Frailty: an in-depth qualitative study exploring the views of community care staff.

BACKGROUND: Frailty is seen across various health and social care settings. However, little is known about how healthcare professionals, particularly those who provide care for older adults living in the community view frailty. There is also a dearth of information about the extent to which a shared understanding of frailty exists across the various disciplines of care. Such an understanding is crucial across care professionals as it ensures consistent assessment of frailty and facilitates interdisciplinary working/collaboration which is a key component in the management of frailty. This study aimed to explore: (i) how community care staff from various specialties viewed frailty; (ii) whether they had a shared understanding; and (iii) how they assessed frailty in everyday practice. METHODS: Semi-structured interviews were conducted with a purposive sample of 22 community care staff from seven specialties, namely: healthcare assistants, therapy assistants, psychiatric nurses, general nurses, occupational therapists, physiotherapists and social workers, recruited from four neighbourhood teams across Cambridgeshire, England. Interviews were analysed thematically. RESULTS: There was a shared narrative among participants that frailty is an umbrella term that encompasses interacting physical, mental health and psychological, social, environmental, and economic factors. However, various specialities emphasised the role of specific facets of the frailty umbrella. The assessment and management of frailty was said to require a holistic approach facilitated by interdisciplinary working. Participants voiced a need for interdisciplinary training on frailty, and frailty tools that facilitate peer-learning, a shared understanding of frailty, and consistent assessment of frailty within and across specialities. CONCLUSIONS: These findings underscore the need to: (i) move beyond biomedical descriptions of frailty; (ii) further explore the interacting nature of the various components of the frailty umbrella, particularly the role of modifiable factors such as psychological and socioeconomic resilience; (iii) care for frail older adults using holistic, interdisciplinary approaches; and (iv) promote interdisciplinary training around frailty and frailty tools to facilitate a shared understanding and consistent assessment of frailty within and across specialities.

A Randomised Clinical Feasibility Trial of a Breast Immobilisation Device: The SuPPORT 4 All Bra.

AIMS: Despite the breast being a mobile organ, there is currently no standard suitable immobilisation device to optimise radiotherapy for women with larger breasts treated after a wide local excision. The SuPPORT 4 All (S4A) bra was co-designed with patients and radiotherapy professionals. The purpose of this study was to test the feasibility of using the S4A bra in the existing breast cancer radiotherapy pathway. MATERIALS AND METHODS: A randomised feasibility trial was conducted in a single institution; the primary feasibility endpoint was the recruitment of 50 participants. Efficacy endpoints were also tested, including assessment of skin reactions, dose to organs at risk and patient comfort. Fifty women were randomised to receive either standard radiotherapy with no immobilisation (control) or radiotherapy with the S4A bra (intervention). A separate planning study was undertaken on the cases randomised to receive the S4A bra. Participants in the intervention arm (S4A bra) underwent two planning computed tomography scans, one with the bra on and one without the bra; allowing direct comparison of organs at risk data for S4A bra versus no bra. RESULTS: All women who started radiotherapy wearing the S4A bra completed treatment with the bra; patient comfort did not change across the 3 weeks of treatment. Positional accuracy using the bra was comparable with existing published accuracy for methods without immobilisation. The mean ipsilateral lung doses showed some improvement when positioning with the S4A bra was compared with the no bra set-up (3.72 Gy versus 4.85 Gy for right-sided cases, 3.23 Gy versus 3.62 Gy for left-sided cases). CONCLUSIONS: The S4A bra is feasible to use in the radiotherapy pathway with good patient adherence. The S4A bra has potential to reduce dose to organs at risk (specifically ipsilateral lung dose) while maintaining good breast tissue coverage, and improved patient dignity, warranting further investigation on a larger scale.

The value of biomedical research training for veterinary anatomic and clinical pathologists.

