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Competing Interests: Funding Support and Author Disclosures Dr Mangner has received personal fees from Edwards Lifesciences, Medtronic, Novartis, Sanofi Genzyme, AstraZeneca, Pfizer, Bayer, Abbott, Abiomed, B. Braun, and Boston Scientific outside the submitted work. Dr Fassl has received speaker fees from CSL Behring and Edwards Lifesciences outside the submitted work. Dr Haussig has received speaker honoraria and consulting fees from Edwards Lifesciences, Abbott, and Boston Scientific outside the submitted work. Dr Linke has received grants from Novartis; personal fees from Medtronic, Abbott, Edwards Lifesciences, Boston Scientific, AstraZeneca, Novartis, Pfizer, Abiomed, Bayer, and Boehringer; and personal fees from Picardia, Transverse Medical, and Claret Medical outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

The immunoglobulin fold (Ig fold) domain is a super-secondary structural motif consisting of a sandwich with two layers of β-sheets that is present in many proteins with very diverse biological functions covering a wide range of physiological processes. This domain presents a modular architecture built with β strands connected by variable length loops that has a highly conserved structural core of four β-strands and quite variable β-sheet extensions in the two sandwich layers that enable both divergent and convergent evolutionary mechanisms in the known Ig fold proteome. The central role of this Ig fold's structural plasticity in the evolutionary success of antibodies in our immune system is well established. Nature has also utilized this Ig fold in all domains of life in many different physiological contexts that go way beyond the immune system. Here we will present a structural and functional overview of the utilization of the Ig fold in different biological processes and in different cellular contexts to highlight some of the innumerable ways that this structural motif can interact in multidomain proteins to enable their diversity of functions. This includes shareable specific protein structure visualizations behind those functions that serve as starting points for further explorations of the biomolecular interactions spanning the Ig fold proteome. This overview also highlights how this Ig fold is being utilized through natural adaptation, engineering, and even building from scratch for a range of biotechnological applications., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: The aim of the study was quantitative and qualitative assessments of scrotal abnormalities diagnosed in boys 8 to 36 months old during ultrasound screening and estimation if these abnormalities influence testes volume., Materials and Methods: High frequency scrotal ultrasound was performed in 1448 patients aged 8-36 months as additional exam during screening ultrasound program for children including cervical and abdominal ultrasound. The mean age of examined boys was 17 months. For further analysis the children were divided in 5 age groups., Results: The abnormalities in scrotal ultrasound were found in 20.1% of boys. Undescended, cryptorchid testes were found in 4.8% of patients, mobile testicle in 7.6% and hydrocele in 2.8%. The volume of undescended testes was statistically lower than volume of the descended testes in 3 youngest groups of boys (p=0.003-0.011). The volume of mobile testicles did not increase with age, while in patients with hydrocele the testicular volume decreased with age., Conclusion: Scrotal screening ultrasound performed in boys up to 3 years old may deliver information about the number and type of existing pathologies as well as their influence on the testicular volume. The volume of the pathological testes was lower than the volume of the normal ones. Improper growth of testes may potentially have important clinical implication for the function of testes in the future., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The modulation of protein-protein interactions (PPIs) by small drug-like molecules is a relatively new area of research and has opened up new opportunities in drug discovery. However, the progress made in this area is limited to a handful of known cases of small molecules that target specific diseases. With the increasing availability of protein structure complexes, it is highly important to devise strategies exploiting homologous structure space on a large scale for discovering putative PPIs that could be attractive drug targets. Here, we propose a scheme that allows performing large-scale screening of all protein complexes and finding putative small-molecule and/or peptide binding sites overlapping with protein-protein binding sites (so-called "multibinding sites"). We find more than 600 nonredundant proteins from 60 protein families with multibinding sites. Moreover, we show that the multibinding sites are mostly observed in transient complexes, largely overlap with the binding hotspots and are more evolutionarily conserved than other interface sites. We investigate possible mechanisms of how small molecules may modulate protein-protein binding and discuss examples of new candidates for drug design., (Published by Elsevier Ltd.)

