Factors associated with depression and anxiety symptoms in family caregivers of patients with incurable cancer.

BACKGROUND: Family caregivers (FCs) are critically important for patients with cancer, yet they may experience psychological distress related to caregiving demands. We sought to describe rates of depression and anxiety in FCs of patients with incurable cancer and identify factors associated with these symptoms to determine those at greatest risk for psychological distress. PATIENTS AND METHODS: We performed a cross-sectional analysis of baseline data from a randomized trial of early palliative care. We assessed depression and anxiety using the Hospital Anxiety and Depression Scale in patients within 8 weeks of diagnosis of incurable lung or gastrointestinal cancer and their FCs. We also assessed patients' quality of life (Functional Assessment of Cancer Therapy-General), coping strategies (Brief COPE), and their report of the primary goal of their cancer treatment. We used linear regression with purposeful selection of covariates to identify factors associated with FC depression and anxiety symptoms. RESULTS: We enrolled 78.6% (n = 275) of potentially eligible FCs. The majority were female (69.1%) and married to the patient (66.2%). While the proportion of FCs and patients reporting depression did not differ (16.4% versus 21.5%, P = 0.13), FCs were more likely to report anxiety compared with patients (42.2% versus 28.4%, P < 0.001). Patients' use of acceptance coping was associated with lower FC depression (B = -0.42, P < 0.001), while emotional support coping was associated with higher FC depression (B = 0.69, P = 0.001) and lower FC anxiety (B = -0.70, P < 0.001). Patient report that their primary goal of their treatment was to 'cure my cancer' was associated with higher FC depression (B = 0.72, P = 0.03). CONCLUSIONS: Patients with incurable cancer and their FCs report high levels of depression and anxiety symptoms. We demonstrated that patients' coping strategies and prognostic understanding were associated with FC depression and anxiety symptoms, underscoring the importance of targeting these risk factors when seeking to address the psychological distress experienced by FCs.

Serum ghrelin is associated with early feeding readiness but not growth in premature infants.

BACKGROUND: Feeding tolerance among premature infants is unpredictable using clinical parameters. Ghrelin, a peptide hormone, acts on the hypothalamus to increase hunger and gut motility. It is present in fetal tissues, promotes intestinal maturation, and is secreted in milk. We hypothesized that higher serum ghrelin levels on days 0-7 are associated with improved feeding tolerance and growth in premature infants. METHODS: Infants (< 1500 g birth weight, n = 36) were recruited on day (D) 0-7. Serum ghrelin was measured by ELISA on D 0-7, D 10-14, and D 24-32, and milk ghrelin in a feeding concurrent with each serum sample. Feeding tolerance was assessed as days to first and full enteral feeds. Growth was quantified as both weight and adipose and muscle deposition by ultrasound. RESULTS: Mean serum ghrelin levels decreased from D 0-7 to D 24-32. Higher ghrelin levels on D 0-7 were correlated with shorter time to first enteral feeding, but not with time to full enteral feeds, rate of weight gain, or rate of accretion of muscle or adipose tissue. Milk ghrelin was not related to serum ghrelin or growth. Abdominal and suprascapular muscle and adipose increased during the first month, but weight gain correlated only with the rate of accretion of abdominal adipose. CONCLUSIONS: Elevated serum ghrelin in the first days of life may contribute to gut motility and readiness to feed. Weight gain in premature infants may primarily indicate abdominal fat accumulation, suggesting that ultrasound measurement of muscle accretion is a better marker for lean body growth.

Successful induction of long-term specific tolerance to fully allogeneic renal allografts in miniature swine.

Major histocompatibility complex class II matching is of overwhelming importance for achieving tolerance to kidney transplants (KTX) in miniature swine. When class II antigens are matched, long-term specific tolerance across complete MHC class I antigen barriers can uniformly be induced by a 12-day perioperative course of cyclosporine. This same regimen is ineffective in fully MHC-mismatched combinations. We hypothesized that initial induction of tolerance to kidney donor class II antigens by bone marrow transplantation might allow tolerance to be induced to a subsequent fully allogeneic KTX in combination with CsA therapy. We report here the results of such fully allogeneic KTX performed in 4 recipients of prior single-haplotype class II-mismatched BMT. All animals received KTX from donors class II matched to the BMT donor and received a 12-day course of intravenous CsA (10 mg/kg/day). All four animals have maintained normal serum creatinine values (less than 2.0 mg/dl) for greater than 200 days posttransplant. Specific hyporesponsiveness to both BMT and KTX donor-type MHC antigens was found in mixed lymphocyte culture and cell-mediated lympholysis assays. Compared with third-party grafts, significantly prolonged survival of BMT donor-specific (P = 0.031) and KTX donor-specific (P = 0.031) skin grafts was observed. These results demonstrate that induction of tolerance to class II antigens by BMT allows a short course of CsA to induce specific tolerance to fully allogeneic renal allografts.

