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We study the small singular values of the 2-dimensional semiclassical differential operator P=2e-ϕ/h∘hDz¯∘eϕ/hon S1+iS1and on S1+iR, where ϕis given by sinyand by y3/3, respectively. The key feature of this model is the fact that we can pinpoint precisely where in phase space the Poisson bracket {p,p¯}=0, where pis the semiclassical symbol of P. We give a precise asymptotic description of the exponentially small singular values of Pby studying the tunneling effects of an associated Witten complex. We use this to determine a Weyl law for the exponentially small singular values of P.

Aktuelle Diskussionen um zeitgemäße Formen der Büroarbeit und der Organisation von Arbeit insgesamt fokussieren einerseits den vermehrten Einsatz digitaler Kommunikationstechnik, andererseits geht es um den Abbau formaler Hierarchien und den Ausbau selbstorganisierter Teams. Dass auch diese mediatisiert arbeitenden Teams Führung brauchen, steht dabei außer Frage. Dieser Umstand aber stellt die herkömmliche, vor allem an formalen, hierarchischen Positionen orientierte Führungsforschung vor eine Schwierigkeit: Wie lässt sich Führung noch beobachten, wenn unklar bleibt, von wem sie ausgeht? Der Artikel schlägt eine Alternative vor, die Führung als sozialen Prozess beschreibt. Denn es ist bemerkenswert, dass in den einschlägigen Publikationen zu Führung unklar bleibt, wie sich Führung eigentlich ereignet. Die Studie liefert hierfür erste Hinweise, indem sie beobachtet, inwiefern Führung in virtuellen Teambesprechungen erforderlich wird. Dazu wird ein sequenzielles Führungsverständnis zugrunde gelegt und erstmals empirisch untersucht, das Führung als „situativ erfolgreiche Einflussnahme in kritischen Momenten“ definiert. Das Ergebnis ist eine erste Typisierung solcher kritischen Momente, welche zukünftiger Forschung als Grundlage dienen kann.

B-cell maturation antigen (BCMA)–targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9—not estimable) and 9.1 (1.5—not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.gov as NCT04133636.

AS SIGNAL EDGE RATES GET FASTER, designers of today's high-speed digital pc boards encounter problems that were unimaginable a few years ago. At less than 1-nsec edge rates, the potential [...]

Despite treatment advances, patients with multiple myeloma (MM) often progress through standard drug classes including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). LocoMMotion (ClinicalTrials.gov identifier: NCT04035226) is the first prospective study of real-life standard of care (SOC) in triple-class exposed (received at least a PI, IMiD, and anti-CD38 mAb) patients with relapsed/refractory MM (RRMM). Patients (N= 248; ECOG performance status of 0–1, ≥3 prior lines of therapy or double refractory to a PI and IMiD) were treated with median 4.0 (range, 1–20) cycles of SOC therapy. Overall response rate was 29.8% (95% CI: 24.2–36.0). Median progression-free survival (PFS) and median overall survival (OS) were 4.6 (95% CI: 3.9–5.6) and 12.4 months (95% CI: 10.3–NE). Treatment-emergent adverse events (TEAEs) were reported in 83.5% of patients (52.8% grade 3/4). Altogether, 107 deaths occurred, due to progressive disease (n= 74), TEAEs (n= 19), and other reasons (n= 14). The 92 varied regimens utilized demonstrate a lack of clear SOC for heavily pretreated, triple-class exposed patients with RRMM in real-world practice and result in poor outcomes. This supports a need for new treatments with novel mechanisms of action.

Background. Non-Hodgkin lymphomas (NHL) account for approximately 50% of neoplasms in patients with ataxia teleangiectasia (AT). Prognosis is poor. Published data regarding the treatment of NHL in patients with AT suggested that these children respond poorly to therapy. The authors report on an infant with AT with mediastinal high-grade T-NHL who remained in continuous complete remission after chemotherapy. Diagnosis of AT was established after tumor diagnosis. Methods and Results. The 7-month-old boy was treated according to the acute lymphoblastic leukemia-Berlin, Frankfurt, Munster 86 protocol. The therapeutic response was prompt, but therapy had to be stopped because of severe side effects. Surprisingly, the boy remained in a stable complete remission for 3 1/2 years. Then tumors in both kidneys occurred and the child died a few months later. Postmortem examination demonstrated large tumors in both kidneys caused by a low-grade malignant lymphoma of B-cell lineage. Conclusion. Congenital immune deficiency should be ruled out at diagnosis of rare malignancies in respect to age. NHL in patients with AT can be cured, but poor tolerance to chemotherapy has to be considered. Patients whose disease has been cured may be at high risk for development of a second independent malignancy. Cancer 1994; 73:1522-5.

