Time to surgery: Is it truly crucial in initially stable patients with penetrating injury?

BACKGROUND: Treatment recommendations for patients with penetrating abdominal injury are well established. Trauma victims with clear indications for surgery, should undergo immediate operative intervention without any delay or additional imaging. However, the optimal time for surgery remains unclear. There are some significant advantages in preoperative abdominal CT, including gathering essential information regarding a few difficult to reach anatomical areas, avoiding unnecessary explorations associated with increased morbidity and assessing the existence of extra-abdominal injuries that may have non-expectable impact on initial therapeutic plan. The aim of this study was to determine the impact of "time-to-surgery" on final medical outcomes in patients with penetrating abdominal trauma with normal blood pressure on admission. METHODS: A retrospective cohort study using the Israeli National Trauma Registry was conducted from 2000- 2018. This study included trauma patients with penetrating injuries and a systolic blood pressure of 90mmHg or above on admission. All patients included in the study were divided into three groups according to the time that lapsed from their admission to surgery: half an hour, an hour, and two hours. We assessed the outcome for each patient, including length of hospital stay, need for intensive care and mortality. Statistical analysis was performed using the Chi-square test, ANOVA test. A p-value of less than 0.05 was considered statistically significant. RESULTS: The study included 1,136 penetrating trauma patients. Among these, 78.0% (886) had sustained low-energy penetrating injury (SWPI) and 22.0% (250) had sustained high-energy penetrating injury (FAPI). Males accounted for 93.5% (1,062) of the patients. Mean age was 30.4. About 29% (327) of all the patients underwent surgery within 30 minutes from admission, 42% (475) within 30-60 min, and 29% (334) patients were operated within one to two hours. Patients who underwent surgery within 30 minutes, had worse ISS and GCS scores and were, therefore, more likely to have worse clinical outcomes. No other differences in outcomes were found in patients who were operated upon within 2 hours. CONCLUSIONS: Time to surgery within two hours from admission has no impact on final outcomes in trauma patients with penetrating injury and normal blood pressure on admission.

The use of aortic balloon occlusion in traumatic shock: first report from the ABO trauma registry.

PURPOSE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique for temporary stabilization of patients with non-compressible torso hemorrhage. This technique has been increasingly used worldwide during the past decade. Despite the good outcomes of translational studies, clinical studies are divided. The aim of this multicenter-international study was to capture REBOA-specific data and outcomes. METHODS: REBOA practicing centers were invited to join this online register, which was established in September 2014. REBOA cases were reported, both retrospective and prospective. Demographics, injury patterns, hemodynamic variables, REBOA-specific data, complications and 30-days mortality were reported. RESULTS: Ninety-six cases from 6 different countries were reported between 2011 and 2016. Mean age was 52 ± 22 years and 88% of the cases were blunt trauma with a median injury severity score (ISS) of 41 (IQR 29-50). In the majority of the cases, Zone I REBOA was used. Median systolic blood pressure before balloon inflation was 60 mmHg (IQR 40-80), which increased to 100 mmHg (IQR 80-128) after inflation. Continuous occlusion was applied in 52% of the patients, and 48% received non-continuous occlusion. Occlusion time longer than 60 min was reported as 38 and 14% in the non-continuous and continuous groups, respectively. Complications, such as extremity compartment syndrome (n = 3), were only noted in the continuous occlusion group. The 30-day mortality for non-continuous REBOA was 48%, and 64% for continuous occlusion. CONCLUSIONS: This observational multicenter study presents results regarding continuous and non-continuous REBOA with favorable outcomes. However, further prospective studies are needed to be able to draw conclusions on morbidity and mortality.

Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab.

Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.

Pitfalls to avoid in the medical management of mass casualty incidents following terrorist bombings: the hospital perspective.

