The relationship between diabetes and depressive symptoms in men with or at risk of HIV infection.

OBJECTIVES: The aim of the study was to compare the prevalence of comorbid diabetes and depressive symptoms in men living with HIV (MLWH) with that in men without HIV infection and to determine associations between glycaemic control and depressive symptoms. METHODS: Participants included 920 MLWH and 840 men without HIV infection from the Multicenter AIDS Cohort Study (MACS) with available data regarding glycaemic status [categorized as normal for fasting blood glucose (FBG) < 100 mg/dL, prediabetes for FBG 100-125 mg/dL, and diabetes, defined by self-report, diabetes medication use or FBG ≥ 126 mg/dL on at least two consecutive visits, with diabetes classified as controlled if Hemoglobin A1c (HbA1C) < 7.5% and uncontrolled if HbA1C ≥ 7.5%]. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) score, with CES-D ≥ 16 scores classified as elevated depressive symptoms. A modified Poisson regression model with robust variance was used and adjusted for covariates including HIV serostatus. RESULTS: Compared to men without HIV infection, MLWH had a higher mean CES-D score, but a similar prevalence of diabetes (11.3% versus 12.8%, respectively; P = 0.33). The concomitant prevalence of diabetes and elevated depressive symptoms did not differ by HIV serostatus (P = 0.215). In an adjusted analysis, men with uncontrolled diabetes had a greater prevalence of depressive symptoms compared to men with normoglycaemia (prevalence ratio = 1.43; 95% confidence interval 1.11, 1.84). The association between glycaemic status and depressive symptoms did not differ by HIV serostatus (P = 0.22 for interaction). CONCLUSIONS: Both controlled and uncontrolled diabetes were independently associated with a greater prevalence of depressive symptoms, regardless of HIV serostatus. These results highlight the importance of identifying depression in people with diabetes.

Cognitive profiles in perimenopause: hormonal and menopausal symptom correlates.

OBJECTIVE: Perimenopause is associated with declines in attention, working memory and verbal memory; however, there are significant individual differences. Further, the contributions of hormones and menopausal symptoms to domain-specific cognitive functions remain unknown. This longitudinal study aimed to determine whether there were distinct cognitive profiles in perimenopause and to identify factors associated with each profile. DESIGN: In a sample of 85 women evaluated over 400 bi-annual visits, we administered a comprehensive neuropsychological battery, assessed menopausal symptoms and measured 17ß-estradiol and follicle stimulating hormone. Multilevel latent profile analysis was used to identify cognitive profiles. Regressions were conducted to determine differences in hormones and symptoms by profile after adjusting for Stages of Reproductive Aging Workshop + 10 (STRAW + 10) stage and demographic factors. RESULTS: Perimenopausal cognitive profiles consisted of cognitively normal (Profile 1; n = 162), weaknesses in verbal learning and memory (Profile 2; n = 94), strengths in verbal learning and memory (Profile 3; n = 98) and strengths in attention and executive function (Profile 4; n = 61). Profile 2 was differentiated by less hormonal variability and more sleep disturbance than Profile 1 (p < 0.05). CONCLUSIONS: There is significant heterogeneity in cognition during perimenopause. While most women do not develop impairments, a significant minority experience weaknesses in verbal learning and memory. Profile analysis may identify at-risk populations and inform interventions.

Distinct risks, clinical characteristics and outcomes by age at time of HIV diagnosis.

