Fetal growth of left-sided structures and postnatal surgical outcome in borderline left heart varies by cardiac phenotype.

OBJECTIVES: There are two borderline left-heart phenotypes in the fetus: (1) severe aortic stenosis (AS), which is associated with a 'short, fat', globular left ventricle (LV), LV systolic dysfunction and LV growth arrest; and (2) severe left-heart hypoplasia (LHH), which is associated with a 'long, skinny' LV, laminar flow across hypoplastic mitral and aortic valves and arch hypoplasia. Both phenotypes may be counseled for possible single-ventricle palliation. We aimed to compare the rates of left-sided cardiac structure growth and Z-score change over gestation and to describe the postnatal outcomes associated with these two phenotypes. We hypothesized that the left-sided structures would grow faster in fetuses with LHH compared to those with AS, and that those with LHH would be more likely to achieve biventricular circulation. METHODS: This was a retrospective cohort study using data collected in an institutional cardiology database between April 2001 and April 2018. We included fetuses with severe AS or severe LHH, and with at least two fetal echocardiograms. Inclusion criteria for the AS group included: aortic-annulus Z-score < -2.0, severe AS, depressed LV function, retrograde systolic flow in the aortic arch and endocardial fibroelastosis. Inclusion criteria for the LHH group included: aortic-annulus Z-score < -2.0, hypoplastic but apex-forming LV, normal LV function and retrograde systolic flow in the aortic arch. Exclusion criteria were: abnormal cardiac connections, other forms of structural congenital heart disease, cardiomyopathy, history of fetal aortic valvuloplasty and participation in a maternal hyperoxygenation study. Measurements and respective Z-scores for the aortic-valve annulus, mitral-valve annulus, LV long- and short-axis dimensions, along with aortic-arch measurements, were collected longitudinally for each fetus and plotted over time for both cohorts. Mean slopes of change in dimension and Z-scores over gestation were calculated and compared between the two groups using mixed generalized linear regression accounting for repeated measures. A subanalysis was performed, matching six fetuses from each group for initial aortic-annulus Z-score and gestational age, due to the significant differences in these two variables between the original cohorts. RESULTS: In total, 53 fetuses with 158 echocardiograms were included. In the AS cohort, there were 20 (38%) fetuses with 65 echocardiograms, and in the LHH cohort there were 33 (62%) fetuses with 93 echocardiograms. On the first echocardiogram, LHH fetuses had a later gestational age and a larger aortic-annulus diameter. The rate of aortic-annulus growth was greater in the LHH group compared with the AS group (mean ± SD, 0.15 ± 0.01 mm/week for LHH vs 0.07 ± 0.01 mm/week for AS (P < 0.001)). While the LHH group had a decrease in aortic-annulus Z-score over time, this was at a slower rate than the decrease in the AS group (mean ± SD, -0.04 ± 0.02/week for LHH vs -0.13 ± 0.02/week for AS (P < 0.001)). A similar pattern was seen for the mitral-valve and LV short-axis-dimension Z-scores. Subanalysis of six fetuses from each group matched for initial aortic-annulus Z-score and gestational age demonstrated similar findings, with the LHH group Z-scores decreasing at a slower rate than those in the AS group. Fifty-two of the 53 fetuses were liveborn, one LHH fetus dying in utero. Of the 20 liveborn in the AS cohort, 15 (75%) infants underwent single-ventricle palliation, two (10%) underwent biventricular repair and three (15%) died prior to intervention. Of the 32 liveborn in the LHH cohort, three (9.4%) underwent single-ventricle palliation, 28 (87.5%) achieved biventricular circulation, of which six required no surgery, and one (3.1%) died prior to intervention. CONCLUSIONS: The left-sided cardiac structures grow at a faster rate in fetuses with severe LHH than they do in fetuses with severe AS, and the Z-scores decrease at a slower rate in fetuses with severe LHH than they do in those with severe AS. The majority of infants in the LHH group did not undergo single-ventricle palliation. This information can be useful in counseling families on the expected growth potential of the fetus's aortic valve, mitral valve and LV, depending on the cardiac phenotype. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension.