BACKGROUND: The unique patterns of injury following explosions together with the involvement of numerous physicians, most of whom are not experienced in trauma, may create problems in the medical management of mass casualty incidents. METHODS: Four hundred patient files admitted in 19 mass casualty events following bombing incidents were reviewed and possible areas which could impact survival were defined. RESULTS: Forty-nine (9.3 %) patients had an Injury Severity Score ≥16. Of 205 patients in whom triage decisions were available, 5 of 25 severely injured patients were undertriaged by the triage officers at the door of the hospital. Following primary evaluation inside the emergency department critical injuries in two patients were missed due to distracting, less serious injuries. Of 68 (16.1 %) patients who were operated, 28 were in need of either immediate, urgent or high-priority operations. Except for neurosurgical cases which needed to be transferred to other hospitals, there was no delay in surgery. One patient underwent negative laparotomy. There were 15 in-hospital deaths, 6 of which were deemed as either anticipated or unanticipated mortality with possibility for improvement. CONCLUSION: Medical management should be evaluated following MCIs as this may illustrate possible problems which many need to be addressed in contingency planning.

Assessment of hospital disaster plans for conventional mass casualty incidents following terrorist explosions using a live exercise based upon the real data of actual patients.

PURPOSE: The National Committee for Hospital Preparedness for Conventional Mass Casualty Incidents and the Hospital Preparedness Division of the Home Front Command are in charge of preparing live exercises held yearly in public hospitals in Israel. Our experience is that live exercises are limited in their ability to test clinical decision making and its influence upon incident management. A live exercise was designed upon real patient data and tested in several public hospitals. The aim of the manuscript is to describe the impact of this new format on clinical decision making in large-scale live exercises. METHODS: A database of histories, physical examination findings, laboratory results and imaging results for 420 patients treated following terrorist explosions was created using information derived from actual patient encounters. Similar information for 100 patients treated following motor vehicle accidents was also collected. Information from the database was used to create victim profiles used during the course of exercises held in eight public hospitals with 60-800-bed capacities. RESULTS: Before implementing the new injury tags, no conclusions could be made concerning the quality of clinical decision making. Conducting the exercise using the new format helped identify deficiencies in the hospital disaster plan in triage, emergency department management and in the proper utilisation of resources such as radiology, operating rooms and the secondary transfer of patients. CONCLUSION: Previous knowledge of patient diagnoses and resource needs allow the identification and quantification of deficiencies and problems identified in clinical decision making, resource utilisation and incident management.

Uncommon acquired fistulae involving the digestive system: summary of data.

PURPOSE: Most gastrointestinal fistulae commonly occur following surgery. A minority is caused by a myriad of other etiologies and is termed by some as "uncommon fistulae". The aim of this study was to review these fistulae and their treatment. METHODS: A literature review was carried out. Searches were conducted in Pubmed and related references reviewed. RESULTS: Except for Crohn's disease and diverticulitis, "uncommon fistulae" are described in case reports or very small case series. Most of the patients were treated by surgery. CONCLUSIONS: The anatomic features of the fistula and the etiology usually dictate the approach. Most patients will eventually need surgery to resolve this pathology.

Evaluation of ability of biochemical markers of bone turnover to predict a response to increased doses of HRT.

Antiresorptive therapy is usually given in a fixed dose, and we hypothesized that some patients receiving standard doses of hormone replacement therapy (HRT) might benefit from a higher dose, particularly if their bone turnover decreases after increasing the dose of HRT. Eighty-eight women who had been receiving standard-dose (0.625 mg/day) conjugated equine estrogens (CEE) for at least one year were randomized to take either standard-dose (0.625 mg/day, n = 36) or high-dose (1.25 mg/day, n = 52) therapy. Subjects with a uterus were allowed to take either 10 mg of medroxyprogesterone cyclically or 5 mg daily, according to personal preference. Bone Mineral Density (BMD) and biochemical markers of bone turnover were followed for 2 years. Mean bone turnover decreased significantly (-4.1% to -19.1%) after 6 months of high-dose CEE. Decreases in serum BSAP (bone-specific alkaline phosphatase) and serum or urine NTX ( N-terminal telopeptide crosslink of type I collagen) on high-dose therapy were not predictive of an improvement in BMD, but a decrease in serum CrossLaps did predict an improvement in BMD. Mean change in BMD in subjects with a significant decrease in serum CrossLaps at the anteroposterior spine was 3.1% +/- 3.9% versus 1.2% +/- 2.9% for subjects with no significant change in CrossLaps, P < 0.02. There was, however, a wide range of changes in BMD in patients with or without a significant change in CTX on high-dose HRT, making it impossible to predict an improvement in BMD based on an individual's changes in turnover. Measuring of bone density and bone turnover with better precision might be more successful in guiding individual dosing of antiresorptive therapy.

