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Topical delivery systems (TDSs) enable the direct transport of analgesics into areas of localized pain and thus minimize the side effects of administration routes that rely on systemic drug distribution. For musculoskeletal pain, clinicians frequently prescribe topical products containing lidocaine or diclofenac. This study assessed whether drug delivery from a TDS into muscle tissue occurs mainly via direct diffusion or systemic transport. An investigational TDS containing 108 mg lidocaine (SP-103, 5.4% lidocaine), a commercially available TDS containing 36 mg lidocaine (ZTlido®, 1.8% lidocaine), and a topical pain relief gel (Pennsaid®, 2% diclofenac) were tested. Using open flow microperfusion (OFM), interstitial fluid from the dermis, subcutaneous adipose tissue (SAT), and muscle was continuously sampled to assess drug penetration in all tissue layers. Ex vivo and in vivo experiments showed a higher diffusive transport of lidocaine compared to diclofenac. The data showed a clear contribution of diffusive transport to lidocaine concentration, with SP-103 5.4% resulting in a significantly higher lidocaine concentration in muscle tissue than commercially available ZTlido® (p = 0.008). These results indicate that SP-103 5.4% is highly effective in delivering lidocaine into muscle tissue in areas of localized pain for the treatment of musculoskeletal pain disorders (e.g., lower back pain). [ABSTRACT FROM AUTHOR]

For disaster victim identification, hundreds of samples of human remains have to be extracted from human bodies rapidly for later DNA analysis, often in situation with high humidity, high temperature and no access to cooling facilities. Genetic typing of these samples may be challenging due to degradation of DNA. Until today, bone and teeth are the preferred biological matrix for genetic identification of decomposed human remains. However, processing these samples is time and cost consuming. To address the challenges associated with workload, finances, and sample preservation in the genetic identification of unknown dead bodies, we tested 44 hand and foot tendons from deceased with advanced post mortem changes as alternative DNA material. In addition, we examined commercially available table salt as potential preservation method with 10 tendons over a period of 12 months. The parameters external appearance, DNA quantity and quality have been analysed. Overall, 39 of 44 tendons examined yielded valuable DNA profiles with at least ten autosomal STR loci. Storage in table salt not only increased DNA yield but also resulted in high quality STR profiles of the preserved tendons throughout the study period of 12 months compared to storage without salt. According to the results of this study, we recommend hand and foot tendons as alternative DNA material from bodies with advanced post mortem changes. We particularly recommend commercially available table salt as a storage medium for the preservation of DNA samples. Under field conditions without cooling facilities and the need to store samples prior to DNA analysis table salt is a good storage medium: it preserves DNA and is easily available. • For decomposed human remains, bone and teeth are used as standard for DNA analysis. • To reduce costs and time, tendons were investigated as an alternative DNA material. • Table salt was tested as preservation method for the tendons at room temperature. • The study showed that tendons and table salt are a good recipe for DNA preservation. • DNA quantity could be preserved for the study period of one year using table salt. [ABSTRACT FROM AUTHOR]

Mongolian spots (MS) are congenital dermal conditions resulting from neural crest-derived melanocytes migration to the skin during embryogenesis. MS incidences are highly variable in different populations. Morphologically, MS present as hyperpigmented maculae of varying size and form, ranging from round spots of 1 cm in diameter to extensive discolorations covering predominantly the lower back and buttocks. Due to their coloring, which is also dependent on the skin type, MS may mimic hematoma thus posing a challenge on the physician conducting examinations of children in cases of suspected child abuse. In the present study, MS incidences and distribution, as well as skin types, were documented in a collective of 253 children examined on the basis of suspected child abuse. From these data, a classification scheme was derived to document MS and to help identify cases with a need for recurrent examination for unambiguous interpretation of initial findings alongside the main decisive factors for re-examination such as general circumstances of the initial examination (e. g., experience of the examiner, lighting conditions) and given dermatological conditions of the patient (e. g., diaper rash). [ABSTRACT FROM AUTHOR]

Background: The goal of this study was to investigate the usefulness of various photographic techniques in visualizing previous tattoos under cover-up tattoos. Material and methods: Ten volunteers with 11 known cover-up tattoos were examined using different photographic techniques: A Canon EOS 6D full-frame digital single-lens reflex camera used in conjunction with a SB600 off-camera flash system and an extension cord; and a Leica M8 digital imaging system camera in conjunction with two different infrared filters (715 nm and 850 nm) and a Metz CL-45 handle-mount flash. A Lumatec Superlite 400 forensic light source was used along with the Canon EOS 6D as a third system. Results: The best results for black cover-up tattoos were achieved with the full-frame digital single-lens reflex camera in conjunction with the off-camera flash system and, for colored cover-up tattoos, with IR-photography at a wavelength of 850 nm. The Lumatec Superlite 400 light source did not provide better results for conventional photography than those obtained with flash lighting. Discussion: In nine out of eleven cover-up tattoos, the previous tattoos could, at least, be partially visualized. The quality of the visualization depended on the color, pattern, density, and quality of the cover-up tattoo as well as on the photographic technique. None of the examined photographic techniques could satisfactorily image the previous tattoo if the cover-up tattoo was large and black, especially not if it was densely inked. Conclusion: Depending on the color of the cover-up tattoo, a full-frame digital single-lens reflex camera in conjunction with a SB600 off-camera flash system (for black cover-ups) or infrared photography with flash lighting and an 850 nm filter (for colored cover-ups) proved to be the best of the investigated techniques to visualize a previous tattoo under a cover-up tattoo. [ABSTRACT FROM AUTHOR]

When people judge the duration of stimuli, judgments are influenced by the physical size of these stimuli. Specifically, people tend to judge the duration of large stimuli longer than the duration of small stimuli. However, some authors (Bottini & Casasanto, 2010; Ma, Yang, & Zhang, 2012) have reported that even implicit size can affect duration estimates. The present study extends the results of these studies. Specifically, we examined whether the imagined size of objects would also influence duration estimates. In each trial, participants reproduced the duration of an animal word. During the presentation of the word, they were asked to imagine the word's referent. The animals employed in all experiments varied in size. In Experiment 1, participants were instructed to imagine the animals in a fixed context. Reproduced duration increased not only with the numbers of letters of the animal word (i.e., physical size) but also with the size of the word's referent (i.e., implicit size of the animal). Experiments 2 and 3 examined whether the effect of size would increase when the size of the animals was made more salient. The results of all experiments showed that reproduced duration increases with implicit stimulus size. In addition, Experiments 2 and 3 provide some evidence that the imagined size effect becomes more pronounced when the participant's attention is drawn to the size differences among the imagined animals. It is argued that the implicit size effect is mediated by mental imagery that operates on pre-existing space-time associations. [ABSTRACT FROM AUTHOR]

The article presents a report on the importance of archives. It states that for a healthy and reliable democracy archives are needed. It states that archives not only preserves the documents, written or recorded in any form, but also keep safe the values and culture of a country. It also mentions about the digitization of archives.

