Search

Concurrently to the recent development of percutaneous tracheostomy techniques in the intensive care unit (ICU), the amount of tracheostomized brain-injured patients has increased. Despites its advantages, tracheostomy may represent an obstacle to their orientation towards conventional hospitalization or rehabilitation services. To date, there is no recommendation for tracheostomy weaning outside of the ICU. We created a pluridisciplinary tracheostomy weaning protocol relying on standardized criteria but adapted to each patient's characteristics and that does not require instrumental assessment. It was tested in a prospective, single-centre, non-randomized cohort study. Inclusion criteria were age > 18 years, hospitalized for an acquired brain injury (ABI), tracheostomized during an ICU stay, and weaned from mechanical ventilation. The exclusion criterion was severe malnutrition. Decannulation failure was defined as recannulation within 96 h after decannulation. Thirty tracheostomized ABI patients from our neurosurgery department were successively and exhaustively included after ICU discharge. Twenty-six patients were decannulated (decannulation rate, 90%). None of them were recannulated (success rate, 100%). Two patients never reached the decannulation stage. Two patients died during the procedure. Mean tracheostomy weaning duration (inclusion to decannulation) was 7.6 (standard deviation [SD]: 4.6) days and mean total tracheostomy time (insertion to decannulation) was 42.5 (SD: 24.8) days. Our results demonstrate that our protocol might be able to determine without instrumental assessment which patient can be successfully decannulated. Therefore, it may be used safely outside ICU or a specialized unit. Moreover, our tracheostomy weaning duration is very short as compared to the current literature., (© 2023. The Author(s).)

Purpose: Outcomes of multiple myeloma (MM) patients who are refractory to daratumumab are dismal and no standard of treatment exists for this patients' population. Here, we investigate the role of pomalidomide combinations in daratumumab-refractory MM patients., Methods: We performed a retrospective analysis of myeloma patients treated at four referral centers (three in Germany and one in Italy). Review chart identified 30 patients with relapsed and refractory myeloma, who progressed during treatment with daratumumab and were treated with pomalidomide-based combinations in the subsequent lines of therapy., Results: Responses improved from 37% with daratumumab to 53% with pomalidomide. Of seven patients with extramedullary MM (EMM), four achieved a clinical stabilization with pomalidomide, including one patient with a long-lasting complete response. Median progression-free survival and overall survival were 6 and 12 months, respectively. Pomalidomide combinations were well tolerated, no patient discontinued treatment due to adverse events., Conclusion: These data show that pomalidomide-based combinations can be an effective and safe salvage regimen for daratumumab-refractory patients, including those with EMM., (© 2023. The Author(s).)

Purpose: Multiple myeloma (MM) remains an incurable hematologic malignancy which ultimately develops drug resistance and evades treatment. Despite substantial therapeutic advances over the past years, the clinical failure rate of preclinically promising anti-MM drugs remains substantial. More realistic in vitro models are thus required to better predict clinical efficacy of a preclinically active compound., Methods: Here, we report on the establishment of a conical agarose 3D co-culture platform for the preclinical propagation of primary MM cells ex vivo. Cell growth was compared to yet established 2D and liquid overlay systems. MM cell lines (MMCL: RPMI-8226, U266, OPM-2) and primary patient specimens were tested. Drug sensitivity was examined by exploring the cytotoxic effect of bortezomib and the deubiquitinase inhibitor auranofin under various conditions., Results: In contrast to 2D and liquid overlay, cell proliferation in the 3D array followed a sigmoidal curve characterized by an initial growth delay but more durable proliferation of MMCL over 12 days of culture. Primary MM specimens did not expand in ex vivo monoculture, but required co-culture support by a human stromal cell line (HS-5, MSP-1). HS-5 induced a > fivefold increase in cluster volume and maintained long-term viability of primary MM cells for up to 21 days. Bortezomib and auranofin induced less cytotoxicity under 3D vs. 2D condition and in co- vs. monoculture, respectively., Conclusions: This study introduces a novel model that is capable of long-term propagation and drug testing of primary MM specimens ex vivo overcoming some of the pitfalls of currently available in vitro models., (© 2022. The Author(s).)