Veterinary pathologists traditionally have been actively engaged in research as principal investigators and as collaborators. Pathologists frequently obtain advanced training in research; however, it appears that in the last 10 years there has been a reversal of a previous trend toward increasing numbers of pathologists obtaining PhD degrees. This has arisen despite an established shortage of veterinarians engaged in research. This article evaluates the benefits of research training for individual pathologists, including a wide spectrum of professional opportunities and additional skill development beyond that usually provided by diagnostic pathology training alone. Various training models are discussed, including combined and sequential diagnostic residency and research degree training as well as the nondegree research fellowship programs more commonly pursued in human medicine. Best-practice recommendations for program infrastructure, mentorship, time management, and a team approach to research and research training are advocated to facilitate the development of successful programs and to encourage a continued emphasis on integrated training for pathologists as both clinical diagnosticians and experimentalists. This article is intended to help prospective and active pathology trainees, their mentors, and educational administrators optimize opportunities to ensure the future vitality of veterinary pathologists, and their contributions, in basic and applied research.

Dental hyponatraemia.

A 14-year-old girl developed dental pain and was treated for acute infected pulpitis of her right upper lateral incisor with drilling and filling. The pain continued and was helped by analgesia, sucking ice cubes and drinking cold water. Forty-eight hours later, she became confused and disoriented. She started to vomit and complained of headache. Investigations revealed hyponatraemia with normal serum potassium levels and initially normal urinary sodium excretion. Over the next 24 hours, she passed 5.45 L of urine and her serum sodium rose from 125 to 143 mmol/L. Self-induced water intoxication has been described during drinking games and initiation ceremonies, but this would appear to an unusual cause. Conservative management proved successful in allowing this girl to recover without sequelae.

Human T lymphocyte virus 1 from a leukemogenic cell line mediates in vivo and in vitro lymphocyte apoptosis.

HTLV-1 is implicated in the development of diverse diseases. However, most HTLV-1-infected individuals remain asymptomatic. How HTLV-1 infection leads to disparate consequences remains a mystery, despite extensive investigation of HTLV-1 isolates from infected individuals. As in human infection, experimental HTLV-1 infection in rabbits is generally benign, although HTLV-1-infected rabbit T cell lines that mediate lethal leukemia-like disease have been reported. We report here that thymuses from mature outbred rabbits inoculated with a lethal leukemia-like disease have been reported. We report here that thymuses from mature outbred rabbits inoculated with a lethal HTLV-1 T cell line (RH/K34) showed morphological and biochemical evidence of apoptosis, whereas thymuses from rabbits inoculated with nonlethal HTLV-1 T cell lines showed no signs of apoptosis. Exposure of rabbit or human lymphocytes to purified virus from RH/K34 caused rapid induction of apoptosis, providing an in vitro correlate to the pathogenic effects. By contrast, virus isolated from a nonlethal cell line mediated dose-dependent lymphocyte proliferation. These data implicate lymphocyte apoptosis as a potential mechanism by which the lethal HTLV-1 cell line causes fulminant disease and provide a means to identify factors contributing to HTLV-1 disease. Results from this HTLV-1 infection model can provide insight into variations in HTLV-1 pathogenicity in human infection.

Selection of rabbit CD4- CD8- T cell receptor-gamma/delta cells by in vitro transformation with human T lymphotropic virus-I.

