Can comprehensive specialised end-of-life care be provided at home? Lessons from a study of an innovative consultant-led community service in the UK.

The Midhurst Macmillan Specialist Palliative Care Service (MMSPCS) is a UK, medical consultant-led, multidisciplinary team aiming to provide round-the-clock advice and care, including specialist interventions, in the home, community hospitals and care homes. Of 389 referrals in 2010/11, about 85% were for cancer, from a population of about 155 000. Using a mixed method approach, the evaluation comprised: a retrospective analysis of secondary-care use in the last year of life; financial evaluation of the MMSPCS using an Activity Based Costing approach; qualitative interviews with patients, carers, health and social care staff and MMSPCS staff and volunteers; a postal survey of General Practices; and a postal survey of bereaved caregivers using the MMSPCS. The mean cost is about 3000 GBP (3461 EUR) per patient with mean cost of interventions for cancer patients in the last year of life 1900 GBP (2192 EUR). Post-referral, overall costs to the system are similar for MMSPCS and hospice-led models; however, earlier referral avoided around 20% of total costs in the last year of life. Patients and carers reported positive experiences of support, linked to the flexible way the service worked. Seventy-one per cent of patients died at home. This model may have application elsewhere.

Assessment of a preclinical model for studying the survival and engraftment of human stem cell derived osteogenic cell populations following orthotopic implantation.

INTRODUCTION: Preclinical studies with osteoprogenitor cells derived from human embryonic stem cells (hESC) do not lead to substantial bone regeneration in vivo. The degree of survival following implantation might play a role in their long term efficiency. We investigated the initial engraftment of hESCs-derived cells during two weeks post-implantation and compared it to such response for adult bone marrow stromal cells (hBMSC)-derived osteoprogenitor cells. METHODS: hBMSC and H9-hES cells pre-treated with osteogenic factors were implanted into a calvarial defect in both adult WT and nude rats. At days 7 and 14 post-implantation, samples were analysed for persistence of implanted cells, initiation of regeneration of host bone, angiogenesis and apoptosis. RESULTS: At day 7, hESC and hBMSC were detected within defects in both rat strains. By day 14 human cells were only detected in immune-deficient rats whilst still maintaining an osteoblastic phenotype and engendered a significant increase in bone formation. In WT animals, the participation of implanted cells was very limited due to their poor survival. CONCLUSION: This study demonstrates the ability of hESC and hBMSC derived osteoprogenitor cells to survive transplantation, to engraft and to develop an osteogenic phenotype during the early stage following implantation, validating the appropriate preclinical model.

Historic emergence, impact and current status of shrimp pathogens in the Americas.

Shrimp farming in the Americas began to develop in the late 1970s into a significant industry. In its first decade of development, the technology used was simple and postlarvae (PLs) produced from wild adults and wild caught PLs were used for stocking farms. Prior to 1990, there were no World Animal Health Organization (OIE) listed diseases, but that changed rapidly commensurate with the phenomenal growth of the global shrimp farming industry. There was relatively little international trade of live or frozen commodity shrimp between Asia and the Americas in those early years, and with a few exceptions, most of the diseases known before 1980 were due to disease agents that were opportunistic or part of the shrimps' local environment. Tetrahedral baculovirosis, caused by Baculovirus penaei (BP), and necrotizing hepatopancreatitis (NHP) and its bacterial agent Hepatobacterium penaei, were among the "American" diseases that eventually became OIE listed and have not become established outside of the Americas. As the industry grew after 1980, a number of new diseases that soon became OIE listed, emerged in the Americas or were introduced from Asia. Spherical baculovirus, caused by MBV, although discovered in the Americas in imported live Penaeus monodon, was subsequently found to be common in wild and farmed Asian, Australian and African penaeids. Infectious hypodermal and hematopoietic necrosis virus (IHHNV) was introduced from the Philippines in the mid 1970s with live P. monodon and was eventually found throughout the Americas and subsequently in much of the shrimp farming industry in the eastern hemisphere. Taura syndrome emerged in Penaeus vannamei farms in 1991-1992 in Ecuador and was transferred to SE Asia with live shrimp by 1999 where it also caused severe losses. White Spot Disease (WSD) caused by White spot syndrome virus (WSSV) emerged in East Asia in ∼1992, and spread throughout most of the Asian shrimp farming industry by 1994. By 1995, WSSV reached the eastern USA via frozen commodity products and it reached the main shrimp farming countries of the Americas located on the Pacific side of the continents by the same mechanism in 1999. As is the case in Asia, WSD is the dominant disease problem of farmed shrimp in the Americas. The most recent disease to emerge in the Americas was infectious myonecrosis caused by IMN virus. As had happened before, within 3years of its discovery, the disease had been transferred to SE Asia with live P. vannamei, and because of its impact on the industry and potential for further spread in was listed by the OIE in 2005. Despite the huge negative impact of disease on the shrimp farming industry in the Americas, the industry has continued to grow and mature into a more sustainable industry. In marked contrast to 15-20years ago when PLs produced from wild adults and wild PLs were used to stock farms in the Americas, the industry now relies on domesticated lines of broodstock that have undergone selection for desirable characteristics including disease resistance.

