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Abstract Vaccination with infectious Plasmodium falciparum (Pf) sporozoites (SPZ) administered with antimalarial drugs (PfSPZ-CVac), confers superior sterilizing protection against infection when compared to vaccination with replication-deficient, radiation-attenuated PfSPZ. However, the requirement for drug administration constitutes a major limitation for PfSPZ-CVac. To obviate this limitation, we generated late liver stage-arresting replication competent (LARC) parasites by deletion of the Mei2 and LINUP genes (mei2 – /linup – or LARC2). We show that Plasmodium yoelii (Py) LARC2 sporozoites did not cause breakthrough blood stage infections and engendered durable sterilizing immunity against various infectious sporozoite challenges in diverse strains of mice. We next genetically engineered a PfLARC2 parasite strain that was devoid of extraneous DNA and produced cryopreserved PfSPZ-LARC2. PfSPZ-LARC2 liver stages replicated robustly in liver-humanized mice but displayed severe defects in late liver stage differentiation and did not form liver stage merozoites. This resulted in complete abrogation of parasite transition to viable blood stage infection. Therefore, PfSPZ-LARC2 is the next-generation vaccine strain expected to unite the safety profile of radiation-attenuated PfSPZ with the superior protective efficacy of PfSPZ-CVac.

Abstract By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi‐agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high‐throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation‐like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including imipramine, induced cancer cell death in combination with the mitochondrial uncoupler niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors CHOP and TFE3, which resulted in cell death through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard‐of‐care chemotherapy paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

Background: With the increasing number of elderly patients, arthroplasties, fractures and diabetic foot infections, the worldwide number of osteoarticular infections (OAI) among the elderly is concomitantly expected to rise. Aims: We explore existing scientific knowledge about OAI in the frail elderly population. Methods: We performed a literature search linking OAIs to geriatric patients and comparing elderly patients (> 65 years) with average adults (range 18–65 years). Results: In this literature, financial aspects, comparison of diverse therapies on quality of life, reimbursement policies, or specific guidelines or nursing recommendations are missing. Age itself was not an independent factor related to particular pathogens, prevention of OAI, nursing care, and outcomes of OAI. However, geriatric patients were significantly more exposed to adverse events of therapy. They had more co-morbidities and more conservative surgery for OAI. Conclusion: Available literature regarding OAI management among elderly patients is sparse. In recent evaluations, age itself does not seem an independent factor related to particular epidemiology, pathogens, prevention, nursing care, rehabilitation and therapeutic outcomes of OAI. Future clinical research will concern more conservative surgical indications, but certainly reduce inappropriate antibiotic use. [ABSTRACT FROM AUTHOR]

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Copyright of Rechtsmedizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

In this study, the effect of sample purification on total signal intensities of samples amplified with genRES MPX-2 (nine-locus multiplex) prior to capillary electrophoretic analysis has been investigated. Sample purification with the Qiaquick PCR purification kit led to an increase of the relative fluorescent signal intensity by a factor of 3.8 ± 0.8. In contrast, the application of larger sample volumes led to a decrease of signal intensities from 20% to 80%, depending on whether the samples were purified or not. In addition, increase of injection time showed a linear increase of signal intensity between 3 s and 10 s. Increasing the number of PCR cycles from 30 to 33 also led to a significant increase of signal intensities. Nevertheless, this increase greatly depended on the fragment lengths and was sometimes accompanied by the appearance of non-specific signals. In combination, optimisation of sample preparation and increase of injection time may intensify signals up to 12-fold, thereby increasing the overall sensitivity of the assay. This may be of special interest for forensic analysis of microspecimens containing limited amounts of DNA. [ABSTRACT FROM AUTHOR]

In a total of 104 individuals who had sustained traumatic brain injury (TBI), the course of glial immunoreactivity was investigated at the injured cortical area during the first 30 weeks after the trauma, in order to provide data for a forensic wound age estimation. Glial cells were stained with antibodies against the intermediate filament protein vimentin, the extracellular matrix protein tenascin and the serine protease inhibitor α1-antichymotrypsin (α1-ACT). Injury-induced glial staining reactions could be observed, at the earliest, after a post-infliction interval of 3.1 h for α1-ACT, 22 h for vimentin and 7 days for tenascin. [ABSTRACT FROM AUTHOR]

