Plasma magnesium should be monitored perioperatively in patients undergoing colorectal resection.

OBJECTIVE: Hypomagnesemia has been shown to have several clinically important sequelae. The aims of this study were: to assess the impact of bowel preparation, with sodium picosulphate (Picolax), on plasma electrolytes, with particular regard to plasma magnesium, in patients undergoing bowel preparation for colonoscopy and colorectal resection and to evaluate the influence of perioperative magnesium levels on postoperative cardiac dysrhythmias. METHOD: Sixty-one patients receiving sodium picosulphate (Picolax) bowel preparation were studied in two groups: Colonoscopy (31 patients) and Colorectal resection (30 patients). Plasma sodium, potassium, magnesium, calcium, urea, creatinine and blood haematocrit were measured in all patients prior to commencement of bowel preparation, at the time of colonoscopy or colorectal resection and 24 h postoperatively (surgery group only). Mean electrolyte and haematocrit levels were then compared. Postoperative cardiac dysrhythmias were recorded and analysed. RESULTS: No significant changes following bowel preparation were observed in plasma sodium, potassium, calcium or creatinine. Plasma urea fell following bowel preparation (colonoscopy P < 0.001, resection P = 0.004) and rose following resection (P = 0.002). Magnesium levels increased following bowel preparation in both groups (colonoscopy P < 0.001, resection P = 0.007) and fell following resection (P < 0.001). Thirty-four per cent (21/60 patients) were hypermagnesemic following bowel preparation and 20% (6/30 patients) became hypomagnesemic following surgery. Postoperative cardiac dysrhythmias were associated with lower magnesium levels at induction and postoperatively (P = 0.022 and P = 0.033). CONCLUSION: Bowel preparation with Picolax does not appear to cause significant electrolyte disturbance, except in elevating plasma magnesium. Postcolorectal resection plasma magnesium dropped significantly suggesting perioperative monitoring and replacement should be routine following colorectal surgery.

Prenatal cocaine exposure: decreased sensitization to cocaine and decreased striatal dopamine transporter binding in offspring.

Pregnant mice were treated with cocaine, 10 mg/kg/day, during days 13 to 20 of gestation. Cocaine sensitization and dopamine transporter binding were evaluated in offspring at 6 weeks of age. Sensitization, defined as the increase in activity after 5 injections of cocaine compared to 1 injection, was reduced in cocaine-exposed mice. Dopamine transporter binding in striatum was also significantly reduced in cocaine-exposed mice compared to controls.

Pregnenolone sulfate potentiation of NMDA-mediated increases in intracellular calcium in cultured chick cortical neurons.

Pregnenolone sulfate (PS) has been reported to selectively augment glutamate-induced depolarizations mediated by the NMDA subtype of the glutamate receptor. The present study examines the ability of this neuroactive steroid to potentiate NMDA-mediated increases in intracellular calcium in cultured chick cortical neurons using the fluorescent dye Fura2. PS, in the absence of NMDA and glycine, significantly elevated intracellular calcium at 250 and 500 microM. This increase in free calcium was significantly attenuated at 250 microM PS by the prior addition of 50 microM CNQX, 10 microM dizocilpine or 1 microM nimodipine. NMDA and glycine, when added to the cells in saturating concentrations of 500 and 50 microM, respectively, consistently increased intracellular free calcium over baseline levels. In the presence of NMDA and glycine, both 50 and 100 microM PS produced a further significant rise in intracellular free calcium. The prior addition of CNQX, dizocilpine or both compounds together significantly inhibited this elevation in free calcium. The application of the endogenous polyamine spermine (250 microM) significantly potentiated the response of chick cortical neuronal cells to NMDA and glycine. PS, in the presence of NMDA, glycine and spermine, produced a further increase in intracellular free calcium at concentrations of 50 and 100 microM. The prior application of CNQX, dizocilpine or both compounds together significantly attenuated this rise in free calcium. These data confirm that PS is a positive allosteric modulator of the NMDA receptor and provide evidence that this neurosteroid does not interact with the polyamine modulatory site.

Characterization of Ca2(+)-mobilizing excitatory amino acid receptors in cultured chick cortical cells.

