Interrogation of the human cortical peptidome uncovers cell-type specific signatures of cognitive resilience against Alzheimer's disease.

Alzheimer's disease (AD) is characterised by age-related cognitive decline. Brain accumulation of amyloid-ß plaques and tau tangles is required for a neuropathological AD diagnosis, yet up to one-third of AD-pathology positive community-dwelling elderly adults experience no symptoms of cognitive decline during life. Conversely, some exhibit chronic cognitive impairment in absence of measurable neuropathology, prompting interest into cognitive resilience-retained cognition despite significant neuropathology-and cognitive frailty-impaired cognition despite low neuropathology. Synapse loss is widespread within the AD-dementia, but not AD-resilient, brain. Recent evidence points towards critical roles for synaptic proteins, such as neurosecretory VGF, in cognitive resilience. However, VGF and related proteins often signal as peptide derivatives. Here, nontryptic peptidomic mass spectrometry was performed on 102 post-mortem cortical samples from individuals across cognitive and neuropathological spectra. Neuropeptide signalling proteoforms derived from VGF, somatostatin (SST) and protachykinin-1 (TAC1) showed higher abundance in AD-resilient than AD-dementia brain, whereas signalling proteoforms of cholecystokinin (CCK) and chromogranin (CHG) A/B and multiple cytoskeletal molecules were enriched in frail vs control brain. Integrating our data with publicly available single nuclear RNA sequencing (snRNA-seq) showed enrichment of cognition-related genes in defined cell-types with established links to cognitive resilience, including SST interneurons and excitatory intratelencephalic cells.

Prosthetic joint infection of the knee - arthroscopic biopsy identifies more and different organisms than aspiration alone.

BACKGROUND: Prosthetic joint infection (PJI) causes significant morbidity and mortality following knee replacement surgery. Identifying causative organisms and antibiotic sensitivities is critical in increasing the chance of infection eradication. This study investigated whether biopsy alone was superior to aspiration alone for serological diagnosis in PJI following knee replacement. Secondly, we investigated whether biopsy identifies the same or new/different microbiological flora as aspiration. METHODS: Since December 2014, the Exeter Knee Reconstruction Unit (EKRU) has prospectively collated data regarding all PJIs referred from our local/regional network which have been reviewed via our Multi-Disciplinary Team (MDT). We identified and included consecutive patients from this MDT from Dec.2014-Mar.2020 and analysed their electronic records. Statistical analysis was performed using Stata. RESULTS: 65/100 patients studied had both pre-operative aspiration and biopsy. 31/65 (48%) had positive aspiration and biopsies. No aspirate samples were positive with corresponding biopsies negative. In 19/65 (29%) of infection positive patients, biopsy identified new (7) or additional (12) organisms not identified by aspiration. Aspiration had a sensitivity of 70%, specificity of 88%, positive predictive value of 90.3% and negative predictive value of 64.7%. Biopsy had a sensitivity of 97.5%, specificity of 88%, positive predictive value of 92.9% and negative predictive value of 95.7%. CONCLUSION: In 29% of confirmed PJI cases, arthroscopic biopsy identified either additional organisms in a polymicrobial PJI when compared to aspiration, or new positive results when aspiration alone was negative. This study demonstrates the benefits of arthroscopic biopsy for serological diagnosis in cases of knee PJI and aids treatment planning.

Vascular and extravascular complications of liver transplantation: comprehensive evaluation with three-dimensional contrast-enhanced volumetric MR imaging and MR cholangiopancreatography.

OBJECTIVE: Our purpose was to evaluate a comprehensive MR imaging strategy for recipients of liver transplants that relies on dynamic interpolated three-dimensional (3D) MR imaging for simultaneous vascular, parenchymal, and extrahepatic imaging. MATERIALS AND METHODS: Twenty-three consecutive adult patients underwent 30 MR imaging examinations between 2 days and 99 months (mean, 15 months) after transplantation using a breath-hold 3D gradient-echo sequence (TR range/TE range, 3.7-4.7/1.8-1.9; flip angle, 12-30 degrees ) with an intermittent fat-saturation pulse and interpolation in the section-select direction to enable pixel size 3 mm or less in all dimensions. Unenhanced and triphasic contrast-enhanced 3D imaging (average dose, 0.13 mmol/kg of gadopentetate dimeglumine) was performed. A subset of patients (n = 13) also underwent MR cholangiopancreatography using half-Fourier single-shot turbo spin-echo imaging. MR imaging examinations were correlated with digital subtraction angiography (n = 8), contrast-enhanced cholangiography (n = 9), sonography (n = 13), and histopathology (n = 14). RESULTS: MR imaging revealed abnormal findings in 27 (90%) of 30 examinations, including vascular disease in nine, biliary complications in four, and evidence of intra- or extra-hepatic hepatocellular carcinoma recurrence in six. Digital subtraction angiography confirmed seven MR angiography examinations but suggested disease overestimation in one. Contrast-enhanced cholangiography confirmed findings of MR cholangiopancreatography in seven cases but suggested disease underestimation in two. CONCLUSION: Dynamic interpolated 3D MR imaging combined with dedicated MR cholangiopancreatography can provide a comprehensive assessment of vascular, biliary, parenchymal, and extrahepatic complications in most recipients of liver transplants.