Previous studies have suggested that unexpected stimuli are perceived as being longer than expected ones (e.g., the temporal oddball effect). These studies manipulated stimulus expectation mostly via stimulus repetitions and stimulus probabilities. However, these manipulations might affect duration judgments not only through the modulation of stimulus expectation. Therefore, the present study introduces a novel paradigm to isolate the effect of stimulus expectation on perceived duration from repetition and probability effects. In 2 experiments, participants vocalized which of 2 possible stimuli they expected in each trial immediately before stimulus presentation (self-generated expectations). Following stimulus presentation, participants performed a temporal bisection task on the duration of the presented stimuli. For both color (Experiment 1) and shape stimuli (Experiment 2), longer perceived durations were observed when stimulus expectations were fulfilled rather than violated. These results contrast with previous studies from which it has been concluded that stimulus expectation shortens perceived duration. Instead, the findings are rather in line with the idea that higher level stimulus expectation enhances stimulus processing and thus prolongs subjective duration (Matthews & Gheorghiu, 2016). Importantly, this also challenges the assumption that higher level stimulus expectation is a key mechanism driving the temporal oddball effect. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that filled intervals are perceived as being longer than empty intervals of the same duration (i.e., the filled - duration illusion). In the present study, we asked whether the motor actions involved in filled and empty reproductions (a single continuous key press vs. two discrete key presses) would affect time estimates in a similar way. We hypothesized that reproductions of intervals of the same duration should be shorter for filled than empty reproductions (i.e., a filled - reproduction illusion). In two experiments, participants reproduced filled and empty intervals (ranging from 400 to 1,600 ms) using filled and empty reproductions. The results provided evidence for both kinds of illusions, even though the evidence was clearer for the filled - duration than for the filled - reproduction illusion. The present study demonstrates that in a situation in which both illusions work in concert, reproductions of the same interval can vary dramatically depending on the combination of interval and reproduction type. [ABSTRACT FROM AUTHOR]

The demographic development in Germany shows a steady increase to senior citizens. The driving suitability of older road-users is of large social and political concern, because awareness and reactivity can be influenced by age-related diseases and potential medication, particularly in combination with the consumption of alcohol. This study provides an overview of senior road-users under the influence of alcohol. Therefore, 404 cases of drunken-driving by road-users aged 70 and over within the purview of the Institute of Legal Medicine at Justus-Liebig-University, Giessen, from the years 2009-2013 were evaluated in retrospect. The vast majority of the drivers were male (88.4% of the cases). Distribution of the blood alcohol concentrations were almost equally in male and female drivers with 62.8% of all cases showing a blood alcohol concentration (BAC) of more than 1.1‰ and 10.9% a BAC of more than 2.0‰. In 48.5% of the cases, drunk driving was associated with an accident. 54.5% of the drivers stated suffering from at least one disease and 60% admitted a regular medication or an intake prior to the incident. Moreover, the collected data includes aspects such as the kind of traffic participation as well as neurological and physiological deficits of the road-users. If accidents were caused by drunk driving, the external circumstances and consequences of these accidents were analyzed, too. The evaluation revealed, that the standard medical examination protocol proved to be improbable to cover polypharmacy and multimorbidity of older alcoholized drivers. So, an evaluation and adaptation of the common medical examination protocol must be considered. [ABSTRACT FROM AUTHOR]

The assessment of ossification of the medial clavicular epiphysis plays a decisive role in the forensic age estimation of living subjects. Primarily for reasons of minimizing the radiation exposure currently associated with such evaluations, non-ionizing methods would be an advance. This study pursued the question whether full union of the medial clavicular epiphysis, visualized by high-frequency sonography, is a reliable criterion for age-threshold determinations. The ossification stage of the medial clavicular epiphysis of 215 female and 195 male volunteers, aged between 14 and 26 years, was evaluated in bilateral sonograms. Stage 4, defined as complete fusion by Schulz et al. (Int J Legal Med 122:163-167, 2008), was observed on at least one body side in 48 of 334 individuals younger than 21 years (14.4 %) and in 32 of 264 individuals younger than 18 years (12.1 %). With the high-frequency ultrasound used in this study, even the smallest convexities of the medial clavicular ending can be visualized. This may have led to overestimation of the ossification stage. It is not clear whether any observed roundings in the sonograms should actually be interpreted in terms of stages 3 and 4 as defined by Schulz. Also, due to the low penetration depth of high-frequency ultrasound waves, epiphyseal plate residues and ossification centers may have remained undetected. Reliable differentiation of the stages 1-4 with high-frequency sonography is thus difficult, and the results suggest that this method is not a radiation-free alternative to computed tomography, the current gold standard for determining age thresholds. [ABSTRACT FROM AUTHOR]

Knowing what one knows and accurately monitoring one's own capacities and performance on a moment-to-moment basis are important determinants of task success. Individual differences in such metacognitive monitoring are well documented, but what determines an individual's monitoring accuracy in a particular context is yet to be fully understood. One candidate contributor to monitoring accuracy is working memory. In this study, we investigated whether and how working memory contributes to the accuracy of monitoring processes. Most evidence for a positive relationship between working memory and monitoring accuracy has been provided by correlational studies. Here, an experimental approach was applied in which confidence judgments were collected after each memory recall in three working memory experiments, and the effect of increasing the working memory demands on monitoring accuracy was examined. A visuospatial complex span task, a verbal complex span task, and an updating task served as the working memory tasks, to cover the range of methods used in working memory research. Confirmatory analyses conducted using cumulative link mixed models indicated that in two out of three experiments, monitoring accuracy suffered when working memory demands increased. As such, the weight of evidence supports a dependent relationship between working memory and monitoring processes, whereby monitoring accuracy can fluctuate during a task depending on the available cognitive resources. This indicates that the sensitivity of metacognitive monitoring is at least partly determined by the nature of the cognitive processing taking place in the primary task. [ABSTRACT FROM AUTHOR]

Abstract: Frequency‐doubled diode laser technology (FDDL) enables direct modulation of 561 nm lasers with unprecedented speeds. It also reaches an ultimate high on/off contrast with zero photons in the off state, which is favorable for laser scanning microscopes and multicolor microscopy techniques. [ABSTRACT FROM AUTHOR]

Three experiments assessed whether participants perceive infrequent stimuli (oddballs) to last longer than frequent ones (standards). The classical oddball paradigm was modified so that participants judged the duration of a target stimulus which could either be a standard or an oddball. The target was always the fifth stimulus in the stream and all stimuli were presented at predefined spatial positions. These modifications enabled a direct comparison of duration judgments for oddballs and standards. In Experiments 1 and 2 not only the duration of oddballs but also the duration of standards was overestimated by virtually the same amount. In other words, the overestimation of oddballs was not due to their oddness but reflected a different temporal dilation such as the negative time-order error. In Experiment 3, all stimuli were presented at the same spatial position. Again, both oddballs and standards were overestimated, however, oddballs more so. The present results highlight the importance of comparing the judged duration of oddballs and standards when evaluating the size of the genuine oddball effect. Furthermore, the findings suggest that the occurrence of temporal oddball effects can depend on spatial features of stimulus presentation. [ABSTRACT FROM AUTHOR]

