Crisis Presentations of Children and Adolescents with Neurodevelopmental Disorders.

Aim To inform the development of a care pathway for children and adolescents with neurodevelopmental disorders presenting to Children's Health Ireland (CHI) at Tallaght Emergency Department. Methods A retrospective study of cases with a neurodevelopmental disorder diagnosis (Autism Spectrum Disorder and/or Mild to Profound Intellectual Disability) presenting to the hospital Child Psychiatry services over a six-year period (Jan 2014 - December 2019). Results 72 patients identified, Autism Spectrum Disorder diagnosis most common (N=67, 93%). Nearly half of cases presenting with risk concerns (N= 35, 49%), same day hospital discharge (N = 53, 74%) and inpatient admission (N=19, 29%). Discussion Access to relevant community disability supports is significantly limited in Ireland with a resultant increase in carer stress and crisis presentations to the emergency department for psychosocial and disability related reasons.

Imaging of adult intestinal failure.

Intestinal failure is the inability to maintain adequate nutrition or hydration through the gut. It is caused by a diverse range of benign and malignant aetiologies. Imaging takes a central role in the multidisciplinary assessment of patients with intestinal failure.

Imaging of intestinal transplantation.

Intestinal transplant is considered in a small number of patients with intestinal failure or locally invasive benign abdominal tumours to improve both quality of life and survival. The complexity of the underlying diseases and postoperative findings are reflected in the imaging undertaken to support this patient group. Increasing numbers of patients are undergoing these procedures. Radiologists are increasingly likely to encounter these patients before and after surgery. This article will discuss the imaging findings that may prompt referral for transplantation assessment. It will also describe surgical anatomy and postoperative complications.

The value of biomedical research training for veterinary anatomic and clinical pathologists.

Veterinary pathologists traditionally have been actively engaged in research as principal investigators and as collaborators. Pathologists frequently obtain advanced training in research; however, it appears that in the last 10 years there has been a reversal of a previous trend toward increasing numbers of pathologists obtaining PhD degrees. This has arisen despite an established shortage of veterinarians engaged in research. This article evaluates the benefits of research training for individual pathologists, including a wide spectrum of professional opportunities and additional skill development beyond that usually provided by diagnostic pathology training alone. Various training models are discussed, including combined and sequential diagnostic residency and research degree training as well as the nondegree research fellowship programs more commonly pursued in human medicine. Best-practice recommendations for program infrastructure, mentorship, time management, and a team approach to research and research training are advocated to facilitate the development of successful programs and to encourage a continued emphasis on integrated training for pathologists as both clinical diagnosticians and experimentalists. This article is intended to help prospective and active pathology trainees, their mentors, and educational administrators optimize opportunities to ensure the future vitality of veterinary pathologists, and their contributions, in basic and applied research.

Antenatal prediction of fetal macrosomia in pregnancies affected by maternal pre-gestational diabetes.