Glycosylation is an important aspect of epigenetic regulation. Glycosyltransferase is a key enzyme in the biosynthesis of glycans, which glycosylates more than half of all proteins in eukaryotes and is involved in a wide range of biological processes. It has been suggested previously that homooligomerization in glycosyltransferases and other proteins might be crucial for their function. In this study, we explore functional homooligomeric states of glycosyltransferases in various organisms, trace their evolution, and perform comparative analyses to find structural features that can mediate or disrupt the formation of different homooligomers. First, we make a structure-based classification of the diverse superfamily of glycosyltransferases and confirm that the majority of the structures are indeed clustered into the GT-A or GT-B folds. We find that homooligomeric glycosyltransferases appear to be as ancient as monomeric glycosyltransferases and go back in evolution to the last universal common ancestor (LUCA). Moreover, we show that interface residues have significant bias to be gapped out or unaligned in the monomers, implying that they might represent features crucial for oligomer formation. Structural analysis of these features reveals that the majority of them represent loops, terminal regions, and helices, indicating that these secondary-structure elements mediate the formation of glycosyltransferases' homooligomers and directly contribute to the specific binding. We also observe relatively short protein regions that disrupt the homodimer interactions, although such cases are rare. These results suggest that relatively small structural changes in the nonconserved regions may contribute to the formation of different functional oligomeric states and might be important in regulation of enzyme activity through homooligomerization., (Published by Elsevier Ltd.)

An interactive audience response system was used to collect information from members of the Obstetric Anaesthetists' Association at the 1997 Annual Meeting about the drug use that is unsupported by the Product Licence. The responses confirm that both licensed and unlicensed drugs are widely used in clinical practice outside the limitations imposed by Product Licence. The commonest types of unlicensed administration in obstetric anaesthetic practice are the use of mixtures and epidural or spinal administration of opioids. Despite widespread awareness of the subject, there appears to be considerable ignorance about the indications for which many commonly used drugs are licensed, even amongst a specialist audience. A majority of audience members expressed a view that the OAA should play a pro-active role, either by polling members about their current practice, or by issuing guidelines on reasonable drug practice in obstetric anaesthesia, or both. Potential implications of these are discussed.

An audit cycle has been completed looking at the availability of information about different types of anaesthesia in labour, their usage and the degree of maternal satisfaction. The initial audit 7 years ago led to the production of an information leaflet on pain relief in labour. The current audit (1996) demonstrated that the majority of patients receive the leaflet and find the information useful. The leaflet may have helped improve satisfaction and selection of analgesia in primigravide. However, the leaflet needs updating to include some information on caesarean section now that this has become such a common form of delivery.

Study Objective: To investigate the efficacy, opioid-sparing effects and any reduction in adverse events of a continuous intravenous (i.v.) infusion of ketorolac following lower abdominal surgery., Design: Randomized, double-blind, placebo-controlled, parallel-group study., Setting: Inpatient elective gynecologic surgical patients., Patients: 60 ASA physical status I or II patients aged 18 to 70 years scheduled for elective abdominal hysterectomy., Interventions: Following standardized preparation and anesthesia, continuous i.v. infusions of either ketorolac or placebo were administered for 24 hours postoperatively with a patients' standardized postoperative protocol. Supplementary analgesia was administered by an i.v. patient-controlled analgesia (PCA) system., Measurements and Main Results: A significantly lower proportion of the patients in the ketorolac group (6%) rated their pain at 24 hours as moderate or severe compared with patients in the placebo group (34%) (p = 0.04). Mean 24-hour morphine consumption was significantly lower in the ketorolac group (43 mg; SEM 5 mg) compared with the placebo group (55 mg SEM 5 mg) (p = 0.02). There was no significant difference in the incidence of postoperative hypoxemia between the groups with respect to mean times per hour spent with oxygen saturation (SPO2) less than 85%, more than 85% but less than 90%, or more than 90% but less than 94%, mean hourly SPO2, or the incidence and duration of severe hypoxemic episodes. Nausea and vomiting were the only significant adverse events, and they occurred in 30% of patients in both groups., Conclusion: Intravenous infusion of ketorolac combined with morphine delivered via a PCA device would appear to be a valuable method of providing balanced analgesia following lower abdominal surgery.