The effects of glutamate and other more selective excitatory amino acid (EAA) analogs on intracellular free calcium concentration ( [Ca2+]i) were examined in Fura 2-loaded cultured chick embryo cortical cells (90% neuronal). Four EAA receptors were evident in these studies: an N-methyl-D-aspartate (NMDA) receptor, a kainate receptor, and two quisqualate receptors. The [Ca2+]i response to NMDA was blocked or reversed by selective antagonists such as 2-amino-5-phosphonovalerate (APV), MK801 and ketamine, as well as by desmethylimipramine and dextromethorphan. Glycine potentiated the [Ca2+]i response to NMDA, and high concentrations of glycine selectively overcame blockade by kynurenic acid, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and cis-piperidine-2,3-dicarboxylic acid (PDA). The [(Ca2+]i response to kainate was generally larger than the NMDA response, and the kainate response desensitized slightly over the first minute. CNQX was more potent as an antagonist of the kainate response than of the NMDA response, even in the absence of added glycine; kynurenic acid and PDA conversely had little effect on the kainate response in these cells at concentrations which blocked the NMDA response. The desensitization of the [Ca2+]i response to kainate was greatly augmented by quisqualate and by the putative ionotropic quisqualate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). In the absence of kainate, both quisqualate and AMPA increased [Ca2+]i though less so than did NMDA or kainate. Quisqualate (and AMPA and glutamate) were not acting as partial agonists at the kainate receptor, since the potency of these agonists in reversing the kainate [Ca2+]i response was independent of kainate concentration. Quisqualate, but not AMPA, also produced a small increase in [Ca2+]i which preceded the negative effect of this agonist on the kainate response. This increase in [Ca2+]i could also be evoked by quisqualate or glutamate after inhibition of the kainate response by AMPA. Quisqualate and glutamate, but not the other EAA agonists, also increased [Ca2+]i after chelation of extracellular calcium with EGTA. This effect appears to be mediated by the metabotropic quisqualate receptor. These cells should provide a useful system for studying regulation and interactions of EAA receptors, and for screening drugs which might act at these receptors.

Polyamine potentiation and inhibition of NMDA-mediated increases of intracellular free Ca2+ in cultured chick cortical neurons.

Polyamine potentiation and inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated Ca2+ changes was studied in cultured chick cortical neurons. Spermidine and spermine potentiated the effect of saturating concentrations of NMDA and glycine. No effect of spermidine or spermine was observed in the absence of NMDA or in the presence of either kainate or quisqualate. Similarly, antagonism of the NMDA receptor complex with dizocilpine (an open channel blocker), or with competitive antagonists to the NMDA or glycine binding sites greatly attenuated or completely abolished the combined effects of polyamines plus NMDA and glycine. N-Acetylspermine and N-acetylspermidine, in the presence or absence of NMDA and glycine, were without effect. These data strongly suggest that spermidine and spermine are potent and selective agonists at the polyamine binding site. Putrescine and diethylenetriamine were ineffective as antagonists of NMDA-mediated intracellular free Ca2+ increases in the presence or absence of added spermine or spermidine. Arcaine and 1,10-diaminodecane, however, antagonized NMDA-mediated intracellular free Ca2+ increases in the presence and absence of spermine and spermidine, and therefore appear to act either as inverse agonists at the polyamine binding site or as open channel blockers of the NMDA receptor.

Polyamine neurotoxicity is antagonized by dizocilpine in cultured chick cortical neurons.

Release of endogenous polyamines may contribute to neuronal loss in ischemia and related conditions. Primary cortical neurons were exposed to spermine and spermidine and subsequently assayed for [3H]ouabain binding to quantify neuronal loss. Neuronal survival was significantly decreased in the presence of spermine at 24 h (500 microM), 48 h (250 microM and 500 microM) and 72 h (10-500 microM) relative to controls. Co-application of 250 microM spermine and 10 microM dizocilpine for 48 h completely inhibited the effect of spermine alone. Spermidine exposure (10-500 microM) did not alter neuronal survival at any of the time points. These data indicate that the polyamine spermine is toxic to neurons in vitro and that toxicity is prevented by the NMDA-associated channel antagonist dizocilpine.

Effects of oxotremorine on neuronal RNA and chromatin in thalamic cholinoceptive sites.

Neuronal nucleic acid responses were examined within the rat thalamic ventrobasal nuclear complex (VBC) and nucleus reticularis (NR) following single intraperitoneal injections of the central muscarinic-cholinergic (M2) receptor agonist oxotremorine (0.1, 0.7, or 1.0 mg/kg). After stoichiometric azure B and Feulgen staining of brain sections, scanning-integrating cytophotometry was used to quantify azure B-ribonucleic acid (RNA) content, Feulgen-DNA levels, and changes in the susceptibility of chromatin to Feulgen acid hydrolysis (F-DNA yield) of neurons on an individual basis. Changes in neuronal nucleolar volume were also determined histometrically. Within the VBC, oxotremorine produced marked dose-dependent elevations in neuronal RNA content and nucleolar volume with increased F-DNA yield (chromatin activation) in a proportion of VBC neurons. In contrast, within the NR, oxotremorine elicited reductions in RNA levels, F-DNA yield and nucleolar volume. The data demonstrate that oxotremorine-induced central muscarinic receptor stimulation is associated with metabolic correlates of thalamic VBC neuroexcitation and NR neuron depression. The overall study lends further credence to the hypothesis that muscarinic-cholinergic mechanisms are operative within the mammalian thalamus.