Temporal preparation usually results in enhanced performance in choice reaction time tasks. The present study investigated to what extent temporal preparation involves increased readiness for task-specific processing requirements as opposed to increased task-independent readiness. Participants performed either a pitch, a letter, or a color discrimination task within a variable foreperiod paradigm and tasks alternated regularly between auditory and visual discriminations. In separate blocks of trials, the upcoming visual discrimination task was either predictable or unpredictable. We observed the standard variable foreperiod effect for both visual discrimination tasks irrespective of task predictability. Importantly, however, the variable foreperiod effect was larger when the visual discrimination task was predictable than when it was unpredictable. These results suggest that temporal preparation in choice reaction time tasks involves increased readiness for both task-independent and task-specific processing requirements. [ABSTRACT FROM AUTHOR]

The neuroprotective blood-brain barrier ( BBB) keeps many drug candidates below therapeutic levels in the central nervous system. Glutathione PEGylated liposomal doxorubicin (2 B3-101) has been developed to safely enhance the delivery of doxorubicin to brain tumors. However, doxorubicin concentration in extracellular brain fluid cannot yet be reliably measured using conventional techniques. Cerebral open flow microperfusion (c OFM), a recently developed sampling technique, allows monitoring of drug concentrations in the brain independent of molecular weight and lipophilicity. In combination with c OFM sampling, sodium fluorescein ( Na F) is used as a marker for BBB integrity. Rats received one intravenous dose of 7 mg/kg of either 2B3-101 or PEGylated liposomal doxorubicin (generic Caelyx®). Blood and c OFM sampling was performed for 5 h after dose injection. Na F concentration in the brain was monitored and remained low indicating an intact BBB. The brain-to-blood ratio of doxorubicin was 4.8-fold higher after administration of 2 B3-101 as compared with generic Caelyx® ( p = 0.0016). In conclusion, by using c OFM it was possible to show that 2 B3-101 leads to enhanced doxorubicin concentration in the brain without affecting the BBB integrity. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:1945-1948, 2014 [ABSTRACT FROM AUTHOR]

Blood-brain barrier (BBB) impairment in systemic inflammation leads to neuroinflammation. Several factors including cytokines, chemokines and signal transduction molecules are implicated in BBB dysfunction in response to systemic inflammation. Here, we have adopted a novel in vivo technique; namely, cerebral open flow microperfusion (cOFM), to perform time-dependent cytokine analysis (TNF-alpha, IL-6 and IL-10) in the frontal cortex of the rat brain in response to a single peripheral administration of lipopolysaccharide (LPS). In parallel, we monitored BBB function using sodium fluorescein as low molecular weight reporter in the cOFM sample. In response to the systemic LPS administration, we observed a rapid increase of TNF-alpha in the serum and brain, which coincides with the BBB disruption. Brain IL-6 and IL-10 synthesis was delayed by approximately 1 h. Our data demonstrate that cOFM can be used to monitor changes in brain cytokine levels and BBB disruption in a rat sepsis model. [ABSTRACT FROM AUTHOR]

The duration of rare stimuli (oddballs) presented within a stream of homogenous standards tends to be overestimated. This temporal oddball effect (OE) has been attributed to perceptual processes. The OE is usually assessed with a comparative judgment task. It has been argued, however, that this task is prone to decision biases. The present experiments employed comparative and equality judgments, since it has been suggested that equality judgments are less vulnerable to such biases. Experiments 1a and 1b used visual stimuli, and Experiment 2 auditory stimuli. The results provide no strong evidence for decision biases influencing the OE. In addition, computational modeling clearly suggests that the equality judgment is not particularly suited to distinguish between perceptual and decisional effects. Taken together, the pattern of the present results is most consistent with a perceptual origin of the OE. [ABSTRACT FROM AUTHOR]

This study investigated the histological tissue reaction to long-term implanted cerebral open flow microperfusion (cOFM) probes in the frontal lobe of the rat brain. Most probe-based cerebral fluid sampling techniques are limited in application time due to the formation of a glial scar that hinders substance exchange between brain tissue and the probe. A glial scar not only functions as a diffusion barrier but also alters metabolism and signaling in extracellular brain fluid. cOFM is a recently developed probe-based technique to continuously sample extracellular brain fluid with an intact blood-brain barrier. After probe implantation, a 2 week healing period is needed for blood-brain barrier reestablishment. Therefore, cOFM probes need to stay in place and functional for at least 15 days after implantation to ensure functionality. Probe design and probe materials are optimized to evoke minimal tissue reaction even after a long implantation period. Qualitative and quantitative histological tissue analysis revealed no continuous glial scar formation around the cOFM probe 30 days after implantation and only a minor tissue reaction regardless of perfusion of the probe. [ABSTRACT FROM AUTHOR]

[Display omitted] This paper describes a new approach to the early-stage optimization of topical products and selection of lead formulation candidates. It demonstrates the application of open flow microperfusion in vitro in conjunction with the Franz diffusion cell to compare time-resolved, 24-hour profiles of diclofenac passive diffusion through all skin layers (including the skin barrier, dermis, and subcutis) resulting from nine topical formulations of different composition. The technique was successfully validated for in vitro sampling of diclofenac in interstitial fluid. A multi-compartmental model integrating the two datasets was analyzed and revealed that the passive diffusion of diclofenac through the dermis and subcutis does not correlate with its diffusion through the skin barrier and cannot be predicted using Franz diffusion cell data alone. The combined application of the two techniques provides a new, convenient tool for product development and selection enabling the comparison of topical formulation candidates and their impact on drug delivery through all skin layers. This approach can also generate the experimental data required to improve the robustness of mechanistic PBPK models, and when combined with clinical sampling via open flow microperfusion – for the development of better in vivo-in vitro correlative models. [ABSTRACT FROM AUTHOR]

The blood-brain barrier ( BBB) limits substance transport to the brain and is therefore the major hurdle to overcome when developing neuroactive drugs. Herein, we report on cerebral open flow microperfusion ( cOFM) as a new membrane-free technique for measuring substance transport across the intact BBB., The cOFM technique is based on a probe that is inserted into the brain, rupturing the BBB. The BBB is re-established within 15 days, which then allows sampling of interstitial brain fluid under physiological conditions. The aims of the present proof-of-concept study were to: (i) determine the time between cOFM probe insertion and BBB re-establishment; and (ii) demonstrate the ability of cOFM to sample the interstitial cerebral fluid with an intact BBB., The cOFM probe was inserted into the frontal lobe of Sprague- Dawley rats, resulting in BBB rupture. Re-establishment of the BBB was determined using Evans blue ( EB) dye, which is an established marker for BBB intactness because it does not cross the intact BBB. Evaluating EB levels in the brain tissue indicated that the BBB was healed 11 days after probe insertion., To demonstrate transport across the healed BBB, we used sodium fluorescein ( Naf), a sensitive, low molecular weight marker that can cross the intact BBB and can be used to monitor changes in BBB permeability. Significantly increased Naf levels were found in the interstitial fluid when hyperosmolar mannitol (known to open the BBB) was introduced via cOFM, which indicated partial opening of the BBB surrounding the cOFM probe., In conclusion, we show herein that cOFM allows monitoring of BBB permeability, which should be useful for measuring pharmacokinetics across the BBB and pharmacodynamics in the brain. [ABSTRACT FROM AUTHOR]

