Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis.

Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11-/-) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation with TGFß1. Following bleomycin-induced lung injury, Il11-/- mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.

Liver and spleen elastography of dogs affected by brachycephalic obstructive airway syndrome and its correlation with clinical biomarkers.

The purpose of this study is to determine whether the brachycephalic obstructive airway syndrome (BOAS) is correlated to alterations in liver and spleen elasticity. Forty-eight brachycephalic and 22 mesocephalic dogs were submitted to a BOAS functional assessment, laboratory tests, abdominal ultrasound and liver and spleen Acoustic Radiation Force Impulse (ARFI) elastography. Dogs clinically affected by BOAS had higher values of liver stiffness (p < 0.001) than healthy dogs: medial lobes (1.57 ± 0.37 m/s), left and right lateral lobes (1.54 ± 0.50 m/s, 1.23 ± 0.28 m/s, respectively) and caudate lobe (1.28 ± 0.42 m/s). Compared to the mesocephalic group, the brachycephalic group (BOAS clinically affected and unaffected dogs) had higher spleen (2.51 ± 0.45 m/s; p < 0.001) and liver stiffness (p < 0.001): medial lobes (1.53 ± 0.37 m/s), left and right lateral lobes (1.47 ± 0.47 m/s, 1.20 ± 0.30 m/s, respectively) and caudate lobe (1.23 ± 0.40 m/s). Principal component analysis explained 70% of the variances composed by liver stiffness increase, erythrocytes and alanine aminotransferase reduction. Brachycephalic dogs had higher spleen and liver stiffness and a subacute inflammatory state, which represent another BOAS systemic effect. Consequently, these dogs can be at higher risk of hepatic disorders compared with mesocephalic dogs, similarly to humans affected by sleep apnea syndrome.

Exploring the potential association among sleep disturbances, cognitive impairments, and immune activation in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.

Frustration and Emotional Regulation in Nonsyndromic Craniosynostosis: A Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nonsyndromic craniosynostosis may manifest with complex behavioral, attentional, and emotional sequelae. The authors characterized higher level brain connectivity in adolescent nonsyndromic craniosynostosis patients in response to emotional frustration. METHODS: Surgically corrected patients older than 9 years with nonsyndromic craniosynostosis were age/sex/handedness matched to controls. Patients participated in a "go/no-go" task, structured as win/lose/recovery paradigms. BioImage Suite was used to analyze whole-brain intrinsic connectivity between tasks with cluster-corrected group-level t maps. A value of p < 0.05 was significant. RESULTS: Seven unilateral coronal (average age, 12.2 years), six metopic (average age, 11.5 years), and controls were included. Unilateral coronal had worse emotional regulation scores on the Behavior Rating Inventory of Executive Function survey (p = 0.065) and performed poorly on the go/no-go task (p < 0.001). Metopic had four regions of interest, with the majority having decreased activity compared with controls, and few differences between tasks. Unilateral coronal patients had 11 regions of interest; the majority decreased during the win and lose conditions, but all increased during the recovery condition. Metopic patients had decreased blood oxygenation level- dependent signal in the posterior cingulate (p = 0.017) and middle temporal gyrus (p = 0.042). Unilateral coronal had decreased signal in the posterior cingulate (p = 0.023), middle temporal gyrus (p = 0.027), and thalamus (p = 0.033), but increased signal in the cuneus (p = 0.009) and cerebellum (p = 0.009). Right unilateral coronal, but not metopic/controls, had increased right brain activity in the caudate (p = 0.030), thalamus (p = 0.011), temporal lobe (p = 0.012), and cerebellum (p = 0.029). CONCLUSIONS: Unilateral coronal patients may have emotional dysregulation in response to frustration, whereas metopic patients may have attenuated emotional reactions. Evidence of right unilateral coronal brain laterality suggests that the area of suture fusion may contribute to the mechanism of dysfunction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Time-dependent changes and prognostic value of lactatemia during the first 24 h of life in brachycephalic newborn dogs.