Clinical assessment of melanoma thickness.

Melanoma tumour thickness is the best current predictor of prognosis. In 92 patients melanoma tumour thickness was estimated preoperatively on clinical assessment and compared to the histological thickness measured from fixed paraffin sections. Overall there was no significant difference between clinical and histological thickness. The two assessments were identical in 20 of 92 cases (22%). In 32 of the 92 cases (35%) there was a discrepancy greater than 25%, but 87 of the 92 patients had appropriate treatment where extent of surgery was tailored to clinical assessment of treatment. Clinical assessment has an important role in identifying occasional spurious histological thickness measurements, resulting from sampling errors. The ability to gauge melanoma thickness preoperatively also aids the planning of a rational treatment policy ranging from conservative treatment for thin lesions to radical surgery, which may include elective node dissection and adjuvant limb perfusion, for thicker tumours.

Suture or graft? Changing trends in melanoma wound closure.

The method of wound repair following excision of primary cutaneous malignant melanoma has been assessed in a consecutive series of 256 melanomas of the trunk and limbs between 1972 and 1986. Excision margins of 1, 2 and 3-5 cm were used according to clinical assessment of tumour thickness. Primary closure was the preferred method of wound repair and split skin grafting when it could not be achieved. 30% of wounds were closed primarily between 1972-81, rising to 54% between 1982-86. This change has been partly due to an increase in the number of thin lesions, but also due to improved surgical technique. Simple interrupted suture was used between 1972-81. In 1982 a multilayer subcutaneous and subcuticular prolene suture was introduced as an improved method of direct closure, and led to a reversal in the ratio of grafting to primary closure. This technique is particularly beneficial for wounds with excision margins of 2 and 3 cm. Complication rates have been lower for primary suture (4%) than split skin graft (12%).

Somatostatinoma of the pancreas with hypercalcaemia. A case report.

A unique case of somatostatinoma of the pancreas complicated by severe hypercalcaemia is described. Surgical resection was not possible owing to tumour extent. A dramatic and prolonged clinical and biochemical response was achieved with streptozotocin.

Cytophotometric analysis of T-2 toxin induced alterations in chromatin condensation and neuronal nuclear volume of rat supraoptic-magnocellular neurons.

Quantitative cytophotometry and ocular filar micrometry were used to monitor T-2 toxin induced alterations in chromatin and neuronal nuclear volume in supraoptic-magnocellular neurons of rat hypo-thalami. Thirty male Sprague-Dawley rats (200-220g) were given a single i.p. injection of T-2 toxin (0.5, 0.75, 1.0 and 1.5 X LD50), a trichothecene mycotoxin; rats were decapitated 8 hours post-dosing. After stoichiometric Feulgen-DNA staining of brain sections, scanning-integrating microdensitometry was used to quantify changes in the susceptibility of chromatin to Feulgen acid hydrolysis. Changes in neuronal nuclear volumes were also determined histometrically. Within the magnocellular neurons of the supraoptic nuclei, significant reductions in F-DNA reactivity were observed in the 0.5, 0.75, and 1.0 X LD50 groups (i.e. 3.7%, 4.4% and 2.5%, respectively); however, rats receiving 1.5 X LD50 T-2 toxin showed no difference in F-DNA reactivity compared to controls. In addition, ocular filar micrometry demonstrated increased neuronal nuclear volumes in all groups receiving T-2 toxin, and following an inverse trend to that seen with F-DNA stainability. Additional observations included pronounced polydipsia, polyphagia and horripilation in the experimental groups, independent of the dosages employed; these changes were evident within 1 hour post-injection. It is postulated that the T-2 toxin induced reduction in the susceptibility of chromatin to Feulgen acid hydrolysis and concomitant increases in neuronal nuclear volumes represent an early indication of impaired metabolic activity. Since these neurons are important sites of vasopressin (antidiuretic hormone) synthesis, these data suggest an impaired osmoregulatory ability. The pronounced polydipsia which occurred shortly after intoxication is further evidence of this impairment. Although these findings do not provide insight relating to the mechanism of osmoregulatory disruption, it is evident that an impaired ability to osmoregulate is among the earliest indications of acute T-2 toxin mycotoxicosis.

