Renal transplantation in older adults: retrospective cohort study to examine the impact of the new 2019 kidney offering scheme on older adult transplant recipients.

INTRODUCTION: In 2019, a new kidney offering scheme was launched in the United Kingdom, aiming to better match estimated patient survival and graft life expectancy. The scheme's impact on older patients undergoing kidney transplantation (KT) is unknown. This study aims to compare the outcomes of older adult KT recipients before and after introduction of the 2019 scheme. METHODS: A retrospective observational cohort study of older adults who underwent KT was undertaken. Group 1 were transplanted between 1 September 2017 and 31 August 2019 (2006 allocation scheme) and group 2 between 1 September 2019 and 31 August 2021 (2019 offering scheme). An older adult was any person ≥60 years old at the time of KT. Univariable binary logistic regression analysis was performed to determine odds ratios (OR) and 95% confidence intervals (CI). RESULTS: There were 107 older adult deceased donor KT recipients, 62 from group 1 and 45 from group 2. Median age at transplantation was 68 (interquartile range [IQR] 62-71) and 67 (IQR 64-73) years, respectively. Univariable analysis showed that re-intervention (OR 6.486, 95% CI 1.306-32.216, p = 0.022) and critical care admission (OR 5.619, 95% CI 1.448-21.812, p = 0.013) were significantly more likely in group 2. Group 2 recipients were significantly more likely to have a level 4 human leucocyte antigen (HLA) mismatch (OR 4.667, 95% CI 1.640-13.275, p = 0.004) and to have undergone previous KT (OR 4.691, 95% CI 1.385-15.893, p = 0.013). CONCLUSIONS: The introduction of the 2019 offering scheme was associated with re-intervention and critical care admission for older KT recipients. We also observed less-favourable HLA matches but more KT in difficult-to-match groups.

The reorganisation of emergency general surgery services during the COVID-19 pandemic in the UK: outcomes of delayed presentation, socio-economic deprivation and Black, Asian and Minority Ethnic patients.

INTRODUCTION: The COVID-19 pandemic is a global public health emergency. Lockdown restrictions and the reconfiguration of healthcare systems to accommodate an increase in critical care capacity have had an impact on 'non-COVID' specialties. This study characterises the utilisation of emergency general surgery (EGS) services during the UK lockdown period at a university teaching hospital with a catchment population that represents one of the most deprived and ethnically diverse areas in the UK. METHODS: EGS admissions during the UK lockdown period (March to May 2020) were compared with the same period in 2019. Patient demographics were recorded together with clinical presentation, hospital stay and treatment outcomes, and readmission data. RESULTS: The study included 645 patients, comprising 223 in the COVID-19 period and 422 in the non-COVID-19 period. There was no difference in age, sex, comorbidity or socio-economic status. A lower proportion of patients of Black, Asian and Minority Ethnicity (BAME) were admitted during the pandemic (20.6% vs 35.4%, p < 0.05). The duration of symptoms prior to presentation was longer, and admission clinical parameters and serum inflammatory markers. More patients presented with an acute kidney injury (9.9% vs 4.7%, p = 0.012). There was no difference in perioperative outcomes or 30-day mortality, but more patients were readmitted following conservative management (10.6% vs 4.7%, p = 0.023). CONCLUSIONS: The reorganisation of EGS to a senior-led model has been successful in terms of outcomes and access to treatment despite a more unwell population. There was a significantly lower proportion of BAME admissions suggesting additional barriers to healthcare access under pandemic lockdown conditions.

Synchronous resection of colorectal cancer and liver metastases: comparative views of colorectal and liver surgeons.

AIM: The optimal management of patients presenting with colorectal cancer and synchronous liver metastases is controversial. This survey was intended to summarize the opinions of UK colorectal and liver surgeons on the specific issues pertaining to synchronous resection. METHOD: A validated electronic survey was sent to the consultant members of the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the Association of Upper Gastrointestinal Surgeons (AUGIS). The questions were structured to allow direct comparison between the two groups of the responses obtained. RESULTS: Four hundred and twenty-four specialist colorectal surgeons and 52 specialist hepatobiliary surgeons were identified from the register of their respective associations. Responses were obtained from 133 (31%) colorectal and 22 (42%) liver surgeons. A majority of both groups of surgeons felt that synchronous resection was a valid therapeutic option. A majority of both groups believed that synchronous resection was justified despite the options of laparoscopic surgery and enhanced recovery programmes for each discipline. Agreed possible advantages of synchronous resections were: a decrease in the overall length of hospital stay, cost and patient anxiety. The major concern about synchronous resections was an excessive overall physiological insult. Specific scenarios indicated that synchronous resection was favoured for major/complex major colorectal resection with minor liver resection or most colorectal resections not involving an anastomosis with either a minor or major liver resection. CONCLUSION: Although significant concerns relating to synchronous resection remain amongst colorectal and liver surgeons, a majority of them felt that synchronous resections could be offered to appropriately selected patients.

