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Biomedical subjects

K J Hardy

Publications and source records attributed to K J Hardy.

At least 37 records · Page 2Linked to original sources
PubMed1999

The early operation for acute severe cholecystitis: the Riedel paper; an introduction and translation.

BACKGROUND: For acute cholecystitis in the latter 19th century and early 20th century, the diagnosis was difficult and the management not defined. METHODS AND RESULTS: Bernhard Riedel of Jena in Germany documented his patients, analysed his results, and described his method of cholecystectomy. CONCLUSIONS: Riedel advocated early operation for acute cholecystitis when the conditions were favourable, as for acute appendicitis. He stressed the importance of good lighting, an experienced surgeon and trained assistants. He advocated conservative treatment for minor cholecystitis (biliary colic) until the diagnosis was certain, followed by elective cholecystectomy to reduce the risk of subsequent acute cholecystitis or bile duct stones. Caution was advised when analysing previous statistics, to ensure appropriate patient comparison.

Acute Disease↗
PubMed1999

Developmental regulation of gastric somatostatin secretion in the sheep.

Gastric somatostatin (SRIF) regulates gastric acidity by inhibiting gastric acid and gastrin secretion. SRIF secretion is increased by gastric acidity and also directly by regulators of gastric acid secretion such as gastrin. This direct effect has not been described in the developing animal, nor have the roles of intermediaries such as histamine and gastric acidity been defined. The present study aimed to establish the regulatory role of gastrin and histamine during development on SRIF secretion and also to determine whether the effects of gastrin and histamine are independent of gastric pH. Pentagastrin and histamine were infused on separate occasions into fetal sheep, newborn lambs, and 28-day-old lambs. To determine the roles of endogenous histamine and gastric pH, ranitidine (a histamine-2 receptor antagonist) and omeprazole (a H+/K+ ATPase inhibitor) were coinfused with the agonists. Plasma SRIF and gastrin concentrations were measured by RIA. Pentagastrin stimulated SRIF secretion in the fetus after 131 days of gestation (term is 147 days), whereas stimulation by histamine was effective only after birth. The SRIF stimulatory effect of pentagastrin in 28-day-old lambs was abolished by ranitidine, which also reduced this effect in the adult sheep. This inhibitory effect of ranitidine was shown to be a result of blockade of stimulatory H2 receptors, because in the adult blockade of acid secretion with omeprazole failed to attenuate the response of histamine. These results indicate that in the fetus, gastrin receptors, but not histamine receptors, are functionally involved in the stimulation of SRIF secretion. After birth, both gastrin and histamine stimulate SRIF, but the effect of gastrin is mediated at least in part by the release of endogenous histamine. These responses occur independently of changes in gastric acidity, supporting the concept of a direct negative feedback between SRIF and gastrin.

Aging↗
PubMed1999

Diabetic nephropathy is associated with an increased familial risk of stroke.

OBJECTIVE: To test the hypothesis that genetic susceptibility to diabetic nephropathy is associated with an increased familial risk of vascular disease, we have examined the causes and rates of death of parents of individuals with type 1 diabetes complicated by diabetic nephropathy compared with the causes and rates of death of parents of control subjects with diabetes uncomplicated by nephropathy. RESEARCH DESIGN AND METHODS: Individuals with at least a 14-year duration of type 1 diabetes complicated by diabetic nephropathy were identified and matched for age, sex, and duration of diabetes to control subjects. A total of 118 patients and 118 matched control subjects were identified and approached to obtain information on parental age and cause of death. For parents who had died, the cause of death was ascertained from the death certificate. RESULTS: Kaplan-Meier curves showed that parents of subjects with nephropathy (PN) had reduced survival compared with parents of diabetic subjects without nephropathy (PC) (log rank test P < 0.05). There was an excess of all vascular deaths and, in particular, strokes in the parents of subjects with nephropathy (PN: 20 of 103 deaths, 19% vs. PC: 3 of 66 deaths, 4%; Fisher's exact test P < 0.01). CONCLUSIONS: Parents of diabetic patients with nephropathy have reduced survival. This seems to be largely explained by an increase in vascular deaths and, in particular, a four-fold increase in the number of strokes. This supports the hypothesis that a common hereditary risk factor predisposes to both vascular death and diabetic renal disease.

