3-O sulfation of syndecan-1 mediated by the sulfotransferase HS3ST3a1 enhances myeloma aggressiveness.

Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs. These cells bound a proliferation inducing ligand (APRIL), a key MM promoting/survival factor. APRIL binding involved the heparan sulfate (HS) chain present on syndecan-1 (SDC-1), and correlated with reactivity to the anti-HS antibody 10e4. 10e4+cells had a high proliferation activity, and were able to form colonies in 3-D cultures. 10e4+ cells were the only cells able to develop in BM after intravenous injection. They also resisted drugs in vivo, since their number increased after treatment in BM. Notably, 10e4+ cells differentiated into 10e4- cells upon in vitro and in vivo expansion. Expression of one sulfotransferase, HS3ST3a1, allowed modification of syndecan-1 to confer reactivity to 10e4 and binding to APRIL. HS3ST3a1 deletion inhibited tumorigenesis in BM. Notably, the two populations coexisted at a variable frequency in the BM of MM patients at diagnosis. In total, our results indicate that 3-O-sulfation on SDC-1 carried out by HS3ST3a1 defines aggressive MM cells, and that targeting of this enzyme could possibly be used to better control drug resistance.

Cleft lip and palate: the psychological burden of affected parents during the first three years of their children's lives.

The surgical treatment of cleft lip and palate (CLP) has been well described in the literature. Nevertheless, little is known about the psychological burden of affected parents. The aim of this study was to investigate the psychological burden in parents of children with CLP within the first 3 years of the children's lives. A standardized questionnaire (Parenting Stress Index, PSI) was administered to 33 parents of children with CLP to evaluate their psychological burden. The corresponding interview was conducted independent of any operative procedure during the yearly routine CLP consultation. Each participant's stress profile was assessed and compared with the average values of parents with non-cleft children. Psychological stress was substantially increased in all participants when compared to the parents of healthy children. This result was highly significant (P < 0.001). Parent depression (P < 0.001) and child-related requirements (P < 0.001) were the most critical subscales in the stress profile. Overall, the child-related burden was greater than the parent-related burden. These results indicate that parents of children with CLP have a higher level of psychological stress than parents of non-cleft children. This psychological stress might be reduced if addressed by specialist clinical psychologists in cleft-treating centres.

Quantitative analysis of soft tissue sagging after lateral midface fractures: A 10-year retrospective study.

BACKGROUND: Lateral midface fractures occasionally require open reduction and internal fixation to restore function and facial symmetry. However, some patients retain facial asymmetry despite undergoing surgery due to hard tissue displacement or soft tissue sagging. This study aimed to determine the influence of soft tissue sagging on the postoperative facial symmetry. METHODS: We examined the medical records of 590 patients who underwent planned plate removal after lateral midface or zygomatic bone fractures. After applying the inclusion and exclusion criteria, we analyzed 106 cases of lateral midface fractures for hard tissue displacement and soft tissue sagging using pre- and postoperative radiological imaging and postoperative face scanning. RESULTS: We observed significantly larger soft tissue sagging (p < 0.001) and hard tissue displacement (p = 0.006) on the fractured side than on the non-fractured side. There was no correlation between differences in the soft tissue sagging and those in the hard tissue displacement (|rho|=0). Linear regression analysis showed no statistical influence of sex or age group on the soft tissue sagging and hard tissue displacement. CONCLUSION: Therefore, we recommend treating soft tissue sagging as a discrete aspect of midfacial fracture treatment to achieve optimal postoperative facial symmetry. From a clinical perspective, we recommend better soft tissue management during open fracture treatment than focusing mainly on the reduction of bony hard tissues.

Correction to: Patient-Specific Mandibular Reconstruction Plates Increase Accuracy and Long-Term Stability in Immediate Alloplastic Reconstruction of Segmental Mandibular Defects.

[This corrects the article DOI: 10.1007/s12663-019-01323-9.].

Osteoporosis is accompanied by reduced CD274 expression in human bone marrow-derived mesenchymal stem cells.

