = -0.94; p < 0.02) to the estimated neuronal loss in PD. We conclude that the presence of MAO-B in dopamine-containing neurons does not contribute to vulnerability in PD. Moreover, its presence in some glial cells might have a protective effect against oxidative stress induced by dopamine metabolism.

Gangliosides and parkinsonism.

The protective effect of GM1 ganglioside against nerve cell death induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was analyzed in monkey mesencephalon. Administration of GM1 before and during MPTP treatment improved motor performances compared with MPTP-treated animals that received saline rather than GM1. Postmortem analysis revealed that GM1 did not protect dopaminergic cell bodies from MPTP intoxication but resulted in an increased immunoreactivity of tyrosine hydroxylase in the perikarya and processes of the surviving neurons. These data suggest that GM1 may be potentially used as a palliative rather than a curative therapy in Parkinson's disease.

Accumulation of Ym1/2 protein in the mouse olfactory epithelium during regeneration and aging.

A unique feature of the olfactory system is its efficiency to produce new neurons in the adult. Thus, destruction of the olfactory receptor neurons (ORNs) using chemical (intranasal perfusion with ZnSO4) or surgical (axotomy or bulbectomy) methods, leads to an enhanced rate of proliferation of their progenitors and to complete ORNs regeneration. The aim of our study was to identify new factors implied in this regenerative process. Using an electrophoretic method, we observed the accumulation of a 42 kDa protein after axotomy in the olfactory mucosa, but not in the olfactory bulb. Its expression started after a few days following injury and increased massively during the phase of ORN regeneration. The purification and the sequence characterization revealed that this protein was Ym1/2, recently identified in activated macrophages present in various tissues during inflammation. Western blotting analysis of Ym1/2 confirmed the accumulation of this protein in the regenerating olfactory mucosa consecutively to olfactory axotomy or bulbectomy but also after ZnSO4 irrigation of the nasal cavity. In the olfactory mucosa of control mice, Ym1/2 was hardly detectable in young animals and became more and more abundant with increasing age. In injured and aged mice, Ym1/2 mainly accumulates in the cytoplasm of supporting cells as well as in other cells located throughout the olfactory epithelium. Our results suggest that Ym1/2 is involved in olfactory epithelium remodeling following several kinds of lesions of the adult olfactory mucosa and support the view of a critical role of inflammatory cues in neurodegeneration and aging.

Does neuromelanin contribute to the vulnerability of catecholaminergic neurons in monkeys intoxicated with MPTP?

The question has been raised as to whether neuromelanin, a by-product of catecholamine metabolism which accumulates during aging in primate midbrain neurons, contributes to the selective vulnerability of subgroups of dopaminergic neurons in Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP+) a metabolite of 1-methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) is toxic to dopaminergic neurons, particularly in primates, producing a motor syndrome similar to that observed in Parkinson's disease. To test whether this neurotoxin preferentially affects melanized neurons, the survival of melanized and non-melanized catecholaminergic neurons was analysed after MPTP intoxication in the midbrain of the cynomolgus monkey (Macaca fascicularis). Experiments were performed on six animals chronically treated with MPTP (two were severely disabled, four moderately affected) and two age-matched control monkeys. Two populations of neurons were examined on regularly spaced sections throughout the midbrain: catecholaminergic neurons, identified by tyrosine hydroxylase immunohistochemistry and neuromelanin-containing neurons, visualized by Masson's method. The total number of neurons of each type was estimated in the different midbrain catecholaminergic cell groups using computer assisted image analysis. In the midbrains of control animals not all catecholaminergic neurons contained neuromelanin. The percentage of melanized neurons compared to the total population of tyrosine hydroxylase-positive neurons was high in the substantia nigra pars compacta (81.5%) and in the locus coeruleus (98%), intermediate in the substantia nigra pars lateralis (70%), in the catecholaminergic cell group A8 (50%), and in the ventral tegmental area (41.5%) and almost nil in the central gray substance. In MPTP-treated monkeys, the severity of the loss of catecholaminergic neurons was variable within the different midbrain cell groups, though of similar intensity in severely and mildly disabled monkeys. A relationship was found between the loss of dopaminergic neurons in the different mesencephalic cell groups of MPTP-intoxicated animals and the percentage of melanized neurons they normally contain (r = 0.98; P = 0.04). The percentage loss of catecholaminergic neurons in the locus coeruleus, the only noradrenergic cell group studied, was lower than expected from the correlation curve obtained for dopaminergic cell groups. Altogether, these findings indicate: (i) that dopaminergic neurons are more vulnerable to MPTP-toxicity than noradrenergic neurons; and (ii) that among dopaminergic neurons, those containing neuromelanin are more susceptible, indicating a possible role of neuromelanin in MPTP-toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunohistochemical study of catechol-O-methyltransferase in the human mesostriatal system.

