Paracetamol absorption from a feeding jejunostomy.

Disposition of paracetamol oral elixir was determined in two male patients after administration via feeding jejunostomy and compared with four male controls who received the same dose by mouth. Area under the plasma concentration-time curve, elimination half-life, and time to maximum concentration were similar in both groups after 650 mg paracetamol elixir. The absolute amounts and ratio of paracetamol glucuronide to sulphate, the major urinary metabolites after therapeutic paracetamol doses, were similar after jejunal administration as compared to oral administration. Paracetamol is absorbed and biotransformed in a similar manner after either jejunal or oral administration. Therefore, it may be administered effectively via jejunostomy tube in patients who require this route of administration.     

Calcium, network activity, and the role of NMDA channels in synaptic plasticity in vitro.

Functionally effective neuronal circuits are constructed through a competitive process that requires patterned neuronal activity elicited by structured input from the environment. To explore the mechanisms of this activity-dependent synaptic restructuring, we have developed an in vitro preparation of mouse spinal cord neurons maintained in a 3-chambered cell-culture system. Sensory afferents that received chronic electrical stimulation for 3-5 d developed stronger synaptic connections than unstimulated afferents converging onto the same postsynaptic spinal cord neuron. Exposure to 100 microM DL-2-amino-5-phosphonovaleric acid (APV), an antagonist of the NMDA channel, during the stimulation period prevented the competitive advantage associated with electric stimulation. However, when APV was applied with a higher concentration of calcium (3 mM), activity-dependent synaptic plasticity was no longer inhibited by the NMDA receptor antagonist. This reversal of APV block of the plasticity was not impaired by reducing transmitter release with 3 mM magnesium (in addition to 3 mM calcium and APV). A suppressant effect of APV on spontaneous activity was observed, which was attributed to loss of the NMDA component of the EPSP. Activity-dependent plasticity was also blocked if spontaneous activity was suppressed with dilute tetrodotoxin (TTX; 5-10 nM), a dosage that reduces excitability of neurons but is insufficient to block sodium-dependent action potentials. These experiments bring into question how NMDA channel activation is involved in the processes of synaptic remodeling during development. The data suggest that postsynaptic activity is required for synaptic remodeling, but this activity need not involve NMDA receptor activation specifically for activity-evoked synaptic plasticity. Instead, the mechanism for plasticity appears to operate through calcium-dependent processes in general.     

Neutropenic enterocolitis in adults with acute leukemia

Neutropenic enterocolitis has been previously described only by case reports and literature reviews. Of 499 adults with acute leukemia seen over a 23-year period (1962 to 1985), 13 cases (2.6%) of neutropenic enterocolitis have been reported. Eleven of these 13 patients were profoundly neutropenic (mean white blood cell count, 472/cu mm) and developed abdominal symptoms during either initial induction or relapse of acute leukemia. Histologic confirmation was available in ten cases, five cases after surgical resection and five cases at autopsy after nonoperative management. Three patients with isolated ileocecal inflammation without infarction at the time of surgery were successfully managed without resection. Five patients treated with surgery died four to 64 weeks postoperatively (mean survival, 21.6 weeks) of nonsurgical complications of leukemia. Three patients were still alive, one patient 42 months after right hemicolectomy and two patients five months after exploration only. All five patients managed medically died an average of 1.4 days (range, zero to four days) after the onset of abdominal pain. Survival in patients with acute leukemia who develop neutropenic enterocolitis is determined by early recognition and appropriate surgical exploration that can be expected to yield an acceptable operative mortality.     

The effects of hyponatraemia and subarachnoid haemorrhage on the cerebral vasomotor responses of the rabbit

Impairment of cerebral autoregulation and development of hyponatraemia are both implicated in the pathogenesis of delayed cerebral ischaemia and infarction following subarachnoid haemorrhage (SAH) but the pathophysiology and interactions involved are not fully understood. We have studied the effects of hyponatraemia and SAH on the cerebral vasomotor responses of the rabbit. Cerebrovascular reactivity to hypercapnia and cerebral autoregulation to trimetaphan-induced hypotension were determined in normal and hyponatraemic rabbits before and 6 days after experimental SAH produced by two intracisternal injections of autologous blood. Hyponatraemia (mean plasma sodium of 119 mM) was induced gradually over 48 h by administration of Desmopressin and intraperitoneal 5% dextrose. Sham animals received normal saline. The cerebrovascular reactivity (% change +/- SD in cortical CBF/mm Hg PaCO2, measured by hydrogen clearance) of hyponatraemic (4.8 +/- 3.0%) and SAH (1.3 +/- 2.0%) animals was significantly less (p less than 0.05) than control (11.6 +/- 4.0%) and sham (8 +/- 2.0%) animals, whereas the reactivity of hyponatraemic-SAH animals was preserved (9.8 +/- 6.0%). Hyponatraemia and SAH alone each significantly impaired CBF autoregulation but their combined effects were not additive. Systemic hyponatraemia impairs normal cerebral vasomotor responses but does not augment the effects of experimental SAH in the rabbit.     