Knowledge on cortical development is based mainly on small rodents besides primates and carnivores, all being altricial nestlings. Ungulates are precocial and born with nearly mature sensory and motor systems. Almost no information is available on ungulate brain development. Here, we analyzed European wild boar cortex development, focusing on the neuropeptide Y immunoreactive (NPY-ir) neuron system in dorsoparietal cortex from E35 to P30. Transient NPY-ir neuron types including archaic cells of the cortical plate and axonal loop cells of the subplate which appear by E60 concurrent with the establishment of the ungulate brain basic sulcal pattern. From E70, NPY-ir axons have an axon initial segment which elongates and shifts closer towards the axon's point of origin until P30. From E85 onwards (birth at E114), NPY-ir neurons in cortical layers form basket cell-like local and Martinotti cell-like ascending axonal projections. The mature NPY-ir pattern is recognizable at E110. Together, morphologies are conserved across species, but timing is not: in pig, the adult pattern largely forms prenatally.

BAL30072 is a new monocyclic β-lactam antibiotic under development which provides a therapeutic option for the treatment of severe infections caused by multi-drug-resistant Gram-negative bacteria. Despite the absence of liver toxicity in preclinical studies in rats and marmosets and in single dose clinical studies in humans, increased transaminase activities were observed in healthy subjects in multiple-dose clinical studies. We, therefore, initiated a comprehensive program to find out the mechanisms leading to hepatocellular injury using HepG2 cells (human hepatocellular carcinoma cell line), HepaRG cells (inducible hepatocytes derived from a human hepatic progenitor cell line), and human liver microtissue preparations. Our investigations demonstrated a concentration- and time-dependent reduction of the ATP content of BAL30072-treated HepG2 cells and liver microtissues. BAL30072 impaired oxygen consumption by HepG2 cells at clinically relevant concentrations, inhibited complexes II and III of the mitochondrial electron transport chain, increased the production of reactive oxygen species (ROS), and reduced the mitochondrial membrane potential. Furthermore, BAL 30072 impaired mitochondrial fatty acid metabolism, inhibited glycolysis, and was associated with hepatocyte apoptosis. Co-administration of N-acetyl-L-cysteine partially protected hepatocytes from BAL30072-mediated toxicity, underscoring the role of oxidative damage in the observed hepatocellular toxicity. In conclusion, BAL30072 is toxic for liver mitochondria and inhibits glycolysis at clinically relevant concentrations. Impaired hepatic mitochondrial function and inhibition of glycolysis can explain liver injury observed in human subjects receiving long-term treatment with this compound.

Multiple myeloma (MM) is a cancer originating from terminally differentiated B lymphocytes, the plasma cells and is classified as a B cell non-Hodgkin lymphoma. As clonal plasma cells secrete immunoglobulin molecules (lacking antigenic specificity), an "M component" can incidentally be detected. Besides intact immunoglobulin molecules, free light chains can be produced. Although there is no specific treatment for monoclonal gammopathy of undetermined significance (MGUS), which is the defined as the presence of clonal bone marrow plasma cells and low levels (serum and/or urine) of the M component, it should be followed up in affected individuals. The symptoms of MM are numerous and often nonspecific. Diagnosis includes the quantification of monoclonal proteins in serum and urine, blood count, electrolytes and renal function, imaging of the skeleton and bone marrow puncture. The cornerstone of therapy includes melphalan- or cyclophosphamide-based regimens incorporating one of the "novel drugs" (i.e. bortezomib, thalidomide, or lenalidomide).

