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Biomedical subjects

S A White

Publications and source records attributed to S A White.

At least 37 records · Page 2Linked to original sources

Learning to communicate.

Of the few animal groups that learn their vocalizations, songbirds are uniquely amenable to molecular, physiological, and behavioral analyses of the neural features responsible for vocal learning. In order to communicate effectively as an adult, a young songbird recognizes and memorizes a model of his species-specific song during a developmentally critical period called sensory acquisition. Factors are now emerging that contribute to the length and strength of this learning phase. In a second critical period, known as sensorimotor learning, the young bird uses auditory feedback to perfect his motor performance, creating a match to the memorized model. New studies show that motor matching can persist beyond sensorimotor learning, and thus a role for the acquired model might also persist into adulthood. Fascinating in their own right, songbirds also provide optimism that mature brains have recourse to plasticity.

Animals↗

Human islet cell transplantation--future prospects.

BACKGROUND: Islet transplantation has the potential to cure diabetes mellitus. Nevertheless despite successful reversal of diabetes in many small animal models, the clinical situation has been far more challenging. The aim of this review is to discuss why insulin-independence after islet allotransplantation has been so difficult to achieve. METHODS: A literature review was undertaken using Medline from 1975 to July 2000. Results reported to the International Islet Transplant Registry (ITR) up to December 1998 were also analysed. RESULTS: Up to December 1998, 405 islet allotransplants have been reported the ITR. Of those accurately documented between 1990 and 1998 (n = 267) only 12% have achieved insulin-independence (greater than 7 days). However with refined peri-transplant protocols insulin independence at 1 year can reach 20%. CONCLUSIONS: There are many factors which can explain the failure of achieving insulin-independence after islet allotransplantation. These include the use of diabetogenic immunosuppressive agents to abrogate both islet allo-immunity and auto-immunity, the critical islet mass to achieve insulin-independence and the detrimental effects of transplanting islets in an ectopic site. However recent evidence most notably from the Edmonton group demonstrates that islet allotransplantation still has great potential to become an established treatment option for diabetic patients.

Animals↗

Pancreas resection and islet autotransplantation for end-stage chronic pancreatitis.

OBJECTIVE: To assess the safety and efficacy of islet autotransplantation (IAT) combined with total pancreatectomy (TP) to prevent diabetes. SUMMARY BACKGROUND DATA: There have been recent concerns regarding the safety of TP and IAT. This is thought to be related to the infusion of large volumes of unpurified pancreatic digest into the portal vein. Minimizing the volume of islet tissue by purifying the pancreatic digest has not been previously evaluated in terms of the postoperative rate of death and complications, pain relief, and insulin independence. METHOD: During a 54-month period, 24 patients underwent pancreas resection with IAT. Islets were isolated using collagenase and a semiautomated method of pancreas digestion. Where possible, islets were purified on a density gradient and COBE processor. Islets were embolized into the portal vein, within the spleen and portal vein, or within the spleen alone. The total median volume of digest was 9.9 mL. RESULTS: The median number of islets transplanted was 140,419 international islet equivalents per kilogram. The median increase in portal pressure was 8 mmHg. Early complications included duodenal ischemia, a wedge splenic infarct, partial portal vein thrombosis, and splenic vein thrombosis. Intraabdominal adhesions were the main source of long-term problems. Eight patients developed transient insulin independence. Three patients were insulin-independent as of this writing. Patients had significantly decreased insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. Of the patients alive and well as of this writing, four had failed to gain relief of their abdominal pain and were still opiate-dependent. CONCLUSION: Combined TP and IAT can be a safe surgical procedure. Unfortunately, almost all patients were still insulin-dependent, but they had decreased daily insulin requirements and glycosylated hemoglobin levels compared with patients undergoing TP alone. A prospective randomized study is therefore needed to assess the long-term benefit of TP and IAT on diabetic complications.

Adult↗

Use of non-heart-beating donors in renal transplantation.

