Can 60 days of feeding lead to increased fitness for transport in cull dairy cows?

Welfare of cull cows during transport to slaughter is a current concern in the Canadian dairy industry. Cull cows sold through auction often have a high prevalence of lameness, low body condition score (BCS), hock lesions, and udder engorgement. To evaluate whether drying off and feeding cull dairy cows before transport can mitigate these challenges, 45 cows designated for culling were randomly assigned to either be fed for 60 d after being dried off (Fed; n = 24) or to serve as controls by being sent directly to slaughter (Direct; n = 21). Two Fed cows were removed for health reasons before completing the feeding period. Both Fed and Direct cows were assessed for locomotion (5-point scale), BCS (5-point scale), hock lesions (3-point scale), udder engorgement (3-point scale) and body weight at the time of enrollment. Fed cows, locomotion, BCS, hock, and udder engorgement scores were assessed weekly until slaughter. Weights of the Fed cows were measured again the day before slaughter. Mixed linear regression models were used to assess continuous outcomes BCS and weight. Mixed logistic regression models were used to assess dichotomous outcomes presence of hock lesions and lameness. Fed cows gained an average of 116.9 kg over the feeding period (SE ± 8.20). Fed cows had an average weight at slaughter of 834.2 kg, whereas Direct cows' average weight was 767.3 kg (SE ± 26.8). The Fed cows' average BCS at the start of the trial was 2.4, and at slaughter was 3.6, with an average gain of 1.2 BCS points. At slaughter, proportion of udders involuted in the Fed group was 45.1% (10 out of 22) and in the Direct cows, was 0% (0 out of 21). There were no differences found in locomotion or hock lesions between the Fed and Direct groups. It is important to weigh potential benefits for the Fed cows with the fact that Direct cows did not endure a drying off procedure, nor were they placed at risk of potential adverse health events. However, despite these potential limitations, due to the improved BCS and udder engorgement scores, cows fed for 60 d may be better prepared for transportation to slaughter, as well as sell for a higher price due to increased body weight and body condition.

Colostrum insulin supplementation to neonatal Holstein bulls affects small intestinal histomorphology, mRNA expression, and enzymatic activity with minor influences on peripheral metabolism.

The objectives of this study were to evaluate how varying colostral insulin concentrations influenced small intestinal development and peripheral metabolism in neonatal Holstein bulls. Insulin was supplemented to approximately 5× (70.0 µg/L; n = 16) or 10× (149.7 µg/L; n = 16) the basal colostrum insulin (12.9 µg/L; BI, n = 16) concentration to maintain equivalent macronutrient intake (crude fat: 4.1 ± 0.06%; crude protein: 11.7 ± 0.05%; and lactose: 1.9 ± 0.01%) among treatments. Colostrum was fed at 2, 14, and 26 h postnatal and blood metabolites and insulin concentration were measured at 0, 30, 60, 90, 120, 180, 240, 360, 480, and 600 min postprandial respective to the first and second colostrum meal. At 30 h postnatal, a subset of calves (n = 8/treatment) were killed to excise the gastrointestinal and visceral tissues. Gastrointestinal and visceral gross morphology and dry matter and small intestinal histomorphology, gene expression, and carbohydrase activity were assessed. Insulin supplementation tended to linearly reduce the glucose clearance rate following the first meal, whereas after the second meal, supplementation linearly increased the rate of glucose absorption and nonesterified fatty acid clearance rate, decreased the time to maximum glucose concentrations, and decreased the time to reach minimum nonesterified fatty acid concentrations. Additionally, insulin clearance rate was linearly increased by insulin supplementation following the second colostrum feeding. However, there were no overall differences between treatments in the concentrations of glucose, nonesterified fatty acids, or insulin in plasma or serum. With respect to macroscopic intestinal development, dry rumen tissue mass linearly decreased when insulin was supplemented in colostrum, and supplementation linearly increased duodenal dry tissue density (g dry matter/cm) while tending to increase duodenal dry tissue weight. Increasing the colostrum insulin concentration improved small intestinal histomorphological development in the distal small intestine, as ileal villi height and mucosal-serosal surface area index were increased by supplementing insulin. Lactase enzymatic activity linearly increased in the proximal jejunum while ileal isomaltase activity linearly decreased with insulin supplementation. These data indicate that changes in colostrum insulin concentrations rapidly affect gastrointestinal growth prioritization and carbohydrase activity. The changes in gastrointestinal ontology result in minor changes in postprandial metabolite availability and clearance.