Abstract Objective To determine the effectiveness of extracorporeal shock wave therapy compared with placebo in the treatment of chronic plantar fasciitis. Design Randomised, blinded, multicentre trial with parallel group design. [...]

Doctors report the first known case of primary lymphangiectasia occurring before birth. This disease is caused by a malformation of lymph vessels, which causes swelling due to fluid retention, diarrhea, growth restriction, and intestinal malabsorption.

Second harmonic generation (SHG) microscopy is a powerful tool for label free ex vivo or in vivo imaging, widely used to investigate structure and organization of endogenous SHG emitting proteins such as myosin or collagen. Polarization resolved SHG microscopy renders supplementary information and is used to probe different molecular states. This development towards functional SHG microscopy is calling for new methods for high speed functional imaging of dynamic processes. In this work we present two approaches with linear polarized light and demonstrate high speed line scan measurements of the molecular dynamics of the motor protein myosin with a time resolution of 1 ms in mammalian muscle cells. Such a high speed functional SHG microscopy has high potential to deliver new insights into structural and temporal molecular dynamics under ex vivo or in vivo conditions.

Martin Vogel, news head of the BBC's business development, believes that the BBC should increase its news coverage to various platforms. According to Vogel, in response to changing habits of the viewing audience, the media concern has introduced BBC News Online.

Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P= .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

For 10 years now, we have been observing an epidemic of acute hepatitis C (AHC) infections among HIV-positive men who have sex with men. First outbreaks have been observed in Europe with recent epidemics also in the United States and Australia. Even though randomized controlled studies on the best management of AHC infections in HIV-positive individuals are still lacking, published data on clinical studies and cohort studies allow to give guidance on epidemiological trends, natural course and treatment of these patients.

The second harmonic generation (SHG) signal intensity sourced from skeletal muscle myosin II strongly depends on the polarization of the incident laser beam relative to the muscle fiber axis. This dependence is related to the second-order susceptibility χ(2), which can be described by a single component ratio γunder generally assumed symmetries. We precisely extracted γfrom SHG polarization dependence curves with an extended focal field model. In murine myofibrillar preparations, we have found two distinct polarization dependencies: With the actomyosin system in the rigor state, γrighas a mean value of γrig = 0.52 (SD = 0.04, n= 55); in a relaxed state where myosin is not bound to actin, γrelhas a mean value of γrel= 0.24 (SD = 0.07, n = 70). We observed a similar value in an activated state where the myosin power stroke was pharmacologically inhibited using N-benzyl-p-toluene sulfonamide. In summary, different actomyosin states can be visualized noninvasively with SHG microscopy. Specifically, SHG even allows us to distinguish different actin-bound states of myosin II using γas a parameter.

Background Early treatment of acute HCV infection has been shown to improve virological response rates in HIV-positive patients; however, details on when and how to best treat acute HCV infection remain unclear at present.Methods In this European multicentre cohort study, HIV-positive patients with acute HCV infection were offered immediate or delayed anti-HCV therapy, pegylated interferon or pegylated interferon plus ribavirin combination therapy for 24 or 48 weeks, depending on the local protocol. The main outcome measure was the rate of sustained virological response (SVR).Results A total of 150 HIV-infected men with acute HCV were enrolled between 2001 and 2006, 111 of whom received anti-HCV therapy. The predominant HCV genotype was type 1 and was present in 71 (64%) patients. Patients were treated with pegylated interferon (n=14) or pegylated interferon plus ribavirin (n=97), with a median duration of treatment of 25 weeks. SVR was obtained in 62% (95% confidence interval 52–71) of patients. There was no difference in SVR by genotype, CD4+T-cell count, HIV RNA, HCV RNA, alanine amino-transferase levels or use of ribavirin. Negative HCV RNA at weeks 4 and 12 were strong predictors of SVR.Conclusions High rates of SVR (62%) were obtained in HIV-coinfected patients with acute HCV infection undergoing early anti-HCV treatment using pegylated interferon alone or in combination with ribavirin. Treatment response at weeks 4 and 12 might be of help to further guide treatment duration. Urgent prospective studies are needed to further determine the optimal treatment regimen and the duration of therapy.

