A 2-year dyadic longitudinal study of mothers' and fathers' marital adjustment when caring for a child with cancer.

OBJECTIVE: Studies examining interrelationships within parental couples confronted with pediatric cancer are scarce. This study explored dyadic longitudinal associations between both partners' family functioning and mood at diagnosis, and marital adjustment 2 years later. METHOD: Parents of children (n = 47 couples) with acute lymphoblastic leukemia (ALL) completed the Family Well-Being Assessment and Profile of Mood States-Bipolar Form at diagnosis, and the Locke-Wallace Marital Adjustment Test 2 years post diagnosis. Multilevel linear models using the actor-partner interdependence model (APIM) and controlling for baseline marital adjustment were conducted to evaluate within subject and dyadic longitudinal effects. RESULTS: For mothers, better marital adjustment 2 years post diagnosis was associated with perception of greater family support and less role conflict and role overload at diagnosis. For fathers, better marital adjustment 2 years post-diagnosis was associated with perception of less role conflict, greater role ambiguity, and being more tired at diagnosis, as well as their partner's perception of less role conflict at diagnosis. CONCLUSIONS: These findings highlight the importance of considering both partners' perspectives in understanding marital adjustment across treatment phases in parents of children with ALL. Early interventions for couples should be tailored to meet each partner's needs in order to foster resilience within the couple.

A systematic review on factors and consequences of parental distress as related to childhood cancer.

The literature including correlates of parental distress as related to childhood cancer is abundant. It is important to identify predictive factors and outcomes of this distress in parents. The objective of this review was to update previous syntheses on factors of distress and to identify outcomes of parents' distress in the recent literature (2007-2012). We performed a systematic review to identify all quantitative studies including measures of parental distress and associated factors during the study period. We found 56 eligible studies, of which 43 had a Low risk of bias (Cochrane guidelines). Forty-two reports included potential predictive factors. Significant relationships were found with clinical history of the child, sex of the parent, coping response and personal resources, pre-diagnosis family functioning, but not education/income or marital status. Twenty-five reports studied potential consequences of distress and focused on psychological adjustment in parents and children. Compared to past periods, a higher proportion of studies included fathers. Measures used to evaluate distress were also more homogeneous in certain domains of distress. This review underscores the need for appropriate methods for selecting participants and reporting results in future studies. Appropriate methods should be used to demonstrate causality between factors/consequences and distress.

Assessment of the regional economic impacts of catastrophic events: CGE analysis of resource loss and behavioral effects of an RDD attack scenario.

We investigate the regional economic consequences of a hypothetical catastrophic event-attack via radiological dispersal device (RDD)-centered on the downtown Los Angeles area. We distinguish two routes via which such an event might affect regional economic activity: (i) reduction in effective resource supply (the resource loss effect) and (ii) shifts in the perceptions of economic agents (the behavioral effect). The resource loss effect relates to the physical destructiveness of the event, while the behavioral effect relates to changes in fear and risk perception. Both affect the size of the regional economy. RDD detonation causes little capital damage and few casualties, but generates substantial short-run resource loss via business interruption. Changes in fear and risk perception increase the supply cost of resources to the affected region, while simultaneously reducing demand for goods produced in the region. We use results from a nationwide survey, tailored to our RDD scenario, to inform our model values for behavioral effects. Survey results, supplemented by findings from previous research on stigmatized asset values, suggest that in the region affected by the RDD, households may require higher wages, investors may require higher returns, and customers may require price discounts. We show that because behavioral effects may have lingering long-term deleterious impacts on both the supply-cost of resources to a region and willingness to pay for regional output, they can generate changes in regional gross domestic product (GDP) much greater than those generated by resource loss effects. Implications for policies that have the potential to mitigate these effects are discussed.

Angiotensin II and its role in tubular epithelial to mesenchymal transition associated with chronic kidney disease.

Activation of the intra-renal renin-angiotensin system (RAS) and the subsequent generation of angiotensin II (Ang II) are important mediators of haemodynamic changes in both health and disease. However, the effects of locally produced Ang II are not limited to haemodynamic actions. Ang II is also an important stimulus for tubular hypertrophy with the induction of growth factors, including transforming growth factor (TGF)-ß(1) and connective tissue growth factor. In this article, we explore the direct pro-fibrotic effects of Ang II and its role in inducing tubular epithelial to mesenchymal transition (EMT, also known as type 2 EMT), a known mediator of renal fibrogenesis. There is accumulating evidence that Ang II is able to induce EMT by both TGF-dependent and TGF-independent actions, both in vitro and in vivo. Moreover, blockade of the RAS has synergistic renoprotective effects across a number of causally different forms of renal disease. There is hope that targeted combinations to offset angiotensin-converting enzyme escape in the setting of RAS blockade will eventually achieve the long-term efficacy that has been expected for so long.