The influence of age and weaning on permeability of the gastrointestinal tract in Holstein bull calves.

Fourteen Holstein bull calves were used in a randomized complete block design to investigate the effect of calf age and weaning on permeability of the gastrointestinal tract (GIT). Calves were randomly assigned to 1 of 2 treatments: (1) a weaning protocol that was initiated on d 35; WN; n=7), or (2) a control treatment where calves were not weaned (CON; n=7). Calves were bottle-fed milk replacer (150 g/L), in 3 equal portions/d targeting 15% of their body weight (BW) in liquid milk intake [approximately 21.1g/kg of BW/d, dry matter (DM) basis]. On d 35, the amount of milk replacer offered to WN calves was reduced to 7.5% of BW for 7 d before calves were weaned on d 42. On d 14, 28, and 42, calves were orally dosed with 500 mL of Cr-EDTA (179 mM Cr-EDTA solution) and housed in a metabolism crate to enable total urine collection and determination of total urinary Cr recovery as an indicator of total-tract permeability. On d 44, calves were killed and tissues from the rumen, omasum, duodenum, jejunum, ileum, cecum, and proximal and distal colon were collected, rinsed, and transported in buffer solution (pH 7.4 at 38.5°C). Tissues were incubated in Ussing chambers under short-circuit conditions with buffer solutions designed to mimic the mucosal and serosal energy source that would be available in vivo (glucose for tissues from the small intestine and short-chain fatty acids for tissues that would be exposed to fermentation; rumen, omasum, and large intestinal tissues). The serosal to mucosal flux of (14)C-mannitol and (3)H-inulin was measured for each region. Although we detected treatment × period interactions for BW and starter intake, dietary treatments did not differ within a week. Overall, the time that ruminal pH was <5.5 was less before weaning than after weaning. We observed a differential response for the appearance of Cr in urine for WN and CON calves, where the appearance of Cr (mg/48 h) in urine decreased for both treatments from d 14 to 28, but increased from d 28 to 42 for WN, whereas Cr appearance continued to decrease for CON. The flux of mannitol and inulin did not differ between treatments but did differ among region of the GIT, with rumen, duodenum, and jejunum having the greatest permeability. These data suggest that permeability of the GIT decreases with age but weaning may disrupt this process. The rumen, duodenum, and jejunum appear to be the regions with greatest permeability.

Colostrum insulin supplementation does not influence immunoglobulin G absorption in neonatal Holstein bulls.

Since insulin has been demonstrated to suppress IgG absorption in other neonatal species, we had the objective to delineate how colostral insulin concentrations affect IgG absorption in neonatal bovines. We enrolled Holstein bull calves (n = 48; body weight = 46.3 ± 0.84 kg) at birth and randomized them by birth order to receive (1) colostrum that contained basal insulin concentrations (12.9 µg/L; n = 16), or colostrum that had been supplemented with an exogenous insulin to increase the insulin concentration to either (2) 5 times (70.0 µg/L; n = 16) or (3) 10 times (149.7 µg/L; n = 16) that of the basal colostrum. Gross colostrum composition (crude fat: 4.1 ± 0.06%; crude protein: 11.7 ± 0.05%; lactose: 1.9 ± 0.01%; IgG: 63.9 ± 1.19 g/L) was similar between treatments and calves were fed (7% body weight, 3.1 ± 0.06 L) their treatments at 2, 14, and 26 h postnatal. Serum was collected at 0, 30, 60, 90, 120, 180, 240, 360, 480, and 600 min postprandial respective to the first and second colostrum feeding and analyzed for IgG concentration. The incremental area under the curve (I-AUC) and apparent efficiency of absorption (AEA) were calculated for the 10-h periods following the first and second colostrum meal. Serum IgG concentrations over time, I-AUC, and AEA were statistically analyzed as a complete randomized design. Colostrum insulin concentration did not affect serum IgG concentrations or the I-AUC or AEA after calves were fed colostrum at 2 and 14 h postnatal. High colostral insulin content is not detrimental or promotive to IgG absorption in neonatal Holstein bulls.

Posttransplant lymphoproliferative disorder presenting as multiple cystic lesions in a renal transplant recipient.