MR imaging as the sole preoperative imaging modality for right hepatectomy: a prospective study of living adult-to-adult liver donor candidates.

OBJECTIVE: Our aim was to investigate the feasibility of MR imaging as a comprehensive preoperative imaging test for examination of liver donor candidates for adult-to-adult right lobe transplantation. SUBJECTS AND METHODS: Twenty-five consecutive donor candidates were examined at 1.5 T using a torso phased array coil with breath-hold T1- and T2-weighted imaging of the abdomen, MR cholangiography using T2-weighted turbo spin-echo imaging, and MR angiography and venography of the liver using two interpolated three-dimensional spoiled gradient-echo sequences (average dose of gadolinium contrast material, 0.17 mmol/kg). Images were interpreted for liver parenchymal and extrahepatic abnormalities; measurements of right and left lobe liver volumes; definition of hepatic arterial, portal venous, and hepatic venous anatomy; and definition of the biliary branching pattern. Findings were compared with those of conventional angiography in 13 patients, 11 of whom also had surgical findings for comparison. RESULTS: Nine patients were excluded as candidates for donation on the basis of MR imaging findings that included parenchymal or extrahepatic abnormalities in five patients, vascular anomalies in two, and biliary anomalies in three. Two patients who did not undergo surgery underwent conventional angiography that confirmed MR angiographic findings except for a small (<2 mm) accessory left hepatic artery missed on MR imaging. Of the nine patients who underwent successful right hepatectomy, all MR imaging findings were corroborated intraoperatively. In two patients, right hepatectomy was aborted at laparotomy because of intraoperative cholangiography findings; in one of them, the biliary finding was unsuspected on MR imaging. CONCLUSION: A comprehensive MR imaging examination has the potential to serve as the sole preoperative imaging modality for living adult-to-adult liver donor candidates provided improvements in definition of intrahepatic biliary anatomy can be achieved.

Siderotic nodules in the cirrhotic liver at MR imaging with explant correlation: no increased frequency of dysplastic nodules and hepatocellular carcinoma.

PURPOSE: To determine the sensitivity of magnetic resonance (MR) imaging for detection of siderotic nodules in patients with cirrhosis and whether the frequency of hepatocellular carcinoma (HCC) and dysplastic nodules is greater if siderotic nodules are present. MATERIALS AND METHODS: MR imaging (1.5 T) was performed within 0-117 days (mean, 30 days) before liver transplantation in 77 patients. Two readers retrospectively evaluated gradient-echo (GRE) (echo time [TE], > or = 9 and 4-5 msec) and turbo short inversion time inversion-recovery or T2-weighted images for low-signal-intensity nodules. Whole-explant pathologic correlation was available in every case. RESULTS: At explantation, 28 (36%) of 77 patients had HCC, 25 (32%) had dysplastic nodules, and nine (12%) had both; 35 (45%) patients had siderotic nodules. The sensitivity of GRE imaging with 9-msec or longer TE for the detection of siderotic nodules was 80% (28 of 35) but decreased to 31% (11 of 35) with 4-5-msec TE. Frequency of HCC was not significantly higher (P =.27) in patients with (43% [15 of 35]) than in patients without (31% [13 of 42]) siderotic nodules. Frequency of dysplastic nodules also was not significantly higher (P =.42) in patients with (37% [13 of 35]) than in patients without (29% [12 of 42]) siderotic nodules. CONCLUSION: Sensitivity of MR imaging for the detection of siderotic nodules was improved with use of GRE pulse sequences with longer TEs of 9 msec or greater (80%) versus 4-5 msec (31%); however, there was no significant increased frequency of HCC or dysplastic nodules in patients with pathologically proved siderotic nodules.