AIMS: Higher rates of fetal macrosomia may occur in infants of women with pre-gestational diabetes compared with non-diabetic controls. Antenatal predication of fetal macrosomia remains challenging. Ultrasound over-estimated fetal weight could result in over-classification of fetuses as macrosomic with corresponding inappropriate clinical interventions. Previously we had studied a measurement - the anterior abdominal wall measurement (AAW) - to predict fetal macrosomia in fetal estimation of weight. The purpose of the study was to study whether specific third trimester ultrasound measurements with measures of glycaemic control (HbA1c) predicted macrosomia in babies born to women with pre-gestational diabetes. In particular, a new variant of this measurement (fetal anterior abdominal wall thickness (AAW), abdominal circumference (AC) ratio: AAW:AC) was investigated. METHODS: This was a prospective cohort study in a tertiary referral maternity hospital. Serial growth scans including measurement of AAW and AC: AAW ratio was performed at 30, 33- and 36-weeks' gestation. Birth-weight data was collected, and macrosomia was defined as >90th centile based on gestational age and gender of the baby. Serial HbA1c as measured at the first antenatal visit, 14, 20- and 36-weeks' gestation were reported for this study. RESULTS: Of the 416 pregnancies analyzed, mean maternal age was 33.3 years. One in five women were primigravida's. The mean birthweight was 3548 g (+/- 581 g), of which 142 (34%) babies were classified as macrosomic. The median gestational age at delivery was 383 weeks (314 - 402 weeks). There were 37 (9%) babies born preterm at <37 weeks' gestation. Mean AC measurements in fetuses that would be born with macrosomia compared with those with a non-macrosomic birth weight were 282 mm vs. 266 mm at 30 weeks, 318.3 mm vs. 297 mm at 33 weeks and 350 mm vs. 325 mm at 36 weeks' gestation (all p < .001). Mean AAW measurements in macrosomic fetuses compared with normal size fetuses were 3.7 mm vs. 3.3 mm at 30 weeks, 4.9 mm vs 4.3 mm at 33 weeks and 5.9 mm vs. 5.3 mm at 36 weeks' gestation (all p < .001). The mean AC: AAW was 0.01 for both normal and macrosomic fetuses at 30 weeks. There was no clinical or statistical difference in AC:AAW ratios between non-macrosomic and macrosomic infants. Binary logistic regression showed that AC at 36 weeks was most predictive of macrosomia (76.5%), followed by AAW at 30 weeks (68.5%). Using a combination of HbA1c booking, 14, 20, 36 weeks and AAW 30, 33, 36 weeks and AC 30, 33, 36 weeks predicted macrosomia in 80.9%. The ratio of AC: AAW did not act as a useful antenatal clinical predictor of macrosomia at birth. CONCLUSIONS: Abdominal circumference at 36 weeks was the single best predictor of fetal macrosomia. A combined model of HbA1c, AC and AAW was the best antenatal predictor of macrosomia, with intriguing clinical possibilities in the possible prevention of maternal and fetal complications of macrosomia.

COVID-19 infection in patients with intestinal failure: UK experience.

BACKGROUND: The direct effect of the coronavirus disease 2019 (COVID-19) pandemic on patients with intestinal failure (IF) has not been described. METHODS: We conducted a nationwide study of UK IF centers to evaluate the infection rates, presentations, and outcomes in patients with types 2 and 3 IF. RESULTS: A total of 45 patients with IF contracted COVID-19 between March and August 2020; this included 26 of 2191 (1.2%) home parenteral nutrition (HPN)-dependent adults and 19 of 298 (6.4%) adults hospitalized with type 2 IF. The proportion of patients receiving nursing care for HPN administration was higher in those with community-acquired COVID-19 (66.7%) than the proportion in the entire HPN cohort (26.1%; P < .01). Two HPN-dependent and 1 hospitalized patient with type 2 IF died as a direct consequence of the virus (6.7% of 45 patients with types 2 or 3 infected). CONCLUSION: This is the first study to describe the outcomes of COVID-19 in a large cohort of patients requiring long-term PN. Methods to reduce hospital and community nosocomial spread would likely be beneficial.

Individually monitoring ligand-induced changes in the structure of the GABAA receptor at benzodiazepine binding site and non-binding-site interfaces.

The mechanisms by which the GABA and benzodiazepine (BZD) binding sites of the GABA-A receptor are allosterically coupled remain elusive. In this study, we separately monitored ligand-induced structural changes in the BZD binding site (alpha/gamma interface) and at aligned positions in the alpha/beta interface. alpha(1)His101 and surrounding residues were individually mutated to cysteine and expressed with wild-type beta2 and gamma2 subunits in Xenopus laevis oocytes. The accessibilities of introduced cysteines to modification by methanethiosulfonate ethylammonium (MTSEA)-Biotin were measured in the presence and absence of GABA-site agonists, antagonists, BZDs, and pentobarbital. The presence of flurazepam or the BZD-site antagonist flumazenil (Ro15-1788) decreased the rate of modification of alpha(1)H101C at the BZD binding site. GABA and muscimol each increased MTSEA-Biotin modification of alpha(1)H101C located at the BZD-site, gabazine (SR-95531, a GABA binding site antagonist) decreased the rate, whereas pentobarbital had no effect. Modification of alpha(1)H101C at the alpha/beta interface was significantly slower than modification of alpha(1)H101C at the BZD site, and the presence of GABA or flurazepam had no effect on its accessibility, indicating the physicochemical environments of the alpha/gamma and alpha/beta interfaces are different. The data are consistent with the idea that GABA-binding site occupation by agonists causes a GABA binding cavity closure that is directly coupled to BZD binding cavity opening, and GABA-site antagonist binding causes a movement linked to BZD binding cavity closure. Pentobarbital binding/gating resulted in no observable movements in the BZD binding site near alpha(1)H101C, indicating that structural mechanisms underlying allosteric coupling between the GABA and BZD binding sites are distinct.