We report a case of a 67-year-old man who experienced allograft dysfunction following a renal transplantation from a donation after cardiac death. The postoperative course was initially complicated by episodes of E. coli urinary sepsis causing pyrexia and a raised creatinine level. Ultrasound scanning 5 weeks posttransplant revealed mild hydronephrosis with several parenchymal cystic areas measuring up to 2 cm with appearances suggestive of fungal balls. Aspirated fluid again grew Escherichia coli, and this was treated with the appropriate antimicrobial therapy. The patient continued to have episodes of culture-negative sepsis; therefore, a computed tomography scan was performed 6 months posttransplant, which revealed multiple lesions in the renal cortex as well as liver and spleen. Subsequent biopsy revealed an Epstein-Barr virus-driven lymphoproliferation consistent with a polymorphic posttransplantation lymphoproliferative disorder (PTLD). This rare case of PTLD presenting as multiple renal, hepatic and splenic lesions emphasizes the need for a high index of clinical suspicion for this condition. Abnormal para-renal allograft masses should be biopsied to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage.

Evaluation of a point-of-care meter for measuring glucose concentrations in dairy calves: A diagnostic accuracy study.

The objective of this cross-sectional, diagnostic accuracy study was to validate a human blood glucose meter (Contour Next One Meter, Ascensia Diabetes Care) for accuracy and precision when measuring blood glucose, and for diagnostic accuracy for hypoglycemic status in dairy calves using whole blood and blood plasma. A total of 49 male dairy calves [body weight (BW): 46.3 ± 0.8 kg] had jugular catheters placed within 75 min after birth. Thereafter, blood was withdrawn from the catheter at specific time points (-10, 10, 20, 30, 45, 60, 90, 120, 180, 240, 360, 480, and 600 min) relative to the first and second colostrum feedings (2 h 15 min and 14 h 5 min postnatal; feeding rate: 7% of BW wt/wt). The reference standard method for plasma glucose concentration was determined colorimetrically and in duplicate using the glucose oxidase-peroxidase reaction. Data were assessed for agreement between the glucose meter and the reference standard using Lin's concordance correlation coefficients (CCC), coefficients of determination (precision), and Bland-Altman plots. In addition, a mixed linear regression model was built using the reference method as the outcome, with the glucose meter and repeated measures of time as the explanatory variables and calf as a random effect. The sensitivity (Se), specificity (Sp), and area under the curve (AUC) for the glucose meter using calf whole-blood and plasma were calculated at a threshold of <4.44 mmol/L to determine hypoglycemia. The precision (CCC = 0.95, R2 = 0.93) and accuracy (AUC = 0.98) of the glucose meter were very high when used on 1,303 blood plasma samples. Youden's index revealed a threshold of <4.45 mmol/L for the glucose meter when used with plasma, leading to Se of 94.2% and Sp of 91.9%, with 92.5% of samples being correctly classified, suggesting high diagnostic accuracy. When using whole blood, precision (CCC = 0.85 and R2 = 0.73) and accuracy (AUC = 0.92) were high when used on 476 samples. Youden's index revealed a threshold of <4.95 mmol/L for the glucose meter when used with whole calf blood, leading to Se of 95.6% and Sp of 80.3%, with 84.7% of samples being correctly classified, suggesting high diagnostic accuracy for use on farm. In summary, this glucose meter was validated for measuring calf blood glucose using both plasma and whole blood. This meter can measure glycemic status in calves and may be useful for clinical and on-farm use to make intervention decisions.

Domain organization of I kappa B alpha and sites of interaction with NF-kappa B p65.

The DNA-binding activity and cellular distribution of the transcription factor NF-kappa B are regulated by the inhibitor protein I kappa B alpha. I kappa B alpha belongs to a family of proteins that contain multiple repeats of a 30- to 35-amino-acid sequence that was initially recognized in the erythrocyte protein ankyrin. Partial proteolysis has been used to study the domain structure of I kappa B alpha and to determine the sites at which it interacts with NF-kappa B. The data reveal a tripartite structure for I kappa B alpha in which a central, protease-resistant domain composed of five ankyrin repeats is flanked by an unstructured N-terminal extension and a compact, highly acidic C-terminal domain that is connected to the core of the protein by a flexible linker. Functional analysis of V8 cleavage products indicates that I kappa B alpha molecules lacking the N-terminal region can interact with and inhibit the DNA-binding activity of the p65 subunit of NF-kappa B, whereas I kappa B alpha molecules which lack both the N- and C-terminal regions are incapable of doing so. Protease cleavage of the N terminus of I kappa B alpha was unaffected by the presence of the p65 subunit of NF-kappa B, whereas bound p65 blocked cleavage of the flexible linker connecting the C-terminal domain to the ankyrin repeat-containing core of the protein. This linker region is highly conserved within the human, rat, pig, and chicken homologs of I kappa B alpha, and while it has been suggested that it represents a sixth ankyrin repeat, it is also likely that this is a flexible region of the protein that interacts with NF-kappa B.