Effect of raloxifene on sexual function in postmenopausal women.

OBJECTIVE: To determine the effects of raloxifene on sexual function in postmenopausal women with pre-existing vaginal atrophy treated with vaginal estrogen cream. METHODS: A total of 187 naturally postmenopausal women, 42-80 years of age, with signs of genitourinary atrophy were enrolled in this 6-month, multicenter, parallel-group study. Subjects were randomized to oral raloxifene HCl 60 mg daily or matching placebo; the same subjects were also randomized to receive one application of either vaginal conjugated estrogen cream 0.5 g twice weekly for 6 months or non-hormonal vaginal moisturizer twice weekly for 3 months, followed by conjugated estrogen cream for 3 months. Both investigators and subjects were masked to the identity of the oral medication. The vaginal preparations were administered in an open-label fashion. The Sexual Activity Questionnaire (SAQ) was administered at baseline and at 3 and 6 months. Safety was assessed throughout the study. RESULTS: A total of 102 women were sexually active at baseline and, of these, 82 were also sexually active at the 6-month end-point. At 6 months, raloxifene and placebo, in the presence of vaginal conjugated estrogen cream, were both associated with improvement from baseline in vaginal dryness and reduced discomfort during sexual activity. There were no significant differences between raloxifene and placebo groups in any SAQ item. Enjoyment of sexual activity significantly increased from baseline with raloxifene but not with placebo. No difference in adverse events was observed between groups. CONCLUSION: Raloxifene had no negative effects on sexual function in postmenopausal women with vaginal atrophy who were treated concomitantly with vaginal estrogen cream.

Antigens shared by malignant plasma cells and normal B cells may be involved in graft versus myeloma.

Cytotoxic T cells play an important role in graft-versus-host-disease (GvHD) and graft-versus-leukaemia/myeloma, which may occur in patients treated with an allogeneic stem cell transplantation (ASCT). Here, we describe the selection of a myeloma reactive CD4+ cytotoxic T cell-line (CTL) and two CD4+ clones from this CTL. The CTL was generated from the blood from a patient with multiple myeloma (MM) with graft versus myeloma/GvHD, following an ASCT. The CTL was stimulated using irradiated peripheral blood mononuclear cells and EBV transformed B cells from the myeloma patient (EBVp), both of which were obtained prior to ASCT. Both the CTL and the two T cell clones specifically lysed EBVp and secreted IFN-gamma after coculture with EBVp and autologous myeloma tumour cells in a class II restricted fashion. These results show that myeloma tumour cells and autologous B cells present a common polymorphic peptide that functions as a target for graft derived cytotoxic T cells. Identification of these proteins will give insight into the relationship between graft versus myeloma (GvM) and GvHD and may provide immunotherapeutical targets in the treatment of MM.

Vascular repair after menstruation involves regulation of vascular endothelial growth factor-receptor phosphorylation by sFLT-1.

Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-alpha, and interleukin-1beta. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation of sFLT-1 in the late menstrual phase likely contributes to the onset of angiogenesis and endothelial repair in the human endometrium.

17Beta-estradiol inhibits proliferation of cultured vascular smooth muscle cells induced by lysophosphatidylcholine via a nongenomic antioxidant mechanism.

