Western Pennsylvania Hospital

Chemotherapy for brain tumours has been limited because of difficulty in achieving adequate exposure to the tumour without systemic toxicity. We have developed a method for local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumour site allows prolonged local exposure with minimal systemic exposure. We conducted a randomised, placebo-controlled, prospective study to evaluate the effectiveness of biodegradable polymers impregnated with carmustine to treat recurrent malignant gliomas. In 27 medical centres, 222 patients with recurrent malignant brain tumours requiring re-operation were randomly assigned to receive surgically implanted biodegradable polymer discs with or without 3.85% carmustine. Randomisation balanced the treatment groups for all of the prognostic factors examined. Median survival of the 110 patients who received carmustine polymers was 31 weeks compared with 23 weeks for the 112 patients who received only placebo polymers (hazard ratio = 0.67, p = 0.006, after accounting for the effects of prognostic factors). Among patients with glioblastoma, 6-month survival in those treated with carmustine-polymer discs was 50% greater than in those treated with placebo (mortality = 32 of 72 [44%] vs 47 of 73 [64%], p = 0.02). There were no clinically important adverse reactions related to the carmustine polymer, either in the brain or systemically. Interstitial chemotherapy delivered with polymers directly to brain tumours at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Posttransplant lymphoproliferative disorders (PTLDs) were diagnosed in 43 patients from the Pittsburgh-Denver series between June 1980 and March 1987. This constitutes a detection rate of 1.7%. Major categories of clinical presentation included a mononucleosislike syndrome, gastrointestinal/abdominal disease, and solid organ disease. The median time of onset in patients initially immunosuppressed with cyclosporine-A (CsA)-containing regimens was 4.4 months after transplant, regardless of tumor clonality. A strong association of PTLD with Epstein-Barr virus (EBV) was observed. A histologic spectrum of lesions from polymorphic to monomorphic was observed. Whereas polymorphic lesions could be either clonal or nonclonal, monomorphic lesions appeared to be clonal in composition. The presence of large atypical cells (atypical immunoblasts) or necrosis did not appreciably worsen the prognosis. Twelve patients had clonal, 13 had nonclonal, and five had both clonal and nonclonal tumors. Clonality was indeterminate in 13 cases. Most patients were treated with a regimen based on reduced immunosuppression and supportive surgery. Almost all nonclonal and about half of the clonal lesions respond to this conservative therapy, indicating that it is an appropriate first line of treatment. This behavior suggests that a spectrum of lesions ranging from infectious mononucleosis to malignant lymphoma constitutes the entity known as PTLD. Some monoclonal tumors can undergo regression, however, apparently in response to host immune control mechanisms. Because of its short latency and strong association with EBV, PTLD is an important model for the study of virus-associated tumor progression in humans.

During the 10-year period (1980 to 1989), 76 patients with hepatocellular carcinoma (HCC) were treated by subtotal hepatic resection (HX) and 105 patients by orthotopic liver transplantation (TX) under cyclosporine-steroid therapy. Overall 1- to 5-year survival rates of the HX group were 71.1%, 55.0%, 47.2%, 37.2%, and 32.9%, respectively, and those of the TX group were 65.7%, 49.0%, 39.2%, 35.6%, and 35.6%, respectively. The survival rates after HX and after TX correlated well with pTNM stages and were similar in each stage between the two groups. However, when HCC was associated with cirrhosis of the liver, the survival rates after TX were significantly better than those after HX at each stage of pTNM classification. The tumor-recurrence rate was high both after HX (50%) and TX (43%), particularly in advanced stages of pTNM classification (60% or more). Twelve patients after HX and 13 patients after TX lived more than 5 years during this 10-year period. Fibrolamellar HCC and early stages of HCC were highly represented among the long-term survivors. Further improvement in survival rates depends on nonsurgical anti-cancer therapy before and/or after surgical removal of HCC.

