Effects of route of administration on oxytocin-induced changes in regional cerebral blood flow in humans.

Could nose-to-brain pathways mediate the effects of peptides such as oxytocin (OT) on brain physiology when delivered intranasally? We address this question by contrasting two methods of intranasal administration (a standard nasal spray, and a nebulizer expected to improve OT deposition in nasal areas putatively involved in direct nose-to-brain transport) to intravenous administration in terms of effects on regional cerebral blood flow during two hours post-dosing. We demonstrate that OT-induced decreases in amygdala perfusion, a key hub of the OT central circuitry, are explained entirely by OT increases in systemic circulation following both intranasal and intravenous OT administration. Yet we also provide robust evidence confirming the validity of the intranasal route to target specific brain regions. Our work has important translational implications and demonstrates the need to carefully consider the method of administration in our efforts to engage specific central oxytocinergic targets for the treatment of neuropsychiatric disorders.

Predicting Amputation and Multiple Debridements in Tooth Knuckle Injuries.

BACKGROUND: Tooth knuckle injuries can be expensive to treat and may necessitate amputation in some cases. Several limitations exist in the literature regarding our knowledge around the factors predicting amputation and the need for multiple debridements in treating this injury. METHODS: A historic cohort study of 321 patients treated for tooth knuckle injuries was undertaken. Twenty-one demographic, clinical and laboratory variables were collected. Two outcome measurements were collected - the need for amputation and the need for more than one surgical debridement. A multivariate logistic regression was performed to determine the relationship between the predictor variables and the outcome measurements. RESULTS: Of the 321 patients examined, 1.6% required amputations and 25% required multiple debridements. Osteomyelitis was found to be a major predictor for amputation in these patients (OR = 35). Delayed presentation (OR = 1.1) and diabetes (OR = 2.6) were found to significantly increase the risk of requiring multiple debridements. CONCLUSIONS: Our models were able to predict what patients were at the greatest risk for amputation and multiple debridement. Reducing rates of osteomyelitis and delays in presentation may help reduce the incidence of amputation and reoperation in this injury.

Predicting serious complications and high cost of treatment of tooth-knuckle injuries: a systematic literature review.

PURPOSE: The tooth-knuckle injury (TKI) is a serious and potentially costly injury seen in orthopaedic practice. The aim was to conduct a systematic literature review on the factors associated with serious complications and high treatment costs in tooth-knuckle injuries. METHODS: MEDLINE, Scopus and CINAHL were used as the literature sources. INCLUSION CRITERIA: Original research papers that reported on factors predicting serious complications and high treatment costs in TKIs were included. There were no restrictions placed on study size, language, study design or date of publication. EXCLUSION CRITERIA: Case studies, case series and review articles were not included. RESULTS: After duplicates were removed, 403 unique studies remained; after titles and abstracts were screened, 48 titles remained and were retrieved in full text. Of these, 14 titles met the inclusion criteria and were included in the data synthesis. Tenosynovitis, septic arthritis, osteomyelitis and residual stiffness were common serious complications occurring in up to 36.3, 70.0, 47.6 and 65.3 % of cases, respectively. Amputation was also common in up to 18.0 % of injuries. Treatment costs were measured by length of hospital stay and the number of debridements required. On average, patients required 3.8-8 days of admission and 1.3-2.7 debridements each. CONCLUSION: Increased time delay from injury to treatment, deeply penetrating injuries, proximal interphalangeal joint (PIPJ) injuries and, possibly, E. corrodens infections were associated with serious complications in TKIs. Delayed treatment, inadequate treatment, PIPJ injuries and deeply penetrating injuries predicted higher treatment costs. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42016029949 ( http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016029949 ).

Treatment of distal radial fractures with the DVR-A plate--the early Bristol experience.

AIM: The aim of the study was to assess how adequately distal radial fracture reduction was reproduced and maintained with the distal volar radius anatomic DVR-A (Biomet, Inc) locking plate. METHODS: We looked at a consecutive series of 111 patients treated with the DVR-A plate at our institution from 2007-2010. The preoperative, intra-operative, and postoperative films were reviewed. The AO and Frykman classification was recorded. The sagittal tilt, radial inclination, and radial length were measured on intra-operative X-rays and compared with final follow-up X-rays. The last recorded range of motion at follow-up and a functional assessment using the Disabilities of the Arm, Shoulder, and Hand (DASH) score was recorded. RESULTS: At final follow-up a mean radial inclination of 22.22 degrees (11 to 38 degrees), radial height of 11.85 mm (6 to 18 mm), and sagittal tilt of 6.71 degrees volar (-9 to 19 degrees) was achieved. From initial post-operative films, to final follow-up X-rays there was a mean increase of 0.17 degrees in radial inclination, a mean loss of 0.36 mm radial height, and a mean loss of 2.17 degrees volar tilt. The mean extension was 46.8 degrees, flexion 48.3 degrees, pronation 77.4 degrees, supination 74.8 degrees, radial deviation 15.3 degrees and the ulnar deviation 19 degrees. The mean DASH score was 12.8 (0-68). CONCLUSION: The DVR-A plate achieved a highly satisfactory reduction of radial length and radial inclination, with a small loss of volar sagittal tilt at final follow-up. A good functional outcome was reported, with a satisfactory range of motion achieved. The DVR-A plate is a safe and effective treatment for unstable and intra-articular displaced distal radius fractures, particularly in younger patients, in the short term.