Anticancer effects of resveratrol in canine hemangiosarcoma cell lines.

Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti-proliferative and/or pro-apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD-1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK) and extracellular signal-regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth-inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro-apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.

Presumed primary immune-mediated neutropenia in 35 dogs: a retrospective study.

OBJECTIVES: To describe, in a cohort of dogs with presumed primary immune-mediated neutropenia, the presenting clinical characteristics, haematology results, bone marrow characteristics, therapies used (drugs and doses), clinical response to treatment, relapse and outcome at six months and one year. METHODS: Multi-institutional recruited retrospective descriptive case series with voluntary submissions. Presumed immune-mediated neutropenia was diagnosed based on a neutrophil concentration <1·5×109 cells/L on a minimum of two complete blood counts, exclusion of other causes of neutropenia based on a diagnostic bone marrow aspirate or biopsy, and exclusion of secondary immune-mediated neutropenia. Dogs meeting these diagnostic criteria between 2006 and 2013, and that had a haematocrit of ≥29% and minimum of two complete blood clounts performed after initiation of therapy, were included. RESULTS: Information on 35 dogs was included. Neutropenia was less than 0·5×109 cells/L in most cases (21 dogs), 0·5 to ·99×109 cells/L in 11, and 1.0 to 1·49×109 cells/L in three. Eight dogs had thrombocytopenia, which was severe (<49·9×109 cells/L) in three. [Correction added on 23 May 2017, after first online publication: the cell numbers were incorrect due to errors in the conversion of cell measurements to international units. The numbers have been corrected throughout the article and Table 2.] Twenty-three dogs had myeloid hyperplasia, 10 dogs had myeloid hypoplasia and two dogs had normal myelopoiesis. Neutropenia resolved in 32 of 33 dogs within two weeks of starting corticosteroid therapy and in all dogs within one month. Relapse of neutropenia occurred in 12 cases within one year. CLINICAL SIGNIFICANCE: Initial response of presumed primary immune-mediated neutropenia cases to corticosteroid therapy can be excellent. Long-term monitoring for relapse is warranted because 34% of cases relapsed during or after taper of immunosuppressive medications.

Female monozygotic twins with selective mutism--a case report.

Selective mutism is a rare social anxiety disorder characterized by a total lack of speech in certain specific situations despite the ability to speak in others. Both genetic and psychosocial factors are thought to be involved in its presentation, persistence, and response to treatment. This case report describes a case of young female monozygotic twins who presented with selective mutism and their treatment spanning a 2-year period. It highlights the strong genetic association along with environmental factors such as social isolation and consequences of maternal social phobia, all contributing to treatment resistance, despite an intensive multimodal biopsychosocial approach. General issues related to the difficulties in treating monozygotic twins are also addressed.

Serum Beta Hydroxybutyrate Concentrations in Cats with Chronic Kidney Disease, Hyperthyroidism, or Hepatic Lipidosis.

BACKGROUND: Ketones, including beta hydroxybutyrate (BHB), are produced in conditions of negative energy balance and decreased glucose utilization. Serum BHB concentrations in cats are poorly characterized in diseases other than diabetes mellitus. HYPOTHESIS: Serum BHB concentrations will be increased in cats with chronic kidney disease (CKD), hyperthyroidism (HT), or hepatic lipidosis (HL). ANIMALS: Twenty-eight client-owned cats with CKD, 34 cats with HT, and 15 cats with HL; 43 healthy cats. METHODS: Prospective observational study. Serum BHB concentrations were measured at admission in cats with CKD, HT, and HL, for comparison with a reference interval established using healthy cats. Results of dipstick urine ketone measurement, when available, were compared to BHB measurement. RESULTS: Beta hydroxybutyrate was above the reference interval (<0.11 mmol/L) in 6/28 cats (21%) with CKD, 7/34 cats (20%) with HT, and 11/15 cats (73%) with HL, significantly exceeding the expected 2.5% above the reference interval for healthy cats (P < .001 for all groups). Elevations were mild in CKD and HT groups (median BHB 0.1 mmol/L for both groups, 80th percentile 0.12 and 0.11 mmol/L, respectively), but more marked in HL cats (median BHB 0.2 mmol/L, 80th percentile 0.84 mmol/L). None of 11 cats with increased serum BHB concentration having urine dipstick analysis performed within 24 h of sampling for BHB were ketonuric. CONCLUSIONS AND CLINICAL IMPORTANCE: Increases in serum BHB concentrations occur in cats with CKD, HT, and HL, and might provide an useful index of catabolism.