Blood lactate concentration is known to be a good prognostic indicator associated with the severity of illness and the patient's outcome both in human and veterinary medicine. It also plays a significant role in the assessment of the newborn, being a good indicator of fetal hypoxia and the ideal predictor of morbidity at term in babies. In veterinary neonatal medicine, hyperlactatemia is considered a valid prognostic marker in critically ill foals; moreover, blood lactate measurement has been proposed for the evaluation of newborn viability and the assessment of fetal distress during delivery in dogs. Unfortunately, only a few studies have been published concerning the canine species. The present work examines 67 brachycephalic newborn dogs and their mothers, with the aim to evaluate the time-dependent changes of blood lactate and glucose concentration during the first 24 h after vaginal or caesarean delivery both in puppies and bitches. To our knowledge, this is the first published study examining the time-dependent changes of these parameters in the bitch after parturition. Within the studied population of puppies, non-surviving was significantly associated with a higher lactatemia and a lower APGAR score. Blood lactate was high at birth then progressively decreased during the first 24 h of life and a lack of normalization of blood lactate levels within this time interval was suggestive for a poor prognosis for the newborn dogs; moreover, the decrease appeared to be slower after vaginal delivery. Lactatemia also showed a positive correlation with glycemia at birth. Concerning the bitches examined, blood lactate was found to be significantly higher after vaginal delivery than after caesarean section; the normalization occurred within 24 h after parturition. Blood glucose level was significantly higher at 2 h from delivery both in the group of bitches submitted to caesarean section and in those undergoing natural whelping but no statistical correlation was found between maternal glycemia and lactatemia. The results of the present study highlighted that the monitoring of lactatemia during the first 24 h of life, in association with the assessment of the APGAR score at birth, can be an useful prognostic tool helping to identify the most severely distressed puppies and to provide them an adequate support.

Whole Blood in Pediatric Craniofacial Reconstruction Surgery.

BACKGROUND: Pediatric complex cranial vault reconstruction (CCVR) surgery is often associated with significant blood loss and transfusion. The authors recently changed our transfusion practice during CCVR to using whole blood (WB) instead of reconstituted blood (RB). The aim of this study was to assess the impact of this practice change. Our hypothesis was that replacement with WB would be as effective as RB for the outcomes of total perioperative blood donor exposures (BDEs) and the incidence of laboratory evidence of postoperative coagulopathy. METHODS: The authors queried the Pediatric Craniofacial Surgery Perioperative Registry for children ages ≤48 months from our institution who underwent CCVR and received either RB or WB. The primary outcomes of total perioperative BDEs and the incidence of laboratory evidence of postoperative coagulopathy were compared between the 2 cohorts. RESULTS: The query returned 59 subjects in the RB cohort and 52 subjects in the WB cohort. There were no significant differences in demographic variables between the 2 groups. Patients in the WB cohort were more likely to have ≤1 BDEs when compared to the RB cohort (62% versus 39%, respectively, P = 0.02). There was no significant difference in the incidence of postoperative coagulation laboratory test abnormalities between the WB and RB cohorts (0% versus 3.4%, respectively, P = 0.50). CONCLUSION: There was no postoperative coagulopathy in the WB cohort. Whole blood was also associated with significantly fewer perioperative BDEs. Whole blood appears to be as effective as RB for replacement of blood loss in craniofacial surgery.

Serum Levels of Cardiac Markers NT-proANP and NT-proBNP in Brachycephalic bitches at Different Gestational Stages.

The aim of this study was to determine serum levels of natriuretic peptide precursors (NT-proANP and NT-proBNP) during pregnancy in brachycephalic bitches. Fifteen healthy multiparous bitches were selected for this prospective study. Serum levels of NT-proANP and NT-proBNP were measured during anoestrous and at 14, 35, 42, 49 and 56 days (2nd, 5th, 6th, 7th and 8th weeks) of pregnancy. Fourteen animals had normal gestations, and one bitch developed single foetus syndrome. The natriuretic peptide levels of this animal were not included in this study; however, it is important to report that its NT-proANP levels were four times greater than those of normal patients. There was no significant difference (p = 0.072) in NT-proBNP levels between anoestrous (0.20 ± 0.10 ng/ml) and the different pregnancy weeks (0.27 ± 0.12 ng/ml). There was a positive correlation (p < 0.0001) between NT-proANP and gestational age, and the levels of this marker increased significantly (p < 0.0001) during the 6th (0.26 ± 0.06 ng/ml), 7th (0.28 ± 0.04 ng/ml) and 8th weeks (0.29 ± 0.05 ng/ml) when compared to anoestrous (0.18 ± 0.02 ng/ml). NT-proANP serum levels are correlated with gestational development and may be indicative of cardiovascular adaptation in canine brachycephalic pregnancy.