Postmortem evidence of interactions of bottlenose dolphins (Tursiops truncatus) with other dolphin species in south-west England.

Reports of violent interactions between bottlenose dolphins (Tursiops truncatus) and harbour porpoises (Phocoena phocoena) in the coastal waters of the UK are well documented. Examination of stranded cetaceans by the Cornwall Wildlife Trust Marine Strandings Network and the UK Cetacean Strandings Investigation Programme has indicated that seven animals, of four other species, found stranded in south-west England, had pathology consistent with bottlenose dolphin interaction, including two juvenile and two adult common dolphins (Delphinus delphis), one juvenile pilot whale (Globicephala melas), one juvenile Risso's dolphin (Grampus griseus) and one adult striped dolphin (Stenella coeruleoalba). Although recorded traumatic lesions were often not as severe as those found in harbour porpoises, it is probable that the interactions did contribute to stranding and/or death in all four of the juvenile animals examined. Furthermore, analysis of photographs taken before establishment of the Marine Strandings Network revealed rake (teeth) marks consistent with bottlenose dolphin interaction on one stranded common dolphin in 1992. A number of causes have been suggested for these interactions in harbour porpoises stranded in the UK and it is possible that any combination of these factors may also be implicated in the cases described in this report.

Revision of an acetabular liner has a high risk of dislocation.

Polyethylene liners of modular acetabular components wear sometimes need to be replaced, despite the metal shell being well fixed. Replacing the liner is a relatively simple procedure, but very little is known of the outcome of revision. We prospectively followed up 1126 Harris-Galante I metal-backed, uncemented components for between nine and 19 years. We found 38 (3.4%) liners of 1126 acetabular components wore and required revision. These revisions were then followed up for a mean of 4.8 years. The rate of dislocation was 28.9%. Nine of the dislocations occurred once and two were recurrent. The overall secondary revision rate was three of 38 total hip replacements (7.9%) at a mean follow-up of 4.8 years. This gives a 92.1% survivorship (35 of 38) at under five years. In isolated revision of a liner, we had a complication rate of 23% (three of 13). In revision of a liner combined with revision of the femoral stem, there was a complication rate of 48% (12 of 25). We discuss possible reasons for the high dislocation rates. Leaving the well-fixed acetabular shell in situ leads to an increased risk of instability. However, this needs to be balanced against the otherwise low complication rate for revision of the liner. Patients should be consented accordingly.

Embryonic and larval respiration in the arboreal foam nests of the African frog Chiromantis xerampelina.

In Zimbabwe, female Chiromantis xerampelina construct spherical foam nests that are suspended above temporary water. The nests average 624 ml in volume and contain 854 eggs. The 1.7 mm ova have exceptionally thin jelly capsules and are dispersed in the foamy core of the nest, which is surrounded by a layer of eggless foam. At 25 degrees C, each embryo requires 3.5 days to reach hatching at developmental stage 22, during which it consumes 30 microliters of oxygen. After hatching, each larva remains in the nest for 2 more days and consumes a further 123 microliters of oxygen. The fresh foam contains 77% air, which is sufficient to supply all of the oxygen requirements of the embryos until well after they hatch. Therefore, the size of the egg mass is not limited by oxygen availability as it is in many other anurans. Oxygen also diffuses into the nest from the atmosphere, but the rate is severely restricted by the wet foam, despite the presence of bubbles. Drying of the outer layer of foam greatly increases its oxygen conductance, but the larvae remain in the inner core of wet foam, where they compete for oxygen at the periphery. With further drying of the nest, the wet foam diminishes in volume and concentrates the larvae at a time when their oxygen demands are approaching the maximum. Oxygen pressures within the wet foam drop below 10 kPa and oxygen uptake by the larvae becomes progressively limited, possibly stimulating their emergence from the nest. The delay between hatching and escape from the nest permits the larvae to grow and mature to a stage at which all of the clutch can emerge simultaneously.