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia.

Pilot study of chronic maternal hyperoxygenation and effect on aortic and mitral valve annular dimensions in fetuses with left heart hypoplasia.

OBJECTIVE: Acute maternal hyperoxygenation (AMH) results in increased fetal left heart blood flow. Our aim was to perform a pilot study to determine the safety, feasibility and direction and magnitude of effect of chronic maternal hyperoxygenation (CMH) on mitral and aortic valve annular dimensions in fetuses with left heart hypoplasia (LHH) after CMH. METHODS: Gravidae with fetal LHH were eligible for inclusion in a prospective evaluation of CMH. LHH was defined as: sum of aortic and mitral valve annuli Z-scores < -4.5, arch flow reversal and left-to-right or bidirectional atrial level shunting without hypoplastic left heart syndrome or severe aortic stenosis. Gravidae with an affected fetus and with ≥ 10% increase in aortic/combined cardiac output flow after 10 min of AMH at 8 L/min 100% fraction of inspired oxygen were offered enrollment. Nine gravidae were enrolled from February 2014 to January 2015. The goal therapy was ≥ 8 h daily CMH from enrollment until delivery. Gravidae who were cared for from July 2012 to October 2014 with fetal LHH and no CMH were identified as historical controls (n = 9). Rates of growth in aortic and mitral annuli over the final trimester were compared between groups using longitudinal regression. RESULTS: There were no significant maternal or fetal complications in the CMH cohort. Mean gestational age at study initiation was 29.6 ± 3.2 weeks for the intervention group and 28.4 ± 1.8 weeks for controls (P = 0.35). Mean relative increase in aortic/combined cardiac output after AMH was 35.3% (range, 18.1-47.9%). Median number of hours per day on CMH therapy was 9.3 (range, 6.5-14.6) and median duration of CMH was 48 (range, 33-84) days. Mean mitral annular growth was 0.19 ± 0.05 mm/week compared with 0.14 ± 0.05 mm/week in CMH vs controls (mean difference 0.05 ± 0.05 mm/week, P = 0.33). Mean aortic annular growth was 0.14 ± 0.03 mm/week compared with 0.13 ± 0.03 mm/week in CMH vs controls (mean difference 0.01 ± 0.03 mm/week, P = 0.75). More than 9 h CMH daily (n = 6) was associated with better growth of the aortic annulus in intervention fetuses (0.16 ± 0.03 vs 0.08 ± 0.02 mm/week, P = 0.014). CONCLUSIONS: CMH is both safe and feasible for continued research. In this pilot study, the effect estimates of annular growth, using the studied method of delivery and dose of oxygen, were small. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

The Influence of Lumbar Spinal Subtype on Lumbar Intervertebral Disc Degeneration in Young and Middle-Aged Adults.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify whether an in vivo correlation exists between lumbar spinal subtype (LSS) and lumbar disc degeneration (LDD) in young adults. SUMMARY OF BACKGROUND DATA: Lumbar disc degeneration has largely been ascribed to biomechanical and structural alterations to the disc, which are attributed to aging and pathological physical loading. Sagittal alignment in the asymptomatic spine has also been considered. A biomechanical study by Roussouly and Pinheiro-Franco proposed level-specific patterns in LDD. To date, no in vivo correlation between the LSS and LDD has been established. METHODS: The authors screened 608 consecutive patients over 5.3 years. Lumbar spinal subtype and pelvic parameters were collected from standing lumbar radiographs and were categorized using the classification of Roussouly and Pinheiro-Franco. Lumbar disc degeneration at all lumbar intervertebral levels was classified using criteria of Pfirrmann et al. A stratified disc degeneration score was derived for each patient. Lumbar disc degeneration in type I, II, and IV LSS was compared using chi-square test. Pelvic incidence was correlated with stratified disc degeneration score using Spearman R, to determine whether a high PI was protective against LDD. Statistical significance was accepted at p < .05. RESULTS: A total of 139 patients were included, with 91 females and a mean age of 32.6 years (range, 13-49 years). For LSS grades I to IV, there were 10 (7.3%), 43 (30.9%), 50 (35.9%), and 36 (25.9%) patients, respectively. The proportion of high-grade (Pfirrmann grades IV and V) LDD increased distally toward the lower intervertebral levels, affecting 2.88%, 2.9%, 5%, 9.4%, 33.1%, and 54% of discs at each sequential lumbar level from T12-L1 to L5-S1, respectively. Age but not gender was statistically significant for higher-grade LDD (p < .0001 and p = .442, respectively). Pelvic incidence across all LSS grades was not significantly correlated with stratified disc degeneration score (Spearman R = 0.0933; p = .335). No LSS (type I-IV) reached statistical significance for a specific pattern of LDD. CONCLUSIONS: In this study, LSS was not statistically significantly correlated with LDD, nor was a high pelvic incidence protective against LDD.