Robotic surgery for endometrial cancer: comparison of perioperative outcomes and recurrence with laparoscopy, vaginal/laparoscopy and laparotomy.

INTRODUCTION: Comparison of perioperative outcomes and recurrence in patients undergoing primary surgical treatment for endometrial cancer by robotics, laparoscopy, vaginal/laparoscopy, or laparotomy approaches. METHODS: Prospective analysis of 67 patients undergoing robotic surgery for endometrial cancer between March 2004 and December 2007. Comparison was made with similar patients operated between November 1999 and December 2006 by laparoscopy (37 cases), laparotomy (99 cases) and vaginal/laparoscopy approach (vaginal hysterectomy, bilateral adnexectomy/laparoscopic lymphadenectomy) (47 cases) and matched by age, body mass index (BMI), histological type and International Federation of Gynecologists and Obstetricians (FIGO) staging. RESULTS: Mean operating times for patients undergoing robotic, laparoscopy, vaginal/laparoscopy or laparotomy approach were 181.9, 189.5, 202.7 and 162.7 min, respectively (p = 0.006); mean blood loss was 141.4, 300.8, 300.0 and 472.6 ml, respectively (p <0.001); mean number of nodes was 24.7, 27.1, 28.6, and 30.9, respectively (p = 0.008); mean length of hospital stay was 1.9, 3.4, 3.5 and 5.6 days, respectively (p < 0.001). There were no significant differences in intra- or postoperative complications among the four groups. The conversion rate was 2.9% for robotics and 10.8% for the laparoscopy group (0.001). There were no differences relative to recurrence rates among the four groups: 9%, 14%, 11% and 15% for robotics, laparoscopy, vaginal/laparoscopy, and laparotomy, respectively. CONCLUSION: Robotics, laparoscopy and vaginal/laparoscopy techniques are preferable to laparotomy for suitable patients with endometrial cancer. Robotics is preferable to laparoscopy due to a shorter hospital stay and lower conversion rate and preferable to vaginal/laparoscopy due to a reduced hospitalization.

Blunting of adaptive responses to resistance exercise training in women over 75y.

BACKGROUND: It is unclear how aging affects adaptive responses to resistance exercise training (RET), especially in women. We hypothesized that (i) increases in muscle mass and function after RET would be blunted in older women, and (ii) reduced 'pro-anabolic' changes in gene expression after a single bout of RE may underlie the blunting. METHODS: Muscle biopsies were obtained from 9 older (76-82y) and 16 younger (19-30y) women at rest and 2.5h after RE (6×20 quadriceps maximal voluntary contractions (MVCs)) for measurement of select anabolic (e.g. IGFs, MyoD) and catabolic (e.g. MAFBx, MuRF-1) transcripts by RT-PCR. Thereafter participants undertook a supervised program of RET (4×15 MVCs 3× wk/12wk). We measured knee extensor muscle volume, fatty infiltration, and mechanical muscle quality before and after RET. RESULTS: Before RET, older women were ~30% weaker (MVC 208 vs. 297N) and had ~40% less quadriceps muscle (0.97 vs. 1.54L) with greater fatty infiltration (14% vs. 10%). The most notable difference in mRNA expression after RE was for regulated in development and DNA damage response 1 (REDD1) (an endogenous suppressor of mammalian target of rapamycin (mTOR) signaling), which was depressed (-80%), but only in young women. Moreover, adaptive responses to RET were blunted in older women with respect to increases in muscle volume (+2.5% (old) vs. +6.2% (young)) and strength (+16% (old) vs. +27% (young)). CONCLUSIONS: Adaptations to RET are markedly blunted in older women, perhaps in-part due to the inability to downregulate REDD1 and thus upregulate mTOR signaling after RE.

