"We can hardly even do it nowadays. So, what's going to happen in 5 years from now, 10 years from now?" The health and community care and support needs and preferences of older people living with HIV in Ontario, Canada: a qualitative study.

INTRODUCTION: The population of people living with HIV (PLWH) is ageing consequent to effective treatment and a steady stream of new diagnoses among older adults. PLWH experience a greater burden of age-related comorbidities and poorer social determinants of health compared to their HIV-negative peers, yet comprehensive requisites for care and support as PLWH age remain poorly understood. Preferences And Needs for Ageing Care among HIV-positive Elderly people in Ontario, Canada (PANACHE ON), explored the health and community care and social support needs and preferences of a diverse group of older PLWH (age 60+) and described life course experiences among older PLWH that shape these needs and preferences and whether they are met. METHODS: PANACHE ON was a qualitative community-based participatory research study. In-person focus groups using a semi-structured interview guide were co-facilitated by pairs of trained older PLWH from July to October 2019. Purposive sampling bolstered the inclusion of communities disproportionately affected by HIV in Ontario. Descriptive analysis was used to summarize demographic data; participatory data analysis was conducted by a subset of the research team, with transcripts double-coded and analysed using NVIVO 12 Plus. RESULTS: A total of 73 PLWH participated, 66% identified as men. The mean age was 64 years (range 55-77) and median time living with HIV was 23 years (range 2-37). The current and anticipated needs of older PLWH, many of which were only partially met, included necessities such as food and housing, mobility and sensory aids, in-home support, social and emotional support, transportation and information. Three experiences-trauma, stigma and uncertainty-intersected in the lives of many of our participants, shaping their needs for care and support, and impacting the ease with which these needs were met. CONCLUSIONS: Unmet health and social needs and limited control over the availability and accessibility of ageing-related care and support due to resource constraints or reduced capacity for self-advocacy results in anxiety about the future among older PLWH, despite their well-developed coping strategies and experience navigating systems of care. These study findings will inform the development of the first national needs assessment of older PLWH in Canada.

Late-Onset Posttransplant Lymphoproliferative Disorders after Solid Organ Transplantation in Adults: A Case Series and Review of the Literature.

The posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of neoplasms that have wide variety of clinical and histological presentations. The management of PTLDs is challenging due to variety of involvement sites and histological types. The length and type of immunosuppression are correlated with the emergence of PTLDs, and most of the cases appear within the first two years after transplant. This case series describes five late-onset PTLDs with rare histological features and multiorgan involvement.

Loss of tumourigenicity of stably ERbeta-transfected MCF-7 breast cancer cells.

Proliferation of breast cancer cells is mediated by estrogen receptors (ER)-ERalpha and ERbeta. At present, contradictory observations complicate the understanding of involvement of ERbeta in breast cancer and functional definition of ERbeta as a prognostic marker. A stable expression of full length ERbeta was established in the ERalpha-positive MCF-7 breast carcinoma cell line to evaluate the role for ERbeta in maintenance of cell viability and estrogenic response, as well as proliferation, morphology and cell cycle progression. In order to verify in vivo tumourigenicity of ERbeta transfectants were transplanted into nude mice. Transfection of ERbeta in MCF-7 resulted in a marginal increase of gelsolin protein expression. Constitutive expression of ERbeta resulted in a significant 30% inhibition of cellular growth compared with transfection of the mock vector alone (p=0.043). This reduction in growth was associated a retardation of transition into S-phase of the cell cycle. The in vitro response to 17beta-estradiol was reversed in cells over-expressing ERbeta (p=0.016). However, no difference in response to the antiestrogens tamoxifen and ICI 182,780 was observed in the presence of ERbeta. Importantly, over-expression of ERbeta prevented establishment and growth of tumours as subcutaneous xenografts in immunodeficient mice in vivo. These observations support the notion that ERbeta is a tumour suppressor and is exploitable in terms of cancer prevention, improving therapeutic response or predicting disease progression.

Allogeneic recombinant soluble MHC class I molecules modify urinary odor cues in rats.

