Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis

Lymphoblasts in bone marrow samples, obtained from 43 children with acute lymphoblastic leukemia at diagnosis, were incubated with 1.0 mumols/L [3H] methotrexate for 24 hours in vitro. Nonexchangeable methotrexate and methotrexate polyglutamates were separated and quantitated. Event-free survival at 5 years was 38% +/- 9% for all 43 patients (27 failures), and 44% +/- 10% for the 35 with non-T, non-B- cell acute lymphoblastic leukemia (20 failures). Of these 35 children, those whose lymphoblasts accumulated more than 100 pmol methotrexate and 500 pmol methotrexate polyglutamates per billion cells experienced better 5-year event-free survival than those whose lymphoblasts did not (65% +/- 12% v 22% +/- 9%, P = .010). This difference characterized "good-risk" patients who were female (P = .014), less than age 7 at diagnosis (P = .005), or had low initial white blood cell counts (less than 20 X 10(9)/L, P = .018). Findings were similar for the 43 children with acute lymphoblastic leukemia and for the "good-risk" children in this total group. Thus, the ability of lymphoblasts to accumulate methotrexate and form methotrexate polyglutamates may be important to the curative properties of current therapy of acute lymphoblastic leukemia in children, particularly for "good-risk" patients. In such patients, inherent rather than acquired drug resistance may be the initial event leading to treatment failure.     

Nucleus of the solitary tract in the C57BL/6J mouse: Subnuclear parcellation,chorda tympani nerve projections,and brainstem connections

The nucleus of the solitary tract (NST) processes gustatory and related somatosensory information rostrally and general viscerosensory information caudally. To compare its connections with those of other rodents, this study in the C57BL/6J mouse provides a subnuclear cytoarchitectonic parcellation (Nissl stain) of the NST into rostral, intermediate, and caudal divisions. Subnuclei are further characterized by NADPH staining and P2X₂ immunoreactivity (IR). Cholera toxin subunit B (CTb) labeling revealed those NST subnuclei receiving chorda tympani nerve (CT) afferents, those connecting with the parabrachial nucleus (PBN) and reticular formation (RF), and those interconnecting NST subnuclei. CT terminals are densest in the rostral central (RC) and medial (M) subnuclei; less dense in the rostral lateral (RL) subnucleus; and sparse in the ventral (V), ventral lateral (VL), and central lateral (CL) subnuclei. CTb injection into the PBN retrogradely labels cells in the aforementioned subnuclei; RC and M providing the largest source of PBN projection neurons. Pontine efferent axons terminate mainly in V and rostral medial (RM) subnuclei. CTb injection into the medullary RF labels cells and axonal endings predominantly in V at rostral and intermediate NST levels. Small CTb injections within the NST label extensive projections from the rostral division to caudal subnuclei. Projections from the caudal division primarily interconnect subnuclei confined to the caudal division of the NST; they also connect with the area postrema. P2X₂‐IR identifies probable vagal nerve terminals in the central (Ce) subnucleus in the intermediate/caudal NST. Ce also shows intense NADPH staining and does not project to the PBN. J. Comp. Neurol. 522:1565–1596, 2014. © 2013 Wiley Periodicals, Inc.     

Exploration of pressure ulcer and related skin problems across the spectrum of health care settings in Ontario using administrative data

This is a prospective cohort study using population‐level administrative data to describe the scope of pressure ulcers in terms of its prevalence, incidence risk, associating factors and the extent to which best practices were applied across a spectrum of health care settings. The data for this study includes the information of Ontario residents who were admitted to acute care, home care, long term care or continuing care and whose health care data is contained in the resident assessment instrument‐minimum data set (RAI‐MDS) and the health outcomes for better information and care (HOBIC) database from 2010 to 2013. The analysis included 203 035 unique patients. The overall prevalence of pressure ulcers was approximately 13% and highest in the complex continuing care setting. Over 25% of pressure ulcers in long‐term care developed one week after discharge from acute care hospitalisation. Individuals with cardiovascular disease, dementia, bed mobility problems, bowel incontinence, end‐stage diseases, daily pain, weight loss and shortness of breath were more likely to develop pressure ulcers. While there were a number of evidence‐based interventions implemented to treat pressure ulcers, only half of the patients received nutritional interventions.     