Underlying pathomechanisms of osteoporosis are still not fully elucidated. Cell-based therapy approaches pose new possibilities to treat osteoporosis and its complications. The aim of this study was to quantify differences in human bone marrow-derived mesenchymal stem cells (hBMSCs) between healthy donors and those suffering from clinically manifest osteoporosis. Cell samples of seven donors for each group were selected retrospectively from the hBMSC cell bank of the Trauma Department of Hannover Medical School. Cells were evaluated for their adipogenic, osteogenic and chondrogenic differentiation potential, for their proliferation potential and expression of surface antigens. Furthermore, a RT2 Osteoporosis Profiler PCR array, as well as quantitative real-time PCR were carried out to evaluate changes in gene expression. Cultivated hBMSCs from osteoporotic donors showed significantly lower cell surface expression of CD274 (4.98 % ± 2.38 %) than those from the control group (26.03 % ± 13.39 %; p = 0.007), as assessed by flow cytometry. In osteoporotic patients, genes involved in inhibition of the anabolic WNT signalling pathway and those associated with stimulation of bone resorption were significantly upregulated. Apart from these changes, no significant differences were found for the other cell surface antigens, adipogenic, osteogenic and chondrogenic differentiation ability as well as proliferation potential. These findings supported the theory of an influence of CD274 on the regulation of bone metabolism. CD274 might be a promising target for further investigations of the pathogenesis of osteoporosis and of cell-based therapies involving MSCs.

Intraoperative real-time navigation and intraoperative three-dimensional imaging for patient-specific total temporomandibular joint replacement.

Customized solutions for replacement of the temporomandibular joint (TMJ) along with surgical guides enable precise and fast transfer of the virtual plan to the patient. However, these guides lack information on screw vectors and length, and well-defined borders for bony resections towards the medial skull base. This retrospective study was performed to investigate the feasibility and benefit of real-time navigation and intraoperative three-dimensional imaging during total TMJ replacement (TJR), as well as patient clinical outcomes. Between 2016 and 2020, 26 customized prostheses were implanted in 21 patients either with or without real-time navigation and instrument tracking. The clinical, surgical, radiological, and navigational data were analysed. The accuracy of navigation registration with instrument tracking, precision of screw insertion, and implant and screw positions were analysed by fusion of the virtual plan and surgical outcome. Real-time navigation aided orientation during lateral skull base dissection and resection. However, the results of real-time navigation-aided drilling were inconclusive regarding vector and length control. At a mean 15.3±3.0 months of follow-up, average mouth opening had improved from 21.69±2.80mm to 36.40±1.25mm; the average pain score decreased from 6.18±0.74 to 1.06±0.52. Thus, intraoperative real-time navigation for TJR assists lateral skull base dissection and resection.

Patient-Specific Mandibular Reconstruction Plates Increase Accuracy and Long-Term Stability in Immediate Alloplastic Reconstruction of Segmental Mandibular Defects.

OBJECTIVES: The aim of the current study was to evaluate potential differences in the accuracy of mandibular reconstruction and long-term stability, with respect to different reconstructive procedures. METHODS: In total, 42 patients who had undergone primary segmental mandibular resection with immediate alloplastic reconstruction, with either manually pre-bent or patient-specific mandibular reconstruction plates (PSMRP), were included in this study. Mandibular dimensions, in terms of six clinically relevant distances (capitulum [most lateral points], capitulum [most medial points], incisura [most caudal points], mandibular foramina, coronoid process [most cranial points], dorsal tip of the mandible closest to the gonion point) determined from tomographic images, were compared prior to, and after surgery. RESULTS: Dimensional alterations were significantly more often found when conventionally bent titanium reconstruction plates were used. These occurred in the area of the coronoid process (p = 0.014). Plate fractures were significantly (p = 0.022) more often found within the manually pre-bent group than within the PSMRP group (17%/0%). CONCLUSION: The results suggest that the use of PSMRP may prevent rotation of the proximal mandibular segment, thus avoiding functional impairment. In addition, the use of PSMRP may potentially enhance the long-term stability of alloplastic reconstructions.

Analysis of historical negative control group data from the rat in vivo micronucleus assay.