Systematic study of human alpha beta T cell receptor V segments shows allelic variations resulting in a large number of distinct T cell receptor haplotypes.

The variation of the alpha beta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two V beta 2 loci and the V alpha 8.1 locus, we found that all exhibited a coding polymorphism. One of the V beta 2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second V beta 2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a V beta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first V beta 2 segment on the known map to define haplotypes with two other polymorphic segments: V beta 1 and V beta 6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that V beta regions are highly variable between individuals. Two alleles exist at the V alpha 8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.

Restricted T cell receptor expression by human T cell clones specific for mycobacterial 65-kDa heat-shock protein: selective in vivo expansion of T cells bearing defined receptors.

We have examined the T cell receptor (TcR) expression of clones specific for epitopes of mycobacterial 65-kDa heat-shock protein (hsp65) in the context of two different HLA molecules, and used this system as a model to assess the selection of T cells responsive to this antigen in vivo. DR3-restricted clones were raised from both the synovial fluid (SF) and peripheral blood (PB) of a patient with reactive arthritis in three separate cloning events. Five of five SF-derived clones tested expressed either V beta 5.2 or a closely related beta chain, V beta 5.6. The alpha chains expressed by V beta 5.2+ and V beta 5.6+ clones were from different families, V alpha 2.4 and V alpha 23.2, respectively. Nine of ten clones derived from two cloning procedures on PB taken 3 years later also expressed either V beta 5.2 or V beta 5.6. This suggests that the TcR repertoire for recognizing this major histocompatibility complex/peptide complex is relatively restricted and favors the use of V beta 5. Conservation of the beta chain third complementarity-determining region (CDR3) sequence was not evident, however. Sequencing alpha and beta chains of representative V beta 5.2+ and V beta 5.6+ PB-derived clones revealed TcR which were identical to those utilized by the SF-derived clones, showing that the repertoire for recognition of this antigen is stable over time. Similar studies of TcR expression were carried out on hsp65-specific, DP4-restricted clones derived from the SF of a patient with rheumatoid arthritis by two independent cloning procedures. There was conservation of alpha chain usage, since all clones expressed a member of the V alpha 1 family, but again CDR3 sequence conservation was not apparent. beta chain usage was not restricted since different clones expressed V beta 6.7, V beta 22.3 and V beta 12. Subtle differences in epitope specificity were detected for two clones with differing TcR. Once more, T cell clones with identical alpha and beta TcR chains were obtained from the separate cloning procedures, suggesting oligoclonalty of T cells with this defined specificity in the patient's SF.

Identification of a CA repeat at the TCRA locus using yeast artificial chromosomes: a general method for generating highly polymorphic markers at chosen loci.

The creation of a comprehensive genetic map in human has been limited by the lack of highly polymorphic markers spaced evenly throughout the human genome. We have utilized yeast artificial chromosomes (YAC) containing large human DNA inserts to help identify highly polymorphic (CA)n repeats at a chosen locus. The DNA of a YAC containing the locus was subcloned in M13 vectors, and the recombinants were screened at high stringency to detect preferentially long (CA)n repeats (n greater than 20). These repeats, which are the most likely to be highly polymorphic, were then studied to confirm both the level of polymorphism and their precise genetic location. This strategy has permitted the identification of a new, highly polymorphic CA repeat (77% heterozygosity) at the T cell receptor alpha chain (TCRA) locus on chromosome 14q. It provides a powerful marker for assessing the role of this locus in the susceptibility to autoimmune and infectious diseases. This approach should permit the development of highly polymorphic markers at any targeted locus and rapidly improve the current human genetic map.

The genetic contribution to human T-cell receptor repertoire.

Recent studies in mice have highlighted the importance of polymorphic genetic loci such as the major histocompatibility complex (MHC) or minor lymphocyte-stimulating antigen (Mls) in determining the nature of the peripheral T-cell receptor (TcR) population. As our knowledge of the equivalent process in humans is incomplete, we have utilized a modification of the polymerase chain reaction (PCR) to determine the overall genetic contribution to the normal human TcR variable V beta gene repertoire. These data demonstrate that the normal human T-cell population contains members of all the major TcR V beta families and that there is considerable variation in the relative amounts of specific TcR V beta transcripts between individuals. We have established that the normal peripheral TcR V beta repertoire is more concordant in identical twins than in unrelated individuals. The relative importance of genetic factors in determining the peripheral TcR repertoire is emphasized by these results and suggests that, in humans, the genetic control of immune responsiveness is mediated in part by the peripheral TcR repertoire.

Endocrines and osmoregulatory mechanisms in the Nile crocodile, Crocodylus niloticus.