Acute lower limb ischemia following pediatric renal transplantation.

Live donor renal transplantation remains the best treatment option for end stage renal failure in pediatric patients (1-3). Better understanding of the hemodynamics of donor-recipient size discrepancy and advances in interventional techniques with improved surgical techniques have decreased the incidence and severity of surgical complications and enhanced graft survival (1, 2). We describe a rare complication occurring intra-operatively in a pediatric renal transplant resulting in acute limb ischemia and the surgical option taken.

Transplantation of adult-sized kidneys in low-weight pediatric recipients achieves short-term outcomes comparable to size-matched grafts.

Low-weight pediatric recipients are disadvantaged by scarcity of size-matched donors. ASK have been successfully used for pediatric recipients. We report the results of renal transplantation using ASK in low-weight pediatric recipients and compare outcomes in weight-matched and unmatched donor-recipient pairs. The outcomes of renal transplants using ASK grafts in low-weight (<20 kg) recipients from a single center over a 10-yr period were reviewed. Two groups, comprising recipients of grafts from weight-matched and mismatched donors, were compared. Primary outcome was one-yr graft survival. Secondary outcomes were one- and two-yr calculated eGFR, changes in recipient body weight, perioperative cardiovascular stability, rates of AR and DGF. Twenty-three low-weight recipients were transplanted. Eleven received ASK grafts from high-weight donors and 12 grafts from low-weight donors. One patient in each group had early graft loss. No significant difference was observed in rates of DGF, AR, one-yr graft or patient survival and perioperative cardiovascular parameters. ASK with considerable donor:recipient weight discrepancies can be safely transplanted into small pediatric recipients with comparable outcomes to grafts with less weight discrepancy.

Submillimeter heterodyne detection of interstellar carbon monoxide at 434 micrometers.

A submillimeter heterodyne radiometer, developed for astronomical applications, uses an optically pumped laser local oscillator and a quasi-optical Schottky diode mixer. The resultant telescope-mounted system, which has a noise temperature less than 4000 K (double sideband) and high frequency and spatial resolution, has been used to detect the J = 6 --> 5 rotational transition of carbon monoxide at 434 micrometers in the Orion molecular cloud. The measurements, when compared with previous millimeter-wave data, indicate that the broad carbon monoxide emission feature is produced by an optically thin gas whose temperature exceeds 180 K.

An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma.

Tumor cell invasion is a primary event in the metastatic progression of hepatocellular carcinoma (HCC). Our recent results indicate a concordant elevated expression of osteopontin (OPN) and matrix metalloproteinase-9 (MMP-9) in primary metastatic HCC. This study hypothesizes an MMP-9-directed cleavage of OPN that biologically contributes to HCC metastasis. We found that MMP-9 cleaved OPN into specific fragments in vitro, of which three could be identified by Edman degradation amino-acid sequencing. One of these fragments (OPN-5 kDa, residues 167-210) induced low-metastatic HCC cellular invasion via CD44 receptors, which was effectively blocked by the addition of small peptides within the region of OPN-5 kDa. Increased expression of an OPN splice variant (OPN-c) was associated with clinical metastatic HCC. Overexpression of OPN-c with physiological levels of MMP-9 enhanced cellular invasion and coincided with elevated OPN-5 kDa levels. Our data suggest that an alternative splicing event (OPN-c) promotes extracellular cleavage of OPN by MMP-9, thus releasing a distinct region of OPN (OPN-5 kDa) that is essential for HCC cellular invasion and appears to correlate with metastatic potential. The findings of this study may help to improve advanced-stage HCC prognosis and suggest the utility of small peptides for novel therapies.

Transmitter-mediated inhibition of N-type calcium channels in sensory neurons involves multiple GTP-binding proteins and subunits.