Percutaneous real-time ultrasound-guided renal biopsy performed solely by nephrologists: A case series.

Renal biopsy is an integral part of the nephrologists' diagnostic armamentarium. Usually it is performed by radiologists or nephrologists with radiologist's assistance. Our aim was to assess the efficacy and safety of percutaneous ultrasound-guided renal biopsy performed solely by nephrologists. We performed real-time ultrasound-guided renal biopsy on 37 patients (N group). The results were then compared with those of a similar number of biopsies done with radiologist's support (NR group) immediately prior to these. In the N group, 36 biopsies (97.3%) were successful and were histopathologically adequate, whereas in the NR group, all biopsies were successful but only 28 were adequate (75.68%). Eighteen patients required only a single attempt in the N group, whereas majority (34 patients) in the NR group required two or more attempts. The average attempt per bit of renal tissue was 1.22 in both the groups. The average number of passes per patient was 1.77 in the N group and 2.32 in the NR group. The mean size of renal tissue obtained was 1.41 ± 0.47 cm in the N group and 1.19 ± 0.42 cm in the NR group. The average number of glomeruli was 15.62 ± 5.26 and 13.7 ± 7.38 in the N and NR groups, respectively (P<0.05). In the N group, there were no complications except two cases of post procedural hematuria that was managed conservatively. There was no need for blood transfusion and both of them were discharged after 48 hours. No patient had peri-renal collection or hematoma on repeat ultrasonography of the abdomen at 24 hours. However, in the NR group, five patients developed complications and one patient required laparotomy. Our study shows that percutaneous ultrasound-guided renal biopsy can be safely and successfully performed entirely by nephrologists without outside assistance. In our series, nephrologists who performed solely took fewer attempts, had better yield and fewer complications when compared to biopsies performed with radiologist's assistance. More and more nephrologists should take up this simple yet vital procedure.

Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial.

We have studied a three-drug combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) on a 28-day cycle in the treatment of newly diagnosed multiple myeloma (MM) patients to assess response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with MM received bortezomib 1.3 mg/m(2) intravenously on days 1, 4, 8 and 11, cyclophosphamide 300 mg/m(2) orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1-4, 9-12 and 17-20 on a 28-day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (>or= partial response) was 88%, with 61% of very good partial response or better (>or=VGPR) and 39% of complete/near complete response (CR/nCR). For the 28 patients who completed all four cycles of therapy, the CR/nCR rate was 46% and VGPR rate was 71%. All patients undergoing stem cell harvest had a successful collection. Twenty-three patients underwent stem cell transplantation (SCT) and are evaluable through day 100 with CR/nCR documented in 70% and >or=VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed MM with manageable toxicity.

Bone tissue formation from human embryonic stem cells in vivo.