The highly polymorphic genes of the major histocompatibility complex (MHC) determine, in part, the odor cues and behavior of an individual. In animal models, MHC-associated odors that regulate distinct behavior have been identified mainly in urine. However, the underlying mechanism is still not clear. Here, we show that injected recombinant soluble (rs) MHC class I molecules (DA, rsRT1.A(a) and Lewis, rsRT1.A(l)) temporarily alter urine odor of Lewis test rats (RT1.A(l)). This change in urinary signals was observed in behavioral assays using the habituation/dishabituation test and in odor signals analysed by gas chromatography (GC) and mass spectrometry (MS). Gas chromatographic analysis revealed that these altered odor signals are caused by quantitative changes of at least two nitrogen-containing urinary compounds. The results suggest that urinary olfactory cues are directly or indirectly influenced by MHC class I gene products.

Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model.

BACKGROUND: In vitro, soluble MHC (sMHC) antigens modulate and induce apoptosis in alloreactive and antigen-specific T cells, demonstrating their potency to regulate T cell-mediated immune responses. However, their efficacy to regulate immunological responses in vivo remains unclear. Here, we report that repetitive intraperitoneal injection of recombinant Lewis rat-derived MHC class I antigens in Dark Agouti (DA) rats modulates alloreactivity. METHODS: RT1.A1 (Lewis derived) genes were cloned into mammalian expression vectors, and RT1.Aa (DA derived) genes were used to transfect a rat myeloma cell line. RT1.A1 molecules were injected intraperitoneally in DA recipients that subsequently underwent transplantation with Lewis-derived cardiac allografts. RESULTS: Soluble class I antigens were secreted by the transfected cells and were shown to be heterodimeric, peptide-loaded, and conformationally folded. Injection of donor-derived soluble MHC significantly reduced the ability of recipient animals to mount a cytotoxic T-cell response to donor-derived tissue. More interestingly, this treatment significantly prolonged donor-graft survival and allowed 60% of treated animals to develop graft tolerance (>120 days), when donor sMHC were combined with a single subtherapeutic dosage of cyclosporine. Thymectomy of recipient animals before transplantation did not interfere with induction of peripheral tolerance. CONCLUSIONS: Donor-derived sMHC are potential tolerogens for down-regulating the cytotoxic T-cell response of animals that undergo transplantation. Thus, these data provide for the first time a rationale for the application of directly injected sMHC in vivo to down-regulate immunological responses and aid the induction of graft tolerance.

Reduction of amphetamine hydroxylamine and other aliphatic hydroxylamines by benzamidoxime reductase and human liver microsomes.

For the reduction of N-hydroxylated derivatives of strongly basic functional groups, such as amidines, guanidines, and aminohydrazones, an oxygen-insensitive liver microsomal system, the benzamidoxime reductase, has been described. To reconstitute the complete activity of the benzamidoxime reductase, the system required cytochrome b(5), NADH-cytochrome b(5)-reductase, and the benzamidoxime reductase, a cytochrome P450 enzyme, which has been purified to homogeneity from pig liver. It was not known if this enzyme system was also capable of reducing aliphatic hydroxylamines. The N-hydroxylation of aliphatic amines is a well-known metabolic process. It was of interest to study the possibility of benzamidoxime reductase reducing N-hydroxylated metabolites of aliphatic amines back to the parent compound. Overall, N-hydroxylation and reduction would constitute a futile metabolic cycle. As examples of medicinally relevant compounds, the hydroxylamines of methamphetamine, amphetamine, and N-methylamine as model compounds were investigated. Formation of methamphetamine and amphetamine was analyzed by newly developed HPLC methods. All three hydroxylamines were easily reduced by benzamidoxime reductase to their parent amines with reduction rates of 220.6 nmol min(-1) (mg of protein)(-1) for methamphetamine, 5.25 nmol min(-1) (mg of protein)(-1) for amphetamine, and 153 nmol min(-1) (mg of protein)(-1) for N-methylhydroxylamine. Administration of synthetic hydroxylamines of amphetamine and methamphetamine to primary rat neuronal cultures produced frank cell toxicity. Compared with amphetamine or the oxime of amphetamine, the hydroxylamines were significantly more toxic to primary neuronal cells. The benzamidoxime reductase is therefore involved in the detoxication of these reactive hydroxylamines.

Oral feeding of an immunodominant MHC donor-derived synthetic class I peptide prolongs graft survival of heterotopic cardiac allografts in a high-responder rat strain combination.