The outcome following fixation of bicondylar tibial plateau fractures.

Unstable bicondylar tibial plateau fractures are rare and there is little guidance in the literature as to the best form of treatment. We examined the short- to medium-term outcome of this injury in a consecutive series of patients presenting to two trauma centres. Between December 2005 and May 2010, a total of 55 fractures in 54 patients were treated by fixation, 34 with peri-articular locking plates and 21 with limited access direct internal fixation in combination with circular external fixation using a Taylor Spatial Frame (TSF). At a minimum of one year post-operatively, patient-reported outcome measures including the WOMAC index and SF-36 scores showed functional deficits, although there was no significant difference between the two forms of treatment. Despite low outcome scores, patients were generally satisfied with the outcome. We achieved good clinical and radiological outcomes, with low rates of complication. In total, only three patients (5%) had collapse of the joint of > 4 mm, and metaphysis to diaphysis angulation of 75º, and five patients (9%) with displacement of > 4 mm. All patients in our study went on to achieve full union. This study highlights the serious nature of this injury and generally poor patient-reported outcome measures following surgery, despite treatment by experienced surgeons using modern surgical techniques. Our findings suggest that treatment of complex bicondylar tibial plateau fractures with either a locking plate or a TSF gives similar clinical and radiological outcomes.

The PCAST report: impact and implications for the pharmaceutical industry.

The President's Council of Advisors on Science and Technology (PCAST) report sets out an ambitious goal: to double the output of innovative, new medicines with increased efficacy and safety within the next 10-15 years. If attainable, this could change the face of medicine and bring great benefit to society. Clear leadership, commitment to action, and unprecedented collaboration will be essential if the goal of the report is to be realized.

Prediction of body water compartments in preterm infants by bioelectrical impedance spectroscopy.

BACKGROUND/OBJECTIVES: To evaluate nutritional interventions in preterm infants, a simple, accurate assessment of the type of growth, that is, change in body composition through the relative contributions of lean body tissue and fat mass to weight gain, is needed. Bioelectrical impedance may provide such a method. The aim of this study was to develop resistivity coefficients appropriate for use in bioelectrical impedance spectroscopy (BIS) analysis of body water volumes in preterm infants. SUBJECTS/METHODS: A total of 99 preterm infants were enrolled (mean gestational age 32 completed weeks). Total body water (TBW) and extracellular water (ECW) were determined using the reference methods of deuterium and bromide dilution. BIS measurements taken at the same time allowed calculation of resistivity coefficients. Predictions of TBW and ECW obtained using these coefficients were then validated against volumes determined using the reference methods in a separate cohort of infants. RESULTS: Data were available for 91 preterm infants. BIS-predicted TBW and ECW correlated well with the measured volumes (Pearson's r(p)=0.825 and 0.75, respectively). There was a small bias (TBW 10 ml and ECW 40 ml) but large limits of agreement (TBW ± 650 ml and ECW ± 360 ml). CONCLUSIONS: BIS appears to have limited clinical utility; however, the relatively small bias means that it may be useful for measurements within a population or for comparisons between groups in which population means rather than individual values are compared.