Kaposi's sarcoma-associated human herpesvirus-8 encodes homologues of macrophage inflammatory protein-1 and interleukin-6.

Human herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in lesions of multicentric Castleman's disease (MCD). We have identified a major gamma-herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vIL-6) shares functional properties with endogenous IL-6 proteins and that both vIL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8' BCBL cell line. Low amounts of constitutive vIL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vIL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cytokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.

Angiotensin II mediates epithelial-to-mesenchymal transformation in tubular cells by ANG 1-7/MAS-1-dependent pathways.

Epithelial-to-mesenchymal transformation (EMT) of tubular cells into a myofibroblastic phenotype is an important mediator of renal scarring in chronic nephropathy. This study examines the role of the renin-angiotensin system (RAS) in this process. NRK-52E cells were exposed to angiotensin (ANG) II and ANG 1-7 in the presence or absence of inhibitors and agonists of RAS signaling. EMT was assessed at 3 days by expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin and the induction of a myofibroblastic phenotype. Expression of fibrogenic growth factors and matrix proteins was assessed by RT-PCR and immunofluorescence microscopy. To confirm findings in vivo, rats were also infused with ANG 1-7 (24 microg*kg(-1)*h(-1)) or saline via an osmotic minipump for 10 days, and renal fibrogenesis was then assessed. Treatment of NRK-52E cells with ANG II induced characteristic changes of EMT. Selective blockade of the AT(1) receptor or the AT(2) receptor failed to inhibit ANG II-induced EMT. However, blockade of the ANG 1-7 receptor, Mas-1, was able to prevent ANG II-dependent EMT. To confirm these findings, both ANG 1-7 and the selective Mas receptor agonist, AVE-0991, were able to induce NRK-52E cells in a dose-dependent manner. Exposing cells to recombinant ACE2 was also able to induce EMT. In addition, an infusion of ANG 1-7 induced the tubular expression of alpha-SMA and the expression of matrix proteins in the kidney. ANG II is a potent stimulus for EMT, but not through conventional pathways. This study points to the possible limitations of conventional RAS blockade, which not only fails to antagonize this pathway, but also may enhance it via augmenting the synthesis of ANG 1-7.

The enhancing effect of the microbial flora on macrophage function and the immune response. A study in germfree mice.

The immune response to bacteria and to a soluble protein was compared in germfree and conventionalized mice. Sixty germfree and 59 conventionalized mice received a suspension of killed Serratia marcescens into one front foot-pad and sterile horse ferritin into the other and were sacrificed in groups from 2 hr to 14 days after inoculation. All mice had no pre-existing antibody to either antigen and the flora of the conventionalized mice never contained Serratia. Lymphatic tissue changes and the fate of the antigens were followed in axillary lymph nodes and the spleens by histologic, fluorescent antibody, and autoradiographic techniques after tritiated thymidine injection. Individual serum antibody titers for both antigens were determined at each time period. The cellular and serologic responses were slightly delayed in the germfree mice but later equaled and sometimes exceeded those of the conventional animals. In all animals, lymph nodes draining the site of Serratia injection showed a more vigorous response than those on the ferritin-injected side but the reaction was qualitatively the same for both antigens. All lymph nodes contained the antigens by 2 hr after foot-pad injection. With time, both antigens lost their particulate nature sooner in conventionalized than in germfree macrophages. In the latter, both antigens persisted throughout the study while no longer demonstrable with fluoresceinated antiserum in conventional macrophages after the first week. While phagocytosis is equal in germfree and conventional mice, a greater digestive capacity of macrophages for antigens seems to result from the continuous exposure of conventional animals to the immunologic effects of the microbial flora. Conversely, the lack of substantial antigenic stimulation of lymphatic tissue in germfree animals fails to develop these macrophage functions beyond their basic ability to degrade foreign substances. Although the onset of the immune response is delayed in germfree mice, the relatively prolonged antigen digestion and the presumably slower release of immunogenic antigen fragments result in a more sustained and sometimes greater response than in conventional animals. This modifying effect of the microflora on the function of macrophages during the immune response is independent of previous experience with, or the nature of, the antigen.

The role of the microbial flora in uremia. II. Uremic colitis, cardiovascular lesions, and biochemical observations.