Axons are subdivided into functionally organized microdomains, which are required for generation and propagation of action potentials (APs). In the central nervous system (CNS), APs are generated near the soma in the axon initial segment (AIS) and propagated by nodes of Ranvier (noR). The crucial role of the membrane adapter proteins ankyrin-B and ankyrin-G as organizers of AIS and noR is now well established. By comparison, little is known on the localization and function of these proteins in sensory axon terminals of the peripheral nervous systems (PNS). Here, we tested the hypothesis that somatosensory PNS terminals are organized by distinct members of the ankyrin protein family. We discovered a specific distribution of ankyrin-B in somatosensory axon terminals of skin and muscle. Specifically, ankyrin-B was localized along the membrane of axons innervating Meissner corpuscles, Pacinian corpuscles and hair follicle receptors. Likewise, proprioceptive terminals of muscle spindles exhibited prominent ankyrin-B expression. Furthermore, ankyrin-B expression extended into nociceptive and thermoceptive intraepidermal nerve fibers. Interestingly, all studied somatosensory terminals were largely devoid of ankyrin-G, indicating that this scaffolding protein does not contribute to organization of mechanoelectric transduction zones in peripheral somatosensory neurons. Instead, we propose that ankyrin-B serves as a major membrane organizer in mechanoreceptive and nociceptive terminals of the PNS.

Rat liver nuclei have been studied by transmission electron microscopy after resuspension in a phosphate-buffered salt solution containing SO2-4 as the quantitatively dominant anion. Owing to the high solubility of chromatin in the presence of SO2-4 instead of Cl- at isotonicity, nuclei are depleted for chromatin by DNase I digestion in this buffer, eliminating the need for high-salt extraction. This shows that at least 75% of the nuclear pore complexes are associated with fibrogranular structures, which ramify as a network throughout the nucleus, interconnecting the nuclear lamina, interchromatin granule clusters and nucleoli. Perichromatin granules are located in this material proximal to the nuclear pore complexes. Most of the chromatin is removed without major impact on the network, but below a level of 25% residual chromatin there is a considerable reduction of this material, and only about 15% of the connections to the nuclear pore complexes are resistant to digestion with DNase I or streptodornase A and B. The percentage of nuclear pore complexes connected to the network is further reduced by salt extraction and RNase treatment. These results suggest that DNA is an integral part of the network, which presumably plays a role in nucleo-cytoplasmic transport of RNA and protein.

Spondylolysis and spondylolisthesis occur predominantly in the lower lumbar spine. Besides congenital defects such as predisposition of spondylolysis the correlation between competitive sports activities and an increased incidence of spondylolysis is proved. In early stages, complete healing can be achieved by conservative treatment (abstinence from sports activities for 3 months, orthesis). Persistence of pain, neurologic symptoms and progression of vertebral slipping are indications for operative treatment (reconstruction of the isthmus, dorso-ventral spondylodesis). The exercise tolerance depends on the extent of instability, progression of vertebral slipping and clinical symptoms. The limits of exercise tolerance vary among the individual athletes and require the decision of the physician. Backstroke swimming, abdominal and back muscle strengthening exercises, and types of sport involving smooth movements are advisable. Sports education in school is possible without restriction in patients with stable spondylolysis and in those with spondylolisthesis without unfavourable concomitant factors.

Spondylolysis and spondylolisthesis occur predominantly in the lower lumbar spine. Besides congenital defects such as predisposition of spondylolysis the correlation between competitive sports activities and an increased incidence of spondylolysis is proved. In early stages, complete healing can be achieved by conservative treatment (abstinence from sports activities for 3 months, orthesis). Persistence of pain, neurologic symptoms and progression of vertebral slipping are indications for operative treatment (reconstruction of the isthmus, dorso-ventral spondylodesis). The exercise tolerance depends on the extent of instability, progression of vertebral slipping and clinical symptoms. The limits of exercise tolerance vary among the individual athletes and require the decision of the physician. Backstroke swimming, abdominal and back muscle strengthening exercises, and types of sport involving smooth movements are advisable. Sports education in school is possible without restriction in patients with stable spondylolysis and in those with spondylolisthesis without unfavourable concomitant factors.