The modulation of voltage-activated Ca2+ channels by neurotransmitters and peptides is very likely a primary means of regulating Ca(2+)-dependent physiological functions such as neurosecretion, muscle contraction, and membrane excitability. In neurons, N-type Ca2+ channels (defined as omega-conotoxin GVIA-sensitive) are one prominent target for transmitter-mediated inhibition. This inhibition is widely thought to result from a shift in the voltage independence of channel gating. Recently, however, voltage-independent inhibition has also been described for N channels. As embryonic chick dorsal root ganglion neurons express both of these biophysically distinct modulatory pathways, we have utilized these cells to test the hypothesis that the voltage-dependent and -independent actions of transmitters are mediated by separate biochemical pathways. We have confirmed this hypothesis by demonstrating that the two modulatory mechanisms activated by a single transmitter involve not only different classes of G protein but also different G protein subunits.

Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis.

By genetically targeting tumorigenesis to specific hypothalamic neurons in transgenic mice using the promoter region of the gonadotropin-releasing hormone (GnRH) gene to express the SV40 T-antigen oncogene, we have produced neuronal tumors and developed clonal, differentiated, neurosecretory cell lines. These cells extend neurites, express the endogenous mouse GnRH mRNA, release GnRH in response to depolarization, have regulatable fast Na+ channels found in neurons, and express neuronal, but not glial, cell markers. These immortalized cells will provide an invaluable model system for study of hypothalamic neurosecretory neurons that regulate reproduction. Significantly, their derivation demonstrates the feasibility of immortalizing differentiated neurons by targeting tumorigenesis in transgenic mice to specific neurons of the CNS.

Immunoglobulins in the hyperimmunoglobulin E and recurrent infection (Job's) syndrome. Deficiency of anti-Staphylococcus aureus immunoglobulin A.

Patients with the hyperimmunoglobulin E and recurrent infection syndrome (HIE) characteristically have frequent skin and respiratory infections caused by Staphylococcus aureus. We have developed a set of enzyme-linked immunosorbent assays that use whole S. aureus (Wood's strain) immobilized on 0.22-micrometers filters and highly specific, affinity-purified enzyme conjugates of goat anti-human IgE, anti-human IgD, anti-human IgG, anti-human IgA, and anti-human IgM. These reagents were used to determine S. aureus-specific immunoglobulin (Ig) levels. As previously published, 10 patients with HIE had markedly higher levels of anti-S. aureus IgE than did 5 patients with eczema and recurrent superficial S. aureus infections (P less than 0.001). The HIE patients were also found to have a deficit of anti-S. aureus serum IgA as compared with 12 normal subjects, 12 patients with chronic granulomatous disease, 5 patients with chronic eczema and recurrent superficial S. aureus infections, and 3 patients with the Chediak-Higashi syndrome (P less than 0.01 for each comparison). In addition the HIE patients had an excess of anti-S. aureus IgM as compared with normal subjects (P less than 0.01). An expected excess of anti-S. aureus IgG was absent. These abnormalities cannot be explained by variations of total serum Ig levels or by a general inability to produce antigen-specific IgA because levels of naturally occurring IgA antibody against Escherichia coli lipopolysaccharide and the antigens of the pneumococcal vaccine are normal. Parotid saliva from patients with HIE contained less salivary IgA per milligram of protein (P less than 0.01) and less salivary anti-S. aureus IgA per milligram of protein (P less than 0.05) than did normal controls. The incidence of infection at mucosal surfaces and adjacent lymph nodes correlated inversely with serum anti-S. aureus IgA (r = -0.647, P = 0.034), serum anti-S. aureus IgE (r = -0.731, P = 0.016), total serum IgE (r = -0.714, P = 0.020), and total serum IgD (r = -0.597, P = 0.049). These findings are evidence of a previously undescribed immunoregulatory defect in patients with HIE, which may contribute to the increased susceptibility to infection in this syndrome.

Activin and inhibin in the human adrenal gland. Regulation and differential effects in fetal and adult cells.

Recent experimental data have revealed that activins and inhibins exert pivotal effects on development. As part of our studies on growth and differentiation of the human fetal adrenal gland, we examined the subunit localization, as well as the mitogenic and steroidogenic actions of activin and inhibin in human fetal and adult adrenals. All three activin and inhibin subunit proteins (alpha, beta A, and beta B) were detected in the fetal and adult adrenal cortex. Immunoreactive activin-A dimer was demonstrated in midgestation fetal and neonatal adrenals. ACTH1-24-stimulated fetal adrenal cell expression of alpha and beta A subunit messenger RNA. In addition, ACTH elicited a rise in levels of immunoreactive alpha subunit secreted by fetal and adult adrenal cells. Human recombinant activin-A inhibited mitogenesis and enhanced ACTH-stimulated cortisol secretion by cultured fetal zone cells, but not definitive zone or adult adrenal cells. Recombinant inhibin-A had no apparent mitogenic or steroidogenic effects. Thus, activin selectively suppressed fetal zone proliferation and enhanced the ACTH-induced shift in the cortisol/dehydroepiandrosterone sulfate ratio of fetal zone steroid production. These data indicate that activin-A may be an autocrine or paracrine factor regulated by ACTH, involved in modulating growth and differentiated function of the human fetal adrenal gland.