Transcription of the mouse ribosomal spacer region.

This paper describes experiments designed to test the hypothesis that DNA sequences upstream from the mouse rRNA promoter are transcribed in vivo or in vitro. Plasmid pB28 contains a SalI restriction fragment that extends from -169 to -1,894 base pairs, with respect to the origin of transcription of pre-rRNA. Labeled RNA synthesized in intact cells does not hybridize to this region. Neither S1 nuclease mapping nor RNA dot blot hybridization revealed the presence of sequences complementary to this region. Transcriptional studies carried out in vitro indicated that this region is not transcribed under conditions that are optimal for utilization of the authentic rRNA promoter. Moreover, this region does not appear to form stable transcription complexes with RNA polymerase I transcription components. These data indicate that the mouse rDNA repeating unit differs from those of Xenopus spp. and Drosophila melanogaster in that reduplicated RNA polymerase I promoters are not found in the mouse rDNA spacer region.

Acute renal failure due to mantle cell lymphoma--a case report and discussion of the literature.

Acute renal failure secondary to lymphomatous infiltration of the kidneys is a rare manifestation raer mantle cell lymphoma (MCL). We present the case of a 76-year-old gentleman with acute renal failure an a background of previously treated low grade non-hodgkin lymphoma. At the time of presentation he complained only of mild lethargy und had no lymphadenopathy or organomegaly. Renal ultrasound revealed bilaterally enlarged kidneys and renal biopsy confirmed MCL. Mantle cell lymphoma runs an aggressive course and accurate diagnosis is very important in guiding appropriate treatment. This case demonstrates the importance of renal biopsy in the diagnosis of renal lymphomatous infiltration but also highlights the potential utility of histological examination in guiding targeted therapy.

Limitations in the ability of NB84 to detect metastatic neuroblastoma cells in bone marrow.

BACKGROUND: The accurate assessment of metastases is an essential component of the staging process for children with neuroblastoma. AIMS: To study the sensitivity of the immunohistochemical marker neuroblastoma 84 (NB84) for the detection of bone marrow infiltrates in children with stage 4 neuroblastoma. METHODS: Primary tumour specimens, bone marrow trephine biopsy specimens and lymph node metastases, taken from children with neuroblastoma that had metastasised to bone marrow, were assessed with a panel of commonly used immunohistochemical markers for neuroblastoma. A comparison was drawn between the sensitivity of the marker NB84 for primary tumours and for bone marrow metastases. RESULTS: NB84 immunolabelled all pre-chemotherapy and post-chemotherapy (n = 24) paired primary tumour specimens, as well as each of a further 20, unpaired, pre-chemotherapy primary tumour specimens. It also labelled all (n = 4) lymph node metastases. Immunolabelling of bone marrow trephine biopsy specimens (21/33) was less sensitive. Of 16 primary tumour specimens with a paired bone marrow trephine biopsy specimen, all immunostained positive, whereas only 62.5% of bone marrow biopsy specimens immunostained positive for NB84. The number of bone marrow biopsy specimens immunostaining for NB84 was significantly lower than the number of paired primary tumour specimens (p = 0.041). CONCLUSIONS: NB84 remains a useful marker for the diagnosis of neuroblastoma in primary tumour specimens, but not for neuroblastoma that has metastasised to bone marrow.

The effect of monensin concentration on dry matter intake, ruminal fermentation, short-chain fatty acid absorption, total tract digestibility, and total gastrointestinal barrier function in beef heifers.