Similar withdrawal severity in adolescents and adults in a rat model of alcohol dependence.

Alcohol use during adolescence leads to increased risk of developing an alcohol use disorder (AUD) during adulthood. Converging evidence suggests that this period of enhanced vulnerability for developing an AUD may be due to the adolescent's unique sensitivity and response to alcohol. Adolescent rats have been shown to be less sensitive to alcohol intoxication and withdrawal susceptibility; however, age differences in ethanol pharmacokinetics may underlie these effects. Therefore, this study investigated alcohol intoxication behavior and withdrawal severity using a modified Majchrowicz model of alcohol dependence that has been shown to result in similar blood ethanol concentrations (BECs) despite age differences. Adolescent (postnatal day, PND, 35) and adult rats (PND 70+) received ethanol according to this 4-day binge paradigm and were observed for withdrawal behavior for 17h. As expected, adolescents showed decreased sensitivity to alcohol-induced CNS depression as evidenced by significantly lower intoxication scores. Thus, adolescents received significantly more ethanol each day (12.3+/-0.1g/kg/day) than adults (9.2+/-0.2g/kg/day). Despite greater ethanol dosing in adolescent rats, both adolescent and adult groups had comparable peak BECs (344.5+/-10.2 and 338.5+/-7.8mg/dL, respectively). Strikingly, withdrawal severity was similar quantitatively and qualitatively between adolescent and adult rats. Further, this is the first time that withdrawal behavior has been reported for adolescent rats using this model of alcohol dependence. A second experiment confirmed the similarity in BECs at various time points across the binge. These results demonstrate that after consideration of ethanol pharmacokinetics between adults and adolescents by using a model that produces similar BECs, withdrawal severity is nearly identical. This study, in combination with previous reports on ethanol withdrawal in adolescents and adults, suggests only a BEC-dependent effect of ethanol on withdrawal severity regardless of age.

The effect of pre-operative counselling on smoking patterns in patients undergoing forefoot surgery.

BACKGROUND: Smoking contributes to higher surgical complication rates. Previous studies assessing smoking cessation interventions examined the provision of comprehensive packages. The use of surgery as an incentive to complement brief advice has not been fully evaluated. METHODS: Smokers were counselled and referred to their general practitioners for specific cessation strategies. Smoking status was recorded prior to surgery, on admission and in post-operative clinics. A telephone survey at a mean of 12 months post-operation ascertained long-term behavioural changes. RESULTS: Ninety-seven patients underwent surgery with twenty-five recorded as smokers. Sixteen stopped smoking pre-operatively; a further four reduced their intake, as a direct consequence of counselling. No patients were previously aware of the detrimental effects of smoking associated with foot surgery. CONCLUSIONS: Surgery provides an incentive for smoking cessation, maintained post-operatively. Although forefoot fusions and arthrodeses were used in our study, the results are transferable to other branches of orthopaedic surgery.

Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84.

Treatment with parathyroid hormone [PTH(1-84)] increases lumbar spine bone mineral density and decreases vertebral fractures, but its effects on bone microarchitecture are unknown. We obtained iliac crest biopsies from postmenopausal osteoporotic women given placebo (n=8) or 100 microg PTH(1-84) for 18 (n=8) or 24 (n=7) months to assess cancellous and cortical bone formation and structure. At 18 months, cancellous bone volume (BV/TV) measured by microcomputed tomography and histomorphometry was 45-48% higher in subjects treated with PTH(1-84) versus placebo, a result of higher trabecular number (Tb.N) and thickness. The higher Tb.N appeared to result from intratrabecular tunneling. Connectivity density was higher and structure model index was lower, indicating a better connected and more plate-like trabecular architecture. Cancellous bone formation rate (BFR) was 2-fold higher in PTH(1-84)-treated subjects, primarily because of greater mineralizing surface. Osteoblast and osteoid surfaces were a nonsignificant 58% and 35%, respectively, higher with PTH(1-84) treatment. Osteoclast and eroded surface were unaffected by PTH(1-84). There were no effects of PTH(1-84) treatment on cortical thickness, or endocortical or periosteal BFR, but cortical porosity tended to be higher. Although cancellous BFR was lower at 24 than at 18 months, measures of cancellous and cortical bone structure were similar at both timepoints. The bone produced by PTH(1-84) had normal lamellar structure and mineralization with no abnormal histology. In conclusion, when compared with placebo, treatment of osteoporotic women with PTH(1-84) was associated with higher BV/TV and trabecular connectivity, with a more plate-like architecture, all consistent with the lower vertebral fracture incidence.