BACKGROUND: Stopping the detrimental effects of the renin-angiotensin system at the most upstream point of the cascade offers theoretical advantages for cardiovascular protection. This study compares the antihypertensive efficacy and safety of the novel oral renin inhibitor aliskiren with placebo and an active comparator. METHODS AND RESULTS: The study was a randomized, multicenter, double-blind, placebo-controlled, active-comparator 8-week trial in patients with mild-to-moderate hypertension (mean sitting diastolic blood pressure [DBP] > or =95 and <110 mm Hg). After a 2-week, single-blind placebo run-in, 652 patients were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150, 300, or 600 mg), irbesartan 150 mg, or placebo. Aliskiren 150, 300, and 600 mg effectively lowered both trough mean sitting DBP and systolic blood pressure (SBP) (P<0.001 versus placebo for both variables). The least-squares mean reductions in trough DBP were 9.3+/-0.8, 11.8+/-0.8, and 11.5+/-0.8 mm Hg, respectively, versus 6.3+/-0.8 mm Hg for placebo, and the least-squares mean reductions in trough SBP were 11.4+/-1.3, 15.8+/-1.2, and 15.7+/-1.2 mm Hg, respectively, versus 5.3+/-1.2 mm Hg for placebo. The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (8.9+/-0.7 and 12.5+/-1.2 mm Hg, least-squares reduction in mean sitting DBP and SBP, respectively, for irbesartan). Aliskiren 300 and 600 mg lowered mean sitting DBP significantly more than irbesartan 150 mg (P<0.05). Aliskiren showed safety and tolerability comparable to those of placebo and irbesartan; the incidence of adverse events and number of patients discontinuing therapy were similar in all groups. CONCLUSIONS: Once-daily oral treatment with aliskiren lowers blood pressure effectively, with a safety and tolerability profile comparable to that of irbesartan and placebo, in patients with mild-to-moderate hypertension. Aliskiren 150 mg is as effective as irbesartan 150 mg in lowering blood pressure.

BACKGROUND: While previous studies have shown an increased rate of suicidal behavior in the relatives of suicide victims, it is unclear if this is attributable merely to increased familial rates of psychiatric disorders. Therefore, we conducted a family study of adolescent suicide victims (suicide probands) and community control probands (controls) to determine if the rates of suicidal behavior were higher in the relatives of adolescent suicide probands even after adjusting for differences in the familial rates of psychiatric disorders. METHOD: The relatives of 58 adolescent suicide probands and 55 demographically similar controls underwent assessment for Axis I and II psychiatric disorders, lifetime history of aggression, and history of suicidal behavior (attempts and completions) using a combination of family study and family history approaches. RESULTS: The rate of suicide attempts was increased in the first-degree relatives of suicide probands compared with the relatives of controls, even after adjusting for differences in rates of proband and familial Axis I and II disorders (odds ratio, 4.3; 95% confidence intervals, 1.1-16.6). On the other hand, the excess rate of suicidal ideation found in the relatives of suicide probands was explained by increased familial rates of psychiatric disorders. Among suicide probands, higher ratings of aggression were associated with higher familial loading for suicide attempts. CONCLUSIONS: Liability to suicidal behavior might be familially transmitted as a trait independent of Axis I and II disorders. The transmitted spectrum of suicidal behavior includes attempts and completions, but not ideation, and the transmission of suicidal behavior and aggression are related.

We describe an outbreak of vancomycin-resistant Enterococcus faecium (vanA phenotype) bacteremia on the oncology ward of a tertiary care community hospital. In 10 of the 11 cases the patients had leukemia and were neutropenic (median duration of neutropenia, 21 days) at the time of bacteremia. On average, patients received six antibiotic agents for a total of 61 agent-days prior to development of vancomycin-resistant E. faecium bacteremia. The mortality rate was 73%. Molecular typing of 22 isolates revealed that the majority (83%) represented a common strain, indicating nosocomial spread. When the 11 cases were compared to 22 matched control patients, gastrointestinal colonization with vancomycin-resistant E. faecium (odds ratio [denominator, 0] infinity, P = .005) and the use of antimicrobial agents with significant activity against anaerobes (metronidazole, clindamycin, and imipenem; odds ratio infinity, P = .02) were found to be risk factors for the development of vancomycin-resistant E. faecium bacteremia. Since no proven therapy for such infection exists, there is an urgent need to identify effective measures to prevent and control the development of vancomycin-resistant E. faecium bacteremia.