Chronic HCV co-infection is present in up to one third of HIV-positive patients in Europe. In recent years, apart from the traditional transmission route of intravenous drug abuse, outbreaks of sexually transmitted acute HCV infections, mainly among HIV-positive men who have sex with men, have contributed to the overall disease burden. Because the natural course of HCV infection is substantially accelerated in HIV-co-infection, end-stage liver disease has become the most frequent cause of non-AIDS related death in this population. Therefore every HIV/HCV co-infected patient should be evaluated for possible anti-HCV therapy with the goal of reaching a sustained virological response and thus cure of hepatitis C infection. The standard of care for the treatment of chronic HCV infection in HIV-infected remains a pegylated interferon in combination with weight-adapted ribavirin. HAART should not be withheld from HCV co-infected patients due to concerns of drug related hepatotoxicity and in patients with reduced CD4-cell counts HAART should be started first. Under pegylated interferon and ribavirin combination therapy drug to drug interactions and cumulated toxicity between nucleoside analogues and anti-HCV therapy may be observed and concomitant didanosine use is contraindicated and zidovudine and stavudine should be avoided if possible. The development of new drugs for the treatment of chronic hepatitis C represents a promising perspective also for HIV positive patients. However, these substances will probably reach clinical routine for HIV patients later than HCV monoinfected patients. Therefore at present waiting for new drugs is not an alternative to a modern pegylated interferon/ribavirin therapy.

End-stage liver disease has become one of the most frequent causes of death in HIV/HCV-coinfected patients. The role of new antiretrovirals in the progression of liver fibrosis has yet to be defined. However with significant toxicities and drug-to-drug interactions of nucleoside reverse transcriptase inhibitors in combination with ribavirin, with drug to drug interaction of HIV protease inhibitors with HCV protease inhibitors and calcineurin-inhibitors, new antiretrovirals lacking these interactions represent attractive alternatives in the setting of anti-HCV therapy or post liver transplantation. In the following review we want to focus on the new class of HIV integrase inhibitors and discuss present data with regard to special issues of HIV and HCV co-infection.

Background Pregnancy affects the pharmacokinetics of most protease inhibitors. Saquinavir, when administered in a tablet formulation, has not been studied extensively in this setting.Methods A pharmacokinetic, prospective, multicentre trial of HIV type-1-infected pregnant women treated with saquinavir (500 mg tablets) boosted with ritonavir at a dose of 1,000/100 mg twice daily plus a nucleoside backbone was conducted. Pharmacokinetic curves were recorded for 12 h in the second trimester (week 20 ±2), the third trimester (week 33 ±2) and post-partum (weeks 4–6). Blood was sampled pre-dosing and at 1, 2, 3, 4, 6, 8, 10 and 12 h post-dosing. Pharmacokinetic parameters were calculated using WinNonlin software version 4.1.Results A total of 37 women were included in the analysis. Mean (±sd) values for saquinavir area under the curve (AUC0–12h) were 23.47 h•mg/l (11.92) at week 20 (n=16), 23.65 h•mg/l (9.07) at week 33 (n=31) and 25.00 h•mg/l (11.81) post-partum (n=9). There was no significant difference in the saquinavir AUC0–12hwhen comparing the data during pregnancy and post-partum. Subtherapeutic plasma concentrations of saquinavir (defined as <0.10 mg/l) were not observed throughout the study. No major safety concerns were noted.Conclusions Saquinavir exposure in the new tablet formulation generates adequate saquinavir concentrations throughout the course of pregnancy and is safe to use; therefore, no dose adjustment during pregnancy is needed.