The changes in body fluid economy and endocrine status associated with exposure of the Nile crocodile, Crocodylus niloticus, to hypertonic media have been related to the responses to altered renin-angiotensin system (RAS) activity observed in fresh water (FW) animals. Animals held in hypertonic media for 7 days showed a 18.2% body weight loss and raised plasma and urinary sodium, potassium, chloride, and osmotic concentrations. Within 6 hr of return to FW rapid imbibition had largely restored body weight and produced significant plasma dilution. Although plasma sodium, chloride, and osmotic concentrations remained higher than in FW controls, plasma levels of corticosterone, aldosterone, and arginine vasotocin were not significantly altered. Angiotensin I (AI) administration in FW crocodiles stimulated drinking and raised plasma aldosterone levels by comparison with animals given the converting enzyme inhibitor, Captopril, together with AI. The compensatory drinking behaviour exhibited by the Nile crocodile may thus involve the RAS. The RAS also appears to influence interrenal steroidogenesis and thus may afford an integrative role in crocodile fluid management as it does in homeotherms.

Characterisation of cis-acting DNA sequences required for the expression of the chicken 5-aminolevulinate synthase gene in Xenopus oocytes.

In this paper, we have constructed deletion and deletion-insertion mutations of the chicken 5-aminolevulinate synthase 5' flanking region and examined the expression of these constructs in microinjected Xenopus oocytes. Utilising this assay, we have delimited the boundary of the 5' flanking region required for expression to be 80 bp upstream from the transcription initiation site. A second major focus of this study has been to define the role of known putative cis-acting sequences in regulating 5-aminolevulinate synthase gene expression. Expression of the insertion-deletion mutants demonstrated that only a TATA box at position -28, and a single GC box at position -78 was necessary for expression of the 5-aminolevulinate synthase gene in Xenopus oocytes. This result is unusual in view of the current state of knowledge of the function of cis-acting sequence elements in transcriptional regulation.

Nile crocodiles, Crocodylus niloticus, and estuarine crocodiles, Crocodylus porosus, show similar osmoregulatory responses on exposure to seawater.

1. Nile crocodiles, reared in fresh water and exposed acutely to seawater, suffer marked dehydration and hypernatraemia. Cloacal urine osmolarity and potassium concentration increased markedly but urine sodium remains low. 2. Hypernatraemia is increased when secretion from the lingual salt glands is prevented. 3. C. niloticus appears not to drink seawater. 4. Similarities in osmoregulatory response between estuarine and Nile crocodiles suggest that the lingual salt glands of C. niloticus are functional in salt water, playing an important role in sodium balance. 5. Significant differences in the function of the renal/cloacal complex of Alligator and Crocodylus emphasize further the differences between these two groups of crocodilian and provide support for the postulated marine ancestry of many or all of the Crocodylidae.

Biologically active gastrin/CCK-related peptides in the stomach of a reptile, Crocodylus niloticus; identified and characterized by immunochemical methods.

We have used immunochemical, chromatographic, and bioassay techniques to characterize peptides related to gastrin and CCK, from the stomach of the reptile Crocodylus niloticus. By immunocytochemistry gastrin/CCK-like peptides were localized in specific mucosal cells of the pylorus and in the duodenum. Boiling water extracts of pyloric antrum cross reacted with four antisera specific for the C-terminal region of gastrin or CCK, but estimates of concentration varied between antisera. Antisera specific for the N-terminus of heptadecapeptide gastrin (G17), intact G17, or the amphibian CCK-like peptide caerulein did not cross react with the crocodile extracts. Gel filtration of the extracts on Sephadex G50 resolved one major peak eluting significantly before G17 or CCK8, suggesting larger molecular size, whereas ion exchange on DE52 cellulose resolved two major immunoreactive peaks, both eluting before G17, indicating that they are less acidic. The more acidic of the two peptides stimulated gastric acid secretion in the rat, but had no CCK-like actions on the rat pancreas. Thus crocodile antrum contains gastrin-like peptides, which are however clearly distinguishable from any of the known mammalian forms of gastrin and CCK.

Heat loss from feet of herring gulls at rest and during flight.

The role of the feet of herring gulls (Larus argentatus) in heat dissipation was estimated during rest and wind-tunnel flight. We determined the blood flow to the feet and the arteriovenous temperature difference and thus estimated heat loss from the feet. Determinations of oxygen consumption and respiratory water loss at rest gave a heat production of about 8 W; 37-56% of this heat was lost from the feet (air temp = 10-35 degrees C). During flight heat production was estimated to be about 57 W and heat loss from the feet was 46 W, about 80% of the heat production in flight. Thus the webbed feet are an important avenue of heat loss in the herring gull.