AKAP150-anchored PKA regulation of synaptic transmission and plasticity, neuronal excitability and CRF neuromodulation in the lateral habenula.

Numerous studies of hippocampal synaptic function in learning and memory have established the functional significance of the scaffolding A-kinase anchoring protein 150 (AKAP150) in kinase and phosphatase regulation of synaptic receptor and ion channel trafficking/function and hence synaptic transmission/plasticity, and neuronal excitability. Emerging evidence also suggests that AKAP150 signaling may play a critical role in brain's processing of rewarding/aversive experiences. Here we focused on an unexplored role of AKAP150 in the lateral habenula (LHb), a diencephalic brain region that integrates and relays negative reward signals from forebrain striatal and limbic structures to midbrain monoaminergic centers. LHb aberrant activity (specifically hyperactivity) is also linked to depression. Using whole cell patch clamp recordings in LHb of male wildtype (WT) and ΔPKA knockin mice (with deficiency in AKAP-anchoring of PKA), we found that the genetic disruption of PKA anchoring to AKAP150 significantly reduced AMPA receptor (AMPAR)-mediated glutamatergic transmission and prevented the induction of presynaptic endocannabinoid (eCB)-mediated long-term depression (LTD) in LHb neurons. Moreover, ΔPKA mutation potentiated GABAA receptor (GABAAR)-mediated inhibitory transmission postsynaptically while increasing LHb intrinsic neuronal excitability through suppression of medium afterhyperpolarizations (mAHPs). Given that LHb is a highly stress-responsive brain region, we further tested the effects of corticotropin releasing factor (CRF) stress neuromodulator on synaptic transmission and intrinsic excitability of LHb neurons in WT and ΔPKA mice. As in our earlier study in rat LHb, CRF significantly suppressed GABAergic transmission onto LHb neurons and increased intrinsic excitability by diminishing small-conductance potassium (SK) channel-mediated mAHPs. ΔPKA mutation-induced suppression of mAHPs also blunted the synaptic and neuroexcitatory actions of CRF in mouse LHb. Altogether, our data suggest that AKAP150 complex signaling plays a critical role in regulation of AMPAR and GABAAR synaptic strength, glutamatergic plasticity and CRF neuromodulation possibly through AMPAR and potassium channel trafficking and eCB signaling within the LHb.

Perception of the medical risk of spaceflight.

We conducted an opinion survey to improve the characterization of medical risk during spaceflight, using a questionnaire designed to elicit space medicine experts' perceptions of the probability, health effect, and mission impact of selected medical events occurring during spaceflight missions of 30-90 d. This questionnaire was directed toward those events about which little data currently exist, therefore medical events that have occurred during spaceflights with some frequency, such as space motion sickness, were excluded from the questionnaire. The questionnaire was mailed to 99 clinical and research professionals involved with NASA medical programs; 65 responses were returned, of which 60 could be analyzed. The experts rated skin disorders as the most likely to occur, but which would have little effect on mission completion or astronaut health. Circulatory diseases were rated as having the lowest probability of occurrence, but the highest effect on the mission or on a crewmember's health. The results of this survey will be combined with data from analogous populations and existing astronaut health data to establish a data set to support decisions about allocation of health care resources.

Severe open tibial fractures. Results treating 202 injuries with external fixation.

Grade III open tibial fractures are known for frequent complications and poor clinical results, yet published series are few and cite conflicting results. To address this dilemma, the authors report a prospective study of 202 consecutive Grade III tibial fractures. All injuries were treated under protocol at the authors' university with primary external fixation and serial debridement. Equinus deformity was prevented with a new tibiometatarsal frame extension. Severe injuries crossing the ankle or knee were temporarily stabilized with external fixation across these joints. Staged reconstruction of soft tissue and then bone was undertaken for 176 of these tibias in patients who survived their multiple injuries. Reconstructive procedures included skin grafts in 57%, muscle flaps in 32%, and bone grafts in 28%. Gastrosoleus myocutaneous flaps were successful in 92% of cases versus 66% for free flaps. Late follow-up data were obtained for 171 (97%). Infection occurred in 15% and led to amputation in 7%. The infection rate was reduced to 9% in the second half of the series largely by removal of all necrotic bone prior to wound coverage. Angulation (greater than 10 degrees) in 9% and delayed union were lessened with early posterolateral grafting followed by progressive fracture loading in the fixator. A 9% incidence of pin tract drainage or loosening was reduced with predrilling and diaphyseal half pins. The time to fixator removal averaged 87 days. Ninety-three percent of the fractures united (median time, nine months) but healing times varied widely according to the amount of tissue injury and bone loss. Eighty-nine percent had satisfactory late clinical function. Results from this study, the largest series of open Grade III tibial fractures reported to date, suggest that successful staged reconstruction is now a reasonable expectation for most of these severe injuries.

External fixation arthrodesis of the ankle joint following trauma.