B-cell maturation antigen (BCMA)–targeting therapies, including bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs), are promising treatments for multiple myeloma (MM), but disease may progress after their use. CARTITUDE-2 is a phase 2, multicohort study evaluating the safety and efficacy of cilta-cel, an anti-BCMA chimeric antigen receptor T therapy, in various myeloma patient populations. Patients in cohort C progressed despite treatment with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and noncellular anti-BCMA immunotherapy. A single cilta-cel infusion was given after lymphodepletion. The primary end point was minimal residual disease (MRD) negativity at 10−5. Overall, 20 patients were treated (13 ADC exposed; 7 BsAb exposed; 1 in the ADC group also had prior BsAb exposure). Sixteen (80%) were refractory to prior anti-BCMA therapy. At a median follow-up of 11.3 months (range, 0.6-16.0), 7 of 20 (35%) patients were MRD negative (7 of 10 [70.0%] in the MRD-evaluable subset). Overall response rate (95% confidence interval [CI]) was 60.0% (36.1-80.9). Median duration of response and progression-free survival (95% CI) were 11.5 (7.9—not estimable) and 9.1 (1.5—not estimable) months, respectively. The most common adverse events were hematologic. Cytokine release syndrome occurred in 12 (60%) patients (all grade 1-2); 4 had immune effector cell-associated neurotoxicity syndrome (2 had grade 3-4); none had parkinsonism. Seven (35%) patients died (3 of progressive disease, 4 of adverse events [1 treatment related, 3 unrelated]). Cilta-cel induced favorable responses in patients with relapsed/refractory MM and prior exposure to anti-BCMA treatment who had exhausted other therapies. This trial was registered at www.clinicaltrials.govas NCT04133636.

ABSTRACTThe objective of this study was a comprehensive analysis of the immune-driven evolution of viruses of human immunodeficiency virus type 1 (HIV-1) clade B in a large patient cohort treated at a single hospital in Germany and its implications for antiretroviral therapy. We examined the association of the HLA-A, HLA-B, and HLA-DRB1 alleles with the emergence of mutations in the complete protease gene and the first 330 codons of the reverse transcriptase (RT) gene of HIV-1, studying their distribution and persistence and their impact on antiviral drug therapy. The clinical data for 179 HIV-infected patients, the results of HLA genotyping, and virus sequences were analyzed using a variety of statistical approaches. We describe new HLA-associated mutations in both viral protease and RT, several of which are associated with HLA-DRB1. The mutations reported are remarkably persistent within our cohort, developing more slowly in a minority of patients. Interestingly, several HLA-associated mutations occur at the same positions as drug resistance mutations in patient viruses, where the viral sequence was acquired before exposure to these drugs. The influence of HLA on thymidine analogue mutation pathways was not observed. We were able to confirm immune-driven selection pressure by major histocompatibility complex (MHC) class I and II alleles through the identification of HLA-associated mutations. HLA-B alleles were involved in more associations (68%) than either HLA-A (23%) or HLA-DRB1 (9%). As several of the HLA-associated mutations lie at positions associated with drug resistance, our results indicate possible negative effects of HLA genotypes on the development of HIV-1 drug resistance.

Background Lopinavir/ritonavir-containing antiretro-viral therapy can cause hyperlipidaemia. However, most statins are contraindicated due to drug-drug interactions. Rosuvastatin undergoes minimal metabolism by CYP450, so no CYP450-based interaction with lopinavir/ritonavir is expected. This study explored the lipid-lowering effect of rosuvastatin and assessed the effect of lopinavir/ritonavir on the pharmacokinetics of rosuvastatin and vice versa.Methods HIV-infected patients on lopinavir/ritonavir (viral load <400 copies/ml) with total cholesterol (TC) >6.2 mmol/l were treated with rosuvastatin for 12 weeks, starting on 10 mg once daily. If fasting target values (TC<5.0 mmol/l, high-density lipoprotein-cholesterol >1.0 mmol/l, low-density lipoprotein-cholesterol [LDL-c] <2.6 mmol/l and triglycerides <2.0 mmol/l) were not reached, rosuvastatin was escalated to 20 mg or 40 mg at week 4 and 8, respectively. Plasma lopinavir/ritonavir trough levels (Cmin) were determined at week 0, 4, 8 and 12 and rosuvastatin Cmin, at week 4, 8 and 12.Results Twenty-two patients completed the study. Mean reductions in TC and LDL-c from baseline to week 4 (on rosuvastatin 10 mg once a day) were 27.6% and 31.8%, respectively. Lopinavir/ritonavir concentrations were not influenced by rosuvastatin (P=0.44 and 0.26, repeated-measures analysis). Median (interquartile range) rosuvastatin Cminfor 10 mg, 20 mg and 40 mg once daily were 0.97 (0.70–1.5), 2.5 (1.3–3.3) and 5.5 (3.3–8.8) ng/ml, respectively.Conclusions Rosuvastatin appeared to be an effective statin in hyperlipidaemic HIV-infected patients. Lopinavir/ritonavir levels were not affected by rosuvastatin, but rosuvastatin levels unexpectedly appeared to be increased 1.6-fold compared with data from healthy volunteers. Until safety and efficacy have been confirmed in larger studies, the combination of rosuvastatin and lopinavir/ritonavir should be used with caution.