OBJECTIVES: New HIV diagnoses in persons aged > 50 years (hereafter 'older persons') are becoming more common; the clinical features and outcomes of these older individuals are poorly described. METHODS: We conducted a retrospective cohort study of all new adult HIV diagnoses between October 1989 and December 2019 in southern Alberta, Canada. Differences in risk for HIV acquisition and screening, sociodemographic/clinical characteristics, and causes of death were compared between individuals younger and older than 50 years at the time of diagnosis. RESULTS: New HIV diagnoses in persons > 50 years old increased from 7% in 1990 to 18% in 2019. Risk for HIV acquisition and screening reasons differed by age. Heterosexual sex (29%) was the greatest risk factor among older persons, contrasting with male same sex activity in younger persons (51%) (P < 0.001). Illness was the most common indication for testing in older persons (47%), whereas younger persons were more likely to have requested testing (34%) (P < 0.001). Relationship status differed, with 33% of older persons being married to an opposite sex partner versus 12% in younger persons (P < 0.001). Although older persons had a lower mean nadir CD4 count (132 cells/µL) than younger persons (181 cells/µL) (P < 0.001), 80% of deaths between 2010 and 2019 in the older group were attributable to non-AIDS-related causes versus 47% in younger patients. Since 2000, AIDS-related deaths and potential years of life lost have declined for both age groups. CONCLUSION: The increase in new HIV diagnoses in persons aged > 50 years in southern Alberta suggests that older individuals require customized approaches for optimizing HIV diagnosis and treatment.

Menopausal symptoms, menopausal stage and cognitive functioning in black urban African women.

Objective: Studies, conducted largely in North America and Europe, demonstrate that menopausal symptoms and menopausal stage influence cognitive function. Here, we evaluate these associations in a large cohort of sub-Saharan African women, a population where these associations are understudied. We hypothesized that premenopausal women would show better cognitive performance than women later in the transition, and that menopausal symptoms would be inversely related to cognition.Methods: This cross-sectional study included 702 black urban South African women between the ages of 40 and 60 years from the Study of Women Entering and in Endocrine Transition. Participants completed the Symbol Digit Modalities Test, a measure of processing speed and incidental recall. Menopausal stage was ascertained using the Stages of Reproductive Aging Workshop+ 10 criteria and symptoms using the Menopause Rating Scale. Multivariable linear regression analyses were used to examine adjusted associations between menopausal stage and menopausal symptoms on cognitive performance.Results: In adjusted analyses, menopausal stage was not associated with processing speed (p = 0.35) or incidental recall (p = 0.64). However, more severe symptoms of hot flushes and anxiety were associated with slower processing speed (all p < 0.05), and more severe mood symptoms were associated with worse incidental recall (p = 0.008).Conclusion: Menopausal symptoms, but not menopausal stage, were associated with cognitive function in this cross-sectional study of sub-Saharan African women.

The birth experience and subsequent maternal caregiving attitudes and behavior: a birth cohort study.

Optimal maternal caregiving is critical for children's healthy development, yet quality of maternal caregiving may be influenced by a negative birth experience. We examined whether the birth experience was associated with maternal caregiving attitudes and behavior throughout the first year. We conducted secondary analysis of the Avon Longitudinal Study of Parents and Children birth cohort on perinatal data. The birth experience was assessed using self-report data on level of support in labor. Maternal caregiving variables were self-report maternal attitudes at one and eight postnatal months, and observed maternal behavior at 12 postnatal months. Data were analyzed using multivariable logistic regression models adjusting for critical covariates at one (N = 4389), eight (N = 4580), and 12 (N = 842) postnatal months. Feeling supported in labor was associated with a report of "immediately falling in love" with one's baby after birth, surveyed at 1 month (adjusted OR 1.41 [95% CI 1.20-1.65]), and with more positive parenting scores at 8 months (adjusted OR 1.56 [95% CI 1.36-1.79]), but not with more positive observed maternal behavior at 12 months. Additional risk factors were identified. Our findings suggest that we may be able to modify the risk of poor postnatal maternal caregiving by supporting women in labor and facilitating a positive birth experience.

Verbal and spatial working memory among drug-using HIV-infected men and women.