Cytophotometric assessment of T-2 toxin induced alterations in azure B-RNA and Coomassie-protein in supraoptic-magnocellular neurons of rat hypothalami.

Quantitative cytophotometry was used to monitor T-2 toxin-induced alterations in azure B-RNA and Coomassie-total cell protein in supraoptic-magnocellular neurons of rat hypothalami. Thirty male Sprague-Dawley rats (200-220g) were given a single i.p. injection of T-2 toxin (0.5, 0.75, 1.00 and 1.50 x LD50), a trichothecene mycotoxin; rats were decapitated 8 hours post-dosing. After stoichiometric azure B-RNA and Coomassie-protein staining of brain sections, scanning-integrating microdensitometry was used to quantify toxin-induced alterations in these well established indices of neuronal toxicity. Within the magnocellular neurons of the supraoptic nuclei, significant reductions in azure B-RNA reactivity were observed in the 0.75, 1.00 and 1.50 x LD50 groups (i.e. 11%, 13% and 8%, respectively); no differences in RNA levels were observed between controls and the 0.50 x LD50 group. In addition, a decrease in Coomassie-total cell protein was seen in animals receiving 0.50, 0.75 and 1.50 x LD50 T-2 toxin (i.e. 33%, 21% and 12%, respectively); however, toxin administration did not alter protein levels in the 1.00 x LD50 group. Furthermore, a dose-dependent decrease in systolic blood pressure was observed at 8 hr. post-injections (i.e., approximately -39%, -52%, -66% and -64% for the 0.50, 0.75, 1.00 and 1.50 x LD50 groups, respectively). Additional observations include pronounced polydipsia, ascites, abdominal and subdural hemorrhage, and horripilation (piloerection) in experimental groups. It is postulated that the T-2 toxin-induced reductions in azure B-RNA and Coomassie-protein represent an early indication of impaired metabolic activity. Since these neurons are important sites of vasopressin (antidiuretic hormone) synthesis, these data suggest an impaired osmoregulatory ability. The pronounced polydipsia which occurred shortly after intoxication is further evidence of this impairment. Although these findings do not provide insight relating to the mechanism of osmoregulatory disruption, it is advanced that the supraoptic-magnocellular compartment represents an important site in T-2 toxin mycotoxicosis. Moreover, these findings support previous claims that T-2 toxin intoxication may critically impair the vasopressinergic response to toxin-induced cardiovascular collapse.

In situ hybridization histochemistry as a method to assess GABA(A) receptor subunit mRNA expression following chronic alprazolam administration.

Previous work in our laboratory has demonstrated region-specific effects for chronic alprazolam on binding and function at the GABA(A) receptor. The present study evaluated regional changes in mRNA expression of several subunits of the GABA(A) receptor following chronic alprazolam administration that might underlie these effects. Mice received alprazolam (2 mg/kg/day) or vehicle via subcutaneously implanted osmotic pumps for 1, 7, 14 or 28 days. In situ hybridization histochemistry was performed on tissue sections using [35S]dATP oligonucleotide probes corresponding to the alpha1 and gamma2 subunits of the GABA(A) receptor. Specific hybridization was clearly demonstrated and alpha1 subunit mRNA expression in frontoparietal cortex (layers II-IV) on day 1 of infusion was reduced in animals receiving alprazolam compared to vehicle. On subsequent days, there were no alterations in the levels of alpha1 subunit mRNA in the frontoparietal cortex, hippocampus or dentate gyrus. Expression of gamma2 subunit mRNA was increased on day 1 in the frontoparietal cortex (layer VI), hippocampus and dentate gyrus. mRNA expression was also increased in the dentate gyrus on day 28 of infusion. Comparison of the present study with the results of chronic treatment with other benzodiazepines clearly demonstrates that the pattern of mRNA subunit alterations obtained is both treatment- and region-specific. This makes a definitive conclusion regarding benzodiazepines and their interactions with GABA(A) receptors difficult at best.

Lorazepam attenuates the behavioral effects of dizocilpine.

To characterize the potential interaction between the excitatory and inhibitory neurotransmitter systems, the effects of dizocilpine, CPP, and lorazepam on open-field behavior and pentylenetetrazol-induced seizures were evaluated in mice. Dizocilpine (0.01-0.1 mg/kg), CPP (1-10 mg/kg), or vehicle was administered intraperitoneally 15 min prior to lorazepam (0.2-2 mg/kg) or vehicle. Behavioral monitoring began 25 min after the lorazepam injection. Upon completion of testing, unrestrained mice were infused intravenously with pentylenetetrazole until the onset of a full tonic-clonic seizure. The highest dose of dizocilpine by itself significantly increased the average distance traveled, the number of rears, and the number of stereotypies during the test period. Lorazepam alone dose dependently decreased activity on all behavioral parameters. Lorazepam also completely antagonized the hyperactivity produced by dizocilpine when the two compounds were coadministered. This antagonism is most likely due to an interaction in the regulation of dopaminergic tone which underlies motor activity. Lorazepam exerted a dose-dependent anticonvulsant effect. Dizocilpine alone had no effect on seizure induction and did not potentiate the anticonvulsive effect of lorazepam when coadministered with lorazepam. CPP reduced the number of rears and the number of stereotypies during the test period. CPP did not alter the pentylenetetrazol-induced seizure threshold and did not influence the anticonvulsant effect of lorazepam.