In a 4 × 4 Latin square design (24-d periods), 4 ruminally cannulated Hereford × Angus/Simmental heifers were used to evaluate the effect of increasing levels of monensin concentration on DMI, ruminal fermentation, short-chain fatty acid (SCFA) absorption across the reticulorumen, and total tract barrier function. Heifers were fed a barley-based finishing diet (76% rolled barley grain, 12% barley silage, 8% mineral and vitamin supplement, and 4% canola meal) containing 0, 22, 33 or 48 mg/kg monensin. Urinary recovery of Cr-EDTA was used as an indicator of total tract barrier function (d 18 to 20). Days 20 to 23 were used to evaluate ruminal fermentation and total tract digestibility measurements, and SCFA absorption was measured using the temporarily isolated and washed reticulorumen technique on d 24. Data were analyzed using PROC MIXED of SAS with linear and quadratic contrasts to evaluate the effect of increasing monensin dose. Increasing monensin linearly decreased DMI (10.0, 9.9, 9.3, and 9.1 kg/d for diets containing 0, 22, 33 or 48 mg/kg monensin, respectively; = 0.01) but did not affect the variation in DMI among days. Urinary Cr-EDTA recovery was not ( ≥ 0. 61) affected by increasing dose of monensin, nor was ruminal pH (mean, minimum, maximum, duration less than 5.5, and area under curve; ≥ 0.21). The acetate-to-propionate ratio linearly decreased (1.9, 1.8, 1.4, and 1.3 for diets containing 0, 22, 33 or 48 mg/kg monensin, respectively; = 0.03) with increasing monensin. There was no response ( ≥ 0. 17) for the rate of SCFA absorption with monensin concentration. Total tract ethanol soluble carbohydrate digestibility linearly increased (77.2, 84.7, 88.0, and 94.0% for diets containing 0, 22, 33 or 48 mg/kg monensin, respectively; = 0.003) whereas starch digestibility quadratically responded (93.8, 93.9, 88.0, and 94.0% for diets containing 0, 22, 33 or 48 mg/kg monensin, respectively; < 0.001), where 33 mg/kg inclusion of monensin had a minimal value. The results from this study indicate that in addition to the known effects of monensin to reduce DMI and the acetate:propionate ratio, monensin inclusion does not affect ruminal pH, SCFA absorption, or total tract barrier function.

Effects of subacute ruminal acidosis and low feed intake on short-chain fatty acid transporters and flux pathways in Holstein steers.

The objective of this study was to investigate the role of protein-mediated transport pathways for short-chain fatty acid flux across the ruminal epithelium, using subacute ruminal acidosis (SARA) and feed restriction as models. Twenty-one Holstein steers (216.8 ± 31.4 kg BW) were individually housed and fed a total mixed ration (TMR) with a 50:50 forage:concentrate ad libitum for 5 d. After the 5 d diet adjustment period, calves were assigned 1 of 3 treatments: control (CTRL) calves were fed the TMR ad libitum on d 1, subacute ruminal acidosis calves were given 25% of their ad libitum DMI on d 1 and then given a barley grain challenge at 30% of ad libitum DMI on d2 (ACID) calves were given 25% of their ad libitum DMI on d 1 and then given a barley grain challenge at 30% of ad libitum DMI on d 2, and feed restriction (FR) calves were given 25% of their ad libitum DMI for 5 d. Reticuloruminal pH was continuously measured during the entire study. At the end of the study, rumen tissue was harvested and acetate and butyrate flux were measured. Selective inhibitors were used to differentiate total flux (TOTAL), protein-mediated flux (PMF), and passive diffusion flux (PDF). The duration that rumen pH was <5.6 was greater in ACID calves compared with CTRL and FR calves (57 ± 90 vs. 519.71 ± 90 vs. 30 ± 90 min/d for CTRL, ACID, and FR, respectively; < 0.01). Total acetate flux was greater in FR than in CTRL (630.6 ± 38.9 vs. 421.1 ± 41.4 nmol/cm × h, respectively; < 0.01), but no difference was observed between CTRL and ACID (421.1 ± 41.4 vs. 455.4 ± 38.9 nmol/cm × h, respectively). Also, total butyrate flux was greater in FR than in CTRL (1,241.9 ± 94.8 vs. 625.5 ± 86.3 nmol/cm × h, respectively; < 0.01), but no difference was detected between CTRL and ACID (625.5 ± 86.3 vs. 716.7 ± 81.0 nmol/cm × h, respectively). For butyrate flux, PMF was greater for FR than for CTRL (479.21 ± 103.9 vs. 99.9 ± 86.3 nmol/cm × h, respectively; < 0.01), but no difference was observed between the CTRL and ACID treatments (99.9 ± 86.3 vs. 90.2 ± 81.0 nmol/cm × h, respectively). Immunofluorescence analysis showed an increase in monocarboxylate cotransporter isoform 1 abundance in the FR treatment compared with the ACID treatment (9,250 ± 1,648 vs. 4,187 ± 1,537 arbitrary units, respectively; = 0.03) but not compared with the CTRL treatment (9,250 ± 1,648 vs. 7,241 ± 1,648 arbitrary units, respectively; = 0.15). These data identify a short-term adaptive response of the ruminal epithelium to dietary changes that involves PMF and PDF.