A 55-year-old male nurse was accused of having introduced his fingers by force into the anus of a 20-year-old female patient. Debris from the fingernails of the suspect recovered 2 days after the incident was analysed with the VNTR locus D1S80, the triplex PCR system AmpF lSTR Blue kit, the AmpF lSTR Profiler kit and the pentaplex system genRES MPX. The D1S80 singleplex reaction revealed indications of DNA from the victim in the fingernail debris of the left hand. Using the AmpF lSTR Blue kit and AmpF lSTR Profiler, DNA alleles of the victim were found at four additional loci, while allelic drop-out was observed at five other loci. Only the pentaplex kit genRES MPX revealed alleles at all loci which could be assigned to the victim. Calculation of likelihood ratios resulted in a value of 1.4 × 105 using the combination of the multiplex systems AmpFlSTR Blue kit and AmpF lSTR Profiler and 2.8 × 108 for the genRES MPX kit. This case demonstrates the high sensitivity of the new genRES MPX kit and that DNA profiling of fingernail debris is possible despite a time lapse of 2 days between the incident and recovery of the evidential material. [ABSTRACT FROM AUTHOR]

In 1998 the Federal Criminal Police Office of Germany (BKA) established a central genetic database of offenders and suspects to facilitate comparisons with biological samples from future criminal offences. The five obligatory short tandem repeat (STR) loci in this database (TH01, SE33, vWA, FGA and D21S11) were co-amplified in a new PCR pentaplex analysing system together with the sex-specific locus amelogenin. Due to overlapping fragment sizes, amplification products were fluorescent dye-labelled with different colours, separated by electrophoresis and detected directly using the ABI PRISM 310 Genetic Analyzer. Reproducible and reliable results were obtained from as low as 125 pg template DNA, indicating high specificity and sensitivity of the assay. Environmental studies and enzymatic digest with DNase I revealed an excellent stability of the pentaplex system with typeable results even in cases of partially degraded DNA. Complete and reproducible DNA typing was possible in bloodstain mixtures with the minor component as low as 10%. Mean stutter peak intensities were analysed for all loci and ranged from 2.7 ± 0.8% (TH01) to 10.6 ± 1.6% (vWA) of the main signal intensity. Allele frequencies were determined in a North Bavarian population sample ( n = 121). The combination of five systems resulted in a mean exclusion chance of 99.86% and a power of discrimination of 99.999996%. No deviation from Hardy-Weinberg equilibrium could be found. [ABSTRACT FROM AUTHOR]

In a total of 104 individuals who had sustained traumatic brain injury (TBI), the time-dependent vascular response was investigated at the injured cortical area during the first 30 weeks after the trauma. The immunohistochemical staining of the cerebral blood vessels was performed with antibodies against laminin, type IV collagen, tenascin, thrombomodulin and factor VIII associated antigen. Compared to the immunoreactivity in unaltered control tissue, a significantly increased vascular expression could be detected in cortical contusions after a postinfliction interval of at least 3 h for factor VIII, after 1.6 days for tenascin or after 6.8 days for thrombomodulin, whereas the immunostaining for laminin and type IV collagen was regularly positive even in the vascular endothelium of uninjured brain tissue. [ABSTRACT FROM AUTHOR]

The course of GFAP expression by astrocytes has been immunohistochemically investigated during the first 30 weeks after human brain injury. In order to provide reliable data for a forensic wound age estimation, a quantitative morphometric analysis was performed considering the different topographic regions of the cortex as well as of the white matter. Compared to the GFAP immunoreactivity in unaltered control tissue, significantly increased numbers of GFAP positive astroglial cells could be detected adjacent to the cortical contusion from 1 day up to 4 weeks after brain injury. [ABSTRACT FROM AUTHOR]

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Copyright of Rechtsmedizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The time-dependent inflammatory cell reaction in human cortical contusions has been investigated during the first 30 weeks after blunt head injury. Immunohistochemical staining was carried out using CD 15 for granulocytes and LCA, CD 3 and UCHL-1 for mononuclear leucocytes. In order to provide reliable data for a forensic wound age estimation, the intensity of the cellular reaction was evaluated with a quantitative image analysis system. CD 15-labelled granulocytes were detectable earliest 10 min after brain injury, whereas significantly increased numbers of mononuclear leucocytes occurred in cortical contusions after a postinfliction interval of at least 1.1 days (LCA), 2 days (CD 3) or 3.7 days (UCHL-1), respectively. [ABSTRACT FROM AUTHOR]