Siderotic nodules at MR imaging: regenerative or dysplastic?

OBJECTIVE: To determine if iron containing "siderotic" nodules detected at magnetic resonance (MR) imaging are regenerative (RN) or dysplastic (DN) and to attempt to identify features that may distinguish them. MATERIAL AND METHODS: MR imaging (1.5 T) was performed on 77 cirrhotic patients who underwent orthotopic liver transplantation within 0-117 days (mean 30 days) of MR imaging. Two readers retrospectively evaluated breath-hold gradient-echo pulse sequences (echo time > or =9.0 ms, flip angle < or =45 degrees) for the presence of hypointense nodules, which were classified as micronodular (< or =3 mm), macronodular (>3 mm), or mixed. Nodule distribution was classified as focal (<5), scattered (5-20), or diffuse (>20) per slice. Thin section pathologic correlation was available in all cases, and Prussian blue iron stains were performed. RESULTS: Of 35 patients with pathologically proven siderotic nodules, 10 (29%) had at least 2 siderotic DN. MR detected siderotic nodules in 10 of 10 (100%) patients with siderotic DN and RN, and in 18 of 25 patients (72%) with siderotic RN only. CONCLUSION: Siderotic RN cannot be reliably distinguished from siderotic DN with MR imaging, and therefore the widely used term "siderotic regenerative nodule" should be avoided and replaced by "siderotic nodule."

Transformation of C3H 10T1/2 cells by low doses of ionising radiation: a collaborative study by six European laboratories strongly supporting a linear dose-response relationship.

For the assessment of radiation risk at low doses, it is presumed that the shape of the low-dose-response curve in humans for cancer induction is linear. Epidemiological data alone are unlikely to ever have the statistical power needed to confirm this assumption. Another approach is to use oncogenic transformation in vitro as a surrogate for carcinogenesis in vivo. In mid-1990, six European laboratories initiated such an approach using C3H 10T1/2 mouse cells. Rigid standardisation procedures were established followed by collaborative measurements of transformation down to absorbed doses of 0.25 Gy of x-radiation resulting in a total of 759 transformed foci. The results clearly support a linear dose-response relationship for cell transformation in vitro with no evidence for a threshold dose or for an enhanced, supralinear response at doses approximately 200-300 mGy. For radiological protection this represents a large dose, and the limitations of this approach are apparent. Only by understanding the fundamental mechanisms involved in radiation carcinogenesis will further knowledge concerning the effects of low doses become available. These results will, however, help validate new biologically based models of radiation cancer risk thus providing increased confidence in the estimation of cancer risk at low doses.

Effect of hormones on the variation of radiosensitivity in females as measured by induction of chromosomal aberrations.

The frequency of dicentrics + ring (dic/cell) and total chromosome aberrations (dicentrics, rings and excess acentrics, etc.) per cell (TAb/cell) has been studied in 50 male and female volunteers after high or low dose rate (HDR, LDR) irradiation of peripheral blood lymphocytes. The mean male aberration frequencies per cell after HDR irradiation were 0.38 dic/cell and 0.61 TAb/cell; following LDR irradiation, the mean aberration frequencies were 0.28 dic/cell and 0.45 TAb/cell. Equivalent female values after HDR irradiation were 0.42 dic/cell and 0.71 TAb/cell; after LDR irradiation, the mean aberration frequencies were 0.30 dic/cell and 0.48 TAb/cell. Analysis of variance showed that there was a highly significant difference between males and females have a greater HDR, but not LDR, irradiation It is concluded from this study that females have a greater variability in their radioresponse, and that this variability is related to progesterone, which has a profound effect upon radiosensitivity, as measured by cytogenetic end points.

Cell survival measurements in an argon, aluminium and sulphur filtered neutron beam: a comparison with 24 keV neutrons and relevance to boron neutron capture therapy.

