The Influence of Xylazine and Clonidine on Lung Ultrasound-Induced Pulmonary Capillary Hemorrhage in Spontaneously Hypertensive Rats.

Induction of pulmonary capillary hemorrhage (PCH) by lung ultrasound (LUS) depends not only on physical exposure parameters but also on physiologic conditions and drug treatment. We studied the influence of xylazine and clonidine on LUS-induced PCH in spontaneously hypertensive and normotensive rats using diagnostic B-mode ultrasound at 7.3 MHz. Using ketamine anesthesia, rats receiving saline, xylazine, or clonidine treatment were tested with different pulse peak rarefactional pressure amplitudes in 5 min exposures. Results with xylazine or clonidine in spontaneously hypertensive rats were not significantly different at the three exposure pulse peak rarefactional pressure amplitudes, and thresholds were lower (2.2 MPa) than with saline (2.6 MPa). Variations in LUS PCH were not correlated with mean systemic blood pressure. Similar to previous findings for dexmedetomidine, the clinical drug clonidine tended to increase susceptibility to LUS PCH.

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer.

PURPOSE: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM). PATIENTS AND METHODS: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading. RESULTS: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced (P = .024; median, 1.5 v 19 days). SOM incidence (43% v 65%; P = .009) and severity (grade 4 incidence, 16% v 30%; P = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing. CONCLUSION: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.

Self-rated health trajectories in the African American health cohort.

BACKGROUND: Self-rated health taps health holistically and dynamically blends prior health histories with current illness burdens and expectations for future health. While consistently found as an independent predictor of functional decline, sentinel health events, physician visits, hospital episodes, and mortality, much less is known about intra-individual changes in self-rated health across the life course, especially for African Americans. MATERIALS/METHODS: Data on 998 African American men and women aged 50-64 years old were taken from a probability-based community sample that was first assessed in 2000-2001 and re-assessed 1, 2, 3, 4, 7, and 9 years later. Using an innovative approach for including decedents in the analysis, semi-parametric group-based mixture models were used to identify person-centered group trajectories of self-rated health over time. Multivariable multinomial logistic regression analysis was then used to differentiate the characteristics of AAH participants classified into the different group trajectories. RESULTS: Four self-rated health group trajectories were identified: persistently good health, good but declining health, persistently fair health, and fair but declining health. The main characteristics that differentiated the self-rated health trajectory groups from each other were age, education, smoking, morbidity (angina, congestive heart failure, diabetes, and kidney disease), having been hospitalized in the year prior to baseline, depressive symptoms, mobility limitations, and initial self-rated health. CONCLUSIONS: This is the first study to examine self-rated health trajectories separately among African Americans. Four qualitatively distinct self-rated health group trajectories were identified that call into question the accuracy of prior reports that a single, average self-rated health trajectory for African Americans adequately captures their within-group heterogeneity.

The nuclear membrane organization of leukotriene synthesis.

Leukotrienes (LTs) are signaling molecules derived from arachidonic acid that initiate and amplify innate and adaptive immunity. In turn, how their synthesis is organized on the nuclear envelope of myeloid cells in response to extracellular signals is not understood. We define the supramolecular architecture of LT synthesis by identifying the activation-dependent assembly of novel multiprotein complexes on the outer and inner nuclear membranes of mast cells. These complexes are centered on the integral membrane protein 5-Lipoxygenase-Activating Protein, which we identify as a scaffold protein for 5-Lipoxygenase, the initial enzyme of LT synthesis. We also identify these complexes in mouse neutrophils isolated from inflamed joints. Our studies reveal the macromolecular organization of LT synthesis.

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue.

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.

Supportive-affective group experience for persons with life-threatening illness: reducing spiritual, psychological, and death-related distress in dying patients.