Arthrodesis is currently the treatment of choice for symptomatic degenerative arthropathy of the ankle. Thirty-seven patients underwent arthrodesis for post-traumatic disorders using either a Hoffmann external fixator or a Calandruccio frame. There was degenerative joint disease in 19 (51%), septic arthritis in 11 (30%), severe comminution in five (14%), and uncontrollable equinus in two (5%). The patients were divided into two groups. Twenty-six (70%) were considered to have sustained high energy open or comminuted injuries and 11 (30%), low energy injuries. Twenty-nine (78%) achieved a radiologic fusion following one operation. Four eventually united with further surgery for a final arthrodesis rate of 89%. In the high energy group 18 of 26 (69%) achieved primary fusion. Four united with additional surgery for a final arthrodesis rate of 85%. Two of these required subsequent amputations and two others, a triple arthrodesis which also failed to control chronic pain. Thus, a total of 18 of the 26 patients (69%) achieved a successful result. Also included in the high energy group were three patients with uncontrolled sepsis who underwent amputation before union occurred and one with a painful non-union. All 11 of the patients (100%) who originally sustained low energy injuries achieved a successful arthrodesis. The most common complication was in pin tract infection requiring incision, drainage, and oral antibiotics in 16 patients (43%). None of these progressed to chronic osteomyelitis.

The symphysis pubis. Anatomic and pathologic considerations.

The symphysis pubis is a nonsynovial amphiarthrodial joint that is situated at the confluence of the two pubic bones. A thick intrapubic fibrocartilaginous disc is sandwiched between thin layers of hyaline cartilage. The inferior pubic ligament provides most of the joint's stability. Anatomic sections demonstrate a symphysis by the end of the second month of gestation. Thick cartilaginous end-plates are present at birth but become thin by the time of skeletal maturity. Congenital diseases resulting in failure of symphysis formation include exstrophy of the bladder and cleidocranial dysostosis. Both pyogenic and tuberculous infectious diseases involve the symphysis. Metabolic disease, such as renal osteodystrophy, produces widening, while ochronosis results in calcific deposits in the symphysis. Inflammatory disease, such as ankylosing spondylitis, results in bony fusion of the symphysis. Osteitis pubis, the most common inflammatory disease, is treated with anti-inflammatory medication and rest. Degenerative joint disease of the symphysis, which can cause groin pain, results from instability or from abnormal pelvic mechanics. As is the case with most joints, the symphysis serves as a barrier to tumor invasion. The patterns of trauma include diastasis, straddle fracture, intraarticular fracture and overlapping dislocation, and combinations of injuries.

Fetal cardiac arrhythmia: antepartum diagnosis of a case of congenital atrial flutter.

A case of antepartum atrial tachyarrhythmia was detected in the 36th week of pregnancy. Cardiotocograph recordings done twice daily enabled close surveillance of the fetal condition after oxytoxin challenge testing had failed to show evidence of hypoxia. After a diagnosis of fetal cardiac arrhythmia had been made, elective caesarean section in the 40th week of pregnancy resulted in delivery of an infant in atrial flutter and cardiac failure. Both these problems were soon resolved by cardioversion and subsequent treatment with digoxin. Cardiac catheterisation showed no underlying cardiac abnormality. Increasing use of antenatal cardiotocography may show that intrauterine tachyarrhythmias are more common than had generally been believed.

The use of the amniotic fluid lecithin/sphingomyelin (L/S) ratio, creatinine concentration and nile blue sulphate tests, individually and in combination, in the assessment of fetal lung maturity.

The lecithin-sphingomyelin (LS) ratio is a good, but not absolute, test of fetal lung maturity. A total of 373 infants was delivered within 72 hours of amniotic fluid collection for assessment of the L/S ratio. Five of 43 infants (11-6 per cent) with an L/S ratio of 2-2 or less developed the respiratory distress syndrome (RDS), whereas only one of 320 infants (0-31 per cent) with a higher L/S ratio developed RDS. The risk of RDS could be further defined by using the creatinine concentration (critical value 19 mg/1) and the Nile blue sulphate test (critical value 4 per cent) in combination with the L/S ratio. All three tests were performed in 320 pregnancies and in each instance delivery took place within 72 hours. When all three test results were low, 3 of 5 infants (60 per cent) developed RDS, whereas when all three results were high, none of 175 infants developed RDS. When one or two results were low, 2 of 140 infants (1-4 per cent) developed RDS.

The benefits and risks of amniocentesis for the assessment of fetal lung maturity.

Amniocentesis for estimation of the lecithin: sphingomyelin (L/S) ratio was performed on 483 patients on 552 occasions. The introduction of this test has been associated with a highly significant (p less than 0-001) decrease of 59 per cent in the incidence of respiratory distress syndrome. The finding of a low L/S ratio (less than 2-0) enabled delivery to be deferred until lung maturity had been reached in 43 (10-3 per cent) of the 419 patients who had successful amniocentesis. Fetal death occurred after amniocentesis in two patients (0-41 per cent). One fetus died after haemorrhage occurred behind an anterior placenta and the other died of exsanguination. Failed amniocentesis occurred in 64 patients (13-2 per cent), and was more common when the placenta was anterior or was not located before the procedure and when fetal growth was retarded. Fetal distress in labour occurred more commonly after failed amniocentesis. Spontaneous labour followed amniocentesis in 47 patients (9-7 per cent) and was significantly more prone to occur after 38 weeks gestation. Rhesus isoimmunization did not occur in any of the rhesus-negative patients who delivered rhesus-positive babies and who were screened six or more months after amniocentesis, although anti-D immunoglobulin was not given routinely after amniocentesis. Suggestions are made as to how the success rate of this valuable procedure can be improved and how some of the serious fetal and maternal sequelae can be avoided.