TheMg( α, p γ) reaction has been studied at α-particle energies of 13, 15, and 15.2 MeV. Using method II of Litherland and Ferguson spin assignments or restrictions thereof could be made to theAl levels at E=5500 keV ( I=11/2, 7/2), 6950 keV ( I=11/2, 7/2), 7226 keV ( I=9/2), 7286 keV ( I=9/2-13/2), 7399 keV ( I=11/2, 7/2) and 7443 keV ( I=13/2, 9/2). Using the Doppler-shift attenuation method a lifetime τ=20-50 fs was obtained for the E=7399 keV level and a limit τ<20 fs for the levels at E=7443, 7286, 7226, 6950, 6718, and 6287 keV, respectively. Further spin assignments inAl were obtained by a study of theMg( p, γ) reaction at the E=2174 keV resonance. From γ-ray angular distributions the resonance spin was determined as I=9/2 (previous assignment I=7/2) and the spin of the E=5959 keV level was determined as I=7/2. Tentative spin assignments were made to the levels at E=6537 keV ( I=7/2) and 6718 keV ( I=9/2). From the combined evidence of theMg( α, p) andMg( p, γ) reactions the spin of the 6287 keV level was found to be I=7/2. The results are compared with shell model calculations and the Nilsson model. [ABSTRACT FROM AUTHOR]

Spin assignments have been made to theMg levels in the E=5-6 MeV region from γ-ray angular distributions measured in theNe( α, n y) reaction at E=8.0 and 8.8 MeV and from p-γ angular correlations measured in theMg( d, p γ) reaction at E=6 MeV. Unique spin assignments of J=7/2, 5/2, 5/2, and 9/2 could be made to the levels at E=5005, 5511, 5851, and 5967 keV, respectively. Ambigious assignments have been made to the levels at E=5245, 5524, 5785, 6032 keV ( J=11/2, 7/2), 5455 keV J=13/2, 9/2), and 5738 keV ( J=3/2, 5/2). The present data confirm previous assignments of J=1/2 to the levels at E=5108 and 5466 keV, respectively. Lifetime estimates have been obtained, using the Doppler-shift attenuation method, for the levels at E=5245 keV ( τ=30-60 fs), 5785 keV ( τ=50-100 fs), 5967 keV ( τ=50-100 fs), and 5455 keV ( τ>1ps). All other levels in the E=5-6 MeV region have τ<60 fs. A breakdown of the K-selection rule has been observed in the γ-decay of some high spin states, indicating a deviation from the strong coupling model. [ABSTRACT FROM AUTHOR]

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Copyright of Rechtsmedizin is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The case of sudden cardiac death of a 23-year-old body builder who used anabolic steroids combined with other performance enhancing drugs is reported. Postmortem investigations revealed cardiac hypertrophy, acute cellular necrosis and interstitial fibrosis of the myocardium. The side-effects and interactions of the substances used are discussed. [ABSTRACT FROM AUTHOR]

The time-dependent expression of p53 protein during wound healing has been investigated by immunochemistry in fibroblastic cells of skin wounds ranging between a few minutes and 11 weeks old. When compared to uninjured skin, an increased expression of p53 was found earliest in a wound with a postinfliction interval of 3 days. The ratio (r) of positively stained cells in relation to the total number of fibroblastic cells in the wound area of this specimen was about 0.2. A considerable increase in the expression of p53 ( r > 0.5) was first found in a wound aged 8 days and in wounds with postinfliction intervals ranging between 3 and 11 weeks, where the ratio of positive cells was between 0.40 and 0.64. Therefore, it can be calculated that r-values of at least 0.5 indicate a postinfliction interval of approximately 1 week or more. Since comparably low numbers of positively stained fibroblastic cells were found in specimens with an advanced wound duration, reliable information for a forensic wound age estimation can only be provided by positive results. [ABSTRACT FROM AUTHOR]