OBJECTIVE: Lysophosphatidylcholine (lysoPC), an active component of oxidized low-density lipoprotein, stimulates proliferation of vascular smooth muscle cells (VSMC). We investigated the direct impact of 17beta-estradiol (E2) on the proliferation of VSMC from rat aorta. RESULTS: VSMC derived from both female and male rats expressed estrogen receptors alpha and beta. Treatments with 1% fetal bovine serum or 5 microM lysoPC increased the incorporation of [3H]-thymidine in VSMC obtained from female rats. 17Beta-E2 did not alter the response to fetal bovine serum, but significantly suppressed the enhanced deoxyribonucleic acid synthesis which had been induced by lysoPC in a dose-dependent manner (10(-4)-10(-6) M). Estrogen also inhibited the proliferation of VSMC from male animals. ICI 182,780, a specific estrogen receptor antagonist, and 17alpha-E2, an inactive form of estradiol, also decreased the mitogenic response to lysoPC in VSMC. In addition, N-acetyl-L-cysteine, a potent antioxidant, inhibited the lysoPC effect. Flow cytometric analysis using the oxidation-sensitive probe 2',7'-dichlorofluorescin diacetate revealed that elevated intracellular formation of reactive oxygen species elicited with lysoPC was depressed significantly by 17beta-E2, ICI 182,780, or 17alpha-E2 as well as by N-acetyl-L-cysteine. CONCLUSION: 17Beta-E2 inhibits in vitro VSMC proliferation induced by lysoPC via a nongenomic antioxidant mechanism.

Preventive health services received by minority women aged 45-64 and the goals of healthy people 2000.

We attempted to evaluate the preventive health services received by minority women aged 45-64 in an underserved region of Boston. We compared two surveys of disease burden and preventive health services to national data sets and the goals of Healthy People 2000. We found that minority women seen both in community health centers and within the community had many cardiovascular risk factors (41-45% had hypertension, 24-29% had cholesterol > 200 mg/dL, and 49-56% had a body mass index of >27.3 kg/m(2)). Women reported that they received low rates of counseling on healthy behaviors but generally received breast and cervical cancer screening. Forty-three percent of women who were interviewed in the community had no health insurance and these women were less likely to have received a Papanicolaou test or mammogram than insured women. Lack of insurance did not predict cancer screening for women already being seen in the community health clinic.

Evidence for the role of high density lipoproteins in mediating the antioxidant effect of estrogens.

Estrogens possess strong antioxidant effects in vitro, but in vivo studies in humans have yielded conflicting results. Little is known regarding factors that mediate the antioxidant effect of estrogens in vivo. In this study the potential role of high density lipoprotein (HDL) was examined. The antioxidant effect of estradiol-17beta (E2) added to low density lipoprotein (LDL) was lost after dialysis. In contrast, the antioxidant effect of E2 added to HDL was conserved after dialysis, suggesting that E2 was bound to HDL. Binding of E2 to LDL increased after esterification (especially to long chain fatty acids). In the presence of HDL, an increased amount of E2 was transferred to LDL. E2-17 ester was as potent as E2 in preventing LDL oxidation in vitro, but 3,17-diesters were not as effective (E2=E2-17 ester>E2-3 ester>E2-3,17 diester). This was also supported by experiments which showed that estrogens with masked 3-OH groups were not effective as antioxidants. These studies provide evidence that HDL could facilitate the antioxidant effect of E2 through initial association, esterification and eventual transfer of E2 esters to LDL. Therefore it is critical that HDL peroxidation parameters be evaluated in subjects receiving estrogen replacement therapy.

Alternatives to estrogen for menopausal women.

Limited acceptable alternatives to hormone replacement therapy exist for use by postmenopausal women. This oversight within the biomedical community is of particular concern considering the increasing number of postmenopausal women and the current low use of hormone replacement therapy. In addition, contraindications to hormone replacement therapy and controversies regarding recommendations for use of hormone replacement therapy also exist. With the notable exception of the advances in prevention of osteoporosis, alternatives to estrogen for other aspects of the sequelae of hypoestrogenism or aging are limited. Furthermore, there is widespread use of complementary therapies among postmenopausal women despite a lack of data on efficacy or safety of such therapies. Increased research into alternatives to estrogen for menopausal women is of clinical, scientific, and health policy importance.

pS2 expression induced by American ginseng in MCF-7 breast cancer cells.