In vitro transformation of rabbit peripheral blood mononuclear cells (PBMC) with human T lymphotropic virus-I (HTLV)-infected human or rabbit cells resulted in CD4- CD8- cell lines, some of which caused acute leukemia when injected into rabbits. Structural analyses of the proviruses from cell lines with diverse pathogenic effects provided no clear correlation with lethality. The rabbit lines were provisionally designated T cells because they express interleukin 2R (IL-2R) and CD5 and lack surface immunoglobulin, but none express functional T cell receptor (TCR) alpha or beta transcripts. A more detailed characterization of the HTLV-I-infected cells was required to determine cell lineage and its potential influence on pathogenic consequences. Probes for rabbit TCR gamma and delta genes were derived and used to detect gamma and delta TCR RNA transcripts, identifying the in vitro transformed lines as gamma/delta T cells. CD4+ and CD8+ lines were derived from PBMC of HTLV-I-infected rabbits and CD4+ TCR-alpha/beta HTLV-I lines were derived from rabbit thymus, eliminating the possibility that the HTLV-I isolates used here transform only CD4- CD8- TCR-gamma/delta cells. The percentage of gamma/delta cells in rabbit PBMC is relatively high (23% in adult rabbits); this with diminution of CD4+ and CD8+ cells in IL-2-supplemented PBMC or thymocyte cultures may account for selection of rabbit HTLV-I-infected gamma/delta T cell lines in vitro. The availability of well-characterized T cell lines with diverse in vivo effects in the rabbit HTLV-I disease model allows evaluation of roles played by cell type in HTLV-I-mediated disease.

The effect of diet on the expression of lipase genes in the midgut of the lightbrown apple moth (Epiphyas postvittana Walker; Tortricidae).

We have identified lipase-like genes from an Epiphyas postvittana larval midgut EST library. Of the 10 pancreatic lipase family genes, six appear to encode active lipases and four encode inactive lipases, based on the presence/absence of essential catalytic residues. The four gastric lipase family genes appear to encode active proteins. Phylogenetic analysis of 54 lepidopteran pancreatic lipase proteins resolved the clade into five groups of midgut origin and a sixth of non-midgut lipases. The inactive proteins formed two separate groups with highly conserved mutations. The lepidopteran midgut lipases formed a ninth subfamily of pancreatic lipases. Eighteen insect and human gastric lipases were analysed phylogenetically with only very weak support for any groupings. Gene expression was measured in the larval midgut following feeding on five artificial diets and on apple leaves. The artificial diets contained different levels of triacylglycerol, linoleic acid and cholesterol. Significant changes in gene expression (more than 100-fold for active pancreatic lipases) were observed. All the inactive lipases were also highly expressed. The gastric lipase genes were expressed at lower levels and suppressed in larvae feeding on leaves. Together, protein motif analysis and the gene expression data suggest that, in phytophagous lepidopteran larvae, the pancreatic lipases may function in vivo as galactolipases and phospholipases whereas the gastric lipases may function as triacylglycerol hydrolases.

Serratia entomophila inoculation causes a defect in exocytosis in Costelytra zealandica larvae.

Rapid elimination of midgut luminal proteinase activity and gut clearance are the two major symptoms of amber disease in Costelytra zealandica larvae because of the three-subunit protein toxin complex produced in Serratia entomophila and Serratia proteamaculans. Quantitative PCR analysis of mRNA from the major serine proteinase gene families showed that loss of proteinase activity did not result from transcriptional downregulation. Unexpectedly, protein levels and rates of protein synthesis increased, rather than decreased, in the midgut of diseased insects. Proteomic analysis of midgut tissues showed marked differences between healthy and diseased midguts. Large increases in soluble forms of both actin and tubulin were identified from 2D-gels, together with concurrent decreases in the levels of polymeric actin-associated proteins: actin depolymerizing factor and cyclophilin. These results suggest that the Serratia toxin acts to cause degradation of the cytoskeletal network and prevent secretion of midgut gut digestive proteinases as both the actin cytoskeleton and microtubules are involved in exocytosis. Proteinases synthesized in the diseased midgut must be rapidly degraded because they do not accumulate in an inactive form.

Androgen deprivation leads to increased carbohydrate metabolism and hexokinase 2-mediated survival in Pten/Tp53-deficient prostate cancer.