Induction of tolerance to renal allografts across single-haplotype MHC disparities in miniature swine.

We have previously demonstrated that a 12-day course of cyclosporine A (CsA) leads to the induction of tolerance to renal allografts in 100% of recipients selectively mismatched at class I for both haplotypes, and in 71% of recipients selectively mismatched at class II for both haplotypes, but in 0% of recipients mismatched for two haplotypes at both class I and class II. We have postulated that the mechanism by which tolerance is induced may therefore require matching for either class I or class II antigens. One might predict from this hypothesis that tolerance would also be induced in donor-recipient combinations sharing one full haplotype (e.g., AC-->AD), which mimics the clinically relevant transplant combination of parent to offspring. We have therefore investigated the effects of the CsA regimen on renal transplants in this combination. Without immunosuppression, such kidney allografts were uniformly rejected (n = 12; 10.6 +/- 2.4 days). In contrast, a course of CsA (10-13 mg/kg/day) during the first 12 postoperative days induced long-term acceptance of the allograft in 67% (4/6) of recipients. Some acceptor animals also showed specific unresponsiveness to donor antigens as measured by in vitro assays and by failure to develop anti-donor antibodies. Tolerance was confirmed in four of these animals by failure to reject a second transplant SLA-matched to the first kidney donor without additional immunosuppression. These results suggest the feasibility of inducing specific tolerance across a single-haplotype mismatch in the majority of the cases, which could have clinical implications for living-related transplants.

Tolerance to class I-disparate renal allografts in miniature swine. Maintenance of tolerance despite induction of specific antidonor CTL responses.

Miniature swine that become tolerant to renal allografts across an MHC class I barrier following a short course of cyclosporine are unresponsive to donor class I antigens in cell-mediated lymphocytotoxicity. However, skin grafts bearing donor class I plus third-party class II antigens are promptly rejected, and the animals then develop marked cell-mediated lymphocytoxic reactivity to donor class I antigens in vitro, but do not reject the kidney transplants. We show here that CTL generation is directed toward the same donor class I antigens as are expressed by the kidney donor, and is not the result of recognition in vitro of the tolerated class I antigen plus peptides of minor antigens shared between the skin graft donor and the stimulator/target cells. We also show that detection by CTLs of peptides expressed by skin but not by kidney is also not a sufficient explantation of the results, since the survival of skin grafts from the kidney donor is also prolonged, even after precursor CTL can be detected in vitro. The data are most consistent with suppression in vivo in tolerant animals of the helper pathways necessary for activation of precursor CTLs. Differences in patterns of cytokine expression by graft infiltrating cells may provide a mechanism for local suppression of help in this model. Finally, we have examined antibody production after sensitizing by skin grafts in long-term tolerant animals and have found that anti-donor class I antibodies are not produced, even though the same animals produce both anti-class II and anti-third-party class I antibodies.

Long-term acceptance of primarily vascularized renal allografts in miniature swine. Systemic tolerance versus graft adaptation.

We have previously demonstrated that tolerance to two-haplotype class I-mismatched renal allografts can be induced uniformly by a short course of cyclosporine. We report here that following transplant nephrectomy, 8 such long-term acceptor animals all accepted a second renal transplant MHC matched to the original donor without additional immunosuppression. These results indicate that the mechanism of tolerance to primarily vascularized renal allografts involves modification of the host's immune system by the first transplant. To assess the possibility that "graft adaptation" is also involved in the maintenance of tolerance, we retransplanted class I-disparate kidneys from tolerant animals into naive recipients MHC matched to the original recipient. Three of 4 such transplants were rejected acutely, while one animal demonstrated a markedly prolonged survival, but also eventually rejected. These results, therefore, demonstrate that: (1) graft adaptation is not required in order to maintain tolerance; (2) graft acceptance involves induction of systemic tolerance; and (3) graft adaptation may participate in kidney graft prolongation but is not sufficient to transfer tolerance to a secondary host.