Boron neutron capture therapy (BNCT) has been advanced as a suitable alternative therapy for the treatment of glioma. BNCT involves the selective uptake of a tumour with a boron-bearing substance and subsequent irradiation with a beam of neutrons. Previous attempts with BNCT have utilized thermal neutrons, but this involves resection of the scalp prior to treatment and is only possible with superficial tumours. An alternative is to use a beam of intermediate-energy neutrons which will produce a peak in the thermal neutron fluence at depth in tissue and so enable deep-seated tumours to be treated. A neutron beam with a mean energy of approximately 9 keV, obtained by filtering neutrons from a reactor with aluminium, argon and sulphur, has been used to explore the radiobiological advantage over thermal and 24 keV neutrons for BNCT. Irradiation of V79 and HeLa cells at various positions in a polythene phantom suggest that the beam is less cytotoxic for a given neutron fluence than the 24 keV neutron beam previously considered as an alternative to thermal neutrons for BNCT. However, optimization of boron distribution via the development of new compounds still appears to be necessary for BNCT to become a safe alternative option for the treatment of glioma.

Rapid donor liver nutritional enhancement in a large animal model.

Organ donors are typically subject to acute hyponutrition that might affect postpreservation liver function. Livers from nutritionally supplemented rats function better after preservation than livers from fasted rats. We have developed a method to glycogenate the liver of large animals in the temporal context of a human donor liver operation and have studied the fate of glycogen stores during preservation. Starved anesthetized pigs were infused with a hexose solution (glucose, fructose or galactose) by way of the superior mesenteric vein for 3 hr. Regular porcine insulin was infused to maintain a hyperglycemic hyperinsulinemic arterial glucose clamp at 12 to 16 mmol/L. Liver biopsy specimens and blood samples were taken before infusion and hourly. At 3 hr the liver was excised, stored for 24 hr at 1 degrees C in University of Wisconsin solution and biopsied. It was then placed at 20 degrees C for 1 hr to simulate the reimplantation stage of transplantation. Glycogen and nucleotide levels were measured, and results were corrected for starch in the University of Wisconsin solution. A 20% glucose infusion produced rapid hepatic glycogenation without side effects. Greater glycogenation was obtained with 20% fructose but at the cost of lactic acidosis and a fall in pH. A combination of 15% glucose and 5% fructose produced intermediary glycogenation without significant side effects. Galactose (20%) was less efficient than glucose alone. The addition of alanine and glutamine (20 mmol/L) did not significantly improve glycogenation. Metabolism of glycogen at 1 degree C did occur. Glycogen content fell 0.15% +/- 0.05% dry weight liver per hour during cold preservation and 5.49% +/- 2.15% per hour during ischemic rewarming.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cold preservation on lymphocyte adherence in the perfused rat liver.

A study was designed to determine if cold preservation induces an increase in lymphocyte adherence to liver sinusoids on reperfusion. Rat livers were stored at 1 degree C in University of Wisconsin solution for 45 min, 8 hr, or 30 hr, and then reperfused for 90 min at 37 degrees C in an isolated perfused rat liver apparatus. Just prior to reperfusion, isogeneic rat lymphocytes prepared on a Ficoll-Paque gradient were added to the perfusate. In some studies lymphocytes were labeled with a fluorescent lipophilic membrane marker. There was no change in the number of circulating lymphocytes in an anhepatic circuit. When livers were present in the circuit, lymphocytes were lost from the perfusate into the liver in all studies, with the most rapid decrease occurring within 10 min of reperfusion. The length of preservation had a marked and statistically significant effect on the rate of disappearance of lymphocytes from the perfusate. Reduction by 50% of the number of lymphocytes infused did not affect the results when expressed as percent lymphocytes remaining in perfusate. To exclude the possibility that the loss of lymphocytes into the liver was due to a damaged subpopulation of lymphocytes, two livers stored 3 for 45 min were put into the circuit in sequence. The percent reduction in cells due to exposure to a second liver was not significantly different from that observed when cells were exposed only to a single liver. Histological studies showed fluorescence-labeled lymphocytes adherent in sinusoids, and the number of labeled cells was directly related to the length of preservation. Cold preservation induces an increase in lymphocyte adherence in the reperfused liver, which might be important in graft malfunction and rejection.

Correlation of donor nutritional status with sinusoidal lining cell viability and liver function in the rat.