Clinical assessment and C-reactive protein (CRP), haptoglobin (Hp), and cardiac troponin I (cTnI) values of brachycephalic dogs with upper airway obstruction before and after surgery.

Brachycephalic dogs have unique upper respiratory anatomy with abnormal breathing patterns that are similar to those in humans with obstructive sleep apnea syndrome (OSAS). The objectives of this multicenter prospective study were to assess the effects of surgical correction on clinical signs in dogs with brachycephalic airway obstructive syndrome (BAOS) and to evaluate the levels of several biomarkers [C-reactive protein (CRP); haptoglobin (Hp), and cardiac troponin I (cTnI)] used to determine systemic inflammation and myocardial damage. This study was conducted on 33 dogs with BAOS that were evaluated before and 1 to 2 mo after surgical correction. Palatoplasty was carried out by means of 2 different surgical techniques: carbon dioxide (CO2) laser (n = 12) and electrical scalpel (n = 21). Biomarker levels (CRP, Hp, and cTnI) were determined before and after surgery. There was a significant reduction in respiratory and gastrointestinal signs in dogs with BAOS after surgical treatment (P < 0.001). A greater reduction in respiratory signs (P < 0.002) was obtained using the CO2 laser. No statistical differences were found between CRP and cTnI levels, either before or after surgical correction. Haptoglobin concentration did increase significantly in the postsurgical period (P < 0.008). Surgical treatment in dogs with BAOS reduces clinical signs, regardless of the anatomical components present. Surgical treatment for BAOS is not useful to reduce CRP and Hp levels, probably because BAOS does not induce as obvious an inflammatory process in dogs as in human patients with OSAS. No reduction in cTnI levels was observed 1 mo after surgery in dogs with BAOS, which suggests that some degree of myocardial damage remains.

Les chiens brachycéphales ont anatomie des voies respiratoires supérieures unique avec les modèles de respiration anormale similaires à ceux des humains avec obstructive apnée du sommeil (SAOS). Les objectifs de cette étude prospective multicentrique étaient d'évaluer les effets de la correction chirurgicale sur les signes cliniques et sur les niveaux de biomarqueurs [protéine C-réactive (CRP), haptoglobine (Hp) et la troponine I cardiaque (cTnI)] utilisée pour déterminer l'inflammation systémique et l'infarctus dommage. Cette étude a été menée sur 33 chiens atteints du syndrome d'obstruction des voies respiratoires brachycéphales (BAOS) évaluée avant et 1­2 mois après la correction chirurgicale. Palatoplasty a été réalisée au moyen de deux techniques chirurgicales différentes, le laser du dioxyde de carbone (CO2) (n = 12) et avec an scalpel électric (n = 21). Les niveaux de biomarqueurs (CRP, HP et cTnI) ont été déterminés avant et après la chirurgie. Il y avait une réduction significative des signes respiratoires et gastro-intestinaux chez les chiens atteints BAOS après le traitement chirurgical (P < 0,001). Une plus grande réduction des signes respiratoires (P < 0,002) ont été obtenues en utilisant le laser CO2. Aucune différence statistiquement significative a été observée entre CRP et les niveaux de cTnI, soit avant, soit après correction chirurgicale. La concentration du Hp a augmenté de manière significative dans la période postopératoire (P < 0,008). Le traitement chirurgical chez les chiens atteints BAOS réduit les signes cliniques, quels que soient les éléments anatomiques présents. Le traitement chirurgical du BAOS n'est pas utile pour réduire les niveaux de CRP et Hp, probablement parce que BAOS n'induit pas un évidente processus inflammatoire chez les chiens à différence des patients humains en souffrant du SAOS. Aucune réduction des niveaux cTnI ont été observés un mois après la chirurgie chez les chiens atteints BAOS, ce qui suggère qu'ils maintien d'un certain degré de lésion myocardique.(Traduit par les auteurs).