A database of micronuclei counts for historical negative control data from rat in vivo micronuclei tests performed in 10 different laboratories was established. Data were available from over 4000 negative control rats from 10 laboratories. The mean frequency of micronucleated cells (MN)/1000 cells ranged from 0.44 to 2.22, a 5-fold range. Overall there were no major sex or strain differences in frequency, although there were some small but statistically significant differences within laboratories. There was appreciable variability between experiments compared with variability within experiments in some laboratories. No specific factor was identified which could explain this variability although it was noted that many different vehicles were used in the experiments. It is hoped that these data will help laboratories beginning studies with the rat micronucleus assay and those involved in the assessment of micronucleus assay results.

Dose-response relationship of temozolomide, determined by the Pig-a, comet, and micronucleus assay.

Temozolomide (TMZ), a monofunctional alkylating agent, was selected as a model compound to determine its quantitative genotoxic dose-response relationship in different tissues (blood, liver, and jejunum) and endpoints [Pig-a-, comet-, and micronucleus assay (MNT)] in male rats. TMZ was administered p.o. over 5 consecutive days (day 1-5), followed by a treatment-free period of 50 days (day 6-56) and a final administration prior to necropsy (day 57-59). TMZ showed a dose-dependent increase in DNA damage in all interrogated endpoints. A statistically significant increase in Pig-a mutant phenotypes was observed on day 44 starting at 7.5 mg/kg/day for mutant reticulocytes (for RETCD59-) and at 3.75 mg/kg/day for mutant red blood cells (RBCCD59-), respectively. In addition, a statistically significant increase in cytogenetic damage, as measured by micronucleated reticulocytes, was observed starting at 3.75 mg/kg/day on day 3 and 1.5 mg/kg/day on day 59. DNA strand breaks, as detected by the comet assay, showed a dose-dependent and statistically significant increase in liver, blood, and jejunum starting at doses of 3.75, 3.75, and 7.5 mg/kg/day, respectively. The dose-response relationships of the Pig-a, MNT, and comet data were analyzed for possible points of departure (PoD) using the benchmark-dose (BMD) software PROAST with different critical effect sizes (CES) (BMD0.1, BMD0.5, BMD1, and BMD1SD). Overall, PoD values show a high concordance between different tissues and endpoints, underlining the suitability of this experimental design to explore quantitative dose-response relationships in a variety of different tissues and endpoints, while minimizing animal use.

Autocrine amplification of immature myeloid cells by IL-6 in multiple myeloma-infiltrated bone marrow.

Multiple myeloma (MM) invariably develops in the bone marrow (BM), indicating the strong requirement of this tumor for the peculiar BM microenvironment, rich in cytokine and hematopoietic precursor cells. Interleukin-6 (IL-6) and a proliferation inducing ligand (APRIL) are key cytokines implicated in MM development. Here, we show that MM cells changed the hematopoietic microenvironment early upon BM infiltration by strongly downregulating hematopoietic precursor cells from all lineages except myeloid precursor cells. Myeloid precursor cells constituted a major source of APRIL in MM-infiltrated BM, and their proliferative response to IL-6 upregulation explained their relative resistance to MM infiltration. The osteolytic molecule receptor activator of NF-kB ligand (RANK-L) expressed by MM cells started this myeloid proliferation by inducing in a contact-dependent manner IL-6 production by myeloid precursor cells themselves. Taken together, our data demonstrate that MM cells do not simply displace hematopoietic cells upon BM infiltration, but rather selectively modulate the BM microenvironment to preserve a pool of high APRIL-producing myeloid precursor cells. Our data also identify a positive regulation of APRIL by IL-6 in myeloid precursor cells.

The effect of aggression management training programmes for nursing staff and students working in an acute hospital setting. A narrative review of current literature.