The efficacy of two synthetic major histocompatibility complex (MHC)-derived DA (RT1.Aa) 25-mer peptides (residues 56-80 and 96-120) to modulate alloreactivity was tested in Lewis (RT1.A1) responder animals. The DA peptide 56-80, but not peptide 96-120, induced delayed-type hypersensitivity (DTH). DTH was significantly reduced by oral feeding of peptide 56-80, P = 0.004. In addition, oral feeding of this peptide in combination with a short course of cyclosporin A (CsA) prolonged graft survival of 60% of heterotope transplanted DA cardiac allografts in Lewis recipient rats. Long-term survivors developed low levels of allo-antibodies against donor tissue as compared to rejecting animals and increased levels of interleukin-4 (IL-4) within the allograft. Similarly, IL-4-secreting splenocytes were identified by flow cytometry in these animals, indicating a Th2-type cytokine pattern. However, graft survival was particularly limited to cardiac allografts because donor-type skin grafts were acutely rejected in tolerant animals. It is interesting that residue alignment of peptide 56-80 to the motif of the RT1.A1 molecule showed a preferred class I motif within this sequence, suggesting indirect presentation of this peptide to recipient T cells. Thus, peptide 56-80 appears to represent a dominant epitope that can be exploited for establishing tolerance in this transplantation strain combination.

A dynamic model of drug initiation: implications for treatment and drug control.

We set up a time-continuous version of the first-order difference equation model of cocaine use introduced by Everingham and Rydell [S.S. Everingham, C.P. Rydell, Modeling the Demand for Cocaine, MR-332-ONDCP/A/DPRC, RAND, Santa Monica, CA, 1994] and extend it by making initiation an endogenous function of prevalence. This function reflects both the epidemic spread of drug use as users 'infect' non-users and Musto's [D.F. Musto, The American Disease: Origins of Narcotic Control, Oxford University, New York, 1987] hypothesis that drug epidemics die out when a new generation is deterred from initiating drug use by observing the ill effects manifest among heavy users. Analyzing the model's dynamics suggests that drug prevention can temper drug prevalence and consumption, but that drug treatment's effectiveness depends critically on the stage in the epidemic in which it is employed. Reducing the number of heavy users in the early stages of an epidemic can be counter-productive if it masks the risks of drug use and, thereby, removes a disincentive to initiation. This strong dependence of an intervention's effectiveness on the state of the dynamic system illustrates the pitfalls of applying a static control policy in a dynamic context.

Conversion of failed ileal pouch-anal anastomosis to continent ileostomy.

PURPOSE: We report the results of converting 42 failed ileal pouch-anal anastomoses to a continent ileostomy (using the Barnett modification of the Kock pouch) performed in the course of 1,334 consecutive continent ostomy procedures. METHOD: Results were obtained from a data registry that tracks long-term outcomes of consecutive continent ostomy procedures performed by 12 surgeons in five centers in the United States. RESULTS: Forty of the 42 patients with failed ileal pouch-anal anastomoses have a functioning continent ostomy. Two patients have had pouch excision. Quality of life for the patients with ileal pouch-anal anastomoses as measured by the SF-36 index improved postoperatively. Long-term outcomes for the patients with ileal pouch-anal anastomoses were similar to those for the larger population of patients who underwent the continent ostomy procedure for other reasons. CONCLUSION: Conversion of a failed ileal pouch-anal anastomosis to a continent ileostomy is a satisfactory alternative to the Brooke ileostomy in appropriate cases.

Sporadic chromosome abnormalities in human lymphocytes and previous exposure to chemicals.

Sporadic abnormalities in lymphocyte cultures are often attributed to in vitro culture variations of no clinical significance. The data presented here compare the findings from 11,873 cells of 230 patients referred with histories of previous chemical exposure (usually to mixtures of solvents and/or pesticides) with 27,050 cells from 855 patients referred for other reasons. Detection of 0.38% or more, structural abnormalities (approximately 1 in 30 cells) was 27.2 times more likely in exposed persons than in controls and the finding of a single autosomal trisomic cell was 14.4 times more likely in exposed persons. These highly statistically significant findings were similar to the frequencies of abnormalities reported in other studies of persons exposed to benzene, pesticides, herbicides and irradiation. It is recommended that findings of sporadic abnormalities in lymphocytes be routinely recorded, and patients with positive findings followed up to discover whether there are past histories of significant exposures.

Cognitive behavioral interventions for adolescents with cystic fibrosis.