Evaluation of arterial blood gases and arterial blood pressures in brachycephalic dogs.

BACKGROUND: Brachycephalic dogs (BD) are prone to congenital upper airway obstruction (brachycephalic syndrome, BS). In humans suffering from sleep apnea, upper airway obstruction is known to cause hypertension. There is no information regarding the influence of BS in dogs on cardiorespiratory physiology. HYPOTHESIS: BD are prone to lower P(a) O(2), higher P(a) CO (2), and hypertension compared with meso- or dolicocephalic dogs (MDD). ANIMALS: Eleven BD and 11 MDD. METHODS: After a questionnaire was completed by the owner, a physical examination was performed. Height and thoracic circumferences were measured. Arterial blood gases, electrolyte concentrations, and packed cell volume (PCV) were measured. Systolic (SAP), mean (MAP), and diastolic (DAP) arterial blood pressure recordings were performed. RESULTS: A total of 7 French and 4 English bulldogs met the inclusion criteria. The control group consisted in 6 Beagles, 2 mixed breed dogs, 1 Staffordshire Bull Terrier, 1 Parson Russell Terrier, and 1 Australian Cattle Dog. Statistically, BD had lower P(a) O(2), higher P(a) CO2, and higher PCV when compared with controls (86.2 ± 15.9 versus 100.2 ± 12.6 mmHg, P = .017; 36.3 ± 4.6 versus 32.7 ± 2.6 mmHg, P = .019; 48.2 ± 3.5 versus 44.2 ± 5.4%, P = .026, respectively). Also, they had significantly higher SAP (177.6 ± 25.0 versus 153.5 ± 21.7 mmHg, P = .013), MAP (123.3 ± 17.1 versus 108.3 ± 12.2 mmHg, P = .014), and DAP (95.3 ± 19.2 versus 83.0 ± 11.5 mmHg, P = .042). BD with a P(a) CO (2) >35 mmHg were significantly older than those with a P(a) CO (2) ≤35 mmHg (58 ± 16 and 30 ± 11 months, P = .004). CONCLUSION: Results of this study suggest that some BD are prone to lower P(a) O(2), higher P(a) CO (2), and hypertension when compared with MDD. Age may be a contributing factor.

Fibrinogen in craniosynostosis surgery.

BACKGROUND: During craniosynostosis repair, massive blood loss, consumption and dilution of clotting factors often result in coagulopathy, for which cryoprecipitate, fresh frozen plasma (FFP), and platelets are recommended for treatment. However, cryoprecipitate is not available in most European countries, and the efficacy of FFP in correcting fibrinogen deficiency is limited. We report our experience with human fibrinogen concentrate (Hemocomplettan) used to improve impaired fibrinogen polymerization in children. METHODS: Results of routine coagulation tests, thrombelastometry (ROTEM), transfusion requirements, administration of fibrinogen concentrate, and data on the postoperative course of nine consecutive children undergoing major craniofacial surgery were retrospectively collected from anesthesia protocols, medical charts, laboratory and ROTEM databases. RESULTS: The nine children aged 12 (8, 22) mo (median [25th, 75th percentile]), weighing 9.5 (9, 10) kg had a calculated blood loss of 80 (49, 92)% of calculated blood volume during the surgery lasting 6.4 (4.5, 7.2) h. Impaired fibrinogen polymerization detected by ROTEM was the main problem underlying dilutional coagulopathy. In all cases, sufficient hemostasis was achieved without adverse effects by administering (if necessary), repeated doses of fibrinogen concentrates (each single dose 30 mg/kg) without FFP or platelet transfusions. All children were successfully weaned from mechanical ventilation within a few hours and were able to be discharged early from the Intensive Care Unit. CONCLUSIONS: Administration of fibrinogen concentrate effectively improves fibrinogen polymerization and total clot strength, which were the main underlying problems of dilutional coagulopathy in children undergoing craniosynostosis surgery.