Uremic colitis of varying severity occurred in the majority of conventionalized rats dying after removal of both kidneys, but was not found in uremic conventionalized and germfree rats sacrificed preterminally, or in germfree and limited-flora rats dying from uremia, or in any of the controls. The lesions were restricted to the cecum and their incidence and severity paralleled a shorter duration of survival. Cardiovascular damage including focal myocardial necrosis and calcification and patchy aortic and coronary calcification were observed in uremic rats regardless of their microbial status. These lesions had a higher incidence, developed more rapidly, and were more severe in the germfree and limited-flora rats than in the conventionalized animals. The presence or severity of the lesions, however, did not correlate with survival time of rats dying from uremia or with total plasma calcium and inorganic phosphorus levels of individual animals. Generalized necrotizing arteritis was not observed. Wound healing was poor in all uremic rats regardless of microbial status. Focal infection was noted in a few conventionalized rats dying from uremia, did not correlate with survival time, and was absent in all other groups. Comparison of biochemical findings between uremic germfree and conventionalized rats show a higher blood urea nitrogen and elevated plasma indoxyl sulfate in the presence of a microbial flora and a greater amount of plasma inorganic phosphorus in its absence. Uremia resulted in a decrease in hematocrit and increase in plasma and muscle potassium that were similar for germfree and conventionalized rats. Plasma and muscle sodium, total plasma calcium, glucose, and total protein were essentially unchanged by microbial status or uremia. Because the foregoing differences in the metabolic and histopathologic changes of uremia are linked to the known difference in microbial status of the fasting bilaterally-nephrectomized rats that were studied, they are a tangible indication of ways by which the indigenous microbial flora and its composition may affect the course of acute uremia.

Navy sonar and cetaceans: just how much does the gun need to smoke before we act?

Cetacean mass stranding events associated with naval mid-frequency sonar use have raised considerable conservation concerns. These strandings have mostly involved beaked whales, with common pathologies, including "bubble lesions" similar to decompression sickness symptoms and acoustic traumas. However, other cetacean species have also stranded coincident with naval exercises. Possible mechanisms for the strandings include a behavioral response that causes deep divers to alter their diving behavior, which then results in decompression sickness-like impacts. Current mitigation measures during military exercises are focused on preventing auditory damage (hearing loss), but there are significant flaws with this approach. Behavioral responses, which occur at lower sound levels than those that cause hearing loss, may be more critical. Thus, mitigation measures should be revised. A growing number of international bodies recognize this issue and have urged increasing scrutiny of sound-producing activities, but many national jurisdictions have resisted calls for increased protection.

The role of tubular epithelial-mesenchymal transition in progressive kidney disease.

The accumulation of interstitial matrix represents the final common pathway of most forms of kidney disease. Much of this matrix is synthesized by interstitial myofibroblasts, recruited from resident fibroblasts and circulating precursors. In addition, a significant proportion is derived from epithelial-mesenchymal transition (EMT) of tubuloepithelial cells. The importance of EMT has been demonstrated in experimental models, where blockade of EMT attenuates renal fibrosis. Although a number of factors may initiate EMT in the kidney, the most potent is transforming growth factor-beta1 (TGF-beta1). Moreover, many other prosclerotic factors have effects on EMT indirectly, via induction of TGF-beta1. Signaling events in this pathway include activation of Smad/integrin-linked kinase (ILK) and connective tissue growth factor (CTGF). Basement membrane integrity is also a key regulator of EMT. In particular, overexpression of matrix metalloproteinase-2 has a key role in the initiation of EMT, membrane dissolution, and the interstitial transit of transformed mesenchymal cells. Endogenous inhibitors of EMT also play an important counterregulatory role both to prevent EMT and stimulate uncommitted cells to regain their tubular phenotype (mesenchymal-epithelial transition). Such inhibitors represent a potential therapeutic approach, offering a mechanism to slow or even redress established renal fibrosis.

Information from the Internet: attitudes of Australian oncology patients.

BACKGROUND: Patients require accurate information about their illness to make informed decisions. Many sources of information exist, although reliability is variable. Our objective was to investigate information seeking behaviour and attitudes toward health-related information from the Internet in a sample of Australian oncology patients. METHOD: During their outpatient attendance, 109 patients completed a self-administered paper-pen format questionnaire. They were required to have a recent cancer diagnosis (<6 months ago) adequate English and no cognitive impairment. RESULTS: Seventy-four per cent of questionnaires were returned. The majority of patients (78%) wanted as much information about their cancer diagnosis as possible and 90% reported receiving adequate information from their treating team. Despite this, more than half actively searched for additional information, with 77% using the Internet. Patients were trusting of information obtained from the Internet. More than half of information searchers discussed information obtained in their search with a health professional. The majority of patients did not believe that information searching adversely affected the doctor-patient relationship. CONCLUSION: Information searching is common in ambulatory Australian oncology patients, with the Internet being a frequently used resource. To ensure patients find reliable and relevant information and to minimize the risk of harm, health professionals involved in treating oncology patients should provide guidance in finding information sources and assistance in interpreting the information obtained.

Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease.

Five patients with acute myelocytic leukemia (AML) after combined modality therapy for Hodgkin's disease (HD) were treated with cyclophosphamide and busulfan followed by bone marrow transplantation (BMT). Four patients received allogeneic transplants from histocompatibility locus antigen (HLA)-compatible siblings and the fifth patient received an autologous marrow treated with 4-hydroperoxycyclophosphamide. Two patients died of complications of acute graft-v-host disease (GVHD) despite prophylaxis with either low-dose cyclophosphamide or cyclosporine. The remaining three patients were alive and disease-free 382, 617, and 620 days after transplant. These initial results are encouraging and more patients with treatment-related AML need to be evaluated with both allogeneic and autologous BMT to fully elucidate the potentially curative role of this intensive therapy in an otherwise fatal hematologic malignancy.

Allogeneic bone marrow transplantation for patients with high-risk acute lymphoblastic leukemia.

Seventy-four consecutive patients with high-risk acute lymphoblastic leukemia (ALL) were given cyclophosphamide (CY; 50 mg/kg on each of 4 days) plus total body irradiation (TBI; 300 rad on each of 4 days) followed by a human leukocyte antigen (HLA)-identical allogeneic bone marrow transplant (BMT). Eighteen patients in first complete remission (CR1), 36 in CR2, 16 in CR3, and four in CR4 were transplanted. Patients in CR1 were transplanted 1 to 8 months (median, 3 months) after attaining CR. All 18 patients in CR1 had one or more poor risk factors: age more than 18 (N = 17), initial leukocyte count greater than or equal to 20,000 (N = 11), Ph 1 chromosome (N = 2), delay in attaining CR more than 6 weeks (N = 8), or extramedullary disease (N = 1). Of those transplanted in CR2, 72% had relapsed on therapy. The 5-year event-free survival (EFS) rates for patients transplanted in CR1, CR2, and CR3 are 42%, 43%, and 25%, respectively, at median follow-up times of 57, 54, and 72 months, respectively. Children aged less than 18 years transplanted in CR2 have a 5-year EFS rate of 54%. All CR4 patients died early after transplant. The actuarial probability of relapse is 20%, 26%, and 48% for those transplanted in CR1, CR2, and CR3, respectively. Although there was substantial transplant-associated mortality, it decreased over the decade of the study (P = .01). This study indicates that BMT offers an attractive alternative to postremission chemotherapy in patients in CR1 with poor prognostic factors and in patients in second remission.

High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease.

Patients with Hodgkin's disease who have failed two or more chemotherapy regimens or who have relapsed after an initial chemotherapy-induced remission of less than 12 months are seldom cured with conventional salvage therapies. We studied the effect of high-dose cytoreductive therapy followed by bone marrow transplantation in 50 such patients with relapsed Hodgkin's disease. Twenty-one patients with histocompatibility locus antigen (HLA)-matched donors had allogeneic marrow transplants, one patient received marrow from an identical twin, and 28 patients without a matched donor received autologous grafts purged with 4-hydroperoxycyclophosphamide. Busulfan plus cyclophosphamide was the preparative regimen for the 25 patients who had received extensive prior irradiation, and the other 25 patients received cyclophosphamide plus total body irradiation. The overall actuarial probability of event-free survival at 3 years was 30%, with a median follow-up of 26 months. The event-free survival following transplantation was influenced by the number of chemotherapy failures and the patient's response to conventional salvage therapy prior to transplant. The 16 patients who were transplanted at first relapse, while still responsive to standard therapy, had a 64% actuarial probability of event-free survival at 3 years. Age, presence of extranodal disease, preparative regimen, and type of graft (autologous v allogeneic) were not significant prognostic factors. The majority of transplant-related deaths were from interstitial pneumonitis; inadequate pulmonary function, multiple prior chemotherapy regimens, and prior chest irradiation all appeared to increase the transplant-related mortality. These results suggest a role for marrow transplantation in a subset of patients with relapsed Hodgkin's disease who are unlikely to be otherwise cured but are still responsive to conventional-dose cytoreductive therapy.

Tubular changes in early diabetic nephropathy.