So far, studies investigating the comparability of breath alcohol concentration (BrAC) with blood alcohol concentration (BAC) have focused on the accuracy of BrAC testing instruments. The presented study, conducted with cases from the district of the Middle Hessian Police Headquarters, is to the best of our knowledge the first to compare both methods under real-life conditions in normal policing situations. For a 1-year period, alcohol-impaired drunk-driving suspects, who were by criminal procedure required to give a blood sample, were offered a voluntary, additional BrAC test with a ''Dräger Alcotest 7110 Evidential''. The BrAC test was to be administered as soon as possible after the suspect had been apprehended, without, however, delaying the collection of the blood sample. Ninety-two cases could be included in our study. In 30 cases, a blood sample was not taken; in 11 cases, a BrAC test could not be performed. In the remaining 51 cases, we found the following pairings of BrAC and BAC results: BrAC ≥ 0.55 mg/l and BAC ≥ 1.1% (n = 39); 0.25 mg/l ⩽ BrAC < 0.55 mg/l and 0.5% ≧ BAC < 1.1% (n = 5); BrAC ≥ 0.55 mg/l and BAC < 1.1% (n = 4); BrAC < 0.55 mg/l and BAC ≧ 1.1% (n = 3). The mean value for the conversion factor, Q, was 2.12% l/mg. In accord with numerous other studies, our study results would suggest a value of 2.1% l/mg to German legislature as a new statutory value for Q. In borderline cases, of which there were already 7 in our study with 51 cases, suspects could benefit both from a BrAC test or a BAC test, with the benefit lastly depending more on early testing time than on the test method used. Our results support the call for the earliest possible measurement of alcohol concentration values after a drunk driving offense was committed. In some situations, this can probably only be accomplished with BrAC testing. A supplementary blood sample and BAC testing could compensate for the known weaknesses of BrAC testing. Thus, the complementary use of both methods might be a viable option. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo. RESEARCH DESIGN AND METHODS--Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide--negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration. RESULTS--The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs.9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 3 2 IU strategy (68±33 vs. 127±93 min; P = 0.01; 38±9 vs. 49±16 min; P<0.01; 23±6 vs.30±10 min; P<0.05). For 932 IU, the area under the GIR curve was greater during the first 60 min (219±89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08). CONCLUSIONS--A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system. [ABSTRACT FROM AUTHOR]

In vivo investigation of brain pharmacokinetics and pharmacodynamics (PK/PD) is an integral part of neurological drug development. However, drugs intended to act in the brain may reach it at very low concentrations due to the protective effect of the blood–brain barrier (BBB). Consequently, very sensitive measurement methods are required to investigate PK/PD of drugs in the brain. Also, these methods must be capable of continuously assessing cerebral drug concentrations with verifiable intact BBB, as disrupted BBB may lead to compound efflux from blood into brain and to biased results. To date, only a few techniques are available that can sensitively measure drug concentrations in the brain over time; one of which is cerebral open flow microperfusion (cOFM). cOFM's key features are that it enables measurement of cerebral compound concentrations with intact BBB, induces only minor tissue reactions, and that no scar formation occurs around the probe. The membrane‐free cOFM probes collect diluted cerebral interstitial fluid (ISF) samples that are containing the whole molecule spectrum of the ISF. Further, combining cOFM with an in vivo calibration protocol (e.g. Zero Flow Rate) enables absolute quantification of compounds in cerebral ISF. In general, three critical aspects have to be considered when measuring cerebral drug concentrations and recording PK/PD profiles with cOFM: (a) the BBB integrity during sampling, (b) the status of the brain tissue next to the cOFM probe during sampling, and (c) the strategy to absolutely quantify drugs in cerebral ISF. This work aims to review recent applications of cOFM for PK/PD assessment with a special focus on these critical aspects. [ABSTRACT FROM AUTHOR]

Introduction: The estimation of age-at-death of unidentified cadavers is a central aspect of the identification process. With increasing age, the incidence of glomerulosclerosis and the thickness of the carotid wall have been observed to also increase. This correlation has been demonstrated in various international histological studies. The aim of our study was to assess whether these correlations also apply to a Western European population. Methodology: In this retrospective observational study, kidney and common carotid artery samples from 216 cases autopsied at the Institute of Legal Medicine at the Justus-Liebig University in Giessen, Germany, were examined. Only cases with available tissue samples from both body sides were included. Exclusion criteria were poor sample quality and an age younger than 21 years. After histological processing, the tissue samples were assessed and digitally evaluated. Regression and classification analyses were used to investigate the correlation between age-at-death and intima-media thickness and age-at-death and the incidence of renal glomerular sclerosis. Results: Of the 216 autopsy cases, 183 were included for evaluation. Analysis of the carotid artery segments showed a strong correlation (Pearson correlation coefficient r = 0.887) between the intima-media-complex thickness and chronological age. Classification of the glomerulosclerotic incidence showed a correlation of 37.7–43.1% with the predicted age group. Discussion: Both the intima-media thickness and the proportion of sclerotic glomeruli can be used to estimate age in Western European cadavers. On the basis of these results, both methods are suited to supplement other already established methods for age-at-death estimation in the identification of an unknown cadaver. [ABSTRACT FROM AUTHOR]

The present study examines for the first time the emission patterns and olfactory signatures of 9 complete human corpses of different stages of decomposition. Air sampling was performed inside the body bags with solid sorbents and analysed by coupled gas chromatography-mass spectrometry after thermal desorption (TD-GC-MS). Furthermore, odour-related substances were detected by gas chromatography-olfactometry (GC-O). Sulfurous compounds (mainly dimethyl di- and trisulfide) were identified as most important to the odour perception. Around 350 individual organic substances were detected by TD-GC-MS, notably sulfurous and nitrogenous substances as well as branched alkanes, aldehydes, ketones, alcohols, carboxylic acids, carboxylic acid esters and ethers. A range of terpenes was detected for the first time in a characteristic emission pattern over all decomposition stages. Concentrations of the substances varied greatly, and no correlation between the emission patterns, the stage of decomposition and the cause of death could be found. While previous studies often analysed pig cadavers or only parts of human tissue, the present study shows the importance of analysing complete human corpses over a range of decomposition stages. Moreover, it is shown that using body bags as a kind of "emission test chamber" is a very promising approach, also because it is a realistic application considering the usual transport and store of a body before autopsy. [ABSTRACT FROM AUTHOR]

