Activation of the cortical pain network by soft tactile stimulation after injection of sumatriptan

The anti-migraine drug sumatriptan often induces unpleasant somatosensory side effects, including a dislike of being touched. With a double-blind cross-over design, we studied the effects of sumatriptan and saline on perception (visual analogue scale) and cortical processing (functional magnetic resonance imaging) of tactile stimulation in healthy subjects. Soft brush stroking on the calf (n=6) was less pleasant (p<0.04) and evoked less activation of posterior insular cortex in the sumatriptan compared to the saline condition. Soft brushing activated pain processing regions (anterior insular, lateral orbitofrontal, and anterior cingulate cortices, and medial thalamus) only in the sumatriptan condition, whereas activation of somatosensory cortices was similar in both conditions. Soft brush stroking on the palm (n=6) was equally pleasant in both conditions. One possible mechanism for the activation of pain processing regions by brush stroking is sensitization of nociceptors by sumatriptan. Another possibility is inhibition of a recently discovered system of low-threshold unmyelinated tactile (CT) afferents that are present in hairy skin only, project to posterior insular cortex, and serve affective aspects of tactile sensation. An inhibition of impulse transmission in the CT system by sumatriptan could disinhibit nociceptive signalling and make light touch less pleasant. This latter alternative is consistent with the observed reduction in posterior insular cortex activation and the selective effects of stimulation on hairy compared to glabrous skin, which are not explained by the nociceptor sensitization account.     

Feasibility of an accelerated PVAL method for the collection of GSR and biological traces

International Journal of Legal Medicine - The polyvinyl alcohol method (PVAL) is known as an effective technique to thoroughly collect traces of gunshot residue (GSR) from different surfaces, e.g.,...     

Pattern of microbial translocation in patients living with HIV-1 from Vietnam,Ethiopia and Sweden

Introduction

The role of microbial translocation (MT) in HIV patients living with HIV from low- and middle-income countries (LMICs) is not fully known. The aim of this study is to investigate and compare the patterns of MT in patients from Vietnam, Ethiopia and Sweden.

Methods

Cross-sectional samples were obtained from treatment-naïve patients living with HIV-1 and healthy controls from Vietnam (n=83; n=46), Ethiopia (n=9492; n=50) and Sweden (n=51; n=19). Longitudinal samples were obtained from a subset of the Vietnamese (n=24) in whom antiretroviral therapy (ART) and tuberculostatics were given. Plasma lipopolysaccharide (LPS), sCD14 and anti-flagellin IgG were determined by the endpoint chromogenic Limulus Amebocyte Assay and enzyme-linked immunosorbent assay.

Results

All three biomarkers were significantly increased in patients living with HIV-1 from all countries as compared to controls. No differences were found between males and females. Vietnamese and Ethiopian patients had significantly higher levels of anti-flagellin IgG and LPS, as compared to Swedes. ART reduced these levels for the Vietnamese. Vietnamese patients given tuberculostatics at initiation of ART had significantly lower levels of anti-flagellin IgG and higher sCD14. The biomarkers were lower in Vietnamese who did not develop opportunistic infection.

Conclusions

Higher MT is common in patients living with HIV compared to healthy individuals, and in patients from LMICs compared to patients from a high-income country. Treatment with tuberculostatics decreased MT while higher levels of MT are associated with a poorer clinical outcome.     

A 5-year follow-up study of adolescents who sought treatment for substance misuse in Sweden

Previous studies have shown that substance misuse in adolescence is associated with increased risks of hospitalizations for mental and physical disorders, convictions for crimes, poverty, and premature death from age 21 to 50. The present study examined 180 adolescent boys and girls who sought treatment for substance misuse in Sweden. The adolescents and their parents were assessed independently when the adolescents first contacted the clinic to diagnose mental disorders and collect information on maltreatment and antisocial behavior. Official criminal files were obtained. Five years later, 147 of the ex-clients again completed similar assessments. The objectives were (1) to document the prevalence of alcohol use disorders (AUD) and drug use disorders (DUD) in early adulthood; and (2) to identify family and individual factors measured in adolescence that predicted these disorders, after taking account of AUD and DUD in adolescence and treatment. Results showed that AUD, DUD, and AUD + DUD present in mid-adolescence were in most cases also present in early adulthood. Prediction models detected no positive effect of treatment in limiting persistence of these disorders. Thus, treatment-as-usual provided by the only psychiatric service for adolescents with substance misuse in a large urban center in Sweden failed to prevent the persistence of substance misuse. Despite extensive clinical assessments of the ex-clients and their parents, few factors assessed in mid-adolescence were associated with substance misuse disorders 5 years later. It may be that family and individual factors in early life promote the mental disorders that precede adolescent substance misuse.     

