Ultra-Early Hemostatic Therapy for Acute Intracerebral Hemorrhage: An Updated Review.

Intracerebral hemorrhage (ICH) is the second most common type of stroke, accounting for approximately 10-20% of all strokes, and is linked to severe neurological disability and death. Since the most accurate predictor of outcome in patients with ICH is hematoma volume, there is a great need for pharmacologic therapy that can reduce hematoma expansion and resultant mass effect and edema. This is especially critical within the ultra-early window of 3-4 hours after the presentation. Hemostatic therapies are exceptionally important for those patients taking antiplatelet or anticoagulant medications to reverse the effects of these medications and therefore prevent hematoma expansion. Furthermore, the recent publication of the 2023 Guideline for the Management of Patients with Aneurysmal Subarachnoid Hemorrhage by the American Heart Association/American Stroke Association, the first update to the guidelines since 2012, underscores the importance of optimizing anticoagulation reversal for this population. The purpose of this selective, nonsystematic review is to examine current literature regarding the use of hemostatic therapies in ICH, with particular attention paid to antiplatelet, anticoagulation, and antifibrinolytic therapies.

Spatially Dependent Tissue Distribution of Thyroid Hormones by Plasma Thyroid Hormone Binding Proteins.

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings. (1) Contrary to postulations that TTR and/or ALB are the major local T4 contributors, the three THBPs may unload comparable amounts of T4 in Liver, a rapidly perfused organ; however, their contributions in slowly perfused tissues follow the order of abundances of T4TBG, T4TTR, and T4ALB. The T3 amounts unloaded from or loaded onto THBPs in a tissue acting as a T3 sink or source respectively follow the order of abundance of T3TBG, T3ALB, and T3TTR regardless of perfusion rate. (2) Any THBP alone is sufficient to maintain spatially uniform TH tissue distributions. (3) The TH amounts unloaded by each THBP species are spatially dependent and nonlinear in a tissue, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end. (4) Spatial gradients of TH transporters and metabolic enzymes may modulate these contributions, producing spatially invariant or heterogeneous TH tissue concentrations depending on whether the blood-tissue TH exchange operates in near-equilibrium mode. In summary, our modeling provides novel insights into the differential roles of THBPs in local TH tissue distribution.

A minimal human physiologically based kinetic model of thyroid hormones and chemical disruption of plasma thyroid hormone binding proteins.

The thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), are under homeostatic control by the hypothalamic-pituitary-thyroid axis and plasma TH binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB). THBPs buffer free THs against transient perturbations and distribute THs to tissues. TH binding to THBPs can be perturbed by structurally similar endocrine-disrupting chemicals (EDCs), yet their impact on circulating THs and health risks are unclear. In the present study, we constructed a human physiologically based kinetic (PBK) model of THs and explored the potential effects of THBP-binding EDCs. The model describes the production, distribution, and metabolism of T4 and T3 in the Body Blood, Thyroid, Liver, and Rest-of-Body (RB) compartments, with explicit consideration of the reversible binding between plasma THs and THBPs. Rigorously parameterized based on literature data, the model recapitulates key quantitative TH kinetic characteristics, including free, THBP-bound, and total T4 and T3 concentrations, TH productions, distributions, metabolisms, clearance, and half-lives. Moreover, the model produces several novel findings. (1) The blood-tissue TH exchanges are fast and nearly at equilibrium especially for T4, providing intrinsic robustness against local metabolic perturbations. (2) Tissue influx is limiting for transient tissue uptake of THs when THBPs are present. (3) Continuous exposure to THBP-binding EDCs does not alter the steady-state levels of THs, while intermittent daily exposure to rapidly metabolized TBG-binding EDCs can cause much greater disruptions to plasma and tissue THs. In summary, the PBK model provides novel insights into TH kinetics and the homeostatic roles of THBPs against thyroid disrupting chemicals.

A Case of COVID-19-Associated Focal Segmental Glomerulosclerosis.

This case report details a 43-year-old female diagnosed with the collapsing variant of focal segmental glomerulosclerosis (FSGS) post-infection with coronavirus disease 2019 (COVID-19). The patient contracted COVID-19 after returning from a trip to Florida and initially presented to the emergency department with gastrointestinal symptoms. Thereafter, the patient was diagnosed with COVID-19 and was admitted for acute kidney injury and worsening COVID-19 infection. FSGS is a glomerulopathy that consists of glomerular scarring that leads to nephrotic syndrome, secondary to podocyte effacement. FSGS has many causes, as well as distinct variants, but is noted to have an association with some viruses, most notably HIV and cytomegalovirus (CMV). Although the association between FSGS and HIV or CMV is well established, the evidence is minimal in regard to other viruses. This case report serves to highlight the potential association of COVID-19 with FSGS.