Adult↗
PubMed1998

Epitope-specific signaling through CD45 on T lymphocytes leads to cAMP synthesis in monocytes after ICAM-1-dependent cellular interaction.

We recently demonstrated that different CD45 monoclonal antibodies (mAb) are able to induce cellular aggregation in human peripheral blood mononuclear cells (PBMC) through LFA-1/ICAM-1 interactions. Such interactions could be down-modulated by protein kinase (PK) A/G inhibitors, but were unaffected by inhibitors of PKC, suggesting the involvement of PKA or PKG in CD45 mAb-induced adhesion. In this study we show that after incubation of PBMC with several (but not all) mAb to CD45, CD45RO and CD45RA, intracellular cAMP, but not cGMP concentrations readily increase, reaching a maximum 30 min after start of activation. As evidenced by several lines of investigation cAMP accumulation was independent of Fc receptor-associated signaling as well as tyrosine phosphatase activity of CD45. In highly pure T lymphocytes, CD45 mAb were unable to induce cAMP synthesis, but readily did so after addition of autologous monocytes. After paraformaldehyde fixation of both quiescent or IFN-gamma/TNF-alpha-preactivated monocytes, cAMP production was no longer detectable, suggesting monocytes as the cell of origin for the increased cAMP synthesis. Further, cAMP accumulation in monocytes occurred after reconstitution to T lymphocytes preincubated with CD45 mAb and extensively washed. Importantly, pretreatment of T lymphocyte/monocyte mixtures with LFA-1 mAb and/or ICAM-1 mAb down-regulated CD45 mAb-induced cAMP synthesis. Finally, we demonstrate that CD45 mAb are not only capable of inducing cAMP production, but also of directly stimulating PKA enzyme activity. Based on the data presented, we propose that CD45 signaling in T lymphocytes subsequently activates cAMP accumulation and PKA activation in monocytes via LFA-1/ICAM-1-dependent cellular interactions.

Antibodies, Monoclonal↗
PubMed1998

Modulation of nitric oxide improves cyclosporin A-induced hypertension in rats and primates.

Cyclosporin-induced hypertension is a major complication of immunosuppression in transplant recipients but its pathophysiology is only partly understood. Cyclosporin reduces endothelium-dependent vasodilation and increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of: (1) nitric oxide enhancement with L-arginine administration and antagonism with N-nitro-L-arginine; and (2) chronic endothelin receptor blockade with the non-peptide endothelin receptor antagonist, bosentan, in two animal models of cyclosporin-induced hypertension. Cyclosporin, administered daily to female Wistar rats (10 mg/kg per day for 30 days, s.c.) and to marmosets (30 mg/kg per day for 20 days, p.o.) significantly elevated tail cuff systolic blood pressure (BP). L-arginine (250 mg/kg, in saline, i.p.), N-nitro-L-arginine (25 mg/kg, in saline, i.p.), bosentan (100 mg/kg, in arabic gum, p.o.) or vehicle were given daily to the rats during the last week of cyclosporin treatment. Marmosets received L-arginine (300 mg/kg, in water, p.o.), bosentan (100 mg/kg/day in arabic gum, p.o.) or vehicle for the last 7 days of cyclosporin treatment. L-arginine, but not saline alone significantly lowered BP in the cyclosporin-hypertensive rats from 129 +/- 2 mm Hg to 122 +/- 3 mm Hg (P < 0.05), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). NOLA significantly increased systolic BP in cyclosporin-treated (from 133 +/- 2 mm Hg at week 3 to 142 +/- 3 mm Hg, P < 0.05) and control rats (from 124.0 +/- 2 mm Hg to 134 +/- 2 mm Hg, P < 0.05) indicating that nitric oxide synthesis in cyclosporin-hypertensive rats could be further antagonised. Bosentan, but not arabic gum alone, also lowered BP in the cyclosporin-hypertensive rats from 134 +/- 1 mm Hg to 122 +/- 3 mm Hg (P < 0.01), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). These results support the roles of both increased endothelin synthesis and decreased nitric oxide activity in the pathogenesis of cyclosporin A-induced hypertension.