The cellular localization of catechol-O-methyltransferase was analysed in the mesostriatal system of human brain post mortem by means of immunohistochemistry. In the human nigral complex, catechol-O-methyltransferase immunostaining was not detected in melanized dopaminergic neurons, except in the ventral tegmental area and substantia nigra pars lateralis, where few neurons displayed intense immunolabelling. In the striatum, catechol-O-methyltransferase immunostaining was found in numerous cell bodies and in the neuropile. Observations at the electron microscope level revealed that catechol-O-methyltransferase immunoreactivity was present in the cell bodies of neurons and their processes, including the dendritic spines. No catechol-O-methyltransferase immunolabelling was observed in striatal nerve terminals in contact with dendritic spines, indicating that dopaminergic nerve terminals do not exhibit catechol-O-methyltransferase immunoreactivity. Catechol-O-methyltransferase-immunoreactive cell bodies and processes of glial cells were also detected in the striatum. The data suggest that catechol-O-methyltransferase is either not expressed or only slightly expressed by the dopaminergic nigrostriatal neurons, whereas it is clearly present in striatal neurons and glial cells. Thus, the catabolic degradation of striatal released dopamine by its O-methylation may involve postsynaptic neurons rather than dopaminergic presynaptic neurons. The presence of catechol-O-methyltransferase in some dopaminergic neurons of the ventral tegmental area and substantia nigra pars lateralis suggests that methylation of dopamine may occur in these neurons, which may consequently be better protected against dopamine auto-oxidation than those of the substantia nigra pars compacta.

GM-1 ganglioside promotes the recovery of surviving midbrain dopaminergic neurons in MPTP-treated monkeys.

We have examined the influence of chronic GM-1 treatment (20 mg/kg i.m. for 16 consecutive days) on the extent of dopaminergic damage induced by acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in cynomolgus monkeys using immunohistochemical and neurochemical analysis. The total number of tyrosine hydroxylase-immunoreactive neurons was reduced in different catecholaminergic mesencephalic regions of MPTP-treated monkeys such as substantia nigra pars compacta, mainly in the ventral portion of the nucleus (39% reduction), substantia nigra pars lateralis (31%), peri- and retrorubral catecholaminergic cell group and ventral tegmental area (A8 and A10 respectively, 20% reduction). A similar degree of neuronal loss was observed in the MPTP+GM-1-treated animals, suggesting that GM-1 ganglioside does not exert a protective effect against MPTP-induced dopaminergic cell loss. Moreover, no neurochemical recovery from the striatal dopaminergic depletion induced by MPTP was found after GM-1 treatment. However, the optical density of tyrosine hydroxylase fibers and the cellular tyrosine hydroxylase content were increased in the substantia nigra pars compacta and ventral tegmental area of the MPTP-treated monkeys which received GM-1 ganglioside, compared with animals treated only with the neurotoxin. These results indicate that GM-1 does not protect against cell death but exerts a neurotrophic effect on surviving dopaminergic neurons in the midbrain of MPTP-lesioned monkeys, suggesting that GM-1 ganglioside may be potentially useful for the treatment of neurodegenerative disorders such as Parkinson's disease.

Region-specific expression of cell cycle inhibitors in the adult brain.

In the adult brain, neural proliferation is almost absent and neurons are generally not renewed. By contrast, in the olfactory organ, olfactory neurons are produced continuously throughout life. To investigate whether specific cell cycle inhibitors are involved in the control of neural quiescence in adulthood, we compared their expression either in different regions of the adult brain weakly or non neurogenic or, for comparison, in the olfactory mucosa. We show that numerous cell cycle inhibitors are expressed in the adult brain either in an ubiquitous fashion (as p19Ink4d) or in specific brain regions (p15Ink4b in the forebrain, p27Kip1 and p21Cip1 in the cerebellum). By contrast p18Ink4c was expressed detectably only in the highly neurogenic olfactory epithelium. The present data suggest that various CDK inhibitors may be involved in a region-specific fashion in the maintenance of nerve cell quiescence in adults.

Tyrosine hydroxylase protein and messenger RNA in the dopaminergic nigral neurons of patients with Parkinson's disease.

To analyze the roles of transcriptional and post-transcriptional regulatory mechanisms of tyrosine hydroxylase (TH) gene expression during dopaminergic denervation in Parkinson's disease (PD), the cellular content of TH messenger RNA (mRNA) and TH protein in the substantia nigra were compared in control subjects and patients with PD. The average amounts of TH mRNA as well as those of TH protein per neuron were variable among controls but correlated to each other. In PD patients, both TH mRNA and TH protein content in nigral neurons were reduced relative to controls, however, the ratio between TH protein and TH mRNA levels was unaffected. The data suggest that, in PD: (1) TH protein content is decreased in the surviving nigral dopaminergic neurons, most likely as a result of a lowered TH mRNA cellular content. Thus the surviving neurons at end stages of the disease may be in a premorbid state. (2) The TH mRNA translation rate is not modified to compensate for dopamine deficiency.

Detection of alpha-L fucose containing carbohydrates in mouse immature olfactory neurons.

The cellular location of alpha-L fucose was studied in mice olfactory epithelium (OE) using the Ulex europaeus agglutinin-I (UEA-I) and Tetragonolobus purpureas agglutinin (TPA). In adult mice, UEA-I and TPA revealed a layer of cells that mostly correspond to immature olfactory neurons. Moreover, autoradiographic studies after 3H-T incorporation showed that UEA-I cell labelling occurred during the week following the division of neural cell precursors. In newborn animals, active neurogenesis process is associated with a higher number of UEA-I labelled cells. Olfactory neurogenesis may thus involve a transient event of protein fucosylation, preceding axonal growth.