Surgicel-Induced Anaphylaxis Post Permacath Placement.

This case report details the resulting anaphylaxis and angioedema following placement of Surgicel hemostatic agent in a 38-year-old male postoperatively. Our patient experienced minor postoperative bleeding at the placement site of a dialysis catheter, which was controlled using Surgicel. Within minutes of the placement of Surgicel in the incision, the patient experienced an anaphylactic reaction with facial angioedema resulting in a Rapid Response being called to intervene. Incidences of Surgicel-induced anaphylaxis and hypersensitivity reactions are rare, but this report aims to bring awareness to this potential complication, as well as to assist with guiding management of future adverse reactions and surveillance of patients afterward.

Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes.

BACKGROUND: Hypereosinophilic syndromes (HESs) are chronic disorders that require long-term therapy to suppress eosinophilia and clinical manifestations. Corticosteroids are usually effective, yet many patients become corticosteroid refractory or develop corticosteroid toxicity. Mepolizumab, a humanized monoclonal anti-IL-5 antibody, showed corticosteroid-sparing effects in a double-blind, placebo-controlled study of FIP1L1/PDGFRA-negative, corticosteroid-responsive subjects with HESs. OBJECTIVE: We evaluated long-term safety and efficacy of mepolizumab (750 mg) in HES. METHODS: MHE100901 is an open-label extension study. The primary end point was the frequency of adverse events (AEs). Optimal dosing frequency, corticosteroid-sparing effect of mepolizumab, and development of antimepolizumab antibodies were also explored. RESULTS: Seventy-eight subjects received 1 to 66 mepolizumab infusions each (including mepolizumab infusions received in the placebo-controlled trial). Mean exposure was 251 weeks (range, 4-302 weeks). The most common dosing interval was 9 to 12 weeks. The incidence of AEs was 932 events per 100 subject-years in the first year, declining to 461 events per 100 subject-years after 48 months. Serious AEs, including 1 death, were reported by the investigator as possibly due to mepolizumab in 3 subjects. The median daily prednisone dose decreased from 20.0 to 0 mg in the first 24 weeks. The median average daily dose for all subjects over the course of the study was 1.8 mg. Sixty-two percent of subjects were prednisone free without other HES medications for ≥ 12 consecutive weeks. No neutralizing antibodies were detected. Twenty-four subjects withdrew before study completion for death (n = 4), lack of efficacy (n = 6), or other reasons. CONCLUSION: Mepolizumab was well tolerated and effective as a long-term corticosteroid-sparing agent in PDGFRA-negative HES.

Expression analysis of melatonin receptor subtypes in the ovary of domestic chicken.

Melatonin (N-acetyl-5-methoxytryptamine), an indole hormone, regulates various biological functions through three different receptor subtypes (Mel-1a, Mel-1b, and Mel-1c). However, the distribution of different melatonin receptor subtypes in chicken reproductive tissues was not known. In the present investigation, the partial sequences of ovarian melatonin receptor subtypes (Mel-1a, Mel-1b, and Mel-1c) were characterized. Further, the expression profile of melatonin receptor subtypes in the granulosa and theca layers of different preovulatory and postovulatory follicles (POF) were studied by semi-quantitative RT-PCR. The expression of all three subtypes of melatonin receptors were observed in the ovary of domestic chicken. Analysis of partial sequences of ovarian melatonin receptors revealed that the melatonin subtypes were identical to the brain receptors. In small white ovary follicles, we observed only the expression of mel-1b receptors, but not mel-1a or mel-1c receptors. In yellow follicles, all the three subtypes of receptors expression were noticed. Interestingly, we observed the expression of mel-1a receptor only in thecal layer, but not in granulosa layer. In contrast, mel-1b and -1c receptors were expressed in both granulosa and thecal layer. During the regression of POF, we observed significant upregulation of melatonin receptors (mel-1a and 1c) expression, that downregulated in the later stages of regression. We assume that the expression of melatonin receptors might have been influenced by the atresia or apoptosis of different follicular layers in POF. Our findings suggest that the differential distribution of melatonin receptor subtypes might have distinct downstream cellular functions in the ovarian tissues.

High doses of dietary zinc induce cytokines, chemokines, and apoptosis in reproductive tissues during regression.