Although the use of embryonic stem cells in the assisted repair of musculoskeletal tissues holds promise, a direct comparison of this cell source with adult marrow-derived stem cells has not been undertaken. Here we have compared the osteogenic differentiation potential of human embryonic stem cells (hESC) with human adult-derived stem cells in vivo. hESC lines H7, H9, the HEF-1 mesenchymal-like, telomerized H1 derivative, the human embryonic kidney epithelial cell line HEK293 (negative control), and adult human mesenchymal stem cells (hMSC) were either used untreated or treated with osteogenic factors for 4 days prior to injection into diffusion chambers and implantation into nude mice. After 11 weeks in vivo chambers were removed, frozen, and analyzed for evidence of bone, cartilage, and adipose tissue formation. All hESCs, when pretreated with osteogenic (OS) factors gave rise exclusively to bone in the chambers. In contrast, untreated hESCs (H9) formed both bone and cartilage in vivo. Untreated hMSCs did not give rise to bone, cartilage, or adipose tissue in vivo, while pretreatment with OS factors engendered both bone and adipose tissue. These data demonstrate that hESCs exposed to OS factors in vitro undergo directed differentiation toward the osteogenic lineage in vivo in a similar fashion to that produced by hMSCs. These findings support the potential future use of hESC-derived cells in regenerative medicine applications.

Comparison of Taura syndrome virus (TSV) detection methods during chronic-phase infection in Penaeus vannamei.

Methods to detect Taura syndrome virus (TSV) were assessed for their ability to detect the virus during chronic phase infection in the Pacific white shrimp Penaeus vannamei. In situ hybridization (ISH), immunohistochemistry (IHC) using monoclonal antibody 1A1, conventional RT-PCR and real-time quantitative (q)RT-PCR were compared using shrimp sampled over 60 wk following experimental TSV infection. Between Weeks 7 and 60, hematoxylin-eosin histology confirmed the presence of lymphoid organ spheroids (LOS) and an absence of lesions in the cuticular epithelium. ISH detected TSV in LOS over the duration of the study. IHC was generally less sensitive than ISH, and after Week 24, was often unable to confirm TSV infection. Detection of TSV by RT-PCR was highly dependent on sample source after Week 43, where viral RNA was detected in 12 of 14 hemolymph samples but only 5 of 16 pleopod samples. qRT-PCR detected TSV over the 60 wk in both hemolymph and pleopods, although RNA copy numbers in pleopods were consistently lower throughout the study. This study demonstrates that ISH and qRT-PCR are the most reliable methods for detecting TSV during late chronic phase infection. RT-PCR was also reliable if hemolymph was used as the sample source.

Mechanisms of action of the congenital diaphragmatic hernia-inducing teratogen nitrofen.

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that results in significant mortality and morbidity. The underlying etiology is poorly understood. Insights will arise from an understanding of the mechanisms by which the teratogen nitrofen induces CDH in rodent models. In this study, we use in vitro cell assays in conjunction with whole animal rodent studies to test hypotheses regarding nitrofen's mechanism of action. The first component examined the interaction of nitrofen with various aspects of the retinoid signaling pathway including uptake proteins, binding proteins, receptors, conversion, and degradation enzymes. The second component examined the interactions of nitrofen and vitamins A, C, and E to test the hypothesis that nitrofen was functioning as an antioxidant to interfere with retinoid signaling. Third, we performed a series of experiments examining the interaction of nitrofen and thyroid signaling. Collectively, the data suggest that the primary aspect of retinoid signaling affected by nitrofen is via inhibition of the rate-limiting enzymes controlling retinoic acid synthesis. Retinoid signaling perturbations do not appear to involve oxidative effects of nitrofen. Any substantial roles of nitrofen-induced perturbations of thyroid hormone signaling or receptor function are not supported.

Selective estrogen receptor modulator inhibits osteocyte apoptosis during abrupt estrogen withdrawal: implications for bone quality maintenance.