Prostate cancer is characterized by a dependence upon androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) is the accepted treatment for progressive prostate cancer. Although ADT is usually initially effective, acquired resistance termed castrate-resistant prostate cancer (CRPC) develops. PTEN and TP53 are two of the most commonly deleted or mutated genes in prostate cancer, the compound loss of which is enriched in CRPC. To interrogate the metabolic alterations associated with survival following ADT, we used an orthotopic model of Pten/Tp53 null prostate cancer. Metabolite profiles and associated regulators were compared in tumors from androgen-intact mice and in tumors surviving castration. AR inhibition led to changes in the levels of glycolysis and tricarboxylic acid (TCA) cycle pathway intermediates. As anticipated for inhibitory reciprocal feedback between AR and PI3K/AKT signaling pathways, pAKT levels were increased in androgen-deprived tumors. Elevated mitochondrial hexokinase 2 (HK2) levels and enzyme activities also were observed in androgen-deprived tumors, consistent with pAKT-dependent HK2 protein induction and mitochondrial association. Competitive inhibition of HK2-mitochondrial binding in prostate cancer cells led to decreased viability. These data argue for AKT-associated HK2-mediated metabolic reprogramming and mitochondrial association in PI3K-driven prostate cancer as one survival mechanism downstream of AR inhibition.

Passage of human T-cell leukemia virus type-1 during progression to cutaneous T-cell lymphoma results in myelopathic disease in an HTLV-1 infection model.

Studies comparing functional differences in human T-cell leukemia virus type 1 (HTLV-1) clones that mediate distinct outcomes in experimentally infected rabbits, resulted in a dermatopathic smoldering adult T-cell leukemia/lymphoma following chronic infection with HTLV-1 strain RH/K34. During the 3.5 years' follow-up, HTLV-1 skin disease progressed to cutaneous T-cell lymphoma. When infection was passed to several naive rabbits, progressive paraparesis due to myelopathic neurodegeneration, analogous to HTLV-associated myelopathy, resulted in one of 4 transfusion recipients. Similar proviral loads were detected in the two diseases, regardless of stage of progression or tissue compartment of infection. Complete proviral sequences obtained from the donor and affected recipient aligned identically with each other and with the inoculated virus clone. Existence of disparate pathogenic outcomes following infectious transmission further extends the analogy of using rabbits to model human infection and disease. Although the experimental outcomes shown are limited by numbers of animals affected, they mimic the infrequency of HTLV-1 disease and authenticate epidemiological evidence of virus sequence stability regardless of disease phenotype. The findings suggest that further investigation of a possible role for HTLV-1 in some forms of cutaneous T-cell lymphoma is warranted.

Source and route of exposure influence infectivity of a molecular clone of human T cell leukemia virus type I.

Infection with human T cell leukemia virus type I (HTLV-I) is typically asymptomatic, but does result in diverse diseases ranging from adult T cell leukemia to spastic neuromyelopathy. To date, differences in HTLV-I provirus structure have not been correlated with pathogenic or asymptomatic outcome of infection. Molecular clones of HTLV-I are now available and represent a powerful tool to link virus structure to pathogenesis. Present studies to explore in vivo infectivity and pathogenicity of an HTLV-I molecular clone, K30p, have utilized the rabbit as a model system. This clone was administered to neonatal or adult rabbits by several different routes and infectivity and pathogenicity were examined. Detection of antiviral humoral immune responses, presence of provirus in tissue samples, and isolation of virus in cultures of blood lymphocytes were used to establish systemic HTLV-I infection. Intramuscular, but not nervous system, exposure to K30p HTLV-I naked DNA resulted in infection. Conversely, neural exposure to T cells that had been transfected with the K30p HTLV-I DNA consistently resulted in systemic infection. Despite detection of HTLV-I provirus in brain and spinal cord of some infected rabbits, no clinical or neuropathological changes occurred. Source and route of virus exposure played a role in infectivity, but did not influence the pathogenic outcome of HTLV-I infection.

Rabbits transfused with human immunodeficiency virus type 1-infected blood develop immune deficiency with CD4+ lymphocytopenia in the absence of clear evidence for HIV type 1 infection.