Role of the thymus in transplantation tolerance in miniature swine: II. Effect of steroids and age on the induction of tolerance to class I mismatched renal allografts.

BACKGROUND: Recent studies in young (5-7 months) miniature swine have demonstrated that the thymus is involved in the rapid induction of stable tolerance to class I mismatched renal allografts after a 12-day course of Cyclosporine (CyA). Because both steroids and age are known to influence the structure and function of the thymus, we have now studied the effects of these two parameters on tolerance induction in this model. MATERIALS AND METHODS: In young swine, the administration of methylprednisolone (MP) during the standard tolerance-inducing regimen (a 12-day course of CyA) produced severe renal dysfunction and acute cellular rejection histologically. However, the renal allografts recovered and were accepted for >100 days with histological evidence of chronic rejection. To test the effect of age, two relatively old swine (55 and 71 months) received transplants of class I mismatched renal allografts and the standard 12-day course of CyA. One animal rejected the allograft acutely on postoperative day 22, and the second also rejected, but more slowly, with manifestations of chronic rejection. CONCLUSION: These findings suggest that both MP and old age interfere with the induction of stable tolerance in a fashion similar to the previously described effect of thymectomy. These results may have important implications for the mechanism of thymic-dependent tolerance, for the use of steroids in clinical protocols for the induction of allograft tolerance, and for the application of such protocols to adult patients.

Retransplantation in miniature swine. Lack of a requirement for graft adaptation for maintenance of specific renal allograft tolerance.

In miniature swine, one-haplotype class I disparate renal allografts are accepted without exogenous immunosuppression by approximately 35% of recipients. Alternatively, transplants bearing a two-haplotype class I mismatch are always rejected acutely. However, long-term acceptance in the latter animals can be achieved uniformly with a 12-day course of cyclosporine. In vitro studies of recipient cell-mediated lymphocytotoxicity responses have shown donor-specific cytotoxic T lymphocyte clones in tolerant animals, suggesting that tolerance may be a local phenomenon or a central phenomenon activated in the milieu of the graft. Six animals were retransplanted with kidneys MHC-matched to their original allograft to determine whether (1) tolerance is a central phenomenon; (2) host tolerance can be broken with a fresh challenge of donor antigen and antigen-presenting cells; and (3) graft adaptation is required for maintenance of tolerance. Four of the retransplanted animals had been spontaneous acceptors of one-haplotype class I-disparate grafts and two had been rendered tolerant to two-haplotype class I-mismatched kidneys with CsA induction. All six explanted allografts showed no histological evidence of rejection and all six retransplants were accepted without exogenous immunosuppression. These findings suggest that in miniature swine tolerance of class I-disparate kidneys is a stable, centrally mediated phenomenon that cannot be broken with a challenge of fresh donor antigen and donor-type APCs. Furthermore, successful retransplantation without immunosuppression in animals receiving CsA induction therapy for their first transplant suggests that graft adaptation is not necessary for the maintenance of tolerance.

Induction of specific tolerance to class I-disparate renal allografts in miniature swine with cyclosporine.

Previous studies in miniature swine have suggested that the mechanism underlying the spontaneous development of tolerance in one third of one-haplotype class I disparate renal allografts (i.e., ag----ad) involves a relative T cell help deficit at the time of first exposure to antigen. If this hypothesis were correct, then one might expect the administration of an immunosuppressive agent capable of inhibiting lymphokine production during this period to lead to the induction of tolerance to class I MHC antigens in two-haplotype class I mismatched renal allografts (i.e., gg----dd), which are otherwise uniformly and acutely rejected. This hypothesis was tested in eight two-haplotype class I disparate, class II matched donor-recipient pairs, in which recipients were treated with cyclosporine 10 mg/kg, i.v. q.d. for 12 days. This protocol led to the induction of long-term (greater than 100 days) specific tolerance in 100% of recipients, as compared with control animals that rejected grafts in 13.7 +/- 0.9 days (P less than 0.0001). The specificity of tolerance was assessed both in vivo with subsequent skin grafts and in vitro by mixed lymphocyte response (MLR) and cell-mediated lymphocytotoxicity (CML). Survival of donor-specific skin grafts was prolonged compared with skin grafts bearing third-party class I antigens (19.5 +/- 2.0 versus 11.5 +/- 2.0 days, n = 4, P less than 0.05). Tolerant recipients had markedly diminished or absent anti-donor MLR and CML responses, but maintained normal reactivity to third party. Four of eight CsA-treated recipients showed detectable levels of anti-donor IgM, while none demonstrated the presence of anti-donor IgG, which was found in all rejecting controls.