Bones found by chance can be of great criminal or historical interest. The nature of their appraisal depends on the individual case, the locally effective legislation and the available resources. To assess whether a find is relevant with respect to criminal investigation, the circumstances of the find and the results of the forensic examination carried out by trained personnel must be considered. The aim of this study was to obtain an overview of the circumstances and nature of the finds as well as the results of the subsequent expert opinions by evaluating bone finds from the federal state of Hesse, Germany. For this purpose, over a 10-year period from 2011 to 2020, all bone finds examined at the Institutes of Legal Medicine in Gießen and Frankfurt am Main, Germany, were evaluated retrospectively with regard to the locations and circumstances of the finds, their nature (human or non-human), the postmortem interval, possible traces of violent impact and the results of further examinations. Of the 288 bone finds evaluated, 38.2% were found in forests, meadows and parks. In 50.7%, the finds contained human bones, of which 37.0% had a forensically relevant postmortem interval of 50 years or less. Evidence of trauma was described in 77.4% of the human bone cases: postmortem damage in 78.8%, peri-mortem injury in 9.7% and ante-mortem injury in 11.5%. DNA examinations were performed in 40.4% of the human bone finds. They yielded STR profiles in 81.3%, leading to a definite identification in 35.4%. Among the non-human bones sent in, the most common were bones from pigs (23.4%), deer (18.1%), cattle (16.4%), roe deer (11.7%) and sheep (11.7%). The macroscopic examination is the first step of the forensic-osteological evaluation and sets the course for further examinations or investigations. DNA examinations are of great importance for the reliable identification of human bones. They were responsible for 70.8% of successful identifications. [ABSTRACT FROM AUTHOR]

Purpose: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. Methods: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. Results: The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject's skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. Conclusions: Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability. [ABSTRACT FROM AUTHOR]

Purpose: Accurate methods to determine dermal pharmacokinetics are important to increase the rate of clinical success in topical drug development. We investigated in an in vivo pig model whether the unbound drug concentration in the interstitial fluid as determined by dermal open flow microperfusion (dOFM) is a more reliable measure of dermal exposure compared to dermal biopsies for seven prescription or investigational drugs. In addition, we verified standard dOFM measurement using a recirculation approach and compared dosing frequencies (QD versus BID) and dose strengths (high versus low drug concentrations). Methods: Domestic pigs were topically administered seven different drugs twice daily in two studies. On day 7, drug exposures in the dermis were assessed in two ways: (1) dOFM provided the total and unbound drug concentrations in dermal interstitial fluid, and (2) clean punch biopsies after heat separation provided the total concentrations in the upper and lower dermis. Results: dOFM showed sufficient intra-study precision to distinguish interstitial fluid concentrations between different drugs, dose frequencies and dose strengths, and had good reproducibility between studies. Biopsy concentrations showed much higher and more variable values. Standard dOFM measurements were consistent with values obtained with the recirculation approach. Conclusions: dOFM pig model is a robust and reproducible method to directly determine topical drug concentration in dermal interstitial fluid. Dermal biopsies were a less reliable measure of dermal exposure due to possible contributions from drug bound to tissue and drug associated with skin appendages. [ABSTRACT FROM AUTHOR]

We report the case of a woman in her thirties who suffered an esophageal rupture while participating in extreme sadomasochistic practices. After herself seeking help in a hospital for complaints alleged to be from a fall, she was initially diagnosed with several broken ribs and a pneumothorax. The cause of the pneumothorax was later discovered to be an esophageal rupture. When confronted with this atypical injury for a fall, the woman admitted to have accidentally swallowed an inflatable gag, which her partner had afterwards inflated. In addition to the esophageal rupture, the patient also had numerous other externally visible injuries of various ages, reportedly also from sadomasochistic acts. Although an in-depth police investigation was conducted and a "slave contract" was found, the woman's consent to the extreme sexual practices performed by her life partner could not be substantiated conclusively. The man was convicted for intentional infliction of serious as well as dangerous bodily injury and sentenced to a long term in prison. [ABSTRACT FROM AUTHOR]

The increasing relevance of improved therapeutic monoclonal antibodies (mAbs) to treat neurodegenerative diseases has strengthened the need to reliably measure their brain pharmacokinetic (PK) profiles. The aim of this study was, therefore, to absolutely quantify the therapeutic antibody ocrelizumab (OCR) as a model antibody in mouse brain interstitial fluid (ISF), and to record its PK profile by using cerebral open flow microperfusion (cOFM). Further, to monitor the blood–brain barrier (BBB) integrity using an endogenous antibody with a similar molecular size as OCR. The study was conducted on 13 male mice. Direct and absolute OCR quantification was performed with cOFM in combination with zero flow rate, and subsequent bioanalysis of the obtained cerebral ISF samples. For PK profile recording, cerebral ISF samples were collected bi-hourly, and brain tissue and plasma were collected once at the end of the sampling period. The BBB integrity was monitored during the entire PK profile recording by using endogenous mouse immunoglobulin G1. We directly and absolutely quantified OCR and recorded its brain PK profile over 96 h. The BBB remained intact during the PK profile recording. The resulting data provide the basis for reliable PK assessment of therapeutic antibodies in the brain thus favoring the further development of therapeutic monoclonal antibodies. [ABSTRACT FROM AUTHOR]

Abstract: A skull without lower jaw was found and brought in for identification. It was suspected to be that of a man reported missing five years ago. An undated antemortal dental chart and two dental films of the 1st and 2nd dental quadrants, both taken about 4 years before the man went missing, were available for comparison. The method of choice in solving the identity question was comparative dental radiography. Despite numerous attempts, it was not possible to obtain radiographs of the upper jaw that duplicated the X-ray beam angulation of the antemortem dental films. The skull was thus scanned with a multislice computed tomography (MSCT) scanner, and virtual radiographs with the desired angulation were generated from the data with the maximum intensity projection (MIP) technique. The resulting virtual radiographs could, however, not be used for superimposition with the antemortem radiographs because of their poor resolution and the occurrence of artifacts caused by metallic dental fillings. The upper jaw was therefore scanned again, this time with a high resolution eLU-CT (eXplore Locus Ultra flat panel CT). The resulting eLU-CT datasets were visualized with the MIP technique and yielded virtual radiographs that could be compared with the antemortem radiographs. Positive identification could be assumed with near certainty after dental features could be matched in the superimposition of antemortem and postmortem radiographs. In the presented case, eLU-CT was used for the first time for a comparative dental radiographic identification. [Copyright &y& Elsevier]