We describe 4-yr experience providing extradural infusion analgesia in a district hospital for treatment of postoperative pain. A total of 770 patients recovering from major surgery were treated on general surgical wards between April 1989 and March 1993. The results of a retrospective audit showed that pain control, assessed with both a visual analogue scale (VAS score (0-10 cm)) and a verbal rating scale (VRS), was good. At rest, more than 80% of patients scored pain as absent or mild (VAS score 0-3) during the first 24 h, with only 4% experiencing severe pain (VAS score 7-10). On movement, 50% of patients had good pain control (VAS score 0-3) while 20% of patients experienced severe pain (VAS score 7-10). Minor complications such as emetic sequelae and pruritus were common; these conditions were mild and rarely required treatment. Hypotension (< 100 mm Hg) occurred in 34% of patients in the first 24 h. Ventilatory frequencies of 8 b.p.m. or less occurred in 2.6% of patients. Four patients (0.52%) developed severe respiratory depression. These patients demonstrated increased sedation but only one had a low ventilatory frequency. Three patients died while receiving extradural infusion analgesia.

We describe a computational approach to protein tertiary structure prediction that combines ideas from the three-dimensional (3D) profile method of Bowie, Lüthy and Eisenberg and the associative memory Hamiltonians of Friedrichs and Wolynes. The ultimate goal of our work is to extend and generalize the capabilities of these heuristics so as to be able to predict novel structures that might be found in nature or designed proteins. In our approach we approximate the interactions between residues through a pseudo-potential function similar to an associative memory Hamiltonian. This function is constructed based on 3D environment principles. Favorable inter-residue contacts for each residue in a target protein are inferred by using 3D environment propensities of the residues and a collection of 3D environment templates derived from a dataset of protein crystal structures. A Hamiltonian encoding this information is used to guide an optimization phase via molecular dynamics with annealing, which then leads to the folded structure. With our algorithm we can recover the structure of dataset proteins and have also succeeded in constructing the fold for a protein with little sequence similarity to any dataset protein.

Forty patients recovering from upper abdominal surgery were allocated randomly to receive i.m. morphine 0.15 mg kg-1 as required or patient-controlled analgesia (PCA), with i.v. morphine 1 mg and a 5-min lock out time. Arterial oxygen saturation (SpO2) was measured continuously the night before and for 24 h immediately after surgery. A significantly greater proportion of patients in the PCA group (nine of 19) rated their analgesia as excellent compared with the i.m. group (two of 20) (P < 0.05). There was no significant difference in the incidence of postoperative hypoxaemia in the two treatment groups. Severe postoperative hypoxaemia (SpO2 < 85% for more than 6 min h-1) was seen in three patients receiving i.m. analgesia and one patient in the PCA group.

We have examined postoperative pain in patients allocated randomly to receive extradural bolus diamorphine 3.6 mg, extradural infusion of 0.15% bupivacaine with 0.01% diamorphine or patient-controlled i.v. administration of diamorphine at a maximum rate of 1 mg per 5 min, after total abdominal hysterectomy. Extradural infusion analgesia produced the smallest pain scores from 12 to 24 h after surgery (P < 0.05). More patients in the extradural infusion group were moderately hypoxaemic (SpO2 < 90% > 12 min h-1) after operation, compared with the two other groups (P < 0.05). The group using patient-controlled analgesia received more diamorphine and suffered a greater incidence of emetic sequelae (P < 0.05).