Working memory (WM) is a critical component of many neurocognitive functions. The literature has demonstrated consistently that WM impairment is more frequent and severe among substance-dependent individuals (SDIs) infected with HIV compared with uninfected SDIs; however, the SDIs who participated in these previous studies were primarily male. There are few published data on WM performance among HIV+ women with or without substance use disorders, and essentially no direct comparisons of WM performance between HIV+ men and women, regardless of substance use. We investigated potential sex and serostatus effects on WM among a sample of 360 SDIs (114 with HIV; 66% female) verified abstinent from alcohol and drugs of abuse at testing and generally comparable on substance use and comorbid characteristics. Participants were tested with the n-back task, a well-established WM measure that is sensitive to HIV-associated cognitive impairment. HIV+ men and women performed spatial and verbal versions of the n-back significantly less accurately compared with HIV- participants. Women showed slower response times compared with men on both versions, regardless of HIV serostatus. Individuals dependent on cocaine showed faster RTs compared with non-dependent users, but this effect was not apparent among opioid- or alcohol-dependent groups. Findings on n-back accuracy are consistent with our previous proposal that WM impairment represents a signature deficit among HIV+ SDIs; however, WM impairment appears less common among HIV+ women without a substance use history. The pattern of sex differences in response speed but serostatus effects on response accuracy is comparable to a recent report by our group of sex differences in learning speed but serostatus effects on delayed recall.

Review of patient decision-making factors and attitudes regarding preimplantation genetic diagnosis.

The increasing technical complexity and evolving options for repro-genetic testing have direct implications for information processing and decision making, yet the research among patients considering preimplantation genetic diagnosis (PGD) is narrowly focused. This review synthesizes the literature regarding patient PGD decision-making factors, and illuminates gaps for future research and clinical translation. Twenty-five articles met the inclusion criteria for evaluating experiences and attitudes of patients directly involved in PGD as an intervention or considering using PGD. Thirteen reports were focused exclusively on a specific disease or condition. Five themes emerged: (1) patients motivated by prospects of a healthy, genetic-variant-free child, (2) PGD requires a commitment of time, money, energy and emotions, (3) patients concerned about logistics and ethics of discarding embryos, (4) some patients feel sense of responsibility to use available technologies, and (5) PGD decisions are complex for individuals and couples. Patient research on PGD decision-making processes has very infrequently used validated instruments, and the data collected through both quantitative and qualitative designs have been inconsistent. Future research for improving clinical counseling is needed to fill many gaps remaining in the literature regarding this decision-making process, and suggestions are offered.

Effects of sex and HIV serostatus on spatial navigational learning and memory among cocaine users.

Spatial learning and memory are critically dependent on the integrity of hippocampal systems. Functional MRI and neuropathological studies show that hippocampal circuitry is prominently affected among HIV-seropositive individuals, but potential spatial learning and memory deficits have not been studied in detail in this population. We investigated the independent and interactive effects of sex and HIV serostatus on performance of a spatial learning and memory task in a sample of 181 individuals with a history of cocaine dependence. We found that men showed faster times to completion on immediate recall trials compared with women and that delayed recall was significantly poorer among HIV-infected compared with HIV-uninfected participants. Additionally, a sex × serostatus effect was found on the total number of completed learning trials. Specifically, HIV-infected men successfully completed more learning trials compared with HIV-infected women. Results are discussed in the context of recent reports of sex and HIV serostatus effects on episodic memory performance.

Childbirth and symptoms of postpartum depression and anxiety: a prospective birth cohort study.

We investigated associations between aspects of childbirth and elevated postpartum symptoms of depression and anxiety. We employed secondary analysis of perinatal data (N = 4657-4946) from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariable logistic regression models (adjusted for covariates) examined predictors of elevated symptoms of postpartum depression and anxiety. Predictors included the following: type of delivery (normal physiological vs. interventive non-physiological), immediate postpartum complications, and maternal perception of the recent birth experience. The Edinburgh Postnatal Depression Scale assessed elevated symptoms of depression (score ≥ 13), and the Crown-Crisp Experiential Index assessed elevated symptoms of anxiety (score ≥ 9) at 2 and 8 months after delivery. A more negative perception of the recent birth experience was associated with elevated symptoms of anxiety at 2 months [odds ratio (OR) 1.52, 95 % confidence interval (CI) 1.25-1.85] and 8 months (OR 1.30, 95 % CI 1.06-1.60) postpartum but was not associated with elevated symptoms of depression at either time point. Type of delivery (physiological vs. non-physiological) and immediate postpartum complications were not associated with elevated symptoms of depression or anxiety. Our findings suggest that improving women's childbirth experience may decrease the likelihood of postpartum anxiety, but not postpartum depression.