Abstract: Human hair is among the most common kind of evidence secured at crime scenes. Although DNA analysis through STR-typing is possible in principle, it is not very promising for telogenic hair or single hairs. For the mixed traces frequently found in practice, composed of different hair from an unknown number of individuals, mtDNA sequencing of each individual hair seems to be the only possible, even if technically elaborate, solution. If it were possible to pool all hair belonging to an individual prior to DNA analysis, then this effort could not only be reduced, but the number of hair for an STR-approach could also be increased. Although it is possible to examine hair microscopically, this method must be considered unsuitable for pooling, since the results depend strongly on examiner experience, and the hair cannot always be correctly attributed to an individual. The goal of this study was to develop an objective non-DNA-contaminative pooling method for hair. To this end, the efficacy of spectral imaging as a method of obtaining information—beyond that obtained from a purely microscopic and morphological approach—for the identification of individuals was investigated. Three hairs each from 25 test persons (female: 18; male: 7) were examined with a SpectraCube®-System and a light microscope. Six spectra were calculated for each hair, and the hairs from each individual were not only compared to each other, but also to those of the other individuals. From a forensic vantage, the examination showed, in particular, that individuals, whose hair could not be distinguished on the basis of morphology, could also not be accurately distinguished with the SpectraCube®. The intra-individual differences were, in part, greater than the inter-individual differences. Altogether, the study shows that a person''s hair color, as perceived, is composed of many naturally different, individual colors. [Copyright &y& Elsevier]

Despite widespread government and public interest, there are significant barriers to translating basic science discoveries into clinical practice. Biophotonics and biomedical optics technologies can be used to overcome many of these hurdles, due, in part, to offering new portable, bedside, and accessible devices. The current JBO special issue highlights promising activities and examples of translational biophotonics from leading laboratories around the world. We identify common essential features of successful clinical translation by examining the origins and activities of three major international academic affiliated centers with beginnings traceable to the mid-late 1970s: The Wellman Center for Photomedicine (Mass General Hospital, USA), the Beckman Laser Institute and Medical Clinic (University of California, Irvine, USA), and the Medical Laser Center Lübeck at the University of Lübeck, Germany. Major factors driving the success of these programs include visionary founders and leadership, multidisciplinary research and training activities in light-based therapies and diagnostics, diverse funding portfolios, and a thriving entrepreneurial culture that tolerates risk. We provide a brief review of how these three programs emerged and highlight critical phases and lessons learned. Based on these observations, we identify pathways for encouraging the growth and formation of similar programs in order to more rapidly and effectively expand the impact of biophotonics and biomedical optics on human health. [ABSTRACT FROM AUTHOR]

Despite the prevalence and the impact on quality of life of dermatological indications, drug products to treat such conditions have rarely been blockbusters. The prevailing perception of a limited commercial potential of dermatological drug products has restricted innovation and encouraged a more conservative development approach. For example, the focus was on repurposing/reformulation of existing active pharmaceutical ingredients (APIs) specifically for the topical delivery route. However, the situation is quite different today catalyzed in part by the blockbuster success of Dupixent (dupilumab), the first monoclonal antibody treatment for atopic dermatitis which has been approved by the US Food and Drug Administration (US FDA) in 2017. Dupixent's success not only encouraged the development of other biologics but also inspired the (re-)development of new dermal drug products that can reap the many benefits of topical administration. We have also witnessed a shift toward outsourcing development efforts (and associated risks) towards small- to mid-size pharmaceutical companies which often require support of contract research and development/manufacturing organizations (CRO and CDMO). Such trends also emphasize the need of greater expertise in topical formulation design, as well as associated commercial and regulatory considerations. Today, we believe that topical drug products remain not only an essential but also commercially viable class of dermatological therapeutics. In this opinion article, we will address the challenges as well as opportunities of coherent development strategies in the current market environment, formulation innovations of topical drug products and technological advances to facilitate rational topical drug formulation development. [Display omitted] [ABSTRACT FROM AUTHOR]

Unusual findings during an autopsy may come from peculiarities in the position, shape, size, weight, consistency, smell or color of organs. The following study was triggered by an autopsy case in which an unusual blue-green discoloration of organs, which changed during the autopsy, was noticed. A review of the local autopsy database, selected cases including the antemortem clinical documentation and the literature has been performed to clarify the etiology of these conspicuous discolorations and to evaluate their diagnostic value. The study showed that certain xenobiotics may lead to such discoloration. After systemic administration of methylene blue, darkening blue-green discoloration of organs, especially the brain and heart, can be observed. In addition, the systemic administration of toluidine blue also appears to be capable of causing such discoloration. Beyond that, drugs (like Rohypnol®) or other foreign substances (like detergents) containing warning colors, i.e. indigocarmin (E132) or Brilliant Blue FCF (E133) may cause discolorations of the upper gastrointestinal tract or the urinary bladder respectively. A blue-green, possibly darkening discoloration of organs during autopsy may point towards an antemortem administration of certain xenobiotics. The affected organs give an indication of the possible route of application and the type of substance. A differentiated interpretation of the etiology of such conspicuous discolorations at autopsy should only be made considering the (medical) history and, if necessary, complementary (toxicological) examinations. [ABSTRACT FROM AUTHOR]

Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established. To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties. The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 h. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC 0to12h and C max using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study. BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible. dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK-based BE approach for topical lipophilic drugs, including lidocaine and prilocaine. [Display omitted] [ABSTRACT FROM AUTHOR]

Skin equivalents and skin explants are widely used for dermal penetration studies in the pharmacological development of drugs. Environmental parameters, such as the incubation and culture conditions affect cellular responses and thus the relevance of the experimental outcome. However, available systems such as the Franz diffusion chamber, only measure in the receiving culture medium, rather than assessing the actual conditions for cells in the tissue. We developed a sampling design that combines open flow microperfusion (OFM) sampling technology for continuous concentration measurements directly in the tissue with microfluidic biosensors for online monitoring of culture parameters. We tested our design with real-time measurements of oxygen, glucose, lactate, and pH in full-thickness skin equivalent and skin explants. Furthermore, we compared dermal penetration for acyclovir, lidocaine, and diclofenac in skin equivalents and skin explants. We observed differences in oxygen, glucose, and drug concentrations in skin equivalents compared to the respective culture medium and to skin explants. [ABSTRACT FROM AUTHOR]

Justification: In Mexico, the number of unidentified bodies has been steadily rising for years. By now, more than 50,000 bodies are considered unidentified. Forensic laboratories that could perform comparative molecular genetic investigation are often overburdened and examinations can take months. Therefore, pragmatic approaches that can help to identify more unknown bodies must be sought. The increased use of distinctive physical features might be one, and the high rate of tattooed people in Mexico points towards a great potential of tattoos as a tool for identification. The prerequisite for a comparison of antemortem (missing persons) and postmortem (unknown bodies) data is an objective description of the particularities, e.g., of the tattoos. The aim of this study was to establish an objective classification for tattoo motives, taking into consideration local preferences. Methods: In the database of the medicolegal services of the Instituto Jaliscience de Ciencias Forenses (IJCF) in Guadalajara, postmortem data of 1000 tattooed bodies from 2019 were evaluated. According to sex and age, the tattooed body localization and the tattoo motives were categorized. Results: The 1000 tattooed deceased showed tattoos on 2342 body localizations. The motives were grouped and linked to the following 11 keywords (with decreasing frequency): letters/numbers, human, symbol (other), plant, symbol (religious), animal, object, fantasy/demon/comic, tribal/ornament/geometry, other, unrecognizable. Conclusion: Using the proposed classification, tattoo motives can be described objectively and classified in a practical way. If used for antemortem (missing persons) and postmortem (unknown bodies) documentation, motives can be searched and compared efficiently—helping to identify unknown bodies. [ABSTRACT FROM AUTHOR]

