A variant in the 5'UTR of ERBB4 is associated with lifespan in Golden Retrievers.

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5'UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer.

Low-dose ketamine infusions reduce opioid use in pediatric and young adult oncology patients.

BACKGROUND: Ketamine is an NMDA-receptor antagonist with analgesic and opioid-sparing properties. Although well studied in adults, more robust evidence supporting ketamine's use for pediatric pain management is needed. This retrospective study evaluates ketamine's opioid-sparing effectiveness in pediatric and young adult oncology and hematology patients. PROCEDURE: Continuous ketamine infusions administered for pain management between 2010-2020 were reviewed. Data including demographic characteristics, oncology/hematology and pain diagnoses, concurrent pain medications, and ketamine infusions' dose and duration were collected. Opioid consumption data based on delivery via patient-controlled analgesia were collected 1 day before (D1), all days during (cumulatively named D2), and 1 day after (D3) ketamine infusions and calculated as morphine-equivalent doses (mg/kg/day). Data were reported for the entire study group as well as for distinct oncology and end-of-life categories, and short-term acute pain circumstances which included vaso-occlusive crises in hematology patients. Side effects were reviewed. RESULTS: Significantly lower daily opioid consumption was noted in the oncology group, while decreases were not significant in the end-of-life group and in the overall study population. The acute pain group did not show an opioid reduction associated with the ketamine infusions. A largely tolerable side-effect profile was observed, with no differences among each group's incidence. CONCLUSIONS: Ketamine infusions were associated with significantly reduced opioid consumption for oncology patients. The opioid-sparing effects of ketamine may vary according to clinical diagnoses and circumstances of use. Overall, low-dose ketamine infusions present an acceptable safety profile in pediatric and young adult patients; nevertheless, individual risks and benefits should be considered.

Identification and Characterization of a Peptide from the Stony Coral Heliofungia actiniformis.

Marine organisms produce a diverse range of toxins and bioactive peptides to support predation, competition, and defense. The peptide repertoires of stony corals (order Scleractinia) remain relatively understudied despite the presence of tentacles used for predation and defense that are likely to contain a range of bioactive compounds. Here, we show that a tentacle extract from the mushroom coral, Heliofungia actiniformis, contains numerous peptides with a range of molecular weights analogous to venom profiles from species such as cone snails. Using NMR spectroscopy and mass spectrometry we characterized a 12-residue peptide (Hact-1) with a new sequence (GCHYTPFGLICF) and well-defined ß-hairpin structure stabilized by a single disulfide bond. The sequence is encoded within the genome of the coral and expressed in the polyp body tissue. The structure present is common among toxins and venom peptides, but Hact-1 does not show activity against select examples of Gram-positive and Gram-negative bacteria or a range of ion channels, common properties of such peptides. Instead, it appears to have a limited effect on human peripheral blood mononuclear cells, but the ecological function of the peptide remains unknown. The discovery of this peptide from H. actiniformis is likely to be the first of many from this and related species.

Hookworm Secreted Extracellular Vesicles Interact With Host Cells and Prevent Inducible Colitis in Mice.

Gastrointestinal (GI) parasites, hookworms in particular, have evolved to cause minimal harm to their hosts, allowing them to establish chronic infections. This is mediated by creating an immunoregulatory environment. Indeed, hookworms are such potent suppressors of inflammation that they have been used in clinical trials to treat inflammatory bowel diseases (IBD) and celiac disease. Since the recent description of helminths (worms) secreting extracellular vesicles (EVs), exosome-like EVs from different helminths have been characterized and their salient roles in parasite-host interactions have been highlighted. Here, we analyze EVs from the rodent parasite Nippostrongylus brasiliensis, which has been used as a model for human hookworm infection. N. brasiliensis EVs (Nb-EVs) are actively internalized by mouse gut organoids, indicating a role in driving parasitism. We used proteomics and RNA-Seq to profile the molecular composition of Nb-EVs. We identified 81 proteins, including proteins frequently present in exosomes (like tetraspanin, enolase, 14-3-3 protein, and heat shock proteins), and 27 sperm-coating protein-like extracellular proteins. RNA-Seq analysis revealed 52 miRNA species, many of which putatively map to mouse genes involved in regulation of inflammation. To determine whether GI nematode EVs had immunomodulatory properties, we assessed their potential to suppress GI inflammation in a mouse model of inducible chemical colitis. EVs from N. brasiliensis but not those from the whipworm Trichuris muris or control vesicles from grapes protected against colitic inflammation in the gut of mice that received a single intraperitoneal injection of EVs. Key cytokines associated with colitic pathology (IL-6, IL-1ß, IFNγ, and IL-17a) were significantly suppressed in colon tissues from EV-treated mice. By contrast, high levels of the anti-inflammatory cytokine IL-10 were detected in Nb-EV-treated mice. Proteins and miRNAs contained within helminth EVs hold great potential application in development of drugs to treat helminth infections as well as chronic non-infectious diseases resulting from a dysregulated immune system, such as IBD.

Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma.

In the developed world, declining prevalence of some parasitic infections correlates with increased incidence of allergic and autoimmune disorders. Moreover, experimental human infection with some parasitic worms confers protection against inflammatory diseases in phase 2 clinical trials. Parasitic worms manipulate the immune system by secreting immunoregulatory molecules that offer promise as a novel therapeutic modality for inflammatory diseases. We identify a protein secreted by hookworms, anti-inflammatory protein-2 (AIP-2), that suppressed airway inflammation in a mouse model of asthma, reduced expression of costimulatory markers on human dendritic cells (DCs), and suppressed proliferation ex vivo of T cells from human subjects with house dust mite allergy. In mice, AIP-2 was primarily captured by mesenteric CD103+ DCs and suppression of airway inflammation was dependent on both DCs and Foxp3+ regulatory T cells (Tregs) that originated in the mesenteric lymph nodes (MLNs) and accumulated in distant mucosal sites. Transplantation of MLNs from AIP-2-treated mice into naïve hosts revealed a lymphoid tissue conditioning that promoted Treg induction and long-term maintenance. Our findings indicate that recombinant AIP-2 could serve as a novel curative therapeutic for allergic asthma and potentially other inflammatory diseases.