Rabbits can be infected with human immunodeficiency virus (HIV-1), but no disease signs similar to acquired immunodeficiency syndrome (AIDS) have been reported to date. In our attempt to develop types of HIV-1 more virulent for rabbits, an immunodeficiency characterized by CD4+ lymphocytopenia and opportunistic infection was induced by transfusion from HIV-1-infected rabbits. The original donor was infected for 27 months; initial passage resulted in infection of two rabbits. Transfusions from these two infected rabbits. Transfusions from these two infected rabbits caused immunodeficiency in 12 recipients. One rabbit died at 3 months and a second at 8 months postransfusion with lymphocyte depletion in lymphoid organs; one of these and another of the CD4+ lymphocytopenic rabbits had opportunistic infections. Lentivirus-like particles were detected in thymus and spleen from an affected rabbit. Despite appearance of AIDS-like disease signs, antibodies to HIV-1 probes were detected in rabbits receiving passaged blood. However, RNA transcripts hybridizing with HIV-1 probes were detected in organs of some rabbits, implicating the initial HIV infection in the disease. Transfusion from uninfected donors produced no signs of immunodeficiency, which suggests the involvement of an HIV-related agent. The present data do not allow definitive characterization of the agent(s) involved in the immunodeficiency. Possibilities include activation of a rabbit retrovirus or, alternatively, development of a mutated HIV-1 strain.

Evidence for humoral and cellular reactivity against keratin and thyroglobulin in HTLV-I infected rabbits.

Human T cell leukemia virus type I (HTLV-I) infection was initially associated with T cell leukemia and a progressive neurologic disease but has since been linked to an increasing number of autoimmune disorders, including Sjogren's syndrome, uveitis, and polyarthritis. A survey of serum samples from a rabbit model of HTLV-I infection revealed that all had antibodies against keratin and thyroglobulin. Sera from several infected rabbits also reacted with collagen, while antibody reactions with other autoantigens tested, including DNA, were rare and sporadic. In addition to antibodies, cellular reactivity to keratin, but not thyroglobulin, was demonstrated by cellular proliferation in presence of IL-2 and keratin. Expanded cell cultures were positive for T cell activation markers and CD8. Association of the auto-reactivity with HTLV-I infection rather than random anti-cellular responses was supported by the fact that no antikeratin or antithyroglobulin was seen in uninfected controls, including that inoculated with uninfected lymphocytes. Finding autoantibodies in rabbits infected using naked HTLV-I DNA clones provided further assurance that infection induced the autoimmune reactions detected.

Binding of Bacillus thuringiensis delta-endotoxins Cry1Ac and Cry1Ba to a 120-kDa aminopeptidase-N of Epiphyas postvittana purified from both brush border membrane vesicles and baculovirus-infected Sf9 cells.

A 120-kDa protein was purified from brush border membrane vesicles of the tortricid moth Epiphyas postvittana (Walker) based both on its activity as an aminopeptidase and the ability to bind the Bacillus thuringiensis delta-endotoxin Cry1Ac. The purified enzyme had a pI of 5.6 and was a leucine aminopeptidase, with some isoleucine, phenylalanine and tryptophan aminopeptidase activity. Further characterisation showed that the protein was also able to bind Cry1Ba. During purification, the molecular weight of the protein decreased from 120 to 115 kDa due to the loss of a glycophosphatidinyl anchor. The protein was N-terminally sequenced and, using this information and conserved regions within other insect aminopeptidase-N (APN) sequences, redundant primers were designed to amplify the aminopeptidase coding sequence from E. postvittana midgut cDNA. The predicted protein sequence from the full-length cDNA was most closely related to the APN protein sequence from Heliothis virescens (61% identity) and shared other features of insect APNs including a Zn(2+) binding site motif and four conserved cysteines. The E. postvittana was expressed in Sf9 cells using baculovirus, yielding a protein of molecular weight 130 kDa, but with unchanged N-terminal sequence. Purified recombinant protein bound both Cry1Ac and Cry1Ba by ligand blot assays. However, despite the protein being expressed on the external surface of the Sf9 cells, it bound neither Cry1Ac nor Cry1Ba in vivo.