Fluid distribution kinetics during cardiopulmonary bypass

OBJECTIVE:

The purpose of this study was to examine the isovolumetric distribution kinetics of crystalloid fluid during cardiopulmonary bypass.

METHODS:

Ten patients undergoing coronary artery bypass grafting participated in this prospective observational study. The blood hemoglobin and the serum albumin and sodium concentrations were measured repeatedly during the distribution of priming solution (Ringer''s acetate 1470 ml and mannitol 15% 200 ml) and initial cardioplegia. The rate of crystalloid fluid distribution was calculated based on 3-min Hb changes. The preoperative blood volume was extrapolated from the marked hemodilution occurring during the onset of cardiopulmonary bypass. Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01115166","term_id":"NCT01115166"}}NCT01115166.

RESULTS:

The distribution half-time of Ringer''s acetate averaged 8 minutes, corresponding to a transcapillary escape rate of 0.38 ml/kg/min. The intravascular albumin mass increased by 5.4% according to mass balance calculations. The preoperative blood volume, as extrapolated from the drop in hemoglobin concentration by 32% (mean) at the beginning of cardiopulmonary bypass, was 0.6-1.2 L less than that estimated by anthropometric methods (p<0.02). The mass balance of sodium indicated a translocation from the intracellular to the extracellular fluid space in 8 of the 10 patients, with a median volume of 236 ml.

CONCLUSIONS:

The distribution half-time of Ringer''s solution during isovolumetric cardiopulmonary bypass was 8 minutes, which is the same as for crystalloid fluid infusions in healthy subjects. The intravascular albumin mass increased. Most patients were hypovolemic prior to the start of anesthesia. Intracellular edema did not occur.     

The global prevalence of headache: an update,with analysis of the influences of methodological factors on prevalence estimates

BackgroundAccording to the Global Burden of Disease (GBD) study, headache disorders are among the most prevalent and disabling conditions worldwide. GBD builds on epidemiological studies (published and unpublished) which are notable for wide variations in both their methodologies and their prevalence estimates.Our first aim was to update the documentation of headache epidemiological studies, summarizing global prevalence estimates for all headache, migraine, tension-type headache (TTH) and headache on ≥15 days/month (H15+), comparing these with GBD estimates and exploring time trends and geographical variations. Our second aim was to analyse how methodological factors influenced prevalence estimates.MethodsIn a narrative review, all prevalence studies published until 2020, excluding those of clinic populations, were identified through a literature search. Prevalence data were extracted, along with those related to methodology, world region and publication year. Bivariate analyses (correlations or comparisons of means) and multiple linear regression (MLR) analyses were performed.ResultsFrom 357 publications, the vast majority from high-income countries, the estimated global prevalence of active headache disorder was 52.0% (95%CI 48.9–55.4), of migraine 14.0% (12.9–15.2), of TTH 26.0% (22.7–29.5) and of H15+ 4.6% (3.9–5.5). These estimates were comparable with those of migraine and TTH in GBD2019, the most recent iteration, but higher for headache overall. Each day, 15.8% of the world’s population had headache. MLR analyses explained less than 30% of the variation. Methodological factors contributing to variation, were publication year, sample size, inclusion of probable diagnoses, sub-population sampling (e.g., of health-care personnel), sampling method (random or not), screening question (neutral, or qualified in severity or presumed cause) and scope of enquiry (headache disorders only or multiple other conditions). With these taken into account, migraine prevalence estimates increased over the years, while estimates for all headache types varied between world regions.ConclusionThe review confirms GBD in finding that headache disorders remain highly prevalent worldwide, and it identifies methodological factors explaining some of the large variation between study findings. These variations render uncertain both the increase in migraine prevalence estimates over time, and the geographical differences. More and better studies are needed in low- and middle-income countries.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01402-2.     