The rate of renal transplantation has plateaued and is now limited by the number of donor organs available. In the past all donor kidneys came from living donors or controlled non-heart beating donors. It was not until the introduction of brainstem death criteria that cadaveric heart beating donors became the main source. Recently, there has been renewed interest in non-heart beating donors, who have already suffered cardiorespiratory arrest. Kidneys from these donors have a unique set of problems associated with increased duration of warm ischaemia. To minimise this, the kidneys are cooled in situ using an intra-aortic balloon catheter and are perfused with cold hyperosmolar citrate. Retrieval can then proceed in the normal fashion. Despite a higher level of delayed graft function, the results from non-heart beating renal transplantation are good, with long term function comparable to cadaveric organs. If used safely, they enable significant expansion of the donor pool. Techniques in the future, such as machine perfusion preservation, may further improve the results from non-heart beating programmes.

Cadaver↗

Rapid determination of gemifloxacin in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

A method was developed for the determination of gemifloxacin (I) in human plasma using high-performance liquid chromatography-tandem mass spectrometry. Prior to analysis, the protein in plasma samples was precipitated with acetonitrile containing [13C2H3] gemifloxacin (II) to act as an internal standard. The supernatant was injected onto a PLRP-S column without any further clean-up. The mass spectrometer was operated in positive ion mode, employing a heat assisted nebulisation. electrospray interface. Ions were detected in multiple reaction monitoring (MRM) mode. The assay requires 50 microl of plasma and is precise and accurate within the range 10-5,000 ng/ml. The average within-run and between-run coefficients of variation were <11% at 10 ng/ml and greater concentrations. The average accuracy of validation standards was generally within +/-7% of the nominal concentration. There was no evidence of instability of I in human plasma following three complete freeze-thaw cycles and samples can safely be stored for at least 6 months at -20 degrees C. The method proved very robust and was successfully applied to the analysis of clinical samples from patients dosed with gemifloxacin.

Anti-Infective Agents↗

Protein-protein recognition, hydride transfer and proton pumping in the transhydrogenase complex.

BACKGROUND: Membrane-bound ion pumps are involved in metabolic regulation, osmoregulation, cell signalling, nerve transmission and energy transduction. How the ion electrochemical gradient interacts with the scalar chemistry and how the catalytic machinery is gated to ensure high coupling efficiency are fundamental to the mechanism of action of such pumps. Transhydrogenase is a conformationally coupled proton pump linking a proton gradient to the redox reaction between NAD(H) and NADP(H). The enzyme has three components; dI binds NAD(H), dII spans the membrane and dIII binds NADP(H). RESULTS: The first crystal structure of a transhydrogenase dI component (from Rhodospirillum rubrum) has been determined at 2.0 A resolution. The monomer comprises two domains. Both are involved in dimer formation, and one has a Rossmann fold that binds NAD+ in a novel mode. The two domains can adopt different conformations. In the most closed conformation, the nicotinamide ring is expelled from the cleft between the two domains and is exposed on the outside of the protein. In this conformation it is possible to dock the structure of dI/NAD+ with that of a dIII/NADP+ complex to provide the first insights into the molecular basis of the hydride-transfer step. CONCLUSIONS: Analysis of the model of the dI/dIII complex identifies residues potentially involved in dI/dIII interaction and shows how domain motion in dI results in a shift in position of the nicotinamide ring of NAD+. We propose that this movement is responsible for switching between the forbidden and allowed states for hydride transfer during proton pumping.

Molecular Sequence Data↗

The high-resolution structure of the NADP(H)-binding component (dIII) of proton-translocating transhydrogenase from human heart mitochondria.