Neue Ionisationstechniken haben in den letzen Jahren immer mehr Analyten – etwa unpolare Substanzen und Biomoleküle mit großen Molmassen – der Massenspektro‐ metrie zugänglich gemacht und so den Einsatzbereich der Methode beträchtlich erweitert.

Background Sexually transmitted acute hepatitis C among HIV-positive homosexual men has been noted as an emerging epidemic.Methods Forty-seven patients with mainly sexually acquired, acute hepatitis C were enrolled in this prospective, multicentre trial, and 36 of these patients were treated within the acute phase of hepatitis C infection with pegylated interferon (peg-IFN) therapy.Results Early treatment resulted in sustained virological response in 61% of patients. Peg-IFN alone showed similar treatment response rates and lower incidence of anaemia compared with peg-IFN+ribavirin combination therapy. Higher treatment response rates were observed in patients treated over 48 weeks compared with 24 weeks.Conclusions Treatment of hepatitis C in HIV-positive individuals in the acute phase of infection leads to high rates of sustained virological response. Optimal time and mode of therapy have yet to be defined.

Kaletra®, a fixed-dose co-formulation of lopinavir/ritonavir, was the first boosted protease inhibitor developed for the treatment of HIV-infection. In September 2000, the US FDA granted Kaletra® fast-track approval as data showed a higher efficacy in the treatment of HIV-infection than standard protease inhibitors of that time. Although potency was of major concern in the early years of highly active antiretroviral therapy (HAART), presently, with the perspective of HIV-infection becoming a chronic but well controllable disease, other issues begin to draw increased attention in the long-term management of HIV-infected patients. Among general health issues such as cardiovascular disease, metabolic disorders or hepatitis co-infection, the long-term toxicity and safety of HAART is an important concern when choosing antiretroviral drugs for each individual patient. In this review, the authors report on the safety of lopinavir/ritonavir in the treatment of HIV-infected patients, and focus on special patient groups and relevant safety issues.

We use second harmonic generation (SHG) imaging to study and quantify a strong intrinsic SHG signal in skeletal muscle fiber preparations and single isolated myofibrils. The intrinsic signal follows the striation pattern of the muscle cells and is positioned at the sarcomeric location of the myosin filaments. Interestingly, the signal is enhanced at the region where the myosin heads are located on the myosin filaments. As the intrinsic signal reflects the subcellular structure in an accurate way, SHG can be used for noninvasive high resolution structural imaging without exogenous labels in living muscle cells. This may be very important for detecting changes in myofibrillar organization occurring under pathophysiological conditions, e.g., in cardiac and skeletal myopathies. Due to the strong dependency of SHG on orientation and symmetries of the tissue, it may allow the study of dynamic interactions between the contractile proteins actin and myosin during force production and muscle shortening. Furthermore, SHG imaging can be combined with other nonlinear microscopical techniques, such as laser scanning multiphoton fluorescence microscopy, to simultaneously measure other dynamic cellular processes, representing a complementary method and extending the range of nonlinear microscopical methods. © 2004 Society of Photo-Optical Instrumentation Engineers.

A subset of patients with type 2 Gaucher disease is characterized by intrauterine onset of rapidly progressive neuropathic disease, arthrogryposis, hydrops fetalis and in some cases restrictive dermopathy. β‐Glucocerebrosidase (β‐glucosidase) activity is usually low or undetectable. In most cases death ensues either in‐utero or within hours or days after birth. We report on an infant born to non‐consanguineous parents of Caucasian origin presenting at birth with hydrops, arthrogryposis, severe respiratory distress, hepatosplenomegaly, and liver failure. Death occurred within several hours after delivery and autopsy revealed typical Gaucher cells in multiple organs in combination with severe apoptotic neurodegeneration throughout the brain. β‐Glucocerebrosidase activity was 1% of the norm in fibroblasts and a novel heterozygous insertion c.1515_1516insAGTGAGGGCAAT was identified by genomic sequencing and an insertion‐specific seminested PCR. In addition, molecular studies revealed a previously described in type 1 Gaucher disease missense mutation c.476G → A which results in a heterozygous substitution of R120Q. Our observations confirm considerable genotypic heterogeneity in patients with type 2 Gaucher disease. The transheterozygous combination of a mutation, previously described in type 1 Gaucher disease, together with a newly identified insertion may result in this severe phenotype. © 2004 Wiley‐Liss, Inc.