OBJECTIVE: A new once-a-day methylphenidate (MPH) formulation, Concerta (methylphenidate HCl) extended-release tablets (OROS MPH), has been developed. This study was conducted to determine the safety and efficacy of OROS MPH in a multicenter, randomized, clinical trial. METHODS: Children with attention-deficit/hyperactivity disorder (ADHD; n = 282), all subtypes, ages 6 to 12 years, were randomized to placebo (n = 90), immediate-release methylphenidate (IR MPH) 3 times a day (tid; dosed every 4 hours; n = 97), or OROS MPH once a day (qd; n = 95) in a double-blind, 28-day trial. Outcomes in multiple domains were assessed, and data were analyzed using analysis of variance and Kaplan Meier product limit estimates for time to study cessation. The primary time point for analysis was the last available patient visit using last observation carried forward. RESULTS: Children in the OROS and IR MPH groups showed significantly greater reductions in core ADHD symptoms than did children on placebo. This was true both at the end of week 1 and at the end of treatment on the basis of mean teacher and parent IOWA Conners ratings. IR MPH tid and OROS MPH qd did not differ significantly on any direct comparisons. Forty-eight percent of the placebo group discontinued early compared with 14% and 16% in the IR MPH and OROS MPH groups, respectively. CONCLUSIONS: For the treatment of core ADHD symptoms, OROS MPH dosed qd and IR MPH dosed tid were superior to placebo and were not significantly different from each other.attention-deficit/hyperactivity disorder, methylphenidate, OROS, Concerta.

Childhood sexual abuse is associated with an increased incidence of age-concurrent and adult psychopathology. Little is known, however, about the biological manifestations and sequelae of childhood sexual abuse. In this study, we characterized the hypothalamic-pituitary-adrenal axis of a self-selected sample of sexually abused and control girls recruited from a prospective longitudinal study. Plasma ACTH and total and free cortisol responses to ovine CRH (oCRH) stimulation were measured in 13 sexually abused and 13 control girls, aged 7-15 yr. Psychiatric profiles and 24-h urinary free cortisol (UFC) measures were also obtained. Sexually abused girls had a greater incidence of suicidal ideation (chi 2 = 4.51; df = 1; P < 0.05), suicide attempts (chi 2 = 4.51; df = 1; P < 0.05), and dysthymia (chi 2 = 8.85; df = 1; P < 0.01) than control girls. Sexually abused girls showed significantly lower basal (t = 2.1; df = 24; P < 0.05), and net oCRH stimulated (t = 2.2; df = 24; P < 0.05) ACTH levels and significantly reduced total ACTH responses (t = 2.5; df = 24; P < 0.05) compared with control subjects. Their total and free basal and oCRH-stimulated plasma cortisol levels and 24-h UFC measures, however, were similar to those in controls. The attenuated plasma ACTH with corresponding robust plasma cortisol responses to oCRH stimulation and normal 24-h UFC measures in sexually abused girls suggest a dysregulatory disorder of the HPA axis in these individuals. This may reflect pituitary hyporesponsiveness to oCRH. The ability of sexually abused subjects to correct for the proposed pituitary hyporesponsiveness to CRH may be related to their young age and the presence of intact glucocorticoid feedback regulatory mechanisms.