Abstract: With the goal of obtaining additional practically applicable methods for estimating the PMI of skeletal remains, 39 samples of human and 5 samples of domestic animal long bones with known PMI (PMI=1 to approximately 2000 years) were tested with two established methods (UV-fluorescence of a freshly sawn cross-section and the luminol test) and two screening tests (Hexagon-OBTI® test and Combur® test) that were being tried out in this context for the first time. The hypothesis underlying this experiment was the supposition that the PMI-related chemiluminescence of the luminol reaction for bone is based on the presence of persisting hemin from hemoglobin molecules in bone. Our results showed that lack of luminescence and reduced UV-fluorescence were more meaningful results for estimating PMI and excluding forensic relevance than a positive luminol reaction or strong UV-fluorescence, as both of the latter findings revealed the limitations of these methods in this particular context. Particularly for cases showing a positive luminol reaction, the use of additional absolute dating methods may be indicated. Against our expectations, both the Combur® test strips and the Hexagon-OBTI® test, which were both devised to demonstrate blood, delivered negative results for all samples. They are thus not suitable for estimating the PMI of skeletal remains. Future research will be necessary to elucidate whether the negative results obtained for these tests may be due to the poor solubility of potentially present hemoglobin or hemoglobin breakdown products in the Tris buffer used in this experiment. [Copyright &y& Elsevier]

Purpose. A2-E is the dominant fluorophore of lipofuscin in the retinal pigment epithelium. In an in-vitro setup, we determined the temperature-dependent changes of the A2-E fluorescence with the aim of also assessing the potential value of such measurements for determining retinal temperature by autofluorescence measurements during laser treatment. Methods. A2-E was biosynthesized and diluted in Dimethyl Sulfoxide (DMSO) to 1 µM. Fluorescence measurements were performed with a photospectrometer under various temperatures ranging from 20°C to 75°C. Autofluorescence was excited at 467 nm, and emission was detected around 632 nm. Results. A2-E fluorescence intensity showed a linear decrease concomitant with temperature increment. At 75°C, the fluorescence intensity decreased by 43% compared to at 20°C. Fluorescence intensity was completely reversible dependent on the temperature, which cannot be explained by thermal A2-E alteration. Conclusions. If the A2-E temperature-dependent fluorescence in-vitro is transferable to human fundus auto-fluorescence, then it may be possible to apply an autofluorescence-based online detection device for noninvasive determination of fundus temperature during in vivo laser treatment. This is of clinical relevance, especially for the application of photodynamic therapy (PDT) and transpupillary thermotherpy (TTT). [ABSTRACT FROM AUTHOR]

: PurposeA novel angiographic technique providing topographic imaging of chorioretinal fluorescence is applied to the characterization of leakage dynamics in exudative chorioretinopathy. The three-dimensional imaging is evaluated with respect to results with conventional two-dimensional fluorescence angiography.: DesignProspective observational case series.: ParticipantsThirty eyes of 30 patients with different exudative maculopathies (pigment epithelium detachment, branch retinal vein occlusion, central serous chorioretinopathy, each n = 10) and 11 eyes of 10 patients with clinically normal appearance.: MethodsDepth-resolved fluorescence angiography using a confocal scanning laser system was performed after complete ophthalmologic examination. The axial distribution of fluorescein and indocyanine green fluorescence at each x/y position within a tomographic scan of 32 images was analyzed. The chorioretinal fluorescence topography was reconstructed by localizing a defined threshold value of fluorescence and displayed as topographic relief. Qualitative description and quantitative measurements of exudation or structural alterations were performed topographically and conventionally.: Main outcome measuresQualitative and quantitative analysis of structural or exudative changes in time course in topographic illustration compared with conventional angiography.: ResultsClinically physiologic eyes were presented topographically as a smooth concave surface of fluorescence with defined illustration of retinal vascular structures and the optic disc. Retinal vascular pathologic conditions induce a precisely demarcated pattern of intraretinal edema with a characteristic temporal evolution. In central serous retinopathy the underlying pathologic condition was identified as a perfusion defect, which was subsequently filled with a peak of exudation with differences in the time of maximum in fluorescein/indocyanine green angiography. Pigment epithelium detachment appeared as a high and well defined elevation, with the origin of exudation within the base of the detachment. Differences in the time of maximum prominence were found in indocyanine green angiography within the pigment epithelium detachment group.: ConclusionsConfocal topographic angiography allows for the first time precise three-dimensional functional imaging of fundus alterations caused by leakage or barrier dysfunction. Compared with conventional angiography, depth-resolved angiographic imaging is less impaired by masking phenomena or low fluorescence intensity, which improves the diagnostic yield of angiography. The characterization and quantification of leakage activity is a promising tool in the assessment of exudative maculopathy. [Copyright &y& Elsevier]

Aim: Selective retinal pigment epithelium (RPE) laser treatment is a new technique which selectively damages the RPE while sparing the neural retina. One difficulty is the inability to visualise the laser lesions. The aim of the study was to investigate whether fundus autofluorescence (AF) is changed because of the RPE damage, and thus might be used for treatment control. Additionally, the clinical course of patients with various macular diseases was evaluated. Methods: 26 patients with macular diseases (diabetic maculopathy (DMP), soft drusen maculopathy (AMD), and central serous retinopathy (CSR)) were treated and followed up for at least 6 months. Treatment was performed with a train of repetitive short laser pulses (800 ns) of a frequency doubled Nd:YAG laser (parameters: 532 nm, 50 and 500 pulses at 100 and 500 Hz, retinal spot diameter 200 µm, pulse energies 75-175 µJ). AF was excited by 488 nm and detected by a barrier filter at 500 nm (HRA, Heidelberg Engineering, Germany). Patients were examined by ophthalmoscopy, fluorescein angiography, and autofluorescence measurements at various times after treatment (10 minutes, 1 hour, 1 and 6 weeks, 3, 6, and 12 months). Results: Fluorescein angiography showed leakage from the irradiated areas for about 1 week after treatment. None of the laser lesions was ophthalmoscopically visible during treatment. Identification of the lesions was possible by AF imaging showing an intensity decay in the irradiated area in 22 out of 26 patients, predominantly in patients with CSR and AMD. Lesions could be identified 10 minutes after treatment as hypoautofluorescent spots, which were more pronounced 1 hour later. During follow up the laser spots became hyperautofluorescent. In patients with DMP some AF images were less helpful because of diffuse oedema and larger retinal thickness. In these cases ICG angiography was able to confirm therapeutic success very well. Most of the patients have had benefit from the... [ABSTRACT FROM AUTHOR]