Development of tolerance to class II-mismatched renal transplants after a short course of cyclosporine therapy in miniature swine.

Our laboratory has reported previously spontaneous acceptance of class II-matched, single haplotype (but not 2 haplotype), class I-mismatched renal allografts in miniature swine. All class II-mismatched animals rejected acutely regardless of class I matching. We have also demonstrated recently that a short course of high dose (10 mg/kg/day for 12 days) CsA uniformly induces donor-specific tolerance to 2-haplotype, class I-mismatched renal allografts. The survival of 2-haplotype, fully MHC mismatched renal allografts was prolonged by the same treatment, but tolerance was not induced, as all animals rejected eventually. We have now tested this short course of immunosuppressive therapy for its effect on renal allografts mismatched selectively for 2 haplotypes at class II. We have observed long-term graft survival in 5 of 7 animals under these conditions. Each of the 5 acceptor animals was demonstrated to be specifically tolerant by its response either to donor-matched skin grafts or to a second donor-matched kidney transplant without further immunosuppression. These data suggest the existence of a common pathway for induction of specific transplantation tolerance to MHC antigens when these antigens are recognized on vascular endothelium under conditions of altered cytokine production. They also suggest that tolerance induction under these conditions requires matching for either class I or class II antigens, which may have implications for the mechanism by which peripheral tolerance is induced, as well as practical implications for the extension of these results to potential clinical practice.

Effect of the good behavior game on disruptive library behavior.

A modification of the good behavior game was used to reduce disruptive behaviors during a weekly library period of children in a fourth-grade class. Modifications included student input in designing rules, attempts to state rules in positive terms, observation of class behavior in the experimental (library) setting as well as in a comparison (classroom) setting, and librarian involvement in instituting the game coupled with teacher involvement in delivering reinforcers. Reinforcers consisted of special classroom activities conducted by the teacher with winning team members. Modification of the good behavior game did not detract from its effectiveness in reducing disruptive and off-task behavior.

Recurrent pathological jealousy.

A 36-year-old man suffered from pathological jealousy during three marriages. The episodes involving delusions of infidelity were usually preceded by premonitory symptoms. At first, the patient responded by discontinuing his medication (a phenothiazine) so that he might remain vigilant. Later he came to recognize the premonitory symptoms as signals indicating a need for help, and he would request hospitalization. In the periods between his marriages he was never troubled by feelings of jealousy. The chief determinant of delusions of infidelity in this instance, as in three reported by Docherty and Ellis, seemed to be exposure to the mother's extramarital sexual relations. This case, in which three different wives were subjected to the same pattern of behavior, would seem to be an exception to the rule that if marital problems occur both partners are responsible for creating them.

Pelger-Huet anomaly in an infant with multiple congenital anomalies.

We report a new case of Pelger-Huet anomaly (PHA) evident from the first day of life in an infant with multiple congenital anomalies suggestive of Fryn syndrome. The infant's parents are not affected by PHA, raising the possibility that the PHA resulted from a spontaneous mutation.

Predicted exocyclic amino group alkylation of 2'-deoxyadenosine and 2'-deoxyguanosine by the isopropyl cation.

Diisopropyltriazene in aqueous 10% acetonitrile (pH 7.0 +/- 0.4) yields N(6)-isopropyl-2'-deoxyAdo as the predominant product and N(2)-isopropyl-2'-deoxyGuo in yields comparable with the O(6) adduct in reactions with 2'-deoxyAdo and 2'-deoxyGuo, respectively. These observations are inconsistent with what is expected on the basis of the regnant hypothesis concerning factors that determine atom site selectivity in diazonium ion-mediated alkylations. An alternative explanation based on the fleeting existence of the reactive intermediates involved is consistent with these observations.