BACKGROUND: Concern has arisen that the use of hand-held cellular telephones might cause brain tumors. If such a risk does exist, the matter would be of considerable public health importance, given the rapid increase worldwide in the use of these devices. METHODS: We examined the use of cellular telephones in a case-control study of intracranial tumors of the nervous system conducted between 1994 and 1998. We enrolled 782 patients through hospitals in Phoenix, Arizona; Boston; and Pittsburgh; 489 had histologically confirmed glioma, 197 had meningioma, and 96 had acoustic neuroma. The 799 controls were patients admitted to the same hospitals as the patients with brain tumors for a variety of nonmalignant conditions. RESULTS: As compared with never, or very rarely, having used a cellular telephone, the relative risks associated with a cumulative use of a cellular telephone for more than 100 hours were 0.9 for glioma (95 percent confidence interval, 0.5 to 1.6), 0.7 for meningioma (95 percent confidence interval, 0.3 to 1.7), 1.4 for acoustic neuroma (95 percent confidence interval, 0.6 to 3.5), and 1.0 for all types of tumors combined (95 percent confidence interval, 0.6 to 1.5). There was no evidence that the risks were higher among persons who used cellular telephones for 60 or more minutes per day or regularly for five or more years. Tumors did not occur disproportionately often on the side of head on which the telephone was typically used. CONCLUSIONS: These data do not support the hypothesis that the recent use of hand-held cellular telephones causes brain tumors, but they are not sufficient to evaluate the risks among long-term, heavy users and for potentially long induction periods.

PURPOSE We report the final, protocol-specified analysis of overall survival (OS) in GOG-0218, a phase III, randomized trial of bevacizumab in women with newly diagnosed ovarian, fallopian tube, or primary peritoneal carcinoma. METHODS A total of 1,873 women with incompletely resected stage III to IV disease were randomly assigned 1:1:1 to six 21-day cycles of intravenous carboplatin (area under the concentration v time curve 6) and paclitaxel (175 mg/m 2 ) versus chemotherapy plus concurrent bevacizumab (15 mg/kg, cycles 2 to 6) versus chemotherapy plus concurrent and maintenance bevacizumab (cycles 2 to 22). Inclusion criteria included a Gynecologic Oncology Group performance status of 0 to 2 and no history of clinically significant vascular events or evidence of intestinal obstruction. OS was analyzed in the intention-to-treat population. A total of 1,195 serum and/or tumor specimens were sequenced for BRCA1/2 and damaging mutations in homologous recombination repair (HRR) genes. Intratumoral microvessel density was studied using CD31 immunohistochemistry. RESULTS Median follow-up was 102.9 months. Relative to control (n = 625), for patients receiving bevacizumab-concurrent (n = 625), the hazard ratio (HR) of death was 1.06 (95% CI, 0.94 to 1.20); for bevacizumab-concurrent plus maintenance (n = 623), the HR was 0.96 (95% CI, 0.85 to 1.09). Disease-specific survival was not improved in any arm. No survival advantage was observed after censoring patients who received bevacizumab at crossover or as second line. Median OS for stage IV bevacizumab-concurrent plus maintenance was 42.8 v 32.6 months for stage IV control (HR, 0.75; 95% CI, 0.59 to 0.95). Relative to wild type, the HR for death for BRCA1/2 mutated carcinomas was 0.62 (95% CI, 0.52 to 0.73), and for non- BRCA1/2 HRR, the HR was 0.65 (95% CI, 0.51 to 0.85). BRCA1/2, HRR, and CD31 were not predictive of bevacizumab activity. CONCLUSION No survival differences were observed for patients who received bevacizumab compared with chemotherapy alone. Testing for BRCA1/2 mutations and homologous recombination deficiency is essential.

One of the most common methods for providing postoperative analgesia is via patient-controlled analgesia (PCA). Although the typical approach is to administer opioids via a programmable infusion pump, other drugs and other modes of administration are available. This article reviews the history and practice of many aspects of PCA and provides extensive guidelines for the practice of PCA-administered opioids. In addition, potential adverse effects and recommendations for their monitoring and treatment are reviewed.