A decline in myometrial nitric oxide synthase expression is associated with labor and delivery.

The mechanisms that maintain relative uterine quiescence during pregnancy remain largely unknown. A possible role for nitric oxide has recently emerged, however, the expression of nitric oxide synthase within human myometrium at midgestation, a time when the uterus is normally quiescent, has not been investigated. The purpose of this study was to identify cell types in human myometrium that contain inducible nitric oxide synthase (iNOS), and to examine changes in its expression during pregnancy and labor. We found that iNOS is expressed in smooth muscle cells of pregnant myometrium. Expression of iNOS was highest in myometrium of preterm not-in-labor patients. At term, iNOS expression fell by 75%, and was barely detectable in preterm in-labor or term in-labor specimens. There was no staining in the myocytes of nonpregnant myometrium. Western blotting also revealed a similar pattern of changes in iNOS expression. In summary, iNOS expression in the myocytes of human myometrium is increased greatly during pregnancy, and declines towards term or with labor. Significantly, preterm inlabor patients also had a large decline in iNOS expression. These data suggest that changes in myometrial iNOS expression may participate in the regulation of uterine activity during human pregnancy.

Metabolism of immunoglobulin E in patients with markedly elevated serum immunoglobulin E levels.

The metabolism of human IgE was studied in normals, severe atopics, and patients with the hyperimmunoglobulin E-recurrent infection (HIE; Job's) syndrome to determine whether IgE metabolism is altered in patients with marked elevation of serum IgE. Purified polyclonal 125I-IgE was administered intravenously and serial plasma and urine samples were obtained. After analysis, the metabolic data support previously published evidence that IgE (at concentrations found in normal individuals) is catabolized at a higher fractional rate than other immunoglobulins and is catabolized by both an intravascular and an extravascular pathway. In addition, the data show that the fractional catabolic rate for IgE is significantly less for the atopic patients (mean +/- SEM = 0.20 +/- 0.01) and for the HIE patients (0.15 +/- 0.02) than for the normal volunteers (0.52 +/- 0.06; P less than 0.01) and is inversely related (r = -0.851; P less than 0.001) to the serum IgE concentration. These findings have specific importance in showing that decreased fractional catabolic rate contributes substantially to elevation of IgE in atopic and HIE patients. In addition, the findings have general significance in that they lead to a unifying hypothesis of immunoglobulin catabolism.

Activin-A as an intraovarian modulator: actions, localization, and regulation of the intact dimer in human ovarian cells.

The actions, localization, and regulation of activin in the human ovary are unknown. Therefore, the aims of this study were (a) to define the effects of recombinant activin-A and its structural homologue, inhibin-A, on mitogenesis and steroidogenesis (progesterone secretion and aromatase activity) in human preovulatory follicular cells; (b) to localize the activin-A dimer in the human ovary by immunohistochemistry; and (c) to examine regulation of intracellular activin-A production in cultured human follicular cells. In addition to stimulating mitogenic activity, activin-A causes a dose- and time-dependent inhibition of basal and gonadotropin-stimulated progesterone secretion and aromatase activity in human luteinizing follicular cells on day 2 and day 4 of culture. Inhibin-A exerts no effects on mitogenesis, basal or gonadotropin-stimulated progesterone secretion and aromatase activity, and does not alter effects observed with activin-A alone. Immunostaining for dimeric activin-A occurs in granulosa and cumulus cells of human ovarian follicles and in granulosa-lutein cells of the human corpus luteum. cAMP, and to a lesser degree human chorionic gonadotropin and follicle-stimulating hormone, but not inhibin-A, activin-A, or phorbol 12-myristate 13-acetate, increased the immunostaining for activin-A in cultured granulosa cells. These results indicate that activin-A may function as an autocrine or paracrine regulator of follicular function in the human ovary.

In vitro antigen-induced antibody responses to hepatitis B surface antigen in man. Kinetic and cellular requirements.