Pharmacodynamic and receptor binding changes during chronic lorazepam administration.

To assess pharmacodynamic and neurochemical aspects of tolerance, lorazepam (2 mg/kg/day), or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice via implantable osmotic pump. Open-field behavior, benzodiazepine receptor binding in vitro, receptor autoradiography, and muscimol-stimulated chloride uptake were examined at both 1 and 14 days. Open-field activity was depressed in lorazepam-treated animals on Day 1. On Day 14, open-field parameters were indistinguishable from those of vehicle-treated animals, indicating behavioral tolerance. Benzodiazepine binding, as determined by the specific binding of [125I]diazepam, was also decreased in cortex on Day 14. Hippocampal binding was unchanged following chronic lorazepam exposure. Apparent affinity in cortical membrane preparations was unchanged, indicating that altered ligand uptake was due to decreased receptor number. Muscimol-stimulated chloride uptake into cortical synaptoneurosomes from lorazepam-treated animals was not significantly different on Day 1 or Day 14 compared to vehicle-treated animals. These results confirm that down-regulation of benzodiazepine receptor binding is closely associated with behavioral tolerance to benzodiazepines. These observed changes in binding are not necessarily associated with robust changes in receptor function.

What becomes of junior surgical trainees? A review of Cardiff registrars 1973-1983.

A survey was conducted of doctors who trained as Rotating Surgical Registrars on the Cardiff Rotational Training Scheme between 1973 and 1983. 51 of 63 former registrars responded. All passed FRCS. 45 remained in surgery on leaving the rotation. 19 are now consultants, 12 senior registrars and 14 are still registrars in 8 different surgical specialties. Orthopaedics was the most popular. 6 doctors left surgery to become either general practitioners, radiologists or radiotherapists. Of the 12 non-responders it is known that at least 6 are surgeons (2 consultants, 2 senior registrars, 2 registrars). It is concluded that the Rotational Training Scheme successfully promoted surgical careers for the majority of trainees.

Internal hernia of the transverse colon. A new syndrome.

A unique abdominal internal hernia is described. A 30-year-old man suffered intestinal obstruction and strangulation due to incarceration of the transverse colon in the subphrenic space. This phenomenon is contrasted with Chilaiditi's syndrome (hepatodiaphragmatic interposition).

Lipids in breast carcinogenesis.

Excess dietary fat has been identified as a risk factor in the development of human breast carcinoma. However, the quality of fat may be more important than the overall quantity. We have studied the growth of human MCF7 breast carcinoma xenografts in athymic mice treated with dietary supplements of N-6 and N-3 series essential fatty acids given as natural preparations of evening primrose oil and fish oil. Olive oil and normal laboratory diet lacking the essential fatty acids served as controls. Animals treated with essential fatty acids developed tumours which were significantly smaller than both control groups (Mann-Whitney U test, P less than 0.001). Median tumour weights according to diet were: evening primrose oil, 133 mg; fish oil, 70 mg; olive oil, 212 mg; and control, 270 mg. Nutritional intervention to increase the proportion of essential fatty acids in the diet may have a role in the management of breast carcinoma.

Carbon fibre used in the late reconstruction of rupture of the extensor mechanism of the knee.

Carbon fibre may be used to repair rupture of the extensor mechanism of the knee when this involves either the patellar ligament or quadriceps tendon. The operative technique is described and the results in five patients are reviewed. This technique may be successful even after other forms of repair have failed.

Naloxone exacerbates hypoxic-ischemic brain injury in the neonatal rat.

Recent reports suggest that naloxone, an opiate antagonist, may adversely affect the asphyxiated fetus. We found that naloxone exacerbated hypoxic-ischemic brain injury in the 7-day-old rat subjected to unilateral common carotid artery ligation and hypoxia. Moreover, there was no amelioration of systemic acidosis or brain edema in naloxone-treated animals compared to animals treated with saline solution. High doses of naloxone may reduce the resistance of the fetus to hypoxic stress.