OBJECTIVE: The objective is to provide an overview of the clinical features, prognosis, differential diagnosis, evaluation, and treatment of postpartum psychosis. METHODS: The authors searched Medline (1966-2005), PsycInfo (1974-2005), Toxnet, and PubMed databases using the key words postpartum psychosis, depression, bipolar disorder, schizophrenia, organic psychosis, pharmacotherapy, psychotherapy, and electroconvulsive therapy. A clinical case is used to facilitate the discussion. RESULTS: The onset of puerperal psychosis occurs in the first 1-4 weeks after childbirth. The data suggest that postpartum psychosis is an overt presentation of bipolar disorder that is timed to coincide with tremendous hormonal shifts after delivery. The patient develops frank psychosis, cognitive impairment, and grossly disorganized behavior that represent a complete change from previous functioning. These perturbations, in combination with lapsed insight into her illness and symptoms, can lead to devastating consequences in which the safety and well-being of the affected mother and her offspring are jeopardized. Therefore, careful and repeated assessment of the mothers' symptoms, safety, and functional capacity is imperative. Treatment is dictated by the underlying diagnosis, bipolar disorder, and guided by the symptom acuity, patient's response to past treatments, drug tolerability, and breastfeeding preference. The somatic therapies include antimanic agents, atypical antipsychotic medications, and ECT. Estrogen prophylaxis remains purely investigational. CONCLUSIONS: The rapid and accurate diagnosis of postpartum psychosis is essential to expedite appropriate treatment and to allow for quick, full recovery, prevention of future episodes, and reduction of risk to the mother and her children and family.

BACKGROUND: We previously reported that 20% of women with chest pain but without obstructive coronary artery disease (CAD) had stress-induced reduction in myocardial phosphocreatine-adenosine triphosphate ratio by phosphorus-31 nuclear magnetic resonance spectroscopy (abnormal MRS), consistent with myocardial ischemia. The prognostic implications of these findings are unknown. METHODS AND RESULTS: Women referred for coronary angiography for suspected myocardial ischemia underwent MRS handgrip stress testing and follow-up evaluation. These included (1) n=60 with no CAD/normal MRS, (2) n=14 with no CAD/abnormal MRS, and (3) n=352 a reference group with CAD. Cardiovascular events were death, myocardial infarction, heart failure, stroke, other vascular events, and hospitalization for unstable angina. Cumulative freedom from events at 3 years was 87%, 57%, and 52% for women with no CAD/normal MRS, no CAD/abnormal MRS, and CAD, respectively (P<0.01). After adjusting for CAD and cardiac risk factors, a phosphocreatine-adenosine triphosphate ratio decrease of 1% increased the risk of a cardiovascular event by 4% (P=0.02). The higher event rate in women with no CAD/abnormal MRS was primarily due to hospitalization for unstable angina, which is associated with repeat catheterization and higher healthcare costs. CONCLUSIONS: Among women without CAD, abnormal MRS consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs. Further evaluation into the underlying pathophysiology and possible treatment options for women with evidence of myocardial ischemia but without CAD is indicated.

UNLABELLED: We studied the interaction between VEGF and BMP2 during bone formation and bone healing. Results indicate that VEGF antagonist inhibited BMP2-elicited bone formation, whereas the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing through modulation of angiogenesis. INTRODUCTION: Angiogenesis is closely associated with bone formation during normal bone development and is important for the bone formation elicited by BMP4. However, it remains unknown whether vascular endothelial growth factor (VEGF) also interacts with other BMPs, especially BMP2, in bone formation and bone healing. MATERIALS AND METHODS: For this study, mouse muscle-derived stem cells were transduced to express BMP2, VEGF, or VEGF antagonist (sFlt1). We studied the angiogenic process during endochondral bone formation elicited by BMP2, a prototypical osteogenic BMP. Using radiographic and histologic analyses, we also evaluated the interaction between VEGF and BMP2 during bone formation and bone healing. RESULTS: Our results indicate that BMP2-elicited bone formation comprises two phases of angiogenesis, with an early phase occurring before the appearance of hypertrophic cartilage, followed by a late phase coupled with the appearance of hypertrophic cartilage. Our finding that the administration of sFlt1, a specific antagonist of VEGF, significantly inhibited BMP2-induced bone formation and the associated angiogenesis indicates that endogenous VEGF activity is important for bone formation. Furthermore, we found that the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing by improving angiogenesis, which in turn led to accelerated cartilage resorption and enhanced mineralized bone formation. Our findings also indicate that the ratio between VEGF and BMP2 influences their synergistic interaction, with a higher proportion of VEGF leading to decreased synergism. Our study also revealed unique VEGF-BMP2 interactions that differ from the VEGF-BMP4 interactions that we have described previously. CONCLUSIONS: This study, along with previously published work, shows that VEGF interacts synergistically with both BMP4 and BMP2 but elicits substantially different effects with these two BMPs.