Estrogens exert positive effects on the quantity and quality of bone, including the maintenance of osteocytes through the inhibition of their apoptosis. Ideally, selective estrogen receptor modulators (SERMs) confer all of the positive bone-associated effects of estrogens without any adverse effects. In a similar way to estrogen, the raloxifene analog LY 117018 has been shown to prevent bone loss in ovariectomized (OVX) rats. In this study, we investigated whether the osteocyte-sparing effect of 17beta-estradiol can be mimicked by the SERM LY 117018 in a rat model of OVX. Twenty-four juvenile female rats were divided into four treatment groups: sham-operated (SHAM), OVX, OVX + 17beta-estradiol (OVX+E(2)), and OVX + LY 117018 (OVX+SERM). At 7 or 14 days following the start of treatment, the radius and ulna were removed. The percentage of apoptotic osteocytes, determined using an in situ nick-translation method, was increased (2.5-fold at 7 days and sixfold at 14 days) in the OVX group compared with SHAM in both the radius and ulna. Treatment of OVX animals with either 17beta-estradiol at a dose rate of 0.125 mg/kg/day or LY 117018 at a dose rate of 3 mg/kg/day prevented these increases in osteocyte apoptosis similarly. These observations demonstrate that LY 117018 exerts a powerful inhibitory effect upon osteocyte apoptosis directly after estrogen loss, in a similar way to the known effect of 17beta-estradiol replacement. These results point to the potential benefits of SERMs on both the quantity and quality of bone in E(2)-depleted rats.

The influence of mechanical stimulation on osteocyte apoptosis and bone viability in human trabecular bone.

It has been shown previously using in vivo and ex vivo animal models, that cyclical mechanical stimulation is capable of maintaining osteocyte viability through the control of apoptotic cell death. Here we have studied the effect of mechanical stimulation on osteocyte viability in human trabecular bone maintained in a 3-D bioreactor system. Bone samples, maintained in the bioreactor system for periods of 3, 7 and 27 days, were subjected to either cyclical mechanical stimulation which engendered a maximum of 3,000 microstrain in a waveform corresponding to physiological jumping exercise for 5 minutes daily or control unloading. Unloading resulted in a decrease in osteocyte viability within 3 days that was accompanied by increased levels of cellular apoptosis. Mechanical stimulation significantly reduced apoptosis (p< or =0.032) and improved the maintenance of osteocyte viability in bone from all patient samples. The percentage Alkaline Phosphatase (ALP) labelled bone surface was significantly increased (p< or =0.05) in response to mechanical stimulation in all samples as was the Bone Formation Rate (BFR/BS) (p=0.005) as determined by calcein label incorporation in the 27-day experiment. These data indicate that in this model system, mechanical stimulation is capable of maintaining osteocyte viability in human bone.

Comparative cohort study of the outcomes of deep lamellar keratoplasty and penetrating keratoplasty for keratoconus.

AIM: To compare the outcomes and complications of deep lamellar keratoplasty (DLK) and penetrating keratoplasty (PK) for keratoconus. METHODS: A cohort of 20 consecutive PKs, for keratoconus, was compared with 20 consecutive DLKs, for keratoconus. The PKs were performed between June 2000 and July 2001, the DLKs between October 2001 and October 2002. Surgery was performed by one surgeon. Best-corrected visual acuities (BCVA), refraction and complications were recorded at the time of surgery, 6 and 12 months postoperatively. chi(2)-tests were used to compare visual acuity outcomes and independent t-tests in the analysis of astigmatism. RESULTS: Groups were comparable for age, sex, and ethnicity. All PKs were uncomplicated. Two of the DLK group had microperforations of Descemet's membrane. There was no significant difference in the proportion of patients achieving 6/9 or better between the PK and DLK groups (85 vs 78%, P=0.54). PK patients were, however, more likely than the DLKs to achieve 6/6 at 1 year; 70% (14/20) of PKs compared to 22% of (4/18) DLKs (P=0.04). Astigmatism was significantly higher in the PKs compared to the DLKs (P=0.022). There were two cases of graft rejection in the PK group, while none in the DLKs. CONCLUSIONS: This study confirms good visual results from both PK and DLK in keratoconus with similarly high percentages reaching 6/9 BCVA. DLK appears to cause less astigmatism and also has the advantage of no endothelial graft rejection. The apparent cost, however, is a reduction in the likelihood of achieving 6/6 BCVA.

Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis.