One to Watch: A Germ Cell Tumor Arising in an Undescended Testicle in Rubinstein-Taybi Syndrome.

A male preterm infant was born with dysmorphic features consistent with Rubinstein-Taybi syndrome (RTS). An undescended right testicle was noted on examination. At 5 months of age he developed a palpable right-sided abdominal mass and an elevated alpha-fetoprotein. Histology revealed a malignant germ cell neoplasm arising within the undescended testis. This is the first reported case of a germ cell tumor occurring in a pediatric patient with RTS. Urologic abnormalities occur in approximately 52% of RTS patients, of which cryptorchidism is the commonest. Given the frequency of undescended testes in this population, closer screening may be warranted.

Isolated acute non-cystic white matter injury in term infants presenting with neonatal encephalopathy.

We discuss possible aetiological factors, MRI evolution of injury and neuro-developmental outcomes of neonatal encephalopathy (NE). Thirty-six consecutive infants diagnosed with NE were included. In this cohort, four infants (11%) were identified with injury predominantly in the deep white matter on MRI who were significantly of younger gestation, lower birthweight with higher Apgars at one and five minutes compared to controls. Placental high grade villitis of unknown aetiology (VUA) was identified in all four of these infants. Our hypothesis states VUA may induce white matter injury by causing a local inflammatory response and/or oxidative stress during the perinatal period. We underline the importance of continued close and systematic evaluation of all cases of NE, including examination of the placenta, in order to come to a better understanding of the clinical presentation, the patterns of brain injury and the underlying pathophysiological processes.

Does the length of the history influence the outcome of pneumatic reduction of intussusception in children?

PURPOSE: Intussusception is the most common cause of acute abdomen in infants and preschool children. Nonoperative reduction using air enema is an established treatment in children with intussusception. The aim of this study was to determine whether length of the history influences the outcome of pneumatic reduction of intussusception in children? METHODS: The medical records of 256 consecutive children with intussusception between July 1998 and June 2010, who underwent air enema reduction regardless of the length of the history were reviewed. In all 256 patients, intussusception was confirmed by ultrasound before proceeding to air enema. RESULTS: The length of history ranged from 2 to 240 h with median time of 18.5 h. The median age in 256 patients was 7 months (range 1 day to 12 years). The presenting clinical features included irritability/abdominal pain (77%), vomiting (80%), bleeding per rectum (36%) and palpable abdominal mass (50%). Air enema reduction was successful in 234 (91.5%) of the 256 patients. In 22 (8.5%) patients, air enema failed to reduce the intussusception and 3 (1.1%) of these patients had colonic perforation during the procedure. All 22 patients required surgery. The duration of symptoms did not influence the outcome of pneumatic reduction. 37 (14%) patients developed recurrence after successful pneumatic reduction of intussusception, with 58% presenting within 48 h of the initial procedure. CONCLUSION: Our data suggest that pneumatic reduction should be first-line treatment in all children with intussusception regardless of the length of the history.

Leukoencephalopathy with anterior temporal cysts due to congenital CMV infection diagnosed retrospectively.

Leukoencephalopathy with subcortical cysts has been described in a variety of conditions. However, few reports have highlighted congenital CMV as a cause of this imaging finding. We report a 1-year-old girl with developmental delay and sensorineural hearing loss whose MRI brain showed abnormal white matter and temporal cysts. Congenital CMV infection was diagnosed retrospectively by examination of dried blood spot from the newborn screening card.

Seizure-induced inflammation in focal cortical dysplasia resulting in imaging progression that simulates neoplasia.

A 5-year-old girl with previously well-controlled partial epilepsy secondary to focal cortical dysplasia (FCD) developed an increase in seizure frequency. Two months later, magnetic resonance showed a substantial alteration in lesion imaging characteristics. The lesion was resected. FCD was confirmed but inflammatory changes were also present. We propose that chronic inflammation was induced by unremitting seizure activity and suggest that inflammation may be implicated as a basis for alteration in the imaging characteristics of FCD.

A case of relapsing flitting bilateral idiopathic orbital inflammation.

Idiopathic orbital inflammation (IOI) is defined as a benign non-infective clinical syndrome characterized by features of non-specific inflammation of the orbit without identifiable local or systemic causes. This can be called orbital myositis if the inflammation is predominantly in the orbital muscles. It is a diagnosis of exclusion based on clinical, radiological, and if necessary, histological findings. The most commons symptoms are swelling, ptosis, proptosis and painful eye movements. To our knowledge, this patient is the first with IOI to demonstrate relapsing flitting bilateral involvement of several individual extra-ocular muscles.

Whole-body magnetic resonance imaging: a useful additional sequence in paediatric imaging.

BACKGROUND: Whole-body MR (WBMR) imaging allows the acquisition of images of the entire body in a matter of minutes. Its use has primarily been in the evaluation of possible metastases in the setting of a known primary tumour. OBJECTIVE: To document the value of WBMR imaging in ten children in whom this was added as an additional sequence when the primary diagnosis had not yet been made. MATERIALS AND METHODS: Ten children, age range 4 months-15 years (mean 7 years 4 months) had WBMR imaging after initial MR showed an abnormality that raised the possibility of systemic disease. Initial scanning was of the brain (n=1), spine (n=2), retroperitoneum (n=4), hips (n=1), femur (n=1) and wrist (n=1