Thoracoscopy as a nonpharmacotherapeutic research modification for limiting postoperative chest pain.

Diminished tissue injury and shortened clinical recovery are benefits of using an endoscopic approach for patients needing operative procedure. In the course of developing an experimental model requiring procurement of topographically precise lung biopsy specimens, we sought to apply thoracoscopy as a research alternative to thoracotomy. In addition, we investigated the influence of thoracoscopy on postprocedure recovery practices using rabbits divided into four treatment groups. Rabbit groups 1 and 2 underwent thoracoscopy and lung biopsy while maintained by one-lung anesthesia. Additionally, group 2 had ketoprofen and bupivacaine HCl analgesics injected for treatment during postprocedure recovery. These two groups were compared to control rabbits in groups 3 and 4, which underwent inhalant anesthesia without thoracoscopy. Control group 3 also received the injection analgesic combination. During recovery, rabbit behavior was systematically assessed for evidence of pain. No behavior considered indicative of pain needing intervention was observed regardless of treatment group. Limited changes in plasma corticosterone, catecholamines, and prostaglandin E2 levels measured during recovery were difficult to associate with any treatment. Unexpectedly, significantly different mean corticosterone and catecholamines levels were detected in rabbits given the injection analgesic combination in the absence of thoracoscopic procedure, as compared to other treatment groups. The results highlight the importance of awareness that analgesic drug administration has the potential to alter homeostasis and affect interpretation of some study findings by its own guise. Correlation of the mean pain study results with plasma biochemical data supports preferential use of thoracoscopy as a refinement for limiting postprocedural pain in research models.

Immunocytochemical detection of Ehrlichia platys antigens in canine blood platelets.

An avidin-biotin immunoperoxidase complex (ABC) immunocytochemical (ICC) stain procedure was optimized for detection of Ehrlichia platys antigens. Positive immunoreactivity was detected with dilutions of canine immune serum on acetone-fixed smears of platelet-rich plasma from E. platys-infected dogs. No E. platys antigens were detected when this ICC stain was applied to frozen or paraffin-embedded formalin- or acetone-fixed tissue sections from dogs with acute E. platys infection. Acetone fixation and freezing preserved ICC staining of ehrlichial antigens in infected blood platelets, whereas formalin treatment of similarly preserved E. platys-infected platelets nullified positive immunoreactivity. Significant E. platys infection of cells and tissues other than platelets may not occur.

Micronema deletrix-induced granulomatous osteoarthritis in a lame horse.

Necropsy of a chronically lame 16-year-old thoroughbred gelding revealed granulomatous osteomyelitis and polyarthritis due to a widely disseminated infection by Micronema deletrix. Diagnosis was based upon the nematode's morphology with its characteristic rhabditiform oesophagus. Granulomata, often containing one or more centrally located M. deletrix, were observed histologically in sections prepared from femur, kidney, stomach, lung, adrenal gland and sublumbar lymph nodes. Neither verminous meningo-encephalitis nor cephalic granulomata, which are the more commonly described lesions, was found.

Screening small for gestational age babies for congenital infection.

The widespread practice in newborn nurseries of screening asymptomatic small for gestational age (SGA) babies for TORCH infection has been evaluated. In a retrospective review, we found that, in 1979, in our nursery 23 (35%) of the sixty-six SGA babies were investigated for TORCH infection. No asymptomatic baby was investigated adequately to exclude infection. The two proven cases of congenital infection were both apparent on other clinical grounds, and neither would have been detected by our routine serologic screening. A review of published information on asymptomatic TORCH infections showed that, in the absence of other clinical signs of infection, intrauterine growth retardation is an unusual manifestation. Clinical investigation of TORCH infection should be confined to those babies with other clinical evidence of infection.