Defective IkappaBalpha in Hodgkin cell lines with constitutively active NF-kappaB.

The molecular mechanisms underlying Hodgkin's disease remain obscure, but it has been recognized that the neoplastic cells display high levels of constitutively active nuclear NF-kappaB. Here we demonstrate that although nuclear NF-kappaB is transcriptionally active, the Hodgkin cells fail to activate NF-kappaB dependent transcription in response to CD40 ligand. In three Hodgkin cell lines examined each had abnormalities in expression of IkappaBalpha which could account for the deregulated NF-kappaB. Although all three cell lines had greater than normal levels of IkappaBalpha mRNA no IkappaBalpha protein could be detected in the KM-H2 cells, while the L428 cell line contains a C-terminally truncated IkappaBalpha species that fails to associate with NF-kappaB. The HDLM-2 cell line contains a more slowly migrating form of IkappaBalpha that can associate with NF-kappaB, but increasing the level of this protein within the cell fails to inhibit nuclear NF-kappaB. Addition of recombinant IkappaBalpha to nuclear extracts from all three cell lines resulted in complete inhibition of NF-kappaB DNA binding activity and introduction of a plasmid expressing IkappaBalpha into the cells inhibited the transcriptional activity of an NF-kappaB dependent reporter plasmid. Thus the constitutive expression of NF-kappaB in Hodgkin cells is a direct consequence of the abnormal expression of IkappaBalpha rather than changes in NF-kappaB that render it refractory to inhibition by IkappaB proteins. These changes could, at least in part, account for the characteristic activated phenotype of Hodgkin cells and their pattern of cytokine secretion, which determine the pathological appearance and clinical manifestations of Hodgkin's disease.

Isolation and characterization of lymphosarcoma P1798 variants selected for resistance to the cytolytic effects of glucocorticoids in vivo and in culture.

Clonal subpopulations of lymphosarcoma P1798 have been subjected to glucocorticoid selection in vivo and in culture and the glucocorticoid binding and responsiveness of the resistant variants have been compared with those of the parental lines. Cell populations that are resistant to the cytolytic effects of glucocorticoids in vivo exhibit a slightly reduced level of glucocorticoid binding, although nuclear translocation of the hormone-receptor complex is not reduced. Sensitive and resistant tumors exhibit similar kinetics of hormone uptake and dissociation following a single injection of dexamethasone. Selection for glucocorticoid resistance in vivo does not result in an increase in the modal number of chromosomes. Cells that are resistant to the cytolytic effects of glucocorticoids in vivo are completely sensitive to the antiproliferative effects of glucocorticoids in culture. Moreover, dexamethasone increases the expression of mouse mammary tumor provirus in cytolysis-resistant and sensitive cells both in vivo and in culture. Selection for glucocorticoid resistance in culture yields variants with decreased glucocorticoid binding and/or nuclear translocation of the hormone-receptor complex. These cells appear to express classical receptor-defective phenotypes. Nevertheless, cells that are resistant to glucocorticoids in culture undergo cytolysis when treated with glucocorticoids in vivo. These data indicate that, under certain circumstances, different mechanisms may be involved in loss of glucocorticoid responsiveness in vivo and in culture.

Loss of nuclear expression of the p33(ING1b) inhibitor of growth protein in childhood acute lymphoblastic leukaemia.

