Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder.

Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, (1)H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use (1)H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and gamma-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

Double-blind comparison of captopril with nifedipine in hypertension complicated by intermittent claudication.

In a double-blind, crossover trial 12 patients with hypertension and peripheral arterial disease were randomized to three months' treatment with captopril 25-50 mg twice daily or nifedipine SR 20-40 mg twice daily. While both treatments were equally effective at lowering blood pressure, postexercise calf blood flow availability was greater during treatment with captopril (P less than 0.04). This was not reflected in walking capacity assessed by treadmill exercise. The results suggest that both captopril and nifedipine are appropriate antihypertensive agents in patients with peripheral arterial disease.

Comparison of iliofemoral and femorofemoral crossover bypass in the treatment of unilateral iliac arterial occlusive disease.

Between 1981 and 1988, 74 synthetic crossover bypass grafts were inserted for unilateral iliac arterial occlusive disease. In 32 patients the bypass procedure was iliofemoral and in 42 femorofemoral. The cumulative patency rate at a mean of 2.7 years was 79 per cent in both groups. There was no significant difference in either postoperative mortality rate or duration of hospital stay. Iliofemoral bypass may offer significant advantages over the femorofemoral approach. In particular it avoids a groin incision in the donor limb, leaving the common femoral artery intact for subsequent angioplasty or reconstruction should proximal stenotic disease develop in the donor iliac vessel.

Wound instillation for postoperative pain relief: a comparison between bupivacaine and saline in patients undergoing aortic surgery.

In a double blind trial 72 patients having elective aortic surgery were randomized to receive either 40 ml of 0.25% bupivacaine or 40 ml of saline through one or two indwelling wound irrigation catheters every four hours over a total of 48 hours. In transverse incisions the two catheters were randomly placed either subcutaneously or in the rectus sheath; in vertical incisions one catheter was placed subcutaneously. Analgesia was assessed by visual analogue score on Postoperative Days 1 and 2 and the number of doses of intramuscular morphine given during the instillation period. Pulmonary function was monitored by forced expiratory volume and peak flow on Postoperative Days 1 to 5; arterial blood gases were monitored preoperatively and Postoperative Day 2. In all parameters evaluated there was no statistically significant difference between the saline (n = 33) or the bupivacaine (n = 37) groups. Site of the catheter in the transverse groups made no difference. Comparing vertical (n = 21) and transverse (n = 49) incisions, the mean visual analogue scores on the first postoperative day were 40 and 29, respectively (p less than 0.05). Wound instillation with bupivacaine neither improves pulmonary function nor reduces morphine requirements when compared to saline. Transverse incisions may be less painful than vertical ones.

Abdominal aortic aneurysm presenting as paraplegia: case report.

A 65-year-old man with a previously undiagnosed abdominal aortic aneurysm presented with acute paraplegia. Elective resection of the aneurysm was undertaken one week later. Following this, almost complete neurological recovery was regained by 11 months.

The effect of dopamine on renal function during aortic cross clamping.

Eighteen male patients undergoing elective surgical reconstruction of the abdominal aorta were divided into two groups. Patients in Group I (nine) were given dopamine intravenously, in a dose of 2 micrograms/kg/min, during the first half of the period of cross-clamping, whilst those in Group II received dopamine during the second half. Each patient acted as his own control and for each, three periods were examined, namely: pre-clamp, clamping with dopamine and clamping without dopamine. Dopamine infusion during aortic clamping caused a significant rise in sodium output (P less than 0.01), potassium output (P less than 0.05), creatinine clearance (P less than 0.05) and urine output (P less than 0.05). We conclude that dopamine infusion during aortic clamping helps to protect the kidney from any deleterious effect of clamping.

Placebo-controlled comparison of captopril, atenolol, labetalol, and pindolol in hypertension complicated by intermittent claudication.

In a six month placebo-controlled cross-over trial twenty patients with hypertension and peripheral arterial disease were randomised to captopril 25 mg twice daily, atenolol 100 mg once daily, labetalol 200 mg twice daily, or pindolol 10 mg twice daily for one month. Although all treatments were equally effective at lowering blood pressure, pain-free and maximum walking distances on a treadmill were decreased by atenolol, labetalol, and pindolol, but not by captopril. Post-exercise calf blood flow availability was impaired by atenolol, labetalol, and pindolol, but not by captopril. Despite ancillary characteristics of cardioselectivity, intrinsic sympathomimetic activity, or combination with alpha-blockade, beta-blockers seem to impair the lower limb circulation in such patients, whereas captopril seems to preserve it, possibly by maintaining the collateral blood supply.

Comparison of extraperitoneal and transperitoneal methods of aorto-iliac reconstruction. Twenty years experience.

The operative technique of extraperitoneal approach to the aorta is described. The results of operation on the aorta using this technique are compared with those using the standard transperitoneal approach.

The effect of povidone-iodine irrigation on perineal wound healing following proctectomy for carcinoma.

Fifty-six patients undergoing abdomino-perineal excision of the rectum for carcinoma were randomized to receive twice daily irrigation of the perineal wound with either 1% povidone-iodine (PVP-I) or normal saline for 5 days following surgery. The incidence of perineal wound infection, primary and delayed wound healing and persistent sinus formation was recorded. There was a highly significant reduction in perineal wound infection in the PVP-I group (P less than 0.01) and this was true even if perineal wound contamination had occurred during operation (P less than 0.05). Primary wound healing was significantly improved in the treatment group (P less than 0.02) and this was found also in the presence of contamination (P less than 0.005). There was no significant difference between the treated and control group in the incidence of delayed wound healing and persistent sinus formation.