Animals↗
PubMed1998

Central venous pressure and its effect on blood loss during liver resection.

BACKGROUND: Any strategy to reduce blood loss in liver resection and decrease blood transfusion would be of benefit to the patient and surgeon. This study evaluates the association of central venous pressure (CVP) with blood loss and blood transfusion during liver resection. METHODS: One hundred consecutive hepatic resections in the period 1986-1996 were studied prospectively concerning CVP, volume of blood lost, and volume of blood transfused. Blood loss volume and blood transfusion were analysed for those with a CVP less than or equal to 5 cmH2O, and greater than 5 cmH2O. A multivariate analysis assessed potential confounding factors in the comparison. RESULTS: The median blood loss in patients with a CVP of 5 cmH2O or less was 200 ml (n=40) and that in those with a CVP above 5 cmH2O was 1000 ml (n=52) (P=0.0001). Only two of 40 patients with a CVP of 5 cmH2O or less had a blood transfusion whereas 25 of 52 patients with a CVP greater than 5 cmH2O required a transfusion (P=0.0008). A multivariate analysis did not show confounding factors. CONCLUSION: The volume of blood lost during liver resection correlates with the CVP. Lowering the CVP to less than 5 cmH2O is a simple and effective way to reduce blood loss during liver surgery.

Aged↗
PubMed1998

Undergraduate surgical examinations: an appraisal of the clinical orals.

The aims of this study of examinations in the final year of undergraduate surgery were to determine whether the long case, short cases/orals reflected students' knowledge of surgery effectively, whether their performance indicated the goals of the medical course relative to surgery were achieved, and whether these examinations gave a good and fair appraisal of student clinical skills. To test validity of these examinations, the scores of the long and short cases/oral were correlated with the aggregate score for the medical course, to the final-year total score, the final-year surgery mark, the written examination mark and the final-year internal medicine mark. Whether the surgical goals of the medical course were achieved was assessed by questionnaire to the surgical examiners, and whether there was a good and relevant appraisal of student clinical skills was assessed by questionnaire to students. The response rates to the questionnaires were 100% and 98%. The results showed a poor but significant correlation between long and short cases/oral (rho = 0.24, P = 0.01). The correlation of the long case and short cases/oral to internal medicine was rho = 0.45 and rho = 0.33 (both P < 0.001), and there was a better correlation of short cases/oral to the aggregate medical course score (rho = 0.53 vs. 0.42, both P < 0.001). The long case and short cases/oral had no correlation with the written paper (rho = 0.10 and 0.69, respectively). The goals of the medical course were considered achieved, but less so with assessment of the injured and acutely surgically ill; students considered the long and short cases/orals as a good and relevant appraisal of their clinical skills. The distribution of short cases marks shifted to the left, indicating lower scores for this part of the examination. In conclusion, this study has demonstrated that the long and short cases/orals tested different aspects of student's skills, and so reinforces the importance of retaining the short and long cases in undergraduate surgical examinations. It is suggested that a single long case may be insufficient to distinguish between adequate and inadequate performance.

Clinical Competence↗
PubMed1998

One hundred liver resections including comparison to non-resected liver-mobilized patients.