Landscape of surfaceome and endocytome in human glioma is divergent and depends on cellular spatial organization

Therapeutic strategies directed at the tumor surfaceome (TS), including checkpoint inhibitor blocking antibodies, antibody drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cells, provide a new armament to fight cancer. However, a remaining bottleneck is the lack of strategies to comprehensively interrogate patient tumors for potential TS targets. Here, we have developed a platform (tumor surfaceome mapping [TS-MAP]) integrated with a newly curated TS classifier (SURFME) that allows profiling of primary 3D cultures and intact patient glioma tumors with preserved tissue architecture. Moreover, TS-MAP specifically identifies proteins capable of endocytosis as tractable targets for ADCs and other modalities requiring toxic payload internalization. In high-grade gliomas that remain among the most aggressive forms of cancer, we show that cellular spatial organization (2D vs. 3D) fundamentally transforms the surfaceome and endocytome (e.g., integrins, proteoglycans, semaphorins, and cancer stem cell markers) with general implications for target screening approaches, as exemplified by an ADC targeting EGFR. The TS-MAP platform was further applied to profile the surfaceome and endocytome landscape in a cohort of freshly resected gliomas. We found a highly diverse TS repertoire between patient tumors, not directly associated with grade and histology, which highlights the need for individualized approaches. Our data provide additional layers of understanding fundamental to the future development of immunotherapy strategies, as well as procedures for proteomics-based target identification and selection. The TS-MAP platform should be widely applicable in efforts aiming at a better understanding of how to harness the TS for personalized immunotherapy.

Cell-surface proteins have a key role in drug development, and approximately two-thirds of approved human drugs target a cell-surface protein (1). Recently, tumor cell–surface proteins integrated with the plasma membrane (tumor surfaceome [TS]) have attracted considerable attention as targets for immunotherapies in cancer. Immune checkpoint-blocking antibodies (e.g., ipilimumab and nivolumab), antibody drug conjugates (ADCs, e.g., trastuzumab emtansin), radioimmunotherapy (RIT, e.g., ⁹⁰Y ibritumomab tiuxetan), and chimeric antigen receptor T (CAR-T) cells are all directed at the TS and currently revolutionize cancer treatment (2–6). With the impressive development of creative methods for antibody and T cell engineering, a remaining challenge is the lack of strategies to comprehensively map potential TS target antigens for the design of more rational, individualized treatments (7). Although advancements in DNA and RNA sequencing provide high throughput data for prediction algorithms, e.g., personalized peptide vaccine trials (8, 9), the predicted proteome derived from these platforms is not necessarily expressed and available for targeting. Moreover, proteomics-based strategies involve analysis of the bulk from disintegrated tumor tissue, resulting in loss of spatial information and limited coverage of the less abundant and hydrophobic TS proteins (10, 11). Of particular relevance, ADC, RIT, and other intracellular drug delivery strategies rely on TS targets that functionally engage in endocytic internalization (12). Clearly, despite its great targeting potential in cancer immunotherapy, the TS remains an elusive treasure for further discovery.Procedures for unbiased mapping of the TS and target identification should include specific labeling of the TS in freshly resected patient tumors with preserved tissue architecture. Enrichment of TS proteins and reduction of noise from intracellular proteins as well as abundant extracellular matrix collagens and glycoproteins would greatly improve downstream mass spectrometry analysis. Moreover, the approach should allow functional and dynamic profiling of TS internalization in an intact tissue environment. With the aim to address these challenges and to provide insight into the complexity of the TS, we have developed a versatile technology for TS mapping (TS-MAP). As proof of concept, we focused on primary brain tumors that remain among the most aggressive forms of cancer and for which attempts to conquer the most common variant, glioblastoma (GBM) (World Health Organization [WHO] grade IV) have failed so far (13). TS-MAP is compatible with spheroids from primary human stem cell–like GBM cultures, as well as mouse and patient brain tumors, and separately profiles surface resident and internalized TS proteins. Moreover, a TS classifier (SURFME) was curated for filtering and categorization of bona fide membrane proteins exposed to the extracellular space. We find significant differences in the TS between the 2D and 3D spheroid format, which underlines the importance of cellular spatial organization. In strong support of the need of individualized approaches, our findings suggest substantial intertumoral heterogeneity in the relative abundance of TS proteins in a cohort of freshly resected patient gliomas.