Parathyroid hormone(1-84) treatment of postmenopausal women with low bone mass receiving hormone replacement therapy.

Treatment of postmenopausal osteoporosis (PMO) is based primarily on antiresorptive agents, including hormone replacement therapy (HT). To evaluate whether anabolic therapy together with HT provides additional benefits in the treatment of PMO, we evaluated the effects of parathyroid hormone (PTH) 1-84 in postmenopausal women with low bone mineral density (BMD) who were receiving chronic (> or =6 months) HT. Subjects were randomized to receive 100 microg PTH(1-84) or placebo injections daily for 24 months (n = 90/group). The primary efficacy outcome was change from baseline in lumbar spine BMD. Secondary end points included changes in hip and distal radius BMD, bone turnover markers, and fracture incidence. The study was terminated early following recommendations regarding HT for PMO. At 18 months, the mean increase in lumbar spine BMD was 7.9% for PTH(1-84) subjects vs. 1.5% for those receiving HT alone; between-group differences were significant at 6 months and persisted throughout the study. Lumbar spine BMD increased in 94% of women receiving PTH(1-84) compared to 59% for HT alone. Femoral neck BMD and bone turnover markers were significantly higher in PTH(1-84)-treated subjects, but the changes in total hip and distal radius BMD were not significant. PTH(1-84) treatment was generally well-tolerated, with hypercalciuria, hypercalcemia, nausea, vomiting, and dizziness reported more frequently in the HT + PTH(1-84) group. In conclusion, addition of PTH(1-84) to stable HT produced marked increases in lumbar spine BMD and may represent an additional approach to the treatment of PMO women receiving HT.

Peripheral parenteral nutrition in a case of chyle leak following neck dissection.

Chylothorax is an uncommon condition which is potentially life-threatening if untreated. The following case study of a 75-year-old man with chyle leak following surgery shows how prompt dietetic action prevented further compromise in immune function and nutritional status. Dietetic recommendation to minimize enteral intake rapidly stopped chyle flow and promoted wound closure. Peripheral parenteral nutrition (PPN) was administered in order to prevent malnutrition. There is limited literature available for evidence of best practice for cases of chyle leakage, however, this particular case demonstrates PPN should be considered despite the potential risks.

A characterisation of long-term depression induced by metabotropic glutamate receptor activation in the rat hippocampus in vitro.

1. In the CA1 region of hippocampal slices prepared from juvenile (12- to 18-day-old) rats, activation of group I metabotropic L-glutamate (mGlu) receptors by the specific agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) induces a form of long-term depression (LTD) of excitatory synaptic transmission. 2. We have used a variety of electrophysiological techniques applied to CA1 neurones in hippocampal slices and from pyramidal cells in dissociated hippocampal cultures to investigate the Ca2+ dependence and locus of expression of DHPG-induced LTD. 3. In patch-clamp experiments from hippocampal slices, bath application of DHPG induced a depression of synaptically evoked responses that persisted for the duration of the recording (up to 2 h after commencing washout of DHPG) in 27 of 29 neurones investigated. 4. DHPG-induced LTD was associated with an increase in both the paired-pulse facilitation ratio and the coefficient of variation of EPSCs. 5. Using dendritic recording, there was a decrease in EPSC success rate (number of trials that elicited a detectable response) but no change in potency (mean EPSC amplitude excluding failures) associated with DHPG-induced LTD. 6. In experiments using dissociated hippocampal cultures, application of DHPG elicited a persistent decrease in the frequency of tetrodotoxin-resistant miniature EPSCs but no change in the amplitude of such events. 7. DHPG-induced LTD was not blocked by intracellular application of the calcium chelator BAPTA. It was also unaffected when intracellular calcium stores were depleted by perfusion with thapsigargin. Furthermore, when synaptic transmission was blocked by perfusing with Ca2+-free medium, DHPG application reliably induced LTD. 8. These data suggest that DHPG-induced LTD is Ca2+ independent and is expressed presynaptically.