BACKGROUND: Factors of liver resection associated with postoperative recovery and survival, the modalities that affect survival with resected colorectal carcinoma liver metastases, the comparison of liver function of liver-resected to liver-mobilized but not resected patients, and observation of early liver regeneration volume over time have not been studied prospectively. This study aimed to prospectively analyse these factors. METHODS: Data were collected prospectively on 100 consecutive liver resections, and 10 liver-mobilized but not resected patients by the Hepatobiliary Unit, University of Melbourne, Austin Campus. Follow-up of patients was 100%. RESULTS: The factors associated with blood loss were the type of liver resection (P = 0.0001), the length of the operation (P = 0.0001) and a central venous pressure greater than 5 cm of water (P = 0.0008). An inverse correlation existed between blood loss and long-term survival (P = 0.003). The only predictor for a postoperative complication was the length of the operation (P = 0.03): a correlation of moderate significance existed between blood loss and a complication (P = 0.052; confidence interval 0.19-1.17). The 5-year cumulative survival for hepatic resection for colorectal carcinoma Dukes A + B was 55%; there was a significantly better survival of Dukes A + B compared to Dukes C (P = 0.03) and also for those 50 years or older, but this did not depend on whether there were one or more lesions present. Resected patients had a significantly higher alanine transaminase (ALT), total bilirubin and international normalized ratio than non-resected patients, but not albumin, total protein, alkaline phosphatase or aspartate aminotransferase. The serum albumin fall was similar in both groups, which indicated that loss of liver tissue was not the cause. The re-resection rate was 8% without mortality and with low morbidity. Liver volume was restored by 64% (510 +/- 170 cc) by 7 days postoperatively. CONCLUSIONS: Major hepatic resection can be performed with low mortality, morbidity and short hospital stay, with a 5-year survival for colorectal carcinoma better than 50%. Resection needs to be considered more frequently for curative management. Serum albumin fall is not caused by loss of liver tissue and blood loss can be controlled by central venous pressure manipulation and vascular isolation. Re-resection is a safe and rewarding treatment and needs to be planned at the first resection.

Blood Loss, Surgical↗
PubMed1998

The anatomical basis for segment III cholangiojejunostomy with analysis of 13 cases.

BACKGROUND: The majority of patients who require palliation for jaundice and pruritus resulting from malignant hilar obstruction are treated by stenting. Stenting is usually achieved from below after performing an endoscopic retrograde cholangiopancreatography. In some cases the rendezvous technique is employed, negotiating the passage through a malignant stricture from above and stenting from below. A minority of cases, such as those who had a previous polyagastrectomy and those in whom attempts at stenting have failed, are considered to be suitable for a Segment III cholangiojejunostomy. We have investigated the anatomical basis for Segment III duct bypass and have critically analysed the results in 13 patients. Ten patients were treated by Segment III duct bypass alone, and three patients had a Segment III duct bypass combined with stenting of the right liver. METHODS: The anatomy of the biliary tree was investigated by dissection of 54 normal livers removed at autopsy. Clinical details of the 13 patients who had Section III cholangiojejunostomy were obtained from hospital records and by contacting treating practitioners. RESULTS: In 64.8% of the anatomical dissections, the findings were favourable for a Section III cholangiojejunostomy. In these specimens the Segment III duct bypass would have drained Segments II, III and IV. In 35.2% of the specimens the anatomical disposition was potentially unfavourable, mainly due to the Segment II or IV ducts joining close to the confluence and therefore liable to obstruction by the tumour. In nine of the 54 specimens the true left hepatic duct was less than 6 mm in length, making it unsuitable for a bypass procedure to drain the left hemi liver. Of the 10 patients who were subjected to a palliative Section III cholangiojejunostomy only, there was one postoperative death. Of the nine patients who survived, six obtained excellent palliation of jaundice and pruritus. CONCLUSIONS: In carefully selected cases, Section III cholangiojejunostomy achieves excellent palliation in patients with unresectable hilar malignancies that have been unable to be stented pre-operatively or who have unresectable tumours at the time of laparotomy.

Bile Duct Neoplasms↗
PubMed1998

Regulation of fundic and antral somatostatin secretion by CCK and gastrin.