In chickens, high levels of dietary zinc cause molting, and the reproductive system undergoes complete remodeling concomitant to feather replacement. In the present study, the expression profiles of cytokines and chemokines were investigated in the ovary and oviduct of control hens and of hens induced to molt by zinc feeding. The zinc-induced feed-intake suppression, the changes in corticosterone levels, the immune cell populations in the reproductive tract, and the apoptosis of reproductive tissues were analyzed. The expression of mRNAs for interleukin-6 (IL-6), interferon-gamma (IFN-gamma), the avian ortholog of mammalian IL-8 (chCXCLi2), and a chicken MIP-1beta-like chemokine (chCCLi2) in the ovary and of mRNAs for IL-1beta, IL-6, IFN-gamma, transforming growth factor-beta2, chCXCLi2, and chCCLi2 in the oviduct were upregulated significantly during zinc-induced molting. A simultaneous feed-intake reduction was observed with higher expression of cytokines and chemokines. The results of the present investigation also suggested that the upregulation of corticosterone was closely associated with the increased expression of cytokines and chemokines. An increase in apoptosis within reproductive tissue during tissue regression was also noted. We had previously observed the upregulation of these cytokines expression in an earlier study (molting by feed withdrawal). However, the pattern and the level of expression were different among these two methods. These findings indicate that cytokines might be a common mediator of tissue regression during molting induced by diverse methods, although the pattern of induction is different. Thus, a high dose of dietary zinc seems to induce reproductive regression via the upregulation of cytokines and chemokines, the suppression of feed intake, and the increase in serum corticosterone, resulting finally in the apoptosis of reproductive tissues.

Spatial expression of chemokines and cytokines mRNA in the largest preovulatory follicle of chicken.

In the present experiment, we studied the spatial expression profiles of chemokines and cytokines mRNA in the granulosa (F1Gr) and theca (F1Th) layers of the largest preovulatory follicle in chicken using semi-quantitative PCR. The mRNAs of IL-1beta, IL-6, GM-CSF, chCXCLi2, chCCLi2, chCCLi4, chCCLi7, IFN-gamma, IL-4, IL-13, IL-10 and TGF-beta2 were expressed in the granulosa (F1Gr) and theca (F1Th) layers of the largest preovulatory follicle. However, the transcripts of IL-2 were not detected in any of the samples tested. Significantly higher levels of IL-6 and GM-CSF mRNA expression were noticed in F1Gr when compared to F1Th layer. Expression of chCXCLi2, a CXC chemokine, was almost similar in F1Gr and F1Th layers. However, the expression of CCL chemokines i.e. chCCLi2, chCCLi4, chCCLi7 mRNAs were almost 2 folds higher in F1Th layer in comparison to F1Gr layer. The expression of Th2 cytokines (IL-4 and IL-13) mRNA was noticed in F1Gr and F1Th layers with higher levels in the former. Expression of IFN-gamma mRNA was noticed in F1Gr and F1Th layers. Significantly higher level of TGF-beta2 expression was observed in F1Th in comparison to F1Gr layer. It was concluded from the present study that the mRNA expression of cytokines and chemokines are differentially regulated in the granulosa and theca layers of the largest preovulatory follicle in chicken.

Expression profile of myostatin mRNA during the embryonic organogenesis of domestic chicken (Gallus gallus domesticus).

Myostatin is a potent growth and differentiation factor involved in skeletal muscle tissue formation in vertebrates. However, recent studies in chicken embryo suggested that the myostatin was expressed even before the establishment of myogenic lineage. No studies have thus far been reported in birds to define the role of myostatin during the embryonic organogenesis. The present experiment was designed for studying the expression profiles of myostatin mRNA in the chicken liver, heart, brain, and intestine during their morphogenesis, using real-time PCR. The myostatin mRNA expression was significantly upregulated in liver during E15-E18. Similar results were observed during the development of chicken heart. In brain, the expression of myostatin was upregulated from E4 onwards. In intestine, the expression of myostatin was significantly increased many folds on E9-E18. Therefore, the increase in myostatin expression might be related to the growth of liver and heart on days E12-E18; morphogenesis and growth of brain during E15-E18; and morphogenesis and differentiation of intestine during E9-E18. In the present study, the tissue-specific expression of myostatin gene in chicken is similar to fishes, but different from that in mammals. Further, the inspection of chicken genome also suggested that there is no differentiation of GDF-8 and -11. A recent finding suggests that the chicken myostatin gene is closely related to mammals than fishes. Therefore, we propose that the chicken myostatin gene might have diverged in its function between teleosts and mammals. Indeed it is possible that its function might have only become fully differentiated to serve as a control of muscle mass in mammals.

Cytokines and chemokines in postovulatory follicle regression of domestic chicken (Gallus gallus domesticus).