Synergistic outside-in regulation of platelet activation by GPIIb/IIIa ligand-induced conformation and oligomerization.

Full platelet activation with serotonin secretion and thromboxane A(2) (TxA(2)) formation induced by a low dose of thrombin receptor agonist peptide (TRAP) or high dose ADP requires platelet aggregation. This requirement can be replaced by pretreatment of platelets with a combination of reagents including: GPIIb/IIIa inhibitors yielding ligand-induced binding sites (LIBS), either arginine-glycine-aspartate-serine (RGDS) peptide or Ro 43-5054, cytochalasin to disrupt actin filaments and crosslinking by a GPIIb/IIIa mAb (pl-62). Crosslinking is required since Fab fragments of pl-62 do not support activation. Engagement of the Fc receptor by the mAb Fc domain is not required for pl-62 augmentation, since it is not blocked by the anti-Fc receptor mAb, IV-3. Another GPIIb/IIIa inhibitor, Ro 44-9883, not yielding LIBS epitopes, serves as a negative control and shows a requirement for LIBS in addition to crosslinking. Focal adhesion kinase tyrosine phosphorylation induced by TRAP is blocked by these GPIIb/IIIa antagonists, but restored by pl-62 crosslinking independent of LIBS induction. Tyrosine phosphorylation of a peptide comigrating with p38 MAP kinase is also inhibited by these antagonists and restored by pl-62 crosslinking. However, p38 MAP kinase activation by low dose TRAP is not affected by these aggregation inhibitors. Tyrosine phosphorylation of a 34-kDa phosphoprotein in the absence of aggregation or TxA(2) formation was uniquely augmented by Ro 43-5054 but not Ro 44-9883 under the above activation conditions.

Functional properties of Drosophila inositol trisphosphate receptors.

The functional properties of the only inositol trisphosphate (IP(3)) receptor subtype expressed in Drosophila were examined in permeabilized S2 cells. The IP(3) receptors of S2 cells bound (1,4,5)IP(3) with high affinity (K(d)=8.5+/-1.1 nM), mediated positively co-operative Ca(2+) release from a thapsigargin-sensitive Ca(2+) store (EC(50)=75+/-4 nM, Hill coefficient=2.1+/-0.2), and they were recognized by an antiserum to a peptide conserved in all IP(3) receptor subtypes in the same way as mammalian IP(3) receptors. As with mammalian IP(3) receptors, (2,4,5)IP(3) (EC(50)=2.3+/-0.3 microM) and (4,5)IP(2) (EC(50) approx. 10 microM) were approx. 20- and 100-fold less potent than (1,4,5)IP(3). Adenophostin A, which is typically approx. 10-fold more potent than IP(3) at mammalian IP(3) receptors, was 46-fold more potent than IP(3) in S2 cells (EC(50)=1.67+/-0.07 nM). Responses to submaximal concentrations of IP(3) were quantal and IP(3)-evoked Ca(2+) release was biphasically regulated by cytosolic Ca(2+). Using rapid superfusion to examine the kinetics of IP(3)-evoked Ca(2+) release from S2 cells, we established that IP(3) (10 microM) maximally activated Drosophila IP(3) receptors within 400 ms. The activity of the receptors then slowly decayed (t(1/2)=2.03+/-0.07 s) to a stable state which had 47+/-1% of the activity of the maximally active state. We conclude that the single subtype of IP(3) receptor expressed in Drosophila has similar functional properties to mammalian IP(3) receptors and that analyses of IP(3) receptor function in this genetically tractable organism are therefore likely to contribute to understanding the roles of mammalian IP(3) receptors.