Correlation of the production of plasminogen activator with tumor metastasis in B16 mouse melanoma cell lines.

The correlation between the production of plasminogen activator (PA) of tumors and their metastatic potential was studied. B16 melanoma cells and "B16 mets" cells (harvested from the pulmonary metastatic nodules of C57BL/6J mice bearing B16 isografts) were examined with respect to their fibrinolytic activity (FA) in tissue culture. B16 mets cells had a significantly higher FA than did B16 cells. F1 (a B16 subline with a lower incidence of metastasis) and F10 (a highly metastatic B16 subline) were also studied. F10 cells produced more FA than did F1 cells. The difference between the FA's of these tumors was due to differences in their PA production. Significant differences in PA production between F1 and F10 could be consistently observed when 10(5) or more cells were cultured for at least 24 hr. The cell-free supernatants harvested from 72-hr cultures of F10 cells had a higher FA than those harvested from F1 cultures. Results suggest that a quantitative difference in PA production between these 2 melanoma sublines does exist and that it may contribute to their different metastatic potential.

Intrapulmonary clotting and fibrinolysis during abdominal aortic aneurysm surgery.

Intravascular clotting and fibrinolysis (C and F) are events which often accompany major surgical trauma. Their role in inducing cardiopulmonary failure is debated and prompted this study of 13 patients undergoing elective AAA. Following intubation, anesthesia and pressure breathing fibrinolytic activity (FA) in arterial blood exceeded that in mixed venous blood (p < 0.001) indicating pulmonary secretion of proteolytic activity. Fibrinogen, plasminogen and fibrin degradation products (FDPs) were normal. During surgery, fibrinogen and plasminogen fell (p < 0.001) while nonplasmin mediated FA and FDPs rose (p < .001). Despite heparinization (5000 U IV) aortic clamping (avg 56 min) led to evidence of C and F within the lungs. Arterial fibrinogen was 33.2 mg/ml lower than mixed venous blood (p < 0.01) and plasminogen was 0.47 Sherry units lower (p < 0.001). Soluble fibrin monomer appeared in arterial blood (p < 0.01). At the same time nonplasmin mediated FA was consumed within the lungs (p < 0.01) and FDPs were produced (44.6 microg/ml higher in arterial blood, p < 0.001). Similar changes were noted after aortic declamping. The transient 5.3 ml/cm H(2)0 fall in dynamic compliance was unrelated to C and F. Pulmonary vascular resistance and arterial pressure were unchanged. During wound closure intrapulmonary C and F ceased. Postoperatively (6 h), the physiologic shunt of 15.1% was similar to tbe preoperative value of 13.3%. All C and F factors returned to normal except FDPs which remained elevated. An average of 0.2 U blood was given prior to aortic clamping and 3.1 U during clamping. Neither the volume nor the type of blood (7 patients received washed RBCs) influenced pulmonary C and F. The results show that pressure breathing will alter pulmonary metabolism from clearance to secretion of fibrinolytic activity. Surgery leads to systemic C and F while intrapulmonary C and F is triggered by aortic clamping despite IV heparin. Delayed functional consequences of C and F are possible. Immediate postoperative effects are not apparent.

Correlation between anergy and a circulating immunosuppressive factor following major surgical trauma.

In order to clarify the relationship between anergy and immunosuppressive activity in the serum, we studied 46 previously well patients before and at three, five, seven and 28 days after surgery. Delayed hypersensitivity was measured by skin testing with four common recall antigens, and serum immunosuppressive activity was determined by the ability of the patient's serum in 10% concentration to suppress by 50% or more the phytohemagglutinin (PHA) stimulation of normal human lymphocytes as compared to pooled normal serum. Prior to surgery, all patients manifested delayed hypersensitivity to one or more antigens, and no patient had immunosuppressive serum. Fifteen patients underwent minor surgery under general anesthesia and did not develop anergy or immunosuppressive serum. Thirty-one patients underwent major cardiovascular surgery. Thirteen of these patients became anergic by day 3 after operation, and 11 of the 13 developed immunosuppressive serum. Eighteen patients maintained delayed hypersensitivity after major surgery, and only three developed immunosuppressive serum. The correlation between anergy and immunosuppressive serum was highly significant (p < 0.001). There was a significant difference in the degree of suppressive activity in the serum of the anergic and reactive patient groups for each postoperative day studied until day 28, when there was recovery of delayed hypersensitivity and lack of immunosuppressive serum. The occurrence of postoperative anergy and immunosuppressive serum was not related to the patient's age, sex, number of perioperative blood transfusions or duration of anesthesia but was associated with an increase in postoperative infectious complications (p < 0.05) and in postoperative days in the hospital (p < 0.01). Pooled immunosuppressive serum from anergic patients was fractionated by ion exchange chromatography, gel filtration and preparative high voltage electrophoresis. The majority of the immunosuppressive activity could be accounted for by an electrophoretically homogenous polypeptide-containing fraction not identified in the serum of patients undergoing minor surgery or in normal individuals. We conclude that anergy occurring after major operative trauma is associated with the appearance of a circulating immunosuppressive molecular species and that these events are in turn associated with increased patient morbidity and increased length of hospitalization.