The mechanism of postovulatory follicle (POF) regression in birds is still poorly understood. In the current study, expression of IL-1beta, IL-6, GM-CSF, IFN-gamma, IL-2, IL-4, IL-13, chCXCLi2, chCCLi2, chCCLi4, chCCLi7, IL-10 and TGF-beta2 mRNAs was estimated in regressing POF by semi-quantitative RT-PCR. In addition, the changes in immune cell population, histological and apoptotic changes were also studied in regressing POF. The expression of cytokines (IL-1beta, IL-6, IL-10 and TGF-beta2) and chemokines (chCXCLi2, chCCLi2, chCCLi4 and chCCLi7) was upregulated in POFs, suggesting a role for these molecules in tissue regression. The histological findings suggested a significant infiltration of immune cells, especially heterophils, lymphocytes and macrophages, into the regressing POF. The flow cytometry analysis of lymphocyte subpopulations revealed that CD3(+), CD4(+), CD8(+) and Bu-1(+) lymphocytes were significantly increased during this regression. The significant up-regulation of chemokines might have attracted the immune cells during POF regression. The percentage of apoptotic cells was significantly increased during the regression of POF. The up-regulation of IL-1beta, IL-6, IL-10 and TGF-beta2 and down-regulation of GM-CSF might have induced apoptosis during the POF regression. However, expression of IFN-gamma, IL-2, IL-4 and IL-13 was not significantly altered during POF regression. In conclusion, cytokines appear to play an important role in the regression of POF in chicken. Furthermore, the regression of chicken POF seems to be an inflammatory event similar to luteolysis of the mammalian corpus luteum.

Caspase-mediated apoptosis in chicken postovulatory follicle regression.

Chicken postovulatory follicle (POF) regression occurs via the process of apoptosis. However, the signals and initiator pathways responsible for regression of the POF are unknown. In the current study, we examined gene expression patterns of various caspases (caspase-1, -2 and -3) involved in apoptosis by semi-quantitative RT-PCR. The percentage of apoptotic cells during POF regression was also quantified by flow cytometry. Expression of caspase-3 mRNA was noted in the largest preovulatory follicle (F1). However, the initiator caspases (caspase-1 and -2) were not expressed in F1. During the regression of the POF, caspase-3 was activated during initial stages, whereas the initiator caspases were upregulated at the later stages (POF4 and POF5). The percentage of apoptotic cells was significantly higher during the regression of the POF. It might be possible that levels of caspase-3 mRNA do not necessarily reflect the cell's potential for facilitating apoptosis, as activation of the caspase-3 by initiator caspases is required for its function. We presume that both caspase-1 and caspase-2 were key initiators in the regression of chicken POF and that the apoptosis-mediated regression of POFs might be similar to mammalian corpus luteum involution.

Reproductive tissue regression: involvement of caspases, inducible nitric oxide synthase and nitric oxide during moulting in White Leghorn hens.

Moulting is a natural physiological process where the reproductive system of birds undergoes complete remodeling in preparation for the next laying cycle. In domestic chickens, moulting is artificially induced by feed withdrawal to recycle the old laying flock for best profit margins. This has received severe criticism from animal welfare organizations, forcing several countries to stop this practice. Several alternative methods to feed withdrawal methods were developed but were found to produce inconsistent results. Understanding the actual mechanism of moulting would help in designing a new animal welfare friendly method. The present investigation attempted to study the molecular mechanism of moulting in White Leghorn hens. Eighty-four layers (75 weeks) were divided into two groups. The birds in the first group were subjected to moulting by feed withdrawal (FW) while the other group received high dietary Zn (ZnF) treatment for 10 days. Six birds from each group were sacrificed on 0, 1-4, 6 and 10 days of moulting and mRNA expression of caspases-1, -2 and iNOS, along with the apoptotic ladder pattern and nitric oxide (NO) in the ovary and oviduct, was investigated. The mRNA expression of iNOS was upregulated with a corresponding increase in NO levels. Caspases-1 and -2 were differentially upregulated in the ovary and oviduct of moulted birds. A constant decline in serum estradiol and progesterone levels was also observed. It can be concluded that the pattern of reproductive regression during moulting by the two methods is different, as the expression of genes studied in the present investigation is different.

Differential expression of lipopolysaccharide-induced TNF-alpha factor (LITAF) in reproductive tissues during induced molting of white leghorn hens.