BACKGROUND: Attention to psycho-socio-spiritual needs is considered critical by patients with life-threatening illnesses and their caregivers. Palliative care interventions that address these needs--particularly spirituality--are lacking. OBJECTIVE: To evaluate the effects of an innovative program to address psycho-socio-spiritual needs in patients with life-threatening illnesses. DESIGN: A group intervention entitled Life-Threatening Illness Supportive-Affective Group Experience (LTI-SAGE) was developed for reducing patient spiritual, emotional, and death-related distress. SETTING/SUBJECTS: African American and Caucasian patients (n = 69) from two hospitals in St. Louis, Missouri, with life-threatening medical conditions (cancer; human immunodeficiency virus/acquired immune deficiency syndrome [HIV/AIDS]; geriatric frailty; liver, kidney, pulmonary, or cardiovascular disease) were randomly assigned to intervention or control groups. Intervention patients participated in a maximum of 12 LTI-SAGE groups over a 12-month period. Control patients received standard care. MEASUREMENTS: Outcome measures were depression symptoms, anxiety, spiritual well-being, and death-related emotional distress. RESULTS: After attrition, 51 (73.9%) patients completed the trial. At the end of the trial, after factoring in compliance, intervention patients had significantly fewer depression symptoms and death-related feelings of meaninglessness and significantly better spiritual well-being than did control patients. CONCLUSIONS: The use of the LTI-SAGE model for enhancing the end-of-life illness experience is promising.

Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma.

PURPOSE: To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas. PATIENTS AND METHODS: From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue. RESULTS: Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively. CONCLUSION: This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies.

Identifying barriers to psychosocial spiritual care at the end of life: a physician group study.

OBJECTIVE: The recent literature addresses the need to improve care for dying patients. The purpose of this study was to identify barriers to the psychosocial spiritual care of these patients by their physicians. Psychosocial spiritual care is defined as aspects of care concerning patient emotional state, social support and relationships, and spiritual well-being. The study was an exploratory means for generating hypotheses and identifying directions for interventions, research, and training in care for the dying. DESIGN AND PARTICIPANTS: The study used a qualitative group discussion format. Seventeen physicians at a university-based health sciences center representing 10 areas of medical specialty--including internal medicine, oncology, pediatrics, and geriatrics met in two groups for 20 75-minute discussion sessions over the course of one year. Discussions were recorded, analyzed, and categorized. RESULTS: Barriers to psychosocial spiritual care were grouped into three domains and seven themes. The cultural domain included the themes of training, selection, medical practice environment, and debt/delay. Participants believed that medical selection and training combine to marginalize psychosocial spiritual approaches to patient care, while the practice environment and debt/delay augment emotional isolation and dampen idealism. The organizational domain included the themes of dissatisfaction and time/business. Physicians indicated that the current reimbursement climate and time pressures contribute to dissatisfaction and the tendency to avoid patient psychosocial spiritual issues. The clinical domain included the theme of communication. Physicians were concerned about their ability to communicate nonmedical issues effectively and manage the patient s reactions and needs in the psychosocial spiritual arena. CONCLUSIONS: This study suggests that research and educational approaches to improving the psychosocial spiritual care of the dying by physicians should address barriers at the cultural, organizational, and clinical levels. Suggestions for interventions at various levels are offered.

Psychosocial-spiritual correlates of death distress in patients with life-threatening medical conditions.

The purpose of this study was to identify demographic, disease, health care, and psychosocial-spiritual factors associated with death distress (death-related depression and anxiety). Cross-sectional baseline data from a randomized controlled trial were used. Outpatients (n=70) were recruited from an urban academic medical centre and proprietary hospital. All patients had life-threatening medical conditions, including cancer; pulmonary, cardiac, liver, or kidney disease; HIV/AIDS; or geriatric frailty. Measures of death distress, physical symptom severity, depression and anxiety symptoms, spiritual well-being, social support, patient-perceived physician communication, and patient-perceived quality of health care experiences were administered. In a hierarchical multiple regression model, higher death distress was significantly associated with living alone, greater physical symptom severity, more severe depression symptoms, lower spiritual well-being, and less physician communication as perceived by the patient. Death distress as a unique experiential construct was discriminable among younger patients with specific, diagnosable life-threatening conditions, but less so among geriatric frailty patients. The findings suggest that the experience of death distress among patients with life-threatening medical conditions is associated with the psychosocial-spiritual dimensions of the patient's life. Attention to these dimensions may buffer the negative affects of death distress.