Factors causing malnutrition in patients with chronic uremia

There is abundant evidence that patients with chronic renal failure (CRF), including those treated by hemodialysis or peritoneal dialysis, have evidence of malnutrition with decreased body weight and subnormal values of serum proteins (suggesting a loss of visceral protein stores). Potential causes of an abnormal nutritional status that have been identified include an inadequate intake of protein or calories, an inability to activate the metabolic responses that are needed to achieve nitrogen and protein balance, or the presence of a disease that prevents activation of these metabolic responses or acts to stimulate the breakdown of body protein stores. Three critical metabolic responses to a limited protein intake have been identified: a reduction in the irreversible degradation of amino acids and the degradation of protein breakdown and an increase in protein synthesis in response to a meal. Metabolic acidosis blocks the first two responses and hence contributes to malnutrition in patients with chronic uremia. Other factors that could contribute to malnutrition include an inadequate intake because of anorexia or hormonal imbalances that impair protein turnover. In evaluating CRF patients with malnutrition, the first task is to ensure an adequate intake and to eliminate factors that impair the ability to achieve nitrogen balance.     

Gait analysis of walking before and after medial opening wedge high tibial osteotomy

Introduction

Medial opening wedge high tibial osteotomy (HTO) is used to treat medial compartment osteoarthritis (OA) of the knee. HTO shifts the weight-bearing line from the medial compartment into the lateral compartment. The aim of this study was to investigate the functional biomechanical consequences of this alteration in alignment.

Methods

Eleven male patients with medial compartment osteoarthritis underwent three-dimensional gait analysis during level walking before 12 months and after medial opening wedge HTO. Nine male control subjects of a similar age were also tested using the same protocol. Sagittal and coronal angles and moments in both operated and non-operated knees were compared. Pre and postoperative radiographic coronal plane alignment was also measured.

Results

Walking speed increased significantly postoperatively (P = 0.0001) and was not different from controls. Preoperatively, maximum knee flexion in stance was reduced compared to control (P = 0.02). Postoperatively, maximum knee flexion increased significantly (P = 0.005) and was the same as the controls. Similar changes were observed for the maximum knee flexion moment. The mean maximum varus angle during stance was reduced from 13.5° preoperatively to 5.4° postoperatively (P = 0.0001) compared to (6.8°) in controls. The mean maximum adduction moment also reduced from 3.9 to 2.7 (% Bw/ht, P = 0.02), compared to 3.6 in control subjects. Interestingly, the adduction moments in the non-operated knee increased postoperatively from 3.3 to 4.1 (% Bw/ht, P = 0.02). The mean radiological mechanical alignment was changed from 172 degrees preoperatively to 180 degrees postoperatively (P < 0.001).

Conclusion

HTO resulted in normalisation of several dynamic knee function parameters such as walking speed, knee flexion and external knee flexion moment. As anticipated, HTO reduced the varus angle and adduction moments of the operated knee. An increased adduction moment in the non-operated knee over the first postoperative year was found.

Level of evidence

Prospective case–control clinical laboratory study, Level III.     

Drug-induced thrombocytopenia is associated with increased binding of IgG to platelets both in vivo and in vitro

Thrombocytopenia is a common serious adverse effect of drug treatment. A variety of in vitro diagnostic techniques to confirm the diagnosis are available, but the majority lack sufficient sensitivity to detect all cases of drug-induced thrombocytopenia. We studied 19 patients with suspected drug-induced thrombocytopenia and demonstrated that platelet- associated IgG (PAIgG) was elevated in all at the time of thrombocytopenia, and PAIgG returned to normal levels as the thrombocytopenia resolved. In the majority of patients, the platelet count rapidly returned to normal after the drug was discontinued; however, in six patients, the thrombocytopenia persisted well beyond the period of time that the offending drug would be expected to be cleared from the blood. In 13 patients, serum obtained after recovery was used to identify the drug responsible for the thrombocytopenia in an in vitro assay. In all cases, the addition of the drug historically associated with the thrombocytopenic episode was associated with an increased binding of IgG to control platelets. For uncertain reasons, the concentration of drug required to increase the in vitro binding of IgG to test platelets was often more than the concentration usually achieved in vivo. Wider application of these techniques may provide better understanding of the clinical characteristics and mechanisms responsible for drug-induce thrombocytopenia.     

The results of combined cataract extraction and trabeculectomy using separate incisions

A method of combined cataract extraction with posterior chamber intraocular lens and trabeculectomy using separate incisions was tested in 44 operations on 38 patients. The mean preoperative intraocular pressure (IOP) of 28.1 ± 11.7 (range 12 to 56) mmHg on maximum medication was lowered to 13.9 ± 3.4 (9 to 23) mmHg at one year, with half the eyes still requiring topical medication. The IOP was 40 mmHg or more preoperatively in eight eyes and 20 mmHg or more in only two patients at one year. There were no rises in IOP above 20 mmHg in the early postoperative period (days 1 and 2). Visual acuity was 6/9 or better in 27 and 6/12 in three eyes. There was an expulsive haemorrhage in one case, rupture of the posterior capsule in two eyes and a choroidal detachment in one eye, but no flat anterior chambers. The two-incision method allowed placement of an intraocular lens with good postoperative pressure control.