Nitrobenzoxadiazole NBD derivatives are determined with limits of detection ranging down to 20 nmol l−1using liquid chromatography-mass spectrometry LC-MS with electron capture EC ionisation. An atmospheric pressure chemical ionisation APCI interface operated in the negative ion mode is used as ionisation source. Amine derivatives of 4-chloro-7-nitro-2,1,3-benzoxadiazole NBDCl as well as the isocyanate derivatives of 4-nitro-7-piperazino-2,1,3-nitrobenzoxadiazole NBDPZ have been analysed using this technique. The parameters favouring electron capture mechanisms have been investigated thoroughly under consideration of the competing mechanism of deprotonation to allow a better understanding of the electron capture process and to improve selectivity of the analysis.

The aim of the current study was to analyze distraction osteogenesis histomorphometrically to investigate the amount of enchondral ossification adjacent to intramembranous ossification.

A diffusive sampling method for the determination of methyl isocyanate (MIC) in air is introduced. MIC is collected using a glass fiber filter impregnated with 4-nitro-7-piperazinobenzo-2-oxa-1,3-diazole (NBDPZ). The urea derivative formed is desorbed from the filter with acetonitrile and analyzed by means of high-performance liquid chromatography (HPLC) using fluorescence detection (FLD) with λ_ex = 471 nm and λ_em = 540 nm. Additionally, a method was developed using tandem mass spectrometric (MS-MS) detection, which was performed as selected reaction monitoring (SRM) on the transition [MIC–NBDPZ + H]+ (m/z 307) to [NBDPZ + H]+ (m/z 250). The diffusive sampler was tested with MIC concentrations between 1 and 35 µg m−3. The sampling periods varied from 15 min to 8 h, and the relative humidity (RH) was set from 20% up to 80%. The sampling rate for all 15 min experiments was determined to be 15.0 mL min−1 (using HPLC-FLD) with a relative standard deviation of 9.9% for 56 experiments. At 80% RH, only 15 min sampling gave acceptable results. Further experiments revealed that humidity did not affect the MIC derivative but the reagent on the filter prior to and during sampling. The sampling rate for all experiments (including long term sampling) performed at 20% RH was found to be 15.0 mL min−1 with a relative standard deviation of 6.3% (N = 42). The limit of quantification was 3 µg m−3 (LC-MS-MS: 1.3 µg m−3) for 15 min sampling periods and 0.2 µg m−3 (LC-MS-MS: 0.15 µg m−3) for 8 h sampling runs applying fluorescence detection.

The determination of selected nitroaromatic compounds in liquid chromatography-mass spectrometry with electron capture (EC) ionisation using a commercial atmospheric pressure chemical ionisation (APCI) interface in the negative mode is described. The electron capture effect is observed for nitroaromatics which do not easily undergo deprotonation under these conditions. Depending on the structure of the analytes, either dissociative or, for the first time in LC-MS, non-dissociative electron capture is observed. Limits of detection and linear range for the determination of the analytes match those obtained for nitroaromatics which undergo deprotonation. The investigated substances comprise numerous substituted nitrobenzenes and nitrobenzooxadiazoles.

The requirement for more effective cryopreservation (CP) methodologies in support of the emerging fields of cell bioprocessing and cell therapy is now critical. Current CP strategies appropriately focus on minimizing the damaging actions of physicochemical stressors and membrane disruption associated with extra- and intracellular ice formation that occurs during the freeze–thaw process. CP protocols derived from this conceptual paradigm, however, yield suboptimal survival rates. We now provide the first report on the identification of delayed-onset cell death following CP and the significance of modulating molecular biological aspects of the cellular responses (apoptosis) to low temperature as an essential component to improve postthaw outcome. In this study we quantitatively examined the molecular basis of cell death associated with CP failure in a canine renal cell model. In addition, we report on the significant improvement in CP outcome through the modulation of these molecular mechanisms by the utilization of an organ preservation solution, HypoThermosol®. Further, the utilization of HypoThermosol® as the preservation medium and the modulation of molecular-based cell death have led to a paradigm shift in biologic preservation methodologies. The recognition of molecular mechanisms associated with CP-induced cell death offers the promise of improved CP of more complex and/or fragile biological systems such as stem cells, engineered tissues, and human organs.