Endothelial cells: adhesion and tight junctions.

This article reviews recent discoveries concerning the identity of endothelial cell adhesion molecules and their participation in intercellular junction formation. Observations relating to the formation of high-resistance tight junctions between brain endothelial cells are emphasized.

Understanding normality: a qualitative analysis of breast cancer patients concepts of normality after mastectomy and reconstructive surgery.

BACKGROUND: As survival rates increase, many people have to adjust to life after cancer. This includes adjusting to life after surgery. While previous research suggests that patients commonly strive to be 'normal' after mastectomy and reconstructive surgery, research surrounding individual perceptions of normality is lacking. AIM: The aim of this study was to explore concepts of normality within a sample of breast cancer patients eligible for reconstructive surgery following mastectomy. METHODS: A total of 35 semi structured interviews, with women who had undergone or were about to undergo breast reconstructive surgery following breast cancer, were analysed using thematic analysis. RESULTS: Four main themes emerged from the data. Women referred to looking normal (appearance); being able to fulfil everyday activities (behaviour); adapting to a new normal (reconstructing normality); and not being ill (health). The importance placed on each area of normality differed between patients. Additionally, patients used different standards to anchor concepts of normality. These included individual standards, social standards and clinical standards. DISCUSSION: The results indicate that although there are commonalities between patients' concepts of normality, it is important for health care professionals to recognise potential individual differences. This may usefully aid communication and help to manage expectations among patients considering surgical options.

Randomized, prospective, placebo-controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis.

OBJECTIVE: Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD). METHOD: Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of > or = 500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed. RESULTS: Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsening of PFT results occurred in 25.6% of patients receiving placebo and 22.5% of those receiving bosentan (P not significant). CONCLUSION: No improvement in exercise capacity was observed in the bosentan-treated group compared with the placebo group, and no significant treatment effect was observed for the other end points. Although many outcome variables were stable, bosentan did not reduce the frequency of clinically important worsening. These data do not support the use of endothelin receptor antagonists as therapy for ILD secondary to SSc.

Comparison of Patients' Ethical Perspectives of Preimplantation Embryo Genetic Testing for Aneuploidy (PGT-A) vs. Monogenic Disorders (PGT-M).

What are the ethical perspectives of preimplantation genetic testing in patients using/considering PGT-A compared to those using/considering PGT-M? A 17-item questionnaire administered online was used to assess ethical perspectives in US patients who recently used/considered PGT-A (n=80) vs. those who used/considered PGT-M (n=72). Kruskal-Wallis, Chi-square, and Fisher exact tests were conducted with STATA. Most PGT-A and PGT-M users/considerers supported using PGT to screen for diseases fatal in childhood (86-89%) and those causing lifelong disabilities (76-79%) and opposed using PGT to screen for non-medical physical (80-87%) or intellectual traits (74-86%). Both groups agreed that PGT aids in parental decision-making, although some expressed concern over its potential to lead to unforeseen consequences for society and the PGT offspring. More PGT-M than PGT-A users/considerers opposed implanting genetically abnormal embryos when requested by parents (29% PGT-A vs. 56% PGT-M, p = 0.007). For embryo disposition, more PGT-A users/considerers favored freezing (95% PGTA vs. 82% PGT-M, p = 0.018) or donating genetically normal embryos to research (73% PGT-A vs. 57% PGT-M, p = 0.044), while more PGT-M users/considerers supported donating embryos with known genetic abnormalities to research (56% PGT-A vs. 81% PGT-M, p = 0.001). Regardless of the reason for using PGT, users generally agreed on the acceptable and unacceptable uses for it, as well as the potential societal impact. PGT-M users/considerers expressed more opposition than PGT-A users/considerers to implanting embryos with a genetic alteration when requested by the parents.

Echocardiographic assessment of hemodynamic changes produced by two methods of inducing fluid deficit in dogs.