BACKGROUND: Alternative medicines are frequently used by patients with breast cancer for general health benefits. American ginseng, an herbal remedy, purportedly alleviates treatment-induced postmenopausal symptoms. METHODS: Estrogenic potential of American ginseng root extract to induce the expression of pS2, an estrogen-regulated gene, was evaluated in breast cancer cell lines MCF-7, T-47D, and BT-20 by Northern and Western blot analysis. Competitive studies were performed with ginseng in combination with tamoxifen. Cell proliferation assays were performed using the tetrazolium dye procedure and direct cell count. RESULTS: Ginseng and estradiol induce the expression of pS2 RNA and protein in MCF-7 cells, whereas tamoxifen suppresses expression. Neither ginseng nor estradiol induced increased pS2 expression in T-47D or BT-20 cell lines. Although estradiol exhibited a proliferative effect and tamoxifen had an inhibitory effect, ginseng demonstrated no significant effect on cell proliferation. CONCLUSIONS: The results of this study suggest that ginseng may exhibit estrogenlike effects on estrogen receptor-positive breast cancer cells by inducing pS2 expression and that the effect of ginseng may be mediated in part through the estrogen receptor. Because ginseng does not exhibit a proliferative effect, it may play a protective role against breast cancer rather than serve as a mitogen.

Adhesion proteins increase cellular attachment, follicle-stimulating hormone receptors, and progesterone production in cultured porcine granulosa cells.

We sought to determine the influence of different constituents of the extracellular matrix on porcine granulosa cell function by assessing cellular attachment, cellular morphology, follicle-stimulating hormone (FSH) receptors, and progesterone production. Cells from immature porcine ovarian follicles were cultured for up to 6 days in serum-free medium containing porcine FSH (pFSH, 10 ng/ml) in culture dishes either uncoated or coated with one of the following adhesion proteins: gelatin (1 mg/cm2), fibronectin (1 microgram/cm2), laminin (1 microgram/cm2), type I collagen (10 micrograms/cm2), or type IV collagen (7.8 micrograms/cm2). Fibronectin, laminin, type I collagen, and type IV collagen increased cellular attachment significantly (P < 0.05). All adhesion proteins except gelatin influenced cellular morphology. Cells cultured on laminin or type IV collagen formed dense clusters of rounded cells. Cells cultured in dishes coated with each adhesion protein except gelatin had higher 125I-pFSH binding per cell than cells cultured in uncoated dishes, with increases of 7- to 12-fold over control (P < 0.05). All adhesion proteins increased progesterone production, ranging from 10- to 50-fold over control (P < 0.05). In summary, not only did adhesion proteins increase attachment to the dishes but they also increased FSH receptors and differentiated function (progesterone production) of granulosa cells from immature porcine ovarian follicles.

Cathepsin D activity in human ovarian tissues and ovarian carcinoma.

OBJECTIVE: This study determined levels of cathepsin D activity in tissue components of normal human ovary to establish a basis for comparison with human ovarian adenocarcinomas. METHODS: Cathepsin D activity per mg tissue, per microgram protein, and per microgram DNA was determined in human ovarian tissues (cortex, follicle, corpus luteum, corpus albicans) from patients of various ages and during the menstrual cycle. Levels of cathepsin D activity were also determined in ovarian adenocarcinomas and other pathologic tissues. RESULTS: Cathepsin D levels (per mg tissue) were significantly greater (P < .001) in ovarian follicle and corpus luteum compared with cortex. Although there was not a clear correlation between enzyme activity in the cortex and day of the menstrual cycle or patient age, levels of enzyme activity appeared to decrease with each parameter. Cathepsin D levels per mg tissue in ovarian adenocarcinoma were 40% higher than in postmenopausal ovarian cortex, but the difference was not statistically significant. CONCLUSION: The diversity of cathepsin D levels in normal ovarian tissue compartments indicates that specific tissues must be used in comparisons with ovarian tumors.

Antioxidant potential of specific estrogens on lipid peroxidation.

Coronary heart disease (CHD) is the leading cause of death in postmenopause. Estrogen administration in postmenopause lowers the risk of CHD by 50%. A variety of estrogen preparations are currently used in postmenopausal hormone replacement therapy. It is unknown, however, if structural differences in the estrogen molecule influence the cardioprotective effects of estrogens. In this communication we have shown that equine estrogens (especially equilin) exhibit higher antioxidant potency (as measured by fatty acids and sterols oxidation) when compared to estrone and estradiol-17 beta.