The time-dependent appearance of signs of cell death was investigated in human skin wounds using in situ end labeling of DNA fragments (ISEL). In the dermal layer an average of not more than 0.3 positively stained fibroblastic cells/0.01 cm × 0.01 cm was found up to a postinfliction interval of approximately 6 h. Average numbers exceeding 1 positive cell/0.01 cm × 0.01 cm were first detectable in a skin wound after 24 h. Therefore, average numbers greater than 1 labeled cell/ 0.01 cm × 0.01 cm indicate a postinfliction interval of approximately 1 day. An increase in the average number of positively stained cells occurred with increasing wound age. Values exceeding 3 cells/0.01 cm × 0.01 cm were first detectable 19 days after wound infliction. Accordingly, values of more than 3 labeled cells indicate a postinfliction interval of approximately 3 weeks or more. Since low numbers of labeled fibroblastic cells or even negative results were found in wounds of advanced age, only positive results provide information which can be useful for a forensic age estimation of human skin wounds. [ABSTRACT FROM AUTHOR]

Skin reddening with or without additional changes such as pinpoint intracutaneous hemorrhages and/or minute superficial scratches was observed in 165 out of 739 physical examinations (reddening with additional changes: n = 81; reddening only: n = 84). The most common site where reddening was observed was the neck region (reddening with additional changes: n = 30; reddening only: n = 34). In over 85% of the cases, the postinfliction interval (Pi) was ≤ 1 day, and there were 12 and 10 cases with 1 < Pi≤ 3 days, respectively. Among these 22 cases, there were 5 cases with 2 < Pi≤ 3 days, (reddening with additional changes: n = 4; reddening only: n = 1). The maximum Pis were almost 3 days, and 2 days and 13 h, respectively. These results demonstrate that reddening of the skin with and that without additional changes (in particular petechiae) were detectable up to approximately 3 and 2 days after the event, respectively. Furthermore, in 17 out of 64 cases with reddening in the neck, petechial hemorrhages were seen in the eyelids and/or conjunctivae (reddening with additional changes: n = 10; reddening only: n = 7). The maximum Pi in which petechial hemorrhages were detectable in the eyelids and/or the palpebral conjunctivae was 1 day and 21 h. The present study indicates that physical examinations within 2 or 3 days after the event seem to be more suitable to find skin reddening and/or petechiae in the eye lids and/or the conjunctivae. [ABSTRACT FROM AUTHOR]

A total of 59 penetrating contact shot wounds to the head caused by handguns was investigated and a comparison was made between the magnitude and the number of fracture lines at the entrance and exit site of the vault and at the base of the skull. It was noted that in approximately 50% of the cases the extent of fractures at the entrance site exceeded those at the exit wound while in the remaining individuals no relevant differences or even greater exit fractures were found. Furthermore, no close correlation between the fracture patterns of the vault and at the base of the skull occurred indicating that differences in the magnitude and the number of entrance or exit fracture lines cannot provide reliable information on direction of fire. Additionally, no further conclusions on the gun used can be drawn from differences in the entrance and exit fracture patterns. It can only be assumed that the absence of fractures in the cranial fossae points to the use of small calibre handguns (≤ 7.65 mm) while a fragmentation of the skull can as a rule be expected after shots from guns with larger calibres (> 7.65 mm). [ABSTRACT FROM AUTHOR]

The time-dependent appearance of hematomas of the eyelids was investigated in 484 cases of head injury. In individuals with apparent signs of direct violence to the orbit or the nose, black eyes could be observed even without relevant post-infliction intervals. Similarly, in victims with fractures at the anterior base of the skull hematomas of the eyelids were found even though death had occurred rapidly within less than 30 min after trauma. Black eyes that can be explained exclusively by a seepage of blood from frontal scalp wounds appeared approximately 4 h after wound infliction at the earliest, indicating a minimum post-infliction interval. Since hemorrhages of the eyelids can also be induced postmortem by direct violence to the orbit, particularly in cases with hypostasis of the face, the presence of black eyes seems not to be an unambiguous sign of vital trauma. [ABSTRACT FROM AUTHOR]

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Copyright of International Journal of Legal Medicine is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Legal Medicine is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Legal Medicine is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of International Journal of Legal Medicine is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)