We have demonstrated that the sinusoidal lining cell injury sustained by rat liver allografts during hypothermic storage is a critical determinant of graft viability. The present study was designed to examine the effect of donor nutritional status on hepatic microcirculation and graft function. Rat livers from four nutritional groups (group I, fasted; group II, fed; group III, intraperitoneal glucose; and group IV, fed plus intraperitoneal glucose) were excised and stored for 24 hr in Marshall's isotonic citrate solution. Then the livers were perfused under anoxic conditions with trypan blue. The percentage of nonviable SLC in each group was 26.7 +/- 8.1, 24.9 +/- 7.9, 17.6 +/- 6.9, and 5.9 +/- 1.9 in groups I, II, III, and IV respectively; i.e., there was a significant improvement in SLC viability with nutritional repletion in group IV. Electron microscopy was performed on livers from groups I and IV following 30-hr preservation in University of Wisconsin solution and after 16-hr preservation in Marshall's isotonic citrate solution. Biopsies were taken at the end of storage and after 1 hr of reperfusion at 37 degrees C. At the end of preservation group IV livers contained glycogen and had much more normal liver ultrastructure than group I livers. After reperfusion there was partial recovery of normal SLC morphology in both groups and depletion of glycogen in group IV. Liver function was studied on the isolated perfused rat liver system at 37 degrees C following 30-hr storage in UW solution. Transaminase release into the perfusate was significantly lower in nutritionally repleted livers than in livers from fasted animals. A significant reduction in perfusate platelet count occurred only in livers from fasted animals. The results show that nutritional repletion can reduce the injury of cold preservation to both hepatocytes and endothelial cells and improve liver function in the postpreservation period.

The radiobiology of 24 keV neutrons. Measurement of the relative biological effect free-in-air, survival and cytogenetic analysis of the biological effect at various depths in a polyethylene phantom and modification of the depth-dose profile by boron 10 for V79 Chinese hamster and HeLa cells.

HeLa human carcinoma cells and V79 Chinese hamster fibroblasts have been irradiated in vitro with a beam of neutrons with a nearly pure 24 keV spectrum. The relative biological effectiveness (RBE) of the filtered neutron beam relative to 60Co gamma radiation was determined by irradiation of cell cultures "free-in-air". The values obtained for the RBE at 37% survival were 5.8 +/- 0.8, at a dose of 0.69 +/- 0.06 Gy for the HeLa cells and 3.14 +/- 1.1 at a dose of 1.09 +/- 0.091 Gy for the V79 cells. Cytogenetic analysis of the damage in irradiated V79 cells gave an RBE of 6.7 +/- 1.4. Irradiation in a polyethylene phantom markedly attenuated the beam's biological effect. For both cell lines 2 cm of polyethylene virtually eliminated cell killing. Addition of boron 10 to the medium led to increased cell killing and a value of 4 was obtained for the RBE of the 10B(n, alpha)7Li reaction in HeLa cells.

The production of chromosome aberration in Chinese hamster fibroblasts exposed to 24 keV neutrons.

A filtered reactor beam, consisting mainly of 24 keV neutrons, was used to study the induction of chromosome aberrations in the V79/4(AH1) Chinese hamster cell line. The yields of both dicentrics and acentrics were linear with dose and the value of relative biological effectiveness (RBE) for dicentrics at low doses was 6.5 +/- 1.4. This value was similar to that found previously for a neutron spectrum with mean energy 2.1 MeV, and suggests that the RBE of neutrons does not increase to very high values in the energy region below 100 keV. This result does not support the suggestions of Davy (1969) and Key (1971) that the neutron RBE rises to very high values in the intermediate energy range.

Inactivation of Chinese hamster V79/4(AH1) and HeLa cells by 24 keV neutrons.

Cell survival studies have been carried out with a filtered neutron beam providing a nearly pure, high intensity source of 24 keV neutrons. These suggest that 24 keV neutrons behave as high LET radiation. The RBE at 37 per cent survival was approximately 2.2 for V79 Chinese hamster cells while HeLa cells gave a value of 2.9.

A critical comparison of the micronucleus yield from high and low LET irradiation of plateau-phase cell populations.

Experimental data are presented which cast doubt on the usefulness of micronucleus assays as a quantitative measure of radiation damage. Synchronised (G1) Syrian hamster fibroblasts (BHK21 C13) were exposed to doses of gamma- or neutron radiation which yielded equivalent survival response. The cultures were examined at intervals during a 120-h post-irradiation incubation, for the appearance of micronuclei. Dose-response curves for the micronucleus yield constructed at a single sample time of 30 h were compared with those for the peak yield, irrespective of sampling time at each dose. When the total production of acentric fragments was compared with the peak yield of micronuclei no clear correlation could be seen. Qualitative hypotheses have been suggested to account for the various features of the data. The production and expression of micronuclei has been found to be a very complicated relationship and is a warning against too simplistic an interpretation of micronuclei data.