Prolonged use of glucocorticoids is associated with decreased bone formation, increased resorption and osteonecrosis, through direct and indirect effects on the activity and viability of bone effector cells, osteoblasts and osteoclasts, and osteocytes. This study has investigated molecular pathways implicated in Dexamethasone-induced apoptosis of osteocytes, using a cell line and primary chicken cells. MLO-Y4 osteocytes were pre-treated with several bisphosphonates representing a range of anti-resorptive activities and conformation/structure relationships, and were subsequently challenged with Dexamethasone. Apoptotic cells were detected at various times after treatment using morphological and biochemical criteria. Dex was shown to induce apoptosis associated with the Fas/CD95 death receptor and in a caspase 8 dependent manner. The apoptotic response was inhibited by all variants of the BP molecules, including those with reduced anti-resorptive activity, indicating that Dex-induced apoptosis is independent of anti-osteoclastic activity. Dex-induced apoptosis was associated with a transient increase in phosphorylated ERK 1/2 and was blocked by the ERK inhibitor UO126. In addition, both UO126 and BPs decreased localization of Fas to the cell membrane. ERK activation by PMA did not induce death or Fas upregulation, suggesting that Fas may be important for the induction of apoptosis and the existence of an additional factor activated by Dex which enables the cooperation between the Dex-activated ERK and Fas pathways, during apoptosis of osteocytes. Furthermore, upregulation of death and Fas was not accompanied by upregulation of FasL, pointing to the possible existence of FasL-independent Fas-associated death in these cells.

Systematic review of the problems and issues of accessing specialist palliative care by patients, carers and health and social care professionals.

OBJECTIVES: To determine the problems and issues of accessing specialist palliative care by patients, informal carers and health and social care professionals involved in their care in primary and secondary care settings. DATA SOURCES: Eleven electronic databases (medical, health-related and social science) were searched from the beginning of 1997 to October 2003. Palliative Medicine (January 1997-October 2003) was also hand-searched. STUDY SELECTION: Systematic search for studies, reports and policy papers written in English. DATA EXTRACTION: Included papers were data-extracted and the quality of each included study was assessed using 10 questions on a 40-point scale. RESULTS: The search resulted in 9921 hits. Two hundred and seven papers were directly concerned with symptoms or issues of access, referral or barriers and obstacles to receiving palliative care. Only 40 (19%) papers met the inclusion criteria. Several barriers to access and referral to palliative care were identified including lack of knowledge and education amongst health and social care professionals, and a lack of standardized referral criteria. Some groups of people failed to receive timely referrals e.g., those from minority ethnic communities, older people and patients with nonmalignant conditions as well as people that are socially excluded e.g., homeless people. CONCLUSIONS: There is a need to improve education and knowledge about specialist palliative care and hospice care amongst health and social care professionals, patients and carers. Standardized referral criteria need to be developed. Further work is also needed to assess the needs of those not currently accessing palliative care services.

Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease.

AIMS: To evaluate the efficacy of 50% autologous serum drops against conventional treatment in ocular surface disorders refractory to normal treatments in a prospective randomised crossover trial. METHOD: Patients fulfilling ophthalmological and haematological entry criteria were randomised to either 3 months of autologous serum 50% followed by 3 months of their conventional treatment, or 3 months of conventional treatment, followed by 3 months of autologous serum. Clinical assessments, including Schirmer's test, rose Bengal, and fluorescein staining, were carried out on entry and at monthly intervals. Impression cytology was performed at entry, 3 and 6 months. Grading was carried out on degrees of squamous metaplasia and goblet cell density. Subjective comfort was recorded daily using the "faces" scale. These categorical scores were converted to linear measurement using Rasch analysis. Statistical analysis was carried out using Wilcoxon's signed rank test and ANOVA. RESULTS: 16 patients were recruited with 31 eyes studied. The ocular surface diseases chiefly included Sjögren's syndrome (n = 6) and keratoconjunctivitis sicca (n = 5). Impression cytology available in 25 of 31 eyes showed significant improvement on serum treatment, p<0.02. Rasch weighted faces scores were statistically significantly better with serum, p<0.01. CONCLUSION: The results of this randomised study provide further evidence of the beneficial effects of autologous serum in severe ocular surface disorders. For most of these patients, autologous serum was superior to conventional treatment for improving ocular surface health and subjective comfort.