BACKGROUND/AIMS: p33(ING1b) is a tumour suppressor protein involved in growth control and apoptosis. Suppression of p33(ING1b) expression is associated with the loss of cellular growth control and immortalisation, whereas its overexpression causes cell cycle arrest. Moreover, normal p33(ING1b) expression is essential for optimal function of p53. Acute lymphoblastic leukaemia (ALL) is the most common malignancy of childhood, accounting for one third of all childhood malignancies. A variety of cytogenetic abnormalities have been described but there is no single abnormality common to all cases. Deregulation of the TP53 pathway is a common genetic abnormality in human malignancies. However, TP53 mutations are uncommon in ALL. It is possible that alternative mechanisms of regulation of the TP53 apoptosis pathway, such as modulation of p33(ING1b) expression, may be important in ALL. The aim of this study was to assess the expression of p33(ING1b) in childhood ALL. METHODS: One hundred and forty five patients with childhood ALL were investigated in this immunohistochemical study of the expression of p33(ING1b). RESULTS: Loss of nuclear expression of p33(ING1b) was seen in 78% of cases. This was associated with increased cytoplasmic expression of the protein. Kaplan Meier survival analysis demonstrated a trend towards a better prognosis for patients with tumours that had lost nuclear p33(ING1b). CONCLUSION: These results suggest that the loss of nuclear p33(ING1b) expression may be an important molecular event in the pathogenesis of childhood ALL.

Kinetics of the interaction of sertraline with the human platelet plasma membrane 5-hydroxytryptamine carrier.

Sertraline, a new selective 5-HT uptake inhibitor showed a mixed pattern of inhibition of human platelet 5-HT uptake with a Ki value of 2.5 nM and K'i value of 25 nM. Imipramine and alaproclate were found to be fully competitive inhibitors of 5-HT uptake with Ki values of 8 and 130 nM respectively. Sertraline was a fully competitive inhibitor of high-affinity [3H]imipramine binding to platelet membranes with a Ki value of 1.3 nM, as was alaproclate and 5-HT with Ki values of 170 and 800 nM respectively. Both sertraline and imipramine, at a concentration of 10 microM caused a fast monophasic dissociation of [3H]imipramine from platelet membranes in contrast to serotonin which caused a slow monophasic dissociation.

Treatment of bipolar affective illness with zimeldine, a 5-HT uptake inhibitor.

A small group of patients who had been successfully treated with lithium for a number of years were treated with zimeldine in order to determine whether this antidepressant could be substituted for lithium in patients with a bipolar affective illness. The proposed treatment period of 6 months was not reached by any patient due to depression, hypomania, mania or unusual adverse symptoms. The results of this pilot study suggest that bipolar patients being treated with lithium should not then be treated by antidepressants including those which are potent and selective inhibitors of 5-HT uptake.

Immediate memory functions in reading disability subtypes.

This study examined immediate memory processes in specific reading disability subtypes. Three subgroups (n = 15 in each subgroup) of reading disabled children were examined: (a) perceptual-motor disorder, (b) verbal disorder-general, and (c) verbal disorder-specific (memory). The three groups were matched for age and full scale IQ. All children received a memory-for-colors task (Color Span Test) designed to evaluate intra- and intermodal serial memory functioning. Comparison of memory profiles for the three reading disability subtypes revealed that patterns varied depending on mode of stimulus presentation or response. Although all three groups performed considerably below normative levels on each of the four subtests of the Color Span Test, all subjects performed significantly better on verbally presented items than on visually presented items. The findings were interpreted to suggest that these reading disabled children may not consistently utilize verbal strategies for coding or retrieval of information when stimuli are visually presented.

A possible suicide by diltiazem overdose.

This report describes a possible suicide by overdosage with diltiazem. The decreased, a 39-year-old male who had been under treatment for an unidentified heart condition, was discovered on the bathroom floor in his residence. Comprehensive drug screens performed on available postmortem specimens revealed the presence of 6.9 mg/L diltiazem, 0.182 g/100 mL ethanol, and a trace of propranolol in blood, and 4.7 mg/L diltiazem and 0.251 g/100 mL ethanol in urine.

Effects of alternative techniques of low-dose heparin administration on hematoma formation.

A small clinical trial was conducted to compare a modified subcutaneous injection technique with the standard subcutaneous method. The data in this study do not strongly support the use of either technique. However, the modified subcutaneous method may be preferable in that fewer injection-site hematomas formed. Further research with a larger population is indicated before either method can be recommended over the other.