The present report describes two fetuses, one female and one male, with thus far undescribed skeletal malformations. The mother was a gravida 2, para 0. Both pregnancies were terminated in the second trimester because of multiple congenital anomalies diagnosed ultrasonographically resembling a short rib‐polydactyly syndrome. Both fetuses were found to have postaxial hexadactyly of the hands and feet, marked bilateral campomelia of the forearm and shank bones, and a Dandy–Walker cyst. In addition, the fourth ventricle was dilated in the first sibling and the second sibling had an inverse intestinal malrotation. A literature search failed to reveal similar observations. Copyright © 2001 John Wiley & Sons, Ltd.

Calcium currents were recorded in contracting and actively shortening mammalian muscle fibers. In order to characterize the influence of extracellular calcium concentration changes in the small unstirred lumina of the transverse tubular system (TTS) on the time course of the slow L-type calcium current (ICa), we have combined experimental measurements of ICa with quantitative numerical simulations of Ca2+ depletion. ICa was recorded both in calcium-buffered and unbuffered external solutions using the two-microelectrode voltage clamp technique (2-MVC) on short murine toe muscle fibers. A simulation program based on a distributed TTS model was used to calculate the effect of ion depletion in the TTS. The experimental data obtained in a solution where ion depletion is suppressed by a high amount of a calcium buffering agent were used as input data for the simulation. The simulation output was then compared with experimental data from the same fiber obtained in unbuffered solution. Taking this approach, we could quantitatively show that the calculated Ca2+ depletion in the transverse tubular system of contracting mammalian muscle fibers significantly affects the time-dependent decline of Ca2+ currents. From our findings, we conclude that ion depletion in the tubular system may be one of the major effects for the ICa decline measured in isotonic physiological solution under voltage clamp conditions.

The present report describes two fetuses, one female and one male, with thus far undescribed skeletal malformations. The mother was a gravida 2, para 0. Both pregnancies were terminated in the second trimester because of multiple congenital anomalies diagnosed ultrasonographically resembling a short rib-polydactyly syndrome. Both fetuses were found to have postaxial hexadactyly of the hands and feet, marked bilateral campomelia of the forearm and shank bones, and a Dandy–Walker cyst. In addition, the fourth ventricle was dilated in the first sibling and the second sibling had an inverse intestinal malrotation. A literature search failed to reveal similar observations. Copyright © 2001 John Wiley & Sons, Ltd.

To estimate the incidence and lethality of placental maturation defect, and to determine the impact of the pattern of placental dysfunction on the risk of recurrent stillbirth or maternal disease in later life.

Objective: To estimate the incidence and lethality of placental maturation defect, and to determine the impact of the pattern of placental dysfunction on the risk of recurrent stillbirth or maternal disease in later life.

In pharmaceutical analysis, ie the analytical development and quality control of drug substances and dosage forms, mass spectrometry (MS) combined with chromatographic separation is perhaps the most powerful technique for the monitoring, characterization and identification of impurities. The addition of further dimensions to chromatographic separations by hyphenated techniques offers unique possibilities of efficiently supporting pharmaceutical development and ensuring the quality and safety of pharmaceuticals. However, the ionization process in MS involves some characteristics which have to be recognized and taken into account for an appropriate application as well as the evaluation of the results. Chromatographic method development and validation can be supported very effectively by MS detection, eg in the investigation of coelution and peak purity. Chiral amino acid analysis is largely facilitated by the mass‐specific detection of the derivatized amino acid enantiomers, which ignores all other interfering substance peaks. Examples are presented for the use of LC‐MS‐MS fragmentation and high‐resolution MS in the structural elucidation of degradation products and impurities. LC‐MS is systematically applied to monitor impurity profiles during pharmaceutical development and scaling up and supports the safety evaluation of batches used in clinical studies. Copyright © 2000 John Wiley & Sons, Ltd.