CCK and gastrin stimulate somatostatin (SOM) secretion and thus modulate their direct effects on the parietal cell. Although SOM is stored in D cells of the fundus and antrum, the nature of the cell type differs, and it is not known whether both regions respond to the stimulatory effects of CCK and gastrin. The objectives of the present study were to determine the separate effects of CCK and gastrin on fundic and antral SOM secretion and to assess the type of receptor involved, using CCK-A (L-364,718) and CCK-B/gastrin (L-365,260) receptor antagonists. Changes in SOM were measured in plasma collected from cannulas draining blood from the fundus (gastric vein) and antrum (gastroepiploic vein) in anesthetized sheep. Both CCK and gastrin significantly stimulated SOM from the fundus and antrum. Sulfated CCK-8 (CCK-8S) increased SOM secretion from the fundus and antrum through interaction with both type A and B receptors. In contrast to CCK-8S, sulfated gastrin-17 (G-17S) stimulated SOM from the fundus via the type B receptor alone, whereas in the antrum G-17S stimulated SOM secretion independent of the A and B receptors. Histamine mediated, at least in part, the SOM-stimulatory effects; an H2-receptor antagonist blocked CCK-stimulated SOM secretion in both the fundus and antrum and reduced gastrin-stimulated SOM secretion in the fundus. The present study demonstrates regionally distinct regulatory mechanisms for gastric SOM secretion by CCK and gastrin.

Anesthesia↗
PubMed1998

Active immunization against somatostatin alters regulation of gastrin in response to gastric acid secretagogues.

We have examined the coupling between somatostatin, gastrin, and gastric acidity, using sheep chronically immunized against somatostatin. All immunized sheep had high-titer (3.2 x 10(5) +/- 1.1 x 10(4) M), high-affinity (1.5 x 10(11) +/- 1.2 x 10(10) l/mol) antibodies. However, basal gastrin and gastric acidity were similar to those in control animals, indicating that an inhibitory somatostatin tone was not required for the maintenance of normal basal gastrin and gastric acidity. Omeprazole (a proton pump inhibitor) increased gastric pH to a similar extent in both the control and immunized groups but resulted in a smaller increase in plasma gastrin in the immunized sheep, thus calling into question the assumption that hypergastrinemia associated with hypochlorhydria is the result of somatostatin withdrawal. Pentagastrin- or histamine-stimulated somatostatin secretion reversed or attenuated the omeprazole-induced hypergastrinemia in control but not immunized sheep, demonstrating a functional role for somatostatin and the biological efficacy of the somatostatin immunization. In a separate series of omeprazole-treated sheep, restoration of an acidic gastric pH with intragastric HCl reversed the hypergastrinemia in both control and immunized animals. We conclude that somatostatin is not essential for the acid-mediated regulation of gastrin. The use of a chronically immunized model as opposed to the acute administration of somatostatin antibodies has important advantages in determining the steady-state regulatory role of somatostatin.

Animals↗
PubMed1997

Nitric oxide synthase in neurons of the human gall-bladder and its colocalization with neuropeptides.

The distributions of nerve cells and fibres that are immunoreactive for nitric oxide synthase (NOS) have been investigated in the human gall-bladder. In addition, the colocalization of NOS immunoreactivity (IR) with neuropeptide Y (NPY), pituitary adenylyl cyclase activating peptide (PACAP), somatostatin (SOM), substance P (SP), tyrosine hydroxylase (TH) and vasoactive intestinal peptide (VIP)-IR was determined. Nitric oxide synthase-IR nerve cell bodies comprised 13 and 30% of nerve cells in ganglia of the fibromuscular and subepithelial layers, respectively. To determine these percentages, neuron-specific enolase-IR was used as a marker for all nerve cells. Although SOM- and VIP-IR nerve cell bodies were found in both ganglia, they rarely contained NOS-IR. In the fibromuscular layer, NOS-IR nerve fibres were abundant and most PACAP-, SOM- and VIP-IR fibres and many NPY-IR fibres were also NOS positive. No colocalization was observed between NOS- and SP- or TH-IR. In the mucosal layer, moderate numbers of NOS-IR fibres were found and the degree of colocalization of NOS-IR with each of NPY-, PACAP-, SOM-, SP- and VIP-IR were as follows: PACAP and NPY > VIP > SOM and SP. Nitric oxide synthase and TH were not colocalized in mucosal fibres. These results suggest that nerve fibres in the fibromuscular layer in the human gall-bladder with the chemical coding NOS/NPY/PACAP/SOM/VIP are axons of inhibitory motor neurons. Nitric oxide synthase-IR fibres in the mucosal layer that contained NPY, PACAP, SOM, SP and VIP with various degrees of colocalization probably contribute to the control of epithelial secretion or absorption.