Developmental neurotoxicology of in utero exposure to industrial solvents in experimental animals

In summary, relatively few solvents have been examined for developmental neurotoxicology. Although most of the studies have not been replicated, the majority of the solvents tested have produced significant differences from controls. Many used inhalation, which is often the most likely route of occupational or environmental exposure. The majority have extended the exposure for much of gestation of rats. The extensive usage of solvents and the proportion of those tested which have produced positive effects (although admittedly some not at environmentally-relevant exposure concentrations), make a strong case for additional testing of industrial solvents for developmental neurotoxicology.     

Neonatal reference values for ionized calcium, phosphate and magnesium. Selection of reference population by optimality criteria

Thirty-one full-term newborn babies were investigated in order to establish reference values for ionized calcium. Only children fulfilling certain optimality criteria (with best possible maternal and infant conditions and uncomplicated pregnancy and delivery) were included. All infants were breast fed. Capillary blood for analysis of ionized calcium was collected by heel puncture on day 1 (6-36 h post partum, p.p.), day 3 (60-84 h p.p.) and day 5 (108-132 h p.p.). Ionized calcium was measured with a semi-automatic electrode system ICA 1 (Radiometer A/S, Copenhagen, Denmark). The reference ranges (mean +/- 2 SD) for days 1, 3 and 5 were 1.05-1.37, 1.10-1.42 and 1.20-1.48 mmol/l, respectively. The mean ionized calcium concentration on day 1 was significantly lower than on days 3 and 5. Reference values are also given for total calcium, magnesium and phosphate. We emphasize that it is impossible to calculate ionized calcium from total calcium or vice versa.     

Intrapartum fetal heart rate patterns and neonatal intraventricular hemorrhage

A goal for the obstetrician and neonatologist is to screen for risk factors associated with intraventricular hemorrhage (IVH) in the low-birthweight infant. Perinatal events that lead to neonatal metabolic and cardiovascular derangements seem to provoke IVH, and conflicting reports have implicated labor as being contributory. A fetal heart rate (FHR) abnormality during premature labor may be a predictor of subsequent neonatal IVH. For this reason, 5 years of FHR tracings at two university medical centers were reviewed for inborn infants who were delivered after premature labor and weighed less than or equal to 2000 gm. Sixty-four infants developed IVH, but pre-existing labor with a discernible FHR pattern was recorded in only 38 (59%) cases. Interpretations were reassuring in 17 (45%) cases, suspicious in 7 (18%) cases, and ominous in 14 (37%) cases. This proportion of FHR patterns was not significantly different from a matched group of premature infants without IVH during the same period. Interpretations of intrapartum FHR patterns of low-birthweight infants are limited, especially before 30 weeks gestation, and not useful in predicting neonatal IVH.     

Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial.

PURPOSE: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with irinotecan-based chemotherapy in first-line treatment of metastatic colorectal cancer (CRC). This randomized, phase II trial compared bevacizumab plus fluorouracil and leucovorin (FU/LV) versus placebo plus FU/LV as first-line therapy in patients considered nonoptimal candidates for first-line irinotecan. PATIENTS AND METHODS: Patients had metastatic CRC and one of the following characteristics: age > or = 65 years, Eastern Cooperative Oncology Group performance status 1 or 2, serum albumin < or = 3.5 g/dL, or prior abdominal/pelvic radiotherapy. Patients were randomly assigned to FU/LV/placebo (n = 105) or FU/LV/bevacizumab (n = 104). The primary end point was overall survival. Secondary end points were progression-free survival, response rate, response duration, and quality of life. Safety was also assessed. RESULTS: Median survival was 16.6 months for the FU/LV/bevacizumab group and 12.9 months for the FU/LV/placebo group (hazard ratio, 0.79; P = .16). Median progression-free survival was 9.2 months (FU/LV/bevacizumab) and 5.5 months (FU/LV/placebo); hazard ratio was 0.50; P = .0002. Response rates were 26.0% (FU/LV/bevacizumab) and 15.2% (FU/LV/placebo) (P = .055); duration of response was 9.2 months (FU/LV/bevacizumab) and 6.8 months (FU/LV/placebo); hazard ratio was 0.42; P = .088. Grade 3 hypertension was more common with bevacizumab treatment (16% v 3%) but was controlled with oral medication and did not cause study drug discontinuation. CONCLUSION: Addition of bevacizumab to FU/LV as first-line therapy in CRC patients who were not considered optimal candidates for first-line irinotecan treatment provided clinically significant patient benefit, including statistically significant improvement in progression-free survival.