AbstractObjective:To determine whether inflammatory cytokine concentrations (Il-1β, Il-6, Il-8 and G-CSF) in umbilical cord blood are useful predictors of an early-onset neonatal infection.Material and methods:240 women and their newborns were enrolled in our study and umbilical cord blood samples collected from neonates (n = 240) were subjected to ELISA for Il-1β, Il-6, Il-8 and G-CSF. Clinical outcome of the neonates was followed and documented. Placenta histology was also available in majority of the cases (n = 195).Results:Early-onset neonatal infection was diagnosed in 5.4% of neonates (13/240) and placental examination showed histologic chorioamnionitis in 17.9% (35/195). Both Il-1β and Il-6 cord blood concentrations were elevated in association with histologic chorioamnionitis (Il-1β – 2.7 vs. 2.1 pg/ml, p < 0.05 and Il-6 15.6 vs. 12.8 pg/ml, p < 0.005). Only Il-6 was elevated (16.0 vs. 13.2 pg/ml, p < 0.05) in neonates with early-onset bacterial infections. ROC analysis showed acceptable diagnostic performance of Il-6 in the identification of acute histologic chorioamnionitis and clinical neonatal infection.Conclusion:Il-6 in umbilical cord blood seems to be a promising predictor for early-onset neonatal infections.

Background:Ciltacabtagene autoleucel (cilta-cel) is a novel chimeric antigen receptor T-cell therapy that is being evaluated in the CARTITUDE-1 trial (NCT03548207) in patients with relapsed or refractory multiple myeloma (RRMM) who are triple-class exposed (to immunomodulatory drugs, proteasome inhibitors, and an anti-CD38 monoclonal antibody). As there is no clear standard of care for this patient population, and due to an absence of direct head-to-head trials evaluating cilta-cel and other relevant treatments, indirect treatment comparisons (ITCs) between cilta-cel and treatments used in current clinical practice, ie, physician's choice of treatment (PCT), have been previously conducted. Meta-analyses were performed to derive single summary effect estimates for overall survival (OS) and progression-free survival (PFS) by pooling ITCs evaluating cilta-cel versus PCT in patients with triple-class exposed RRMM.

Introduction:There are several treatment options for patients (pts) with progressive multiple myeloma (MM) who are refractory to lenalidomide but most pts relapse shortly after receiving salvage treatment. Cilta-cel is a CAR-T therapy expressing 2 BCMA-targeting, single-domain antibodies that demonstrated early, deep, and durable responses in pts with MM who had received ≥3 prior lines of therapy (LOT) in the phase 1b/2 CARTITUDE-1 study (Berdeja, Lancet, 2021). The multicohort, open-label, phase 2 CARTITUDE-2 study (NCT04133636) is evaluating cilta-cel safety and efficacy in various clinical settings for pts with MM and exploring suitability of outpatient administration. Initial analysis (median follow-up 5.8 mo) of pts in CARTITUDE-2 cohort A (lenalidomide-refractory with 1-3 prior LOT) demonstrated an overall response rate (ORR) of 95%, with 75% of pts achieving complete response or better (≥CR) and 85% achieving very good partial response or better (≥VGPR). Here, we present updated results for this population.

Introduction:The introduction of new treatments over the past 2 decades has improved survival outcomes in patients with multiple myeloma (MM), yet MM remains incurable. Despite therapeutic advances, most patients with MM eventually relapse and/or become refractory to treatment, and cycle through standard drug classes of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs), becoming triple-class exposed. These triple-class exposed patients represent a population with an urgent unmet clinical need and are a major focus for the development of new therapies. There are currently no prospective data outside of clinical trials on standard-of-care (SOC) in MM patients who progress after these treatment regimens. LocoMMotion (NCT04035226) is the first prospective study to assess the efficacy and safety of real-life SOC treatments in triple-class exposed patients with relapsed/refractory MM (RRMM). Initial analysis at a median follow-up of 3.7 months (range: 0.0-12.7) showed an overall response rate (ORR) of 20.1% (95% CI: 15.0-26.0), with only 5% of patients achieving very good partial response or better. Here, we report updated results from LocoMMotion with a longer median duration of follow-up (7.8 months), along with progression-free survival (PFS) and overall survival (OS) data.