Gallbladder↗
PubMed1997

Drug doping in senior Australian rules football: a survey for frequency.

OBJECTIVES: To determine by survey whether the frequency of use of performance enhancing drugs (drug doping) is significant in elite players of Australian Rules football, and to compare this frequency with that in other competitions. METHODS: Randomised unannounced prospective urine testing during the period 1990-95 of players from the Australian Football League out of competition, in competition matches, and in finals matches; testing was performed according to Olympic International Committee protocols and standards. The players' identities and clubs were unknown during testing. RESULTS: Of 900 random urine tests, no positive results were obtained for anabolic steroids, diuretics, caffeine, or peptide hormones. Five positive results (0.6%) were obtained-for pseudoephedrine in two instances, and for probenecid, methoxyphenamine, and dextropropoxyphene in one instance each. Each were inadvertent medical doping and declared before testing. CONCLUSIONS: Drug doping is not a problem in the Australian Football League. This is probably because no doping method is considered to be of value to Australian Rules football, because an educational programme is run by football authorities, and because random during season and out of season testing for drugs occurs.

Anabolic Agents↗
PubMed1996

Production of interleukin-10 in human fracture soft-tissue hematomas.

Clinical trauma suppresses immunity and experimental wound fluids have been shown to be immunosuppressive. To ascertain whether human wounds contain immunosuppressive cytokines, we assayed serum from fracture/soft-tissue hematomas (FSTH) of 22 patients for interleukin (IL)-10, transforming growth factor (TGF)-beta 1, and IL-4. Results were correlated to concurrent plasma cytokine concentrations in the same patients and in volunteer plasma. IL-10 was present in high concentration (1376 +/- 539 pg/mL) in all (7/7) FSTH < 24 h old. In FSTH > 24 h old, IL-10 was found intermittently and at lower levels (239 +/- 106 pg/mL, p = .011 vs. FSTH < 24 h old). IL-10 was rarely detectable in fracture patient plasma and never detectable (< 20 pg/mL) in normal plasma. No significant variations of IL-4 or total TGF-beta 1 were found in FSTH or plasma. FSTH are significant potential sources of IL-10 activity in trauma patients, which may be overlooked when only plasma is assayed. The potential for a relationship between cytokines found locally at sites of injury and clinical immune modulation in trauma requires further study.

Adult↗
PubMed1996

Premedication with cyclosporine and perindopril modifies the ischaemia-reperfusion injury during liver resection in rats.

The aim of the present study was to determine whether pretreatment with cyclosporine (CsA), or perindopril (an angiotensin converting enzyme inhibitor) would modify the ischaemia-reperfusion injury of vascular occlusion during liver resection. Rats were allocated to four groups (n = 20 for each group): (i) sham operated; (ii) liver resection only; (iii) CsA (15 mg/kg); and (iv) perindopril (4 mg/kg during the three days before ischaemia-reperfusion injury with liver resection). The ischaemia was produced by a 30 min continuous occlusion. The model was designed to study liver function tests as the principal parameter. Compared with liver resection only, bilirubin was significantly lower with perindopril on days 8 and 23, but significantly higher with CsA on days 1 and 2. The alanine aminotransferase peak (day 1) was significantly lower with both perindopril and CsA. The prothrombin time was significantly less on days 2 and 4 with perindopril and day 4 with CsA. Liver histological changes were minimal in all groups at 30 min ischaemia, but were significantly less severe in the perindopril group. There was a significant decrease in the weight of the regenerated liver at day 23 with perindopril and a significantly lower drop in weight on day 1 and the rate of gain was significantly greater. Perindopril (4 mg/kg) and CsA (15 mg/kg) significantly alter liver function tests, liver histology and bodyweight following an ischaemia-reperfusion injury associated with liver resection. These findings could limit ischaemia-reperfusion injury for major liver resections in the clinical setting.

Angiotensin-Converting Enzyme Inhibitors↗