Far from being bystanders in diabetic nephropathy, changes in the proximal tubule are important for the development of progressive diabetic kidney disease. The proximal tubule is uniquely susceptible to a variety of metabolic and hemodynamic factors associated with diabetes. Renal function and prognosis correlate better with structural lesions in the tubuli and cortical interstitium than with classical glomerular changes of diabetic nephropathy. The proximal tubules show a variety of poorly characterized changes, which have led to the notion that tubular damage represents a "final common pathway" for proteinuric renal injury. However, tubular hypertrophy, reduced organic ion transport, and other tubular changes reviewed in this paper, are already apparent before the onset of proteinuria in diabetes. Indeed, increased tubuloglomerular feedback and defective uptake and lysosomal processing may independently contribute to hyperfiltration and urinary protein loss, respectively. This finding does not mean that glomerular or vascular dysfunction do not contribute to progressive nephropathy. However, although subdividing the nephron for the purposes of analysis and scientific discovery may be useful, the interactions between tubule, glomerulus, and interstitium are likely key to the understanding of complex disorders such as diabetic nephropathy. From this "holonephric" point of view, an understanding of the changes in the diabetic tubule forms an important component to the understanding of kidney disease in diabetes.

Hemorrhagic cystitis associated with adenovirus infection in bone marrow transplantation.

A retrospective study of bone marrow transplant recipients shedding adenovirus type 11 in the urine was carried out to determine the association between viral shedding and hemorrhagic cystitis in this population. Weekly urine virology surveillance cultures were obtained during the first 100 days following transplantation. Adenovirus type 11 was cultured from five of 502 bone marrow transplant recipients from 1977 through 1984. In four of these five patients there was associated hemorrhagic cystitis. This contrasts with an overall incidence of hemorrhagic cystitis of 20% in this bone marrow transplant population. A case of hemorrhagic cystitis occurred in a patient following bone marrow transplantation. Recognition of a viral origin of hemorrhagic cystitis may explain the occurrence of late hemorrhagic cystitis in patients despite interventions designed to prevent cyclophosphamide-induced hemorrhagic cystitis. Hemorrhagic cystitis may be the presenting sign of a lethal adenoviral infection.

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.

Serum progesterone levels predict success of in vitro fertilization/embryo transfer in patients stimulated with leuprolide acetate and human menopausal gonadotropins.

Serum progesterone (P4) levels greater than 2.86 nmol/L (0.9 ng/mL) on the day of hCG administration are reportedly associated with decreased pregnancy rates in in vitro fertilization/embryo transfer (IVF/ET) cycles. To further assess this phenomenon we measured serial serum P4, LH, and estradiol levels in 115 consecutive patients undergoing stimulation for IVF/ET with midluteal leuprolide acetate and human menopausal gonadotropins. IVF/ET cycle outcome was retrospectively correlated with P4 levels on the day of hCG administration. Two critical breakpoints were identified, 1.27 nmol/L (0.4 ng/mL) and 286 nmol/L (0.9 ng/mL). Clinical pregnancies occurred in 9 of 18 patients in group I (P4, less than 1.27 nmol/L) compared to 11 of 81 patients in group II (1.27 less than P4 less than 2.86 nmol/L; P = 0.001) and 0 of 14 patients in group III (P4, less than or equal to 2.86 nmol/L) (P = 0.001). Eleven patients in group III had cryopreservation of embryos during that cycle. Six subsequently underwent frozen embryo transfer, and clinical pregnancies occurred in 2, both of whom have delivered. These findings demonstrate that even modest increases in serum P4 levels (greater than 1.27 nmol/L) are associated with reduced pregnancy rates in IVF/ET cycles. In addition, it appears that the mechanism may not exclusively involve poor oocyte quality.

Interstitial pneumonitis after allogeneic bone marrow transplantation. Nine-year experience at a single institution.

Of 386 patients with allogeneic bone marrow transplants (BMT) treated during a 9-year interval, 166 developed interstitial pneumonitis (IP). Idiopathic and cytomegalovirus (CMV) IP constituted 90% of the 113 cases in which tissue was examined. Risk factors for IP overall were acute graft-versus-host disease (AGVHD), remote transplant date, the diagnosis of leukemia, and GVHD prophylaxis with agents other than cyclosporine. Risk factors for CMV IP were pre-transplant CMV seropositivity, CMV excretion, age greater than 10 years, AGVHD, GVHD prophylaxis with agents other than cyclosporine, and a remote transplant date. Patients transplanted for aplastic anemia were at lower risk for idiopathic IP than those transplanted for leukemia. The incidence of IP in patients given busulfan plus cyclophosphamide was equivalent to that in patients receiving cyclophosphamide plus total body irradiation. The incidence of idiopathic IP remained constant over this 9-year period while CMV IP declined significantly.