BACKGROUND: Transhydrogenase, located in the inner membranes of animal mitochondria and the cytoplasmic membranes of bacteria, couples the transfer of reducing equivalents between NAD(H) and NADP(H) to proton pumping. The protein comprises three subunits termed dI, dII and dIII. The dII component spans the membrane. The dI component, which contains the binding site for NAD(+)/NADH, and the dIII component, which has the binding site for NADP(+)/NADPH, protrude from the membrane. Proton pumping is probably coupled to changes in the binding affinities of dIII for NADP(+) and NADPH. RESULTS: The first X-ray structure of the NADP(H)-binding component, dIII, of human heart transhydrogenase is described here at 2.0 A resolution. It comprises a single domain resembling the classical Rossmann fold, but NADP(+) binds to dIII with a reversed orientation. The first betaalphabetaalphabeta motif of dIII contains a Gly-X-Gly-X-X-Ala/Val 'fingerprint', but it has a different function to that in the classical Rossmann structure. The nicotinamide ring of NADP(+) is located on a ridge where it is exposed to interaction with NADH on the dI subunit. Two distinctive features of the dIII structure are helix D/loop D, which projects from the beta sheet, and loop E, which forms a 'lid' over the bound NADP(+). CONCLUSIONS: Helix D/loop D interacts with the bound nucleotide and loop E, and probably interacts with the membrane-spanning dII. Changes in ionisation and conformation in helix D/loop D, resulting from proton translocation through dII, are thought to be responsible for the changes in affinity of dIII for NADP(+) and NADPH that drive the reaction.

Amino Acid Sequence↗

Sub-clinical acute rejection detected using protocol biopsies in patients with delayed graft function.

Acute rejection in renal transplants is difficult to diagnose when patients have delayed graft function (DGF) in the early post-transplant period. In this study protocol, renal transplant biopsies were performed in an attempt to detect sub-clinical acute rejection episodes. Eighty-three patients were eligible for the study, of whom 33 had DGE All had protocol renal transplant biopsies performed under ultrasound control at 7 days post-transplant, and those with DGF had further biopsies weekly until the graft functioned. All histologically confirmed acute rejection episodes were treated. Sub-clinical acute rejection was detected in 6/33 (18%) patients with DGF compared to 2/50 (4%) in the other patients (P < 0.05). Borderline rejection was present in 4/33 (12%) and 4/50 (8%) patients, respectively. Because of the high detection rate of sub-clinical acute rejection and the low morbidity of renal transplant biopsies, their use is recommended in patients with DGF.

Acute Disease↗

The feasibility of spleen-preserving pancreatectomy for end-stage chronic pancreatitis.

BACKGROUND: It is considered difficult to preserve the spleen at the time of distal or total pancreas resection for chronic pancreatitis (CP). The aim of this study was to assess the feasibility of preserving the spleen in patients requiring total or completion pancreatectomy for CP. METHODS: All patients having total or completion pancreatectomy for CP were evaluated postoperatively in terms of morbidity, mortality, and pain relief. To assess splenic vascularity, all patients underwent abdominal ultrasound and power doppler imaging to assess splenic perfusion and the patency of the remaining splenic vessels. RESULTS: Of 35 patients having total pancreatectomy, the spleen was preserved in 30 patients (19 women, 11 men; median age 40 years). The etiology of CP was mainly idiopathic (n = 14) or alcohol related (n = 12). All patients presented with chronic abdominal pain (median 5 years) requiring opiate-derived analgesia for pain relief. Fifteen patients (50%) had undergone previous therapeutic intervention for pain relief. The spleen was preserved with either an intact splenic artery and vein in 19 patients and or the short gastric vessels (n = 11). The mean duration of the procedure was 7 hours (range 5 to 11) and mean blood loss was 1,090 mL. The 30-day mortality was 3.8% (n = 1). Five patients had splenic complications (17%). These included splenectomy (n = 2), intrasplenic collection (n = 2), and a wedge splenic infarct (n = 1). Two of these complications were related to intrasplenic islet autotransplants. Follow-up with abdominal ultrasound and power doppler scanning showed no other abnormalities; blood flow was demonstrable in all patients with intact splenic arteries and vein (n = 19). The mean hospital stay was 25 days. Of the 24 patients who were beyond 6 months' follow-up, 82% (n = 20) have complete relief of pain, and 4 still require opiate analgesia. CONCLUSIONS: Spleen-preserving pancreatectomy is a feasible procedure for chronic pancreatitis, providing complete pain relief in 80% of patients. When the splenic artery and vein cannot be preserved, there is a minimal risk of splenic complications that may require further treatment; but for the majority of patients, splenectomy is avoided.

Adult↗