The benefits, risks and resource implications of providing an Acute Pain Service were assessed during the first year of the service. Six hundred and sixty patients recovering from major surgery were treated with patient-controlled analgesia (510 patients) or extradural infusion analgesia (150 patients). The results of a prospective outcome study showed that pain control was good: more than 60% of patients scored their pain as mild during the first 24 h. Only 10% of patients complained of severe postoperative pain. Eight patients developed potentially serious complications including respiratory depression and hypotension; the diagnosis and management of these problems on general wards is discussed. Retrospective analysis of the incidence of postoperative chest infection in surgical patients showed a marked reduction during the first year of the service (1.3% in 1988, 0.4% in 1989-90 (P less than 0.01].

The efficacy of domperidone 20 mg, droperidol 2.5 mg, metoclopramide 10 mg or placebo (saline) administered i.v. before induction of anaesthesia, was studied in 199 women undergoing gynaecological surgery as day cases. Following a standardized general anaesthetic technique, droperidol or metoclopramide significantly reduced the incidence of nausea and vomiting; domperidone decreased the incidence of postoperative nausea alone. The occurrence of extrapyramidal reactions was similar in all groups. Patients treated with antiemetics were no more sedated than those given placebo. Those receiving droperidol complained of significantly less postoperative pain than those who had received domperidone or metoclopramide.

Fifty-seven women received extradural morphine 3 mg, buprenorphine 0.18 mg or buprenorphine 0.09 mg after elective Caesarean section carried out under extradural bupivacaine. Supplementary sublingual buprenorphine was available on demand. Ten-centimetre visual analogue pain scores were completed regularly; emesis, pruritus and urinary retention were recorded for 24 h. Patients who received buprenorphine 0.09 mg had more pain, and required more supplementary analgesia, than those who received morphine 3 mg. Pain scores and analgesic requirements after buprenorphine 0.18 mg were not significantly different from either of the other two groups. Emesis was not significantly different in the three groups. More itching occurred after morphine 3 mg and buprenorphine 0.18 mg than after buprenorphine 0.09 mg; pruritus of the face, legs and perineum was more common after morphine than buprenorphine. Twenty-eight percent of patients without a urinary catheter developed retention of urine. Seventy-five to 84% of patients were satisfied with analgesia during the first day after operation. Analgesia and adverse effects were similar when morphine 3 mg or buprenorphine 0.18 mg was given extradurally after Caesarean section.

Domperidone 20 mg, droperidol 2.5 mg, metoclopramide 10 mg and placebo (saline) were given i.v. 10 min before the end of anaesthesia, to 200 women undergoing major gynaecological surgery, and the incidence of postoperative nausea and vomiting following a standard anaesthetic technique was assessed. Droperidol was significantly more effective than domperidone, metoclopramide or placebo in reducing emetic sequelae. There were no significant differences between the groups in the incidence of extrapyramidal effects and postoperative sedation. Patients given droperidol required less postoperative analgesia than those given domperidone or metoclopramide. It was concluded that, of the drugs studied, droperidol alone was effective in protecting against nausea and vomiting after major gynaecological surgery.

Winnie and co-workers described a technique of blocking the lateral cutaneous nerve of thigh, femoral and obturator nerves using one injection of local anaesthetic into the fibrous sheath surrounding the femoral nerve. We studied 40 patients undergoing biopsy of vastus medialis for investigation of malignant hyperpyrexia, for onset, quality and recovery from this block. The patients were assigned in a random double-blind fashion to receive 0.6 ml kg-1 of one of two anaesthetic solutions: 1% lignocaine with 1 in 100,000 noradrenaline or 0.25% bupivacaine. Bupivacaine produced a similar onset time but longer duration of action compared with lignocaine. Median peak plasma concentrations of six patients in each group did not approach values associated with toxicity. This study demonstrated a 12.5% and 87.5% partial and complete femoral nerve block, respectively, and a 67.5% success rate for lateral cutaneous nerve of thigh using Winnie's technique. There was no clinical evidence of obturator nerve block.