Postmortem detection of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) after the exhumation of a corpse can become important, e.g. in the case of subsequent medical malpractice allegations. To date, data on possible detection periods [e.g. by reverse transcription polymerase chain reaction (RT-PCR)] or on the potential infectivity of the virus after an exhumation are rare. In the present study, these parameters were examined in two cases with a time span of approximately 4 months between day of death and exhumation. Using SARS-CoV-2 RT-PCR on swabs of both lungs and the oropharynx detection was possible with cycle threshold (Ct) values of about 30 despite signs of beginning decay. RT-PCR testing of perioral and perinasal swabs and swabs collected from the inside of the body bag, taken to estimate the risk of infection of those involved in the exhumation, was negative. Cell culture-based infectivity testing was negative for both, lung and oropharyngeal swabs. In one case, RT-PCR testing at the day of death of an oropharyngeal swab showed almost identical Ct values as postmortem testing of an oropharyngeal swab, impressively demonstrating the stability of viral RNA in the intact corpse. However, favorable climatic conditions in the grave have to be taken into account, as it was wintertime with constant low temperatures. Nevertheless, it was possible to demonstrate successful postmortem detection of SARS-CoV-2 infection following exhumation even after months in an earth grave. [ABSTRACT FROM AUTHOR]

• Hanging and the use of firearms is the most common mode of complex suicides. • Not all cases of complex suicide necessarily have a combined cause of death. • Special attention must be paid to findings allowing the reconstruction of events. Suicides are the second most common cause of non-natural death in Germany after accidents. Most common is death by hanging, followed by the use of firearms. More frequent "simple" suicides in which one suicide method is used are distinguished from rare "complex" suicides, in which several methods are applied, whereby the combination of gunshot and strangulation is frequently chosen. Such cases require a thorough criminalistic and forensic medical examination to check the plausibility of assumed sequences of events and to detect covered-up homicides. A retrospective analysis of 5,400 post-mortem examinations at the Institute of Legal Medicine Giessen (2009–2018) revealed three cases in which gunshot and hanging were used to commit a planned complex suicide. Case 1: The body of a 66-year-old carcinoma patient was found hanging from a tree in a kneeling position with a bullet through the head. The post-mortem examination revealed a penetrating head shot, uninjured soft tissues of the neck, no injuries to the hyoid bone or larynx and no signs of congestion. After autopsy, the gunshot through the head was considered as cause of death. Case 2: An 82-year-old man was found dead with two bullet wounds in the chest, hanging in free suspension in a factory hall. The necropsy showed two chest entry wounds with injuries to the heart and lungs as well as a vital ligature mark and fractures of the hyoid bone and larynx without signs of congestion. The combination of hanging and the gunshot wounds was concluded as cause of death. Case 3: The body of an 81-year-old pain patient was found in his home next to a small-caliber rifle, with a noose around his neck, attached to a suspension torn from the wall. The autopsy revealed a tangential shot through the skull with superficial injury to the frontal brain and a vital cord mark on the neck with fractures of the hyoid bone and larynx without signs of strangulation. In this case, hanging was identified as cause of death. Complex suicides are rare events, that require a thorough criminalistic and forensic medical examination Although being called complex suicides and one of the methods usually being suitable to cause death, the cause of death is not always a combined one. [ABSTRACT FROM AUTHOR]

Purpose: Central serous chorioretinopathy (CSC) is a disease presenting with detachment of the neurosensory retina and characteristic focal leakage on fluorescein angiography. The spontaneous remission rate is 84% within 6 months. In this study, the efficacy of selective retina therapy (SRT) was examined in patients with therapy refractory persistent acute CSC defined by symptoms for at least 6 months and persistent subretinal fluid (SRF) despite eplerenone therapy. Material and methods: This is a prospective, monocentric observational study in 17 eyes (16 patients, mean age 42 years, 2 female). SRT was performed with the approved R:GEN laser (Lutronic, South Korea), a micropulsed 527-nm Nd:YLF laser device, with a train of 30 pulses of 1.7 μs at 100-Hz repetition rate at the point of focal leakage determined by fluorescein angiography (FA) at baseline (BSL). Visits on BSL, week 4 (wk4), and week 12 (wk12) included best corrected visual acuity (BCVA, logMar), central retinal thickness (CRT) on spectral domain optical coherence tomography (SD-OCT), and FA. Statistical analysis was performed by pair-by-pair comparisons of multiple observations in each case with Bonferroni correction for multiple testing. (IBM SPSS Statistics 25®). Results: Mean CRT at BSL was 387.69 ± 110.4 μm. CRT significantly decreased by 106.31 μm in wk4 (95%-KI: 21.42–191.2; p = 0.01), by 133.63 μm in wk12 (95%-KI: 50.22–217.03; p = 0.001) and by 133.81 μm (95%-KI: 48.88–218.75; p = 0.001) compared to BSL. Treatment success defined as complete resolution of SRF occurred at wk4 in 7/17 eyes (35.3%) and at wk12 in 10/17 eyes (58.8%). Re-SRT was performed in 7/17 eyes (41.2%) after an average of 107.14 ± 96.59 days. Treatment success after Re-SRT was observed in 4/6 eyes (66.6%, 12 weeks after Re-SRT). Mean BCVA did not change significantly from BSL to any later timepoint after adjusting for multiple testing. Notably, eyes with treatment success showed better BCVA at all timepoints and gained more letters compared to failures. Conclusion: Single or repetitive SRT may be an effective and safe treatment in 2 of 3 patients suffering from acute persistent CSC after 6 months of symptoms or more. We observed complete resolution of SRF in around 60% of eyes 12 weeks after first SRT treatment and also 12 weeks after Re-SRT treatment in eyes with persistent or recurrent SRF. Results on the long-term course after SRT are still pending. [ABSTRACT FROM AUTHOR]

Burn injuries initiate numerous processes such as heat shock response, inflammation and tissue regeneration. Reliable burn models are needed to elucidate the exact sequence of local events to be able to better predict when local inflammation triggers systemic inflammatory processes. In contrast to other ex vivo skin culture approaches, we used fresh abdominal skin explants to introduce contact burn injuries. Histological and ultrastructural analyses confirmed a partial-thickness burn pathology. Gene expression patterns and cytokine production profiles of key mediators of the local inflammation, heat shock response, and tissue regeneration were analyzed for 24 h after burn injury. We found significantly increased expression of factors involved in tissue regeneration and inflammation soon after burn injury. To investigate purely inflammation-mediated reactions we injected lipopolysaccharide into the dermis. In comparison to burn injury, lipopolysaccharide injection initiated an inflammatory response while expression patterns of heat shock and tissue regeneration genes were unaffected for the duration of the experiment. This novel ex vivo human skin model is suitable to study the local, early responses to skin injuries such as burns while maintaining an intact overall tissue structure and it gives valuable insights into local mechanisms at the very beginning of the wound healing process after burn injuries. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. Methods: Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. Results: Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7–33-fold higher than the dISF concentrations. Conclusions: Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution. [ABSTRACT FROM AUTHOR]