In this report we define the parameters of the human immune response after immunization with hepatitis B vaccine. 2 wk after booster immunization, there is significant spontaneous secretion of antibody to hepatitis B surface antigen (anti-HBs IgG), which is not further augmented by stimulation with antigen or pokeweed mitogen (PWM). By 4 wk there is little spontaneous secretion of specific antibody, and low doses of antigen or PWM produce significant increases in the amount of anti-HBs IgG produced. By 8 wk the peripheral blood mononuclear cells are refractory to stimulation by antigen, but anti-HBs IgG is produced in response to PWM. 0.5 yr or more after the last immunization, some individuals will manifest an antigen-induced specific antibody response. This induction of anti-HBs IgG by hepatitis B surface antigen (HBsAg) is monocyte- and T cell-dependent. Note that there is a dichotomy in the T cell response to HBsAg. The specific antibody response is clearly T cell dependent, but no in vitro T cell proliferative response to HBsAG could be demonstrated in the immunized individuals. Although the precise reason for the absent proliferative response to HBsAg despite well-established humoral immunity has not been determined, there was no evidence to suggest nonspecific suppression by HBsAg or the presence of an adherent suppressor cell population. The ability to evaluate antigen-induced, antigen-specific responses to HBsAg will be useful in defining the unique interaction between the human immune response and this clinically important viral agent.

Congenital diaphragmatic hernia causing cardiac arrest in a 30-year-old woman.

Congenital diaphragmatic hernia (CDH) usually presents in infancy with respiratory failure requiring urgent surgical correction. Mortality in this group of patients remains poor and persistent pulmonary hypertension is a significant contributor. It is therefore rare for patients to reach adulthood undiagnosed. CDH is often identified incidentally in adults but when symptoms arise, they relate to the organ involved, and include gastrointestinal symptoms of dyspepsia and obstruction, as well as respiratory complaints such as dyspnoea. We present the case of a 30-year-old woman who was admitted with non-specific symptoms of upper abdominal discomfort but whose deteriorating condition culminated in a cardiac arrest, as an unreported presentation of CDH. The patient presented initially with severe left upper quadrant pain. Her chest x-ray on admission suggested a raised left hemidiaphragm. She went on to have computed tomography (CT) of the thorax and abdomen as well as oesophagogastroduodenoscopy, which raised the suspicion of diaphragmatic eventration. Repeat CT was performed after the patient collapsed on the ward five days following admission, revealing tracheal deviation, and a strangulated Bochdalek hernia containing stomach and spleen. After transfer to the anaesthetic room, she suffered a cardiac arrest. Advanced life support was required to return spontaneous cardiac function. She was intubated and ventilated, and a needle thoracostomy was performed to decompress the tension gastrothorax. Emergency laparotomy revealed a gangrenous stomach and spleen. Total gastrectomy with primary Roux-en-Y reconstruction, splenectomy and insertion of a feeding jejunostomy were performed. The patient recovered well postoperatively and was discharged two weeks following surgery.

Analysis of the Herschel/HEXOS Spectral Survey Towards Orion South: A massive protostellar envelope with strong external irradiation.

We present results from a comprehensive submillimeter spectral survey toward the source Orion South, based on data obtained with the HIFI instrument aboard the Herschel Space Observatory, covering the frequency range 480 to 1900 GHz. We detect 685 spectral lines with S/N > 3σ, originating from 52 different molecular and atomic species. We model each of the detected species assuming conditions of Local Thermodynamic Equilibrium. This analysis provides an estimate of the physical conditions of Orion South (column density, temperature, source size, & V LSR ). We find evidence for three different cloud components: a cool (T ex ~ 20 - 40 K), spatially extended (> 60″), and quiescent (ΔVFWHM ~ 4 km s -1) component; a warmer (T ex ~ 80 - 100 K), less spatially extended (~ 30″), and dynamic (ΔVFWHM ~ 8 km s -1) component, which is likely affected by embedded outflows; and a kinematically distinct region (T ex > 100 K; V LSR ~ 8 km s -1), dominated by emission from species which trace ultraviolet irradiation, likely at the surface of the cloud. We find little evidence for the existence of a chemically distinct "hot core" component, likely due to the small filling factor of the hot core or hot cores within the Herschel beam. We find that the chemical composition of the gas in the cooler, quiescent component of Orion South more closely resembles that of the quiescent ridge in Orion-KL. The gas in the warmer, dynamic component, however, more closely resembles that of the Compact Ridge and Plateau regions of Orion-KL, suggesting that higher temperatures and shocks also have an influence on the overall chemistry of Orion South.