Examined the effectiveness of a cognitive behavioral intervention to help adolescents with cystic fibrosis (CF) cope with daily stressors. Five youths were referred for the therapy by medical staff because of perceived problems with anxiety or coping. Treatment impact was assessed on measures of coping, anxiety, perceptions of functional disability, and parental reports of behavior. A multiple baseline design across subjects was used. Reductions in anxiety, a decrease in maladaptive coping efforts with CF-related problems, and an increase in positive coping with CF-related problems were obtained. Youths also reported a decrease in functional disability due to CF after the initiation of the intervention. Follow-up assessment indicated that most youths maintained gains in anxiety and perceived functional disability, but not coping efforts. Results suggest that cognitive behavioral treatment is a viable intervention for anxious youths with CF.

Causes and consequences of backdrafting of vented gas appliances.

House depressurization occurs when household equipment such as a kitchen or bathroom fan or a fireplace exhausts air from the house and lowers the pressure indoors with respect to the outside. The operation of air handlers for forced-air heating or cooling systems also can have a depressurization effect. This depressurization can hinder the natural draft from vented combustion appliances and lead to backdrafting, which in turn can result in combustion gases spilling into the indoor airspace. Extensive spillage can cause elevated indoor levels of combustion products such as carbon dioxide (CO2) and water vapor, as well as contaminants such as carbon monoxide (CO) and nitrogen dioxide (NO2). The focus of this paper is to review studies on depressurization-induced backdrafting and spillage from gas-fired, drafthood equipped furnaces and domestic hot water heaters. Qualitative and quantitative techniques that were used in depressurization and backdrafting studies conducted in Canada, Europe, and the United States are analyzed. These studies have shown that exhaust fans operated simultaneously with fireplaces depressurize houses by 3 to 8 Pa on average. The CO indoor concentrations due to spillage, as reported in these studies, generally have been lower than 5 ppm. However, such low CO concentrations do not necessarily imply that a potential problem associated with backdrafting does not exist. Other combustion products, such as NO2, rarely have been measured in prior backdrafting studies. It can be concluded from the literature review that causes of house depressurization are well understood. However, more comprehensive research is needed to better understand the frequency, duration, and severity of depressurization-induced spillage in a broad cross section of houses. Efforts in this direction have begun recently in the United States through a workshop to define research issues, pilot studies to develop comprehensive measurement protocols, and consensus standard development activities to prepare standardized methods and protocols.

California residential air exchange rates and residence volumes.

UNLABELLED: Air exchange rate data from two residential indoor air quality studies are presented. In the first investigation, over 500 residences in Southern California were sampled for three one-week periods from 1984 to 1985. Those data provided seasonal information for a broad range of residential characteristics in a large metropolitan area. In the second study, a probability sample of nearly 300 residences were sampled for a two-day period during the winter of 1991-1992 throughout the state of California. Air exchange rate is summarized by season, geographic area, and appliance type. Residence volumes are presented by cooking and heating appliance. The data approximately followed lognormal distributions. IMPLICATIONS: Indoor air quality and human exposure models often require estimates of air exchange rate and residence volumes. Application of those models to California residences can be improved by using the data distributions provided in this manuscript. Data distributions presented for heating and cooking appliances are useful for modeling the impact of indoor sources specific for those appliance types. Measured air exchange rate is also useful for modeling energy use for heating and cooling in residences.

Comparison of cyclosporin A absorption from LCT and MCT solutions following intrajejunal administration in conscious dogs.

Absorption from the intestine of cyclosporin A (CsA), dissolved in either a medium-chain (MCT) or a long-chain triglyceride (LCT) solution, was investigated in a chronic dog model. Following intrajejunal administration of 20 mg of CsA/kg of body weight, absorption, judged by the portalvenous appearance of CsA, was determined by measuring whole blood CsA concentrations in the portalvenous and arterial blood and the portalvenous flow. Appearance of CsA from LCT commenced earlier and attained significantly higher mean peak values (+/- SEM) in the portalvenous blood (2557 +/- 436 ng/mL) than from MCT (274 +/- 80 ng/mL). Portalvenous concentrations of CsA were always higher than arterial concentrations for both LCT and MCT, suggesting that CsA is transported by portalvenous blood following uptake from the gut. Absorption of CsA, measured over 300 min, was 10 times higher with LCT (9.96 +/- 2.00%) than with MCT (0.95 +/- 0.21%). This significant difference is believed to result from the formation of mixed micelles which occurs during digestion of LCT but not MCT.