Adult Intestinal and Multivisceral Transplantation: Experience From a Single Center in the United Kingdom.

Cambridge is one of two designated adult intestinal transplant centers in the United Kingdom and has performed 60 transplants on 54 patients since 2007; 52% of these were undertaken in the last 3 years. This increasing trend is in contrast with that reported worldwide; 27% were small bowel grafts (SBT), 15% modified multivisceral (MMVT), and 58% multivisceral (MVT). Median recipient age was 47 years; the female-to-male ratio was 27/33. Primary diseases included visceral arterial thromboses (17%), Crohn's disease (17%), motility disorders (12%), visceral venous thromboses (12%), familial adenomatous polyposis (FAP)/desmoids (8%), alcoholic cirrhosis (3%), nonalcoholic fatty liver disease (3%), ulcerative colitis (2%), and other (15%). Indications for transplant included intestinal failure-associated liver disease (IFALD) (27%), loss of central venous access (17%), FAP/desmoid disease (5%), extensive portomesenteric venous thrombosis (PMVT) (20%), widespread mesenteric arterial ischemia (WMAI) (13%), re-transplant (8%), and other (10%). Overall 1-year/5-year patient survival rates were 77%/62%. One-year/5-year patient survival rates were 92%/83%, 85%/65%, and 71%/33% for SBT, MMVT, and MVT. One-year/5-year survival rates for patients with IFALD, PMVT, and other indications who underwent MVT were 80%/20%, 65%/55%, and 55%/35%. The greatest proportion of patient deaths occurred during the first year after transplant (50% in year 1, 23% in year 2, 9% in year 3, 5% in year 4, and 14% in year 5), particularly in the MVT group. Referrals to our United Kingdom center are increasing, and the indications for transplant are becoming more diverse. Our patient survival rates remain comparable with figures reported worldwide.

Cytomegalovirus Infection and Rates of Antiviral Resistance Following Intestinal and Multivisceral Transplantation.

BACKGROUND: Cytomegalovirus (CMV) disease is a common and clinically significant complication following intestinal or multivisceral transplantation. CMV disease is more common in cases of serologic mismatch between donor and recipient. Though in some cases it may be asymptomatic, in the immunosuppressed population it often manifests with evidence of systemic infection or end-organ disease. METHODS: We conducted a retrospective review of all patients undergoing intestinal or multivisceral transplantation over 8 years at our institution. RESULTS: Forty-eight transplantations were performed, with 40% of the patients (19/48) having ≥1 episode of CMV viremia, which rose to 90% in the "donor-positive, recipient-negative" (DPRN) serologic mismatch group. The median time to 1st episode following transplantation was 22.3 weeks (range, 1-78) and median duration of each episode was 4.9 weeks (range, 1.6-37.4). Six of the 19 viremic patients (31.6%) developed virologic resistance with 4 of these occurring in the DPRN group. Four of the 6 patients with drug-resistant CMV died with CMV viremia. All patients with drug resistance acquired ganciclovir resistance; these patients were more challenging to manage with second-line toxicity-limited treatments, including foscarnet, cidofovir, and leflunomide. CMV immunoglobulin has been used and we briefly discuss the use of CMV-specific adoptive T-lymphocyte transfer in the management of 1 case. CONCLUSIONS: Post-transplantation CMV disease continues to be challenging to manage, and there is little consensus on optimal management strategies in this patient group, with a significant requirement for novel therapies; these may be pharmacologic or cell based. Extensive multidisciplinary discussion is important for most cases, but particularly for those patients who acquire virologic resistance.