BACKGROUND: Hydration status is important to the cardiovascular system because of its effects on preload. Decreased preload can alter echocardiographic measurements of systolic and diastolic function, potentially confounding interpretation of results. HYPOTHESIS/OBJECTIVES: Mild fluid deficits are associated with measurable echocardiographic changes that are validated by physical and biochemical markers of decreased intravascular volume. ANIMALS: Twenty-five healthy staff/student-owned dogs with no evidence of cardiac or renal disease. METHODS: Prospective, interventional laboratory study. Dogs were randomly assigned to water deprivation (WD) alone for 8 hours (n = 13) or to furosemide treatment (FTx, 2.5mg/kg IV) followed by WD for 8 hours (n = 12). Echocardiograms, biochemical sampling, and physical parameters were measured at baseline, and after 4 and 8 hours. RESULTS: Both protocols induced fluid deficit as indicated by significant (P < .00001) decreases in weight at 4 hours (WD, 1.1%; FTx, 3.7%) and 8 hours (WD, 2.7%; FTx, 4.5%). Furosemide significantly decreased left ventricular end-diastolic volume (54.3 +/- 19.3-42.1 +/- 17.3 mL, P < .0001), cardiac index (4.2 +/- 1.1-2.9 +/- 0.9 L/min/M2, P < .0001), and mitral valve E wave velocity (0.79 +/- 0.2-0.66 +/- 0.2 m/s, P = .0004). These changes were accompanied by significant increases in blood urea nitrogen concentration (13.8 +/- 2.6-14.8 +/- 2.7 mg/dL, P = .04), vasopressin concentration (1.4 +/- 1.2-3.3 +/- 1.9 pg/mL, P = .045), and PCV (49.8 +/- 4.5-53.2 +/- 6.5%, P = .006). Effects of water deprivation alone were similar, but less pronounced. CONCLUSIONS AND CLINICAL IMPORTANCE: Mild fluid deficits have measurable hemodynamic effects in dogs. Hydration status should be considered when evaluating cardiac function by echocardiogram.

End-points and clinical trial design in pulmonary arterial hypertension: have we made progress?

There is enormous interest in the treatment of pulmonary arterial hypertension (PAH), so it is appropriate to consider the design of trials of new therapies and the end-points to be measured when trying to decide whether or not a therapy is effective. In May 2003, the first meeting devoted solely to the discussion of end-points and trial design in PAH was held in Gleneagles, UK. At that time, most of the randomised controlled trials in PAH had used 6-min walking distance and/or resting haemodynamics as their primary end-points. The present article considers the progress that has been made since 2003. It deals with aspects of clinical trial design (such as noninferiority, superiority and withdrawal trials), considers end-points used in previous and current studies (such as 6-min walking distance, time to clinical worsening, haemodynamics, imaging and plasma brain natriuretic peptide), and considers what end-points might be used in the future. The second end-points meeting was held in Turnberry, UK, in June 2007. It had a similar format to the first meeting. Much of what is presented here is a summary of the workshops from that meeting. An attempt has been made to both summarise the current state of end-points and trial design and suggest new ways in which they could be improved. The present article forms one of a series being published in the European Respiratory Journal on pulmonary hypertension.

Acetylcholine receptor clustering and nuclear movement in muscle fibers in culture.

We have studied the formation of acetylcholine receptor (AChR) clusters and the behavior of myonuclei in rat and chick skeletal muscle cells grown in cell culture. These cells were treated with a factor derived from Torpedo electric extracellular matrix, which causes a large increase in their number of AChR clusters. We found that these clusters were located preferentially in membrane regions above myonuclei. This cluster-nucleus colocalization is explained by our finding that most of the nuclei near clusters remain relatively stationary, while most of those away from clusters are able to translocate throughout the myotube. In some cases, clusters clearly formed first, then nuclei migrated underneath and became immobilized. If clustered AChRs later dispersed, their associated nuclei resumed moving. These results suggest that AChR clustering initiates an extensive cytoskeletal rearrangement that causes the subcluster localization of organelles, potentially providing a stable source of newly synthesized AChRs for insertion into the cluster.