The reproductive remodeling during molting appears to be a complex physiological mechanism regulated by multiple host factors. Lipopolysaccharide (LPS) induced TNF-alpha factor (LITAF) is one of the transcription factors controlling the expression of TNF-alpha and other cytokines. In the present investigation, we studied the involvement of LITAF in the regression of reproductive tissues of molting birds. Semi-quantitative RT-PCR analysis revealed that LITAF mRNA was generally expressed in both ovary and oviduct. In the molting birds, i.e. those subjected to feed withdrawal (FW) or fed high levels of zinc (ZnF) birds, the LITAF expression was upregulated significantly in the ovary after 4 days of molting (DOM). However, LITAF mRNA levels were three-fold higher in ZnF birds, which might be responsible for a greater degree of follicular atresia. In the oviduct of FW birds, peak LITAF expression was noticed on 4DOM and the levels remained significantly higher until the end of the experiment. In ZnF birds, LITAF expression reached its peak on 1DOM and subsequently downregulated to basal levels on 2DOM. This indicated that constantly higher LITAF expression might be required for complete regression of the oviduct during molting. In conclusion, LITAF might be one of the major transcription factors controlling reproductive regression in chicken, as the expression levels were associated with the regression pattern.

Nitric oxide: a possible mediator of ovulation and postovulatory follicle regression in chicken.

Nitric oxide (NO) has recently emerged as a regulator of functional and structural regression in mammalian reproductive tissues. However, the role of NO in ovulation and postovulatory follicles (POF) that undergo regression in laying birds is unclear. In the present investigation, the expression profiles of iNOS mRNA, tissue NO levels and the percentage of apoptotic cells were studied in the regressing chicken postovulatory follicle (POF). The postovulatory follicles gradually lost weight during its regression and reached the lowest weight on POF5. The number of apoptotic cells was increased significantly during the regression of POF. The mRNA expression of iNOS was noticed in the second largest preovulatory follicle (F2) that subsequently increased in the largest preovulatory follicle (F1). However, the level of iNOS mRNA was declined immediately after ovulation and thereafter upregulated again to reach a peak in POF3 with a subsequent reduction in POF5 to below the basal level. The tissue NO levels followed a similar pattern except with a peak production in POF4. The gross regression and apoptosis in POFs were well associated with iNOS expression and NO production. In conclusion, NO appears to play a role in ovulation and regression of postovulatory follicle in chicken.

Cytokines in reproductive remodeling of molting White Leghorn hens.

The role of cytokines in regression of the ovary and oviduct during induced molting in chickens was investigated by evaluating the expressions of IL-1beta, IL-6, IFN-gamma, IL-2, TGF-beta2, MIP-1beta and IL-8 in the regressing ovary and oviduct by semi-quantitative RT-PCR. In addition, serum hormonal profiles (estrogen, progesterone and corticosterone), along with the gross regression and histological changes of the ovary and oviduct, were investigated. The correlation between expression of cytokines and hormonal changes during the induced molting was also studied. The expression of IL-6, IL-8, MIP-1beta and IFN-gamma mRNAs in the ovary, and IL-1beta, IL-6, IL-8, MIP-1beta, IFN-gamma and TGF-beta2 mRNAs in the oviduct, were up-regulated significantly during induced molting, suggesting their role in tissue regression. However, histological findings suggested no significant increase in immune cells in the regressing oviduct and ovary. Significant up-regulation of TGF-beta2 in the regressing oviduct might have suppressed leukocyte recruitment thereby preventing the inflammatory response and tissue damage. The down-regulation of estrogen and progesterone and up-regulation of corticosterone is well correlated with increased expression of cytokines. It appears that cytokines released during the process of induced molting may have a role in decreasing ovarian steroids and increasing the corticosterone levels in chicken. From this study, it may be concluded that cytokines play a major role in regression of the ovary and oviduct during induced molting in chickens.

A survey of clinical trials of antibiotic prophylaxis in colon surgery: evidence against further use of no-treatment controls.

To evaluate the use of antibiotics given prophylactically of colon surgery, we examined 26 trials published from 1965 to 1980 in which patients given various antibiotic regiments were compared with controls given no antibiotic treatment. In 22 (85 per cent of these trials) antibiotics reduced postoperative wound infection (p less than 0.05 in 14). Combining the results of the trials published from 1965 to 1975 reveals a 95 per cent confidence interval from the true difference in infection rates of 14 +/- 6 per cent (36 per cent for control group vs. 22 per cent for treatment group) and the true difference in death rates of 6.7 +/- 4.4 per cent (11.2 per cent for control group vs 4.5 per cent for treatment group). Yet trials employing control groups given no treatment continue to be reported. Since the use of such controls is justified only when no effective alternative therapy exists, we believe that any further trials of antibiotic prophylaxis in colon surgery should employ a previously proved standard. However, steadily increasing efficacy of treatment means that comparisons of new therapies with standard therapies will become prohibitively expensive because of the large number of patients required.