The relative amount of cRNA coding for gamma2 subunits affects stimulation by benzodiazepines in GABA(A) receptors expressed in Xenopus oocytes.

Benzodiazepine (BZD) potentiation of GABA-activated Cl(-)-current (I(GABA)) in recombinant GABA(A) receptors requires the presence of the gamma subunit. When alpha1, beta2 and gamma2S cRNA are expressed in a 1:1:1 ratio in Xenopus oocytes, BZD potentiation of I(GABA) is submaximal, variable and diminishes over time. Potentiation by BZDs is increased, more reproducible and is stabilized over time by increasing the relative amount of cRNA coding for the gamma2S subunit. In addition, GABA EC(50) values for alpha1beta2gamma2 (1:1:1) receptors are intermediate to values measured for alpha1beta2 (1:1) and alpha1beta2gamma2 (1:1:10) receptors. We conclude that co-expression of equal ratios of alpha1, beta2 and gamma2 subunits in Xenopus oocytes produces a mixed population of alpha1beta2 and alpha1beta2gamma2 receptors. Therefore, for accurate measurements of BZD potentiation it is necessary to inject a higher ratio of gamma2 subunit cRNA relative to alpha1 and beta2 cRNA. This results in a purer population of alpha1beta2gamma2 receptors.

Spontaneous pregnancy-induced hypertension and intrauterine growth restriction in rats.

The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is advanced as a novel and suitable non-primate model of pregnancy-associated hypertension and fetal growth restriction because it simultaneously has spontaneous pregnancy-associated hypertension, small for gestational age (SGA) offsprings, and altered placental gene expression. Pregnancy-associated hypertension is a major contributor to maternal and fetal morbidity and mortality with the potential to result in maternal death and the need for iatrogenic preterm delivery. It has been reported to develop spontaneously in humans, but not in animals; consequently, progress in identifying the cause and pathogenesis of this disorder has been hampered. Spontaneous hypertension and heart failure rats develop hypertension spontaneously as they age, therefore we sought to determine whether these rats developed hypertension and SGA offsprings during pregnancy. Our results show that systolic blood pressure (BP) increased >40 mm Hg by the end of the first trimester and remained at this elevated level for the remainder of pregnancy, but decreased after parturition. Placenta weights of SHHF rats (0.60 +/- 0.02 g, n = 36) were significantly higher than Wistar-Kyoto (WKY) rats (0.42 +/- 0.01 g, n = 22, P < .05), but pup weights were significantly lower (2.68 +/- 0.06 g for SHHF rats compared to 3.24 +/- 0.06 g for WKY controls, P < .05). Histologic examination revealed pathologic lesions in neither heart, liver, placenta, nor kidney. L-Arginine administered in drinking water prevented the elevation of BP, particularly during the third trimester. Placentas from SHHF rats displayed altered expression of several genes whose protein products have been implicated in preeclampsia, including serotonin receptor, sodium channel, carbonic anhydrase, estrogen receptor regulator, major histocompatibility complex proteins, superoxide dismutase, and angiotensiogen. In addition, gene expression profiling showed alteration of a number of subcellular putative myristoylproteins not previously associated with preeclampsia, particularly those engaged in post-translational modifications in the placenta. Thus, SHHF rats may be a valuable tool, because it simultaneously has spontaneous pregnancy-associated hypertension, SGA offsprings, and altered placental gene expression.

Production of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor by carcinomas in a dog and a cat with paraneoplastic leukocytosis.

A dog with a pulmonary papillary carcinoma and a cat with a dermal tubular adenocarcinoma had profound paraneoplastic neutrophilic leukocytosis with no clinically detectable inflammatory foci. To investigate the mechanism of the leukocytosis, oligonucleotide primers were designed from the cDNA sequences of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) of dogs. Reverse transcription polymerase chain reaction was performed on tumor tissues, and specific amplification of G-CSF and GM-CSF was obtained with the tumor RNA in the dog. The tumor RNA in the cat demonstrated specific amplification of G-CSF but not GM-CSF. These findings are consistent with the production of G-CSF and/or GM-CSF by neoplasms as a mechanism for paraneoplastic leukocytosis in small animals.