Microinjection of a monoclonal antibody against a 37-kD protein (tropomyosin 2) prevents the formation of new acetylcholine receptor clusters.

We have shown previously that chick muscle cells transformed with Rous sarcoma virus are unable to form clusters of acetylcholine receptors (AChRs) (Anthony, D. T., S. M. Schuetze, and L. L. Rubin. 1984. Proc. Natl. Acad. Sci. USA. 81:2265-2269) and are missing a 37-KD tropomyosin-like protein (TM-2) (Anthony, D. T., R. J. Jacobs-Cohen, G. Marazzi, and L. L. Rubin. 1988. J. Cell Biol. 106:1713-1721). In an attempt to clarify the role of TM-2 in the formation and/or maintenance of AChR clusters, we have microinjected a monoclonal antibody specific for TM-2 (D3-16) into normal chick muscle cells in culture. D3-16 injection blocks the formation of new clusters but does not affect the preexisting ones. In addition, TM-2 is concentrated at rat neuromuscular junctions. These data suggest that TM-2 may play an important role in promoting the formation of AChR clusters.

Blocking cytochrome c activity within intact neurons inhibits apoptosis.

Cytochrome c has been shown to play a role in cell-free models of apoptosis. During NGF withdrawal-induced apoptosis of intact rat superior cervical ganglion (SCG) neurons, we observe the redistribution of cytochrome c from the mitochondria to the cytoplasm. This redistribution is not inhibited by the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (ZVADfmk) but is blocked by either of the neuronal survival agents 8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate (CPT-cAMP) or cycloheximide. Moreover, microinjection of SCG neurons with antibody to cytochrome c blocks NGF withdrawal-induced apoptosis. However, microinjection of SCG neurons with cytochrome c does not alter the rate of apoptosis in either the presence or absence of NGF. These data suggest that cytochrome c is an intrinsic but not limiting component of the neuronal apoptotic pathway.

p120, a p120-related protein (p100), and the cadherin/catenin complex.

Cadherins and catenins play an important role in cell-cell adhesion. Two of the catenins, beta and gamma, are members of a group of proteins that contains a repeating amino acid motif originally described for the Drosophila segment polarity gene armadillo. Another member of this group is a 120-kD protein termed p120, originally identified as a substrate of the tyrosine kinase pp60src. In this paper, we show that endothelial and epithelial cells express p120 and p100, a 100-kD, p120-related protein. Peptide sequencing of p100 establishes it as highly related to p120. p120 and p100 both appear associated with the cadherin/catenin complex, but independent p120/catenin and p100/catenin complexes can be isolated. This association is shown by coimmunoprecipitation of cadherins and catenins with an anti-p120/p100 antibody, and of p120/p100 with cadherin or catenin antibodies. Immunocytochemical analysis with a p120-specific antibody reveals junctional colocalization of p120 and beta-catenin in epithelial cells. Catenins and p120/p100 also colocalize in endothelial and epithelial cells in culture and in tissue sections. The cellular content of p120/p100 and beta-catenin is similar in MDCK cells, but only approximately 20% of the p120/p100 pool associates with the cadherin/catenin complex. Our data provide further evidence for interactions among the different arm proteins and suggest that p120/p100 may participate in regulating the function of cadherins and, thereby, other processes influenced by cell-cell adhesion.

Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons.

The signaling pathways that mediate the ability of NGF to support survival of dependent neurons are not yet completely clear. However previous work has shown that the c-Jun pathway is activated after NGF withdrawal, and blocking this pathway blocks neuronal cell death. In this paper we show that over-expression in sympathetic neurons of phosphatidylinositol (PI) 3-kinase or its downstream effector Akt kinase blocks cell death after NGF withdrawal, in spite of the fact that the c-Jun pathway is activated. Yet, neither the PI 3-kinase inhibitor LY294002 nor a dominant negative PI 3-kinase cause sympathetic neurons to die if they are maintained in NGF. Thus, although NGF may regulate multiple pathways involved in neuronal survival, stimulation of the PI 3-kinase pathway is sufficient to allow cells to survive in the absence of this factor.