Blood sparing in craniosynostosis surgery.

One of the main risks of craniosynostosis surgery is the possible need for an allogenic blood transfusion (ABT). Most patients are operated on in the first months of life, when physiological conditions are particularly sensitive to even limited blood losses. Furthermore, most surgical techniques proposed in the past were based on extensive craniectomies and cranial remodeling. Because of the known infective and immunologic risks of ABT, in recent years more attention has been dedicated to factors that might help reduce the risk of ABT. We review recent preoperative (ie, erythropoietin administration), intraoperative (ie, acute normovolemic hemodilution, intraoperative blood salvage), and postoperative (ie, clinical monitoring, postoperative blood salvage) anesthesiologic procedures developed with this aim in mind. We also consider operative techniques and technical apparatus that reduce surgical invasiveness, particularly preoperative planning, age selection, and the role of endoscopic assistance and gradual distraction devices.

Blood salvage in craniosynostosis surgery.

In the history of surgery, every single step forward in the development of complex surgical techniques has been sustained by the acquisition of more reliable and effective methods for controlling hemostasis. For many years, in fact, uncontrolled hemorrhages, together with infections, represented the most deadly hazard of surgical procedures. In the last century, technical advances in surgical hardware and homologous blood transfusions have been utilized to counteract operative and postoperative anemia and hypovolemia. At the end of this millennium, however, new revelations about the infective and noninfective risks of allogeneic blood transfusions have led to a new acceleration in patients' and physicians' demands for autologous transfusions and more efficient blood conservation techniques. Specific surgical protocols, based on the preoperative administration of r-HuEPO, preoperative autologous blood donation, acute preoperative normovolemic hemodilution and intraoperative blood salvage techniques, have been designed by pediatric neurosurgeons to minimize the exposure of patients affected by craniosynostoses to allogeneic blood and blood components even when the surgical procedure is to be realized at an early age. In spite of the evolution expected in this area in the immediate future, the implementation of these blood concentration methodologies may prove to be highly effective only when associated with a concerned attitude of the surgeon toward blood-sparing intraoperative strategies.

Blood loss during repair of craniosynostosis.

Surgical repair of craniosynostosis carries a high risk with large blood losses. Over a 2-yr period, we have managed 115 patients undergoing craniosynostosis repair with peroperative haemodilution to achieve a final PCV of 0.28-0.35. Measurements of PCV allowed calculation of estimated blood losses and transfused volumes in terms of red blood cell mass. Total estimated red cell volume lost was 91 +/- 66% of patient's estimated red blood cell volume during the peroperative period. The type of skull deformation and surgical procedure determined the extent of peroperative bleeding. Peroperative transfusion was satisfactory in 48% of patients and slight overtransfusion was noted in 32%. During the postoperative period, liberal administration of blood led to overtransfusion and possibly unnecessary transfusion in 74% of patients. Because of the well known risks of transmission of infectious disease, strict volume compensation with development of haemodilution and autotransfusion procedures should be used to limit these risks.

Fluid, blood, and blood product management in the craniofacial patient.

This report is a retrospective review of the perioperative management of 56 children who underwent craniofacial surgical procedures. The use of a combination of 5% dextrose in normal saline or 5% dextrose in Ringer's lactate and normal saline resulted in postoperative sodium values in a normal range. In patients receiving a combination of 5% dextrose and electrolyte No. 48 and normal saline, the mean postoperative sodium level was 130 mEq/l with 9 of 18 patients below 130 mEq/l. Two patients in the series suffered clinical seizures on postoperative day 1 as a result of serum sodium levels of 122 and 121 mEq/l, respectively. We recommend that only solutions with a sodium content between 77 and 154 mEq/l be used routinely in the perioperative management of craniofacial patients.