OBJECTIVE: To evaluate the efficacy and safety of fluconazole for prevention of fungal infections. DESIGN: A randomized, placebo-controlled, double-blind, multicenter trial. PATIENTS: Adults (257) undergoing chemotherapy for acute leukemia. INTERVENTION: Patients were randomly assigned to receive either fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity. MEASUREMENTS: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality. MAIN RESULTS: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%] placebo patients compared with 11 of 123 [9%] fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (6%) fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [64%] placebo patients colonized at end of prophylaxis compared with 11 of 119 [9%] fluconazole patients, P < 0.001; 22 of 132 [17%] placebo patients infected compared with 7 of 123 [6%] fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups. CONCLUSION: Prophylactic fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths.

OBJECTIVE: This study examined effects of bereavement 21 months after a parent's death, particularly death by suicide. METHOD: The participants were 176 offspring, ages 7-25, of parents who died by suicide, accident, or sudden natural death. They were assessed 9 and 21 months after the death, along with 168 nonbereaved subjects. RESULTS: Major depression and alcohol or substance abuse 21 months after the parent's death were more common among bereaved youth than among comparison subjects. Offspring with parental suicide or accidental death had higher rates of depression than comparison subjects; those with parental suicide had higher rates of alcohol or substance abuse. Youth with parental suicide had a higher incidence of depression than those bereaved by sudden natural death. Bereavement and a past history of depression increased depression risk in the 9 months following the death, which increased depression risk between 9 and 21 months. Losing a mother, blaming others, low self-esteem, negative coping, and complicated grief were associated with depression in the second year. CONCLUSIONS: Youth who lose a parent, especially through suicide, are vulnerable to depression and alcohol or substance abuse during the second year after the loss. Depression risk in the second year is mediated by the increased incidence of depression within the first 9 months. The most propitious time to prevent or attenuate depressive episodes in bereaved youth may be shortly after the parent's death. Interventions that target complicated grief and blaming of others may also improve outcomes in symptomatic youth with parental bereavement.

The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60% died. A multivariate Cox proportional hazards analysis showed that patients whose creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001), allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96; P=.017) were associated with greater risk of death, whereas patients undergoing solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data indicate that elevated creatinine levels during amphotericin B treatment are associated with a substantial risk for hemodialysis and a higher mortality rate, but the risks vary in different patient groups.

There is increasing evidence for an association between the alteration of cytokine concentrations in blood and the pathophysiology of depressive disorders. Studies in humans have not investigated CSF cytokine concentrations and their relationship to depressive disorders. This study reports on the association of the CSF concentration of proinflammatory cytokines, IL-1beta, IL-6 and TNFalpha, and major depressive disorders. CSF samples were obtained from 13 hospitalized patients with acute unmedicated severe depression and were compared with 10 control subjects. Compared to the control group, the depressed patient group had higher CSF concentrations of IL-1beta, lower IL-6 and no change in TNFalpha. A positive correlation was found between serum IL-1beta and the severity of depression. These results indicate a unique profile for CSF proinflammatory cytokines in acute depression. These findings merit further investigation and if replicated may possibly offer immunological treatment options for depression.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.