BACKGROUND: Patient aggression is a longstanding problem in general hospital nursing. Staff training is recommended to tackle workplace aggression originating from patients or visitors, yet evidence on training effects is scarce. AIMS: To review and collate current research evidence on the effect of aggression management training for nurses and nursing students working in general hospitals, and to derive recommendations for further research. DESIGN: Systematic, narrative review. DATA SOURCES: Embase, MEDLINE, the Cochrane library, CINAHL, PsycINFO, pubmed, psycArticles, Psychology and Behavioural Sciences Collection were searched for articles evaluating training programs for staff and students in acute hospital adult nursing in a 'before/after' design. Studies published between January 2000 and September 2011 in English, French or German were eligible of inclusion. REVIEW METHODS: The methodological quality of included studies was assessed with the 'Quality Assessment Tool for Quantitative Studies'. Main outcomes i.e. attitudes, confidence, skills and knowledge were collated. RESULTS: Nine studies were included. Two had a weak, six a moderate, and one a strong study design. All studies reported increased confidence, improved attitude, skills, and knowledge about risk factors post training. There was no significant change in incidence of patient aggression. CONCLUSION: Our findings corroborate findings of reviews on training in mental health care, which point to a lack of high quality research. Training does not reduce the incidence of aggressive acts. Aggression needs to be tackled at an organizational level.

[Prevalence and symptoms of vitamin D deficiency in general practices]. / Prävalenz und Symptomatik des Vitamin-D-Mangels in der Hausarztpraxis.

In 776 primary care patients serum vitamin D level was measured in month of september showing deficiency (<50 nmol/l) in 45,1%, severe deficiency (<30 nmol/l) in 9,8% and serum levels below the recommended target level of 75 nmol/l in 88,9% of cases. Three possible symptoms of vitamin D deficiency were assessed by a visual analogue scale (0-10): fatigue, muscle weakness, and muscle and joint pain. A significant correlation between muscle weakness and degree of vitamin D deficiency was shown (p=0,04), whereas there was no correlation in the two other symptoms. However, patients with vitamin D deficiency more frequently reported fatigue (p=0,02) and muscle weakness (p=0,009) than patients without deficiency did, and no difference was seen concerning muscle and joint pain.

[Characteristics of consultations by general practitioners in Switzerland - time, topics and verbal behaviour]. / Die Konsultationen beim Hausarzt: Aufbau, Themen und Redeverteilung.

To conduct consultations is the main task of general practitioners. This study concerns itself with consultations, what they are about, how they are structured and how their achievements can be described. In total, 127 recorded consultations were analysed. The 12 recorded general practitioners were themselves involved in the data analysis. The analysis confirms that in comparison to the European average, the Swiss consultation is rather long with a consultation length of 12.5 minutes. 80% of the consultation time is taken up by mere conversation. Per average, three medical topics are discussed within that time. Thus, about three minutes are at disposal per topic. In every consultation we can also find one non-medical topic. The structure of a consultation is complex and changes continually depending on the performed tasks.

[Smoking behaviour and willingness to stop smoking in patients admitted in an internal medicine ward]. / Untersuchung der Rauchgewohnheiten und der Bereitschaft zum Rauchstopp bei Patienten einer internistischen Abteilung.

Smoking is one of the leading preventable risk factors for the development of lung-, cardio-vascular diseases and cancer. We report results of a prospective survey regarding smoking behaviour and willingness to stop smoking in patients of an internal medicine clinic. Twenty percent of participants admitted smoking cigarettes in the previous 7 days. Smokers were more often males and were younger than non- or ex-smokers. Every second smoker reported being told to stop smoking by a physician before but only about a third was offered active support in doing so. About half of the smoking participants were interested to quit smoking and to participate in a hospital-based smoking cessation program. In patients admitted to the hospital, smoking behaviour and willingness to quit smoking should be recorded and help in quitting smoking should be offered actively. Beside recording smoking behaviour and willingness to quit, patients who are admitted in the hospital should be offered help to quit smoking or to join a proactive structured smoking cessation program.

[Fatigue and anemia]. / Müdigkeit und Anämie.

We herein report on an 80-year old male patient with a history of muscle weakness, fatigue and weight loss since several months. Because of a pathologic synacthen test in combination with decreased levels of ACTH, we diagnosed a secondary chronic adrenal insufficiency. Because of a normochromic, normocytic, and hypo-proliferative anemia, bone marrow puncture was performed, showing an anemia of chronic disease. We initiated hydrocortisone and anemia and patients' symptoms were fully reconstituted.