Potent antisense oligonucleotides to the human multidrug resistance-1 mRNA are rationally selected by mapping RNA-accessible sites with oligonucleotide libraries.

Antisense oligonucleotides can vary significantly and unpredictably in their ability to inhibit protein synthesis. Libraries of chimeric oligonucleotides and RNase H were used to cleave and thereby locate sites on human multidrug resistance-1 RNA transcripts that are relatively accessible to oligonucleotide hybridization. In cell culture, antisense sequences designed to target these sites were significantly more active than oligonucleotides selected at random. This methodology should be generally useful for identification of potent antisense sequences. Correlation between oligonucleotide activity in the cell culture assay and in an in vitro RNase H assay supports the proposed role of the enzyme in the mechanism of antisense suppression in the cell.

A new obligately chemolithoautotrophic, nitrite-oxidizing bacterium, Nitrospira moscoviensis sp. nov. and its phylogenetic relationship.

A gram-negative, non-motile, non-marine, nitrite-oxidizing bacterium was isolated from an enrichment culture initiated with a sample from a partially corroded area of an iron pipe of a heating system in Moscow, Russia. The cells were 0.9-2.2 microns x 0.2-0.4 microns in size. They were helical- to vibroid-shaped and often formed spirals with up to three turns 0.8-1.0 micron in width. The organism possessed an enlarged periplasmic space and lacked intracytoplasmic membranes and carboxysomes. The cells tended to excrete extracellular polymers, forming aggregates. The bacterium grew optimally at 39 degrees C and pH 7.6-8.0 in a mineral medium with nitrite as sole energy source and carbon dioxide as sole carbon source. The optimal nitrite concentration was 0.35 mM. Nitrite was oxidized to nitrate stoichiometrically. The doubling time was 12 h in a mineral medium with 7.5 mM nitrite. The cell yield was low; only 0.9 mg protein/l was formed during oxidation of 7.5 mM nitrite. Under anoxic conditions, hydrogen was used as electron donor with nitrate as electron acceptor. Organic matter (yeast extract, meat extract, peptone) supported neither mixotrophic nor heterotrophic growth. At concentrations as low as 0.75 g organic matter/l or higher, growth of nitrite-oxidizing cells was inhibited. The cells contained cytochromes of the b- and c-type. The G+C content of DNA was 56.9 +/- 0.4 mol%. The chemolithoautotrophic nitrite-oxidizer differed from the terrestrial members of the genus Nitrobacter with regard to morphology and substrate range and equaled Nitrospira marina in both characteristics. The isolated bacterium is designated as a new species of the genus Nitrospira.(ABSTRACT TRUNCATED AT 250 WORDS)

Barnett continent intestinal reservoir. Multicenter experience with an alternative to the Brooke ileostomy.

PURPOSE: Since 1988, surgeons at five hospitals have been performing the Barnett continent intestinal reservoir (BCIR). The BCIR includes modifications to the original Kock pouch, designed to reduce the incidence of valve slippage and fistula formation. Principle modifications include an intestinal collar, an isoperistaltic valve, and a lateral pouch design. METHOD: This unique collaborative study includes 510 ulcerative colitis or familial polyposis patients, with a follow-up time from one to five years postoperatively. RESULTS: Ninety-two percent still have functioning reservoirs. Six and one-half percent have had their pouches removed and replaced with conventional Brooke ileostomies. Reoperation rate for major pouch-related complications (other than pouch removal) was 12.8 percent. These complications included slipped valve (6.3 percent), valve fistulas (4.5 percent), and pouch fistulas (6.3 percent). Several questions were administered to patients whose responses revealed a significant improvement in general quality of life, state of mind, and overall health. CONCLUSIONS: The BCIR represents a successful alternative to patients with a conventional Brooke ileostomy or those who are not candidates for the ileal pouch-anal anastomosis.

A neural network model for the prediction of membrane-spanning amino acid sequences.

The architecture and weights of an artificial neural network model that predicts putative transmembrane sequences have been developed and optimized by the algorithm of structure evolution. The resulting filter is able to classify membrane/nonmembrane transition regions in sequences of integral human membrane proteins with high accuracy. Similar results have been obtained for both training and test set data, indicating that the network has focused on general features of transmembrane sequences rather than specializing on the training data. Seven physicochemical amino acid properties have been used for sequence encoding. The predictions are compared to hydrophobicity plots.