Design, construction, and first commissioning results of superconducting source for ions at NSCL/MSU.

A new electron cyclotron resonance ion source (ECRIS) was constructed at the NSCL/MSU to replace the existing SC-ECRIS. This ECRIS operates at 18+14.5 GHz microwave frequencies with a planned upgrade to 24-28 GHz in the second phase of commissioning. A superconducting hexapole coil system produce the radial magnetic field; the axial trapping is produced with six superconducting solenoid coils enclosed in an iron yoke to allow the optimization of the distance between the plasma electrode and the resonant zone in the plasma. We report the details of the design, construction, and initial commissioning results of this new ECRIS.

Inhibitory ligand-gated ion channels as substrates for general anesthetic actions.

General anesthetics have been in clinical use for more than 160 years. Nevertheless, their mechanism of action is still only poorly understood. In this review, we describe studies suggesting that inhibitory ligand-gated ion channels are potential targets for general anesthetics in vitro and describe how the involvement of y-aminobutyric acid (GABA)(A) receptor subtypes in anesthetic actions could be demonstrated by genetic studies in vivo.

Cortical glutamatergic neurons mediate the motor sedative action of diazepam.

The neuronal circuits mediating the sedative action of diazepam are unknown. Although the motor-depressant action of diazepam is suppressed in alpha1(H101R) homozygous knockin mice expressing diazepam-insensitive alpha1-GABA(A) receptors, global alpha1-knockout mice show greater motor sedation with diazepam. To clarify this paradox, attributed to compensatory up-regulation of the alpha2 and alpha3 subunits, and to further identify the neuronal circuits supporting diazepam-induced sedation, we generated Emx1-cre-recombinase-mediated conditional mutant mice, selectively lacking the alpha1 subunit (forebrain-specific alpha1(-/-)) or expressing either a single wild-type (H) or a single point-mutated (R) alpha1 allele (forebrain-specific alpha1(-/H) and alpha1(-/R) mice, respectively) in forebrain glutamatergic neurons. In the rest of the brain, alpha1(-/R) mutants are heterozygous alpha1(H101R) mice. Forebrain-specific alpha1(-/-) mice showed enhanced diazepam-induced motor depression and increased expression of the alpha2 and alpha3 subunits in the neocortex and hippocampus, in comparison with their pseudo-wild-type littermates. Forebrain-specific alpha1(-/R) mice were less sensitive than alpha1(-/H) mice to the motor-depressing action of diazepam, but each of these conditional mutants had a similar behavioral response as their corresponding control littermates. Unexpectedly, expression of the alpha1 subunit was reduced in forebrain, notably in alpha1(-/R) mice, and the alpha3 subunit was up-regulated in neocortex, indicating that proper alpha1 subunit expression requires both alleles. In conclusion, conditional manipulation of GABA(A) receptor alpha1 subunit expression can induce compensatory changes in the affected areas. Specifically, alterations in GABA(A) receptor expression restricted to forebrain glutamatergic neurons reproduce the behavioral effects seen after a global alteration, thereby implicating these neurons in the motor-sedative effect of diazepam.

[Therapy-refractory arterial hypertension in a young patient]. / Therapierefraktäre arterielle Hypertonie bei einem jungen Patienten.

We report on a 41-year-old patient admitted for refractory arterial hypertension that had developed after a curative chemotherapy regimen due to seminoma stadium IIb four years ago. After exclusion of secondary forms of arterial hypertension (actually unsuccessfully treated with 5 different antihypertensive drugs) we performed a controlled medication intake-trial in our outpatient clinic. 90 minutes after taking the pills the patient complained of dizziness and perspiration while hypotension and bradycardia were measured simultaneously. Due to the difficult psychosocial situation (conflicts with the insurance and in the family, financial problems) and the suspected narcisstic personality disorder the issue of the proven malcompliance was not openly discussed in order to preserve the patient-doctor alliance. The antihypertensive regimen was then reduced to a double regimen. In the second part of the article the most common reasons for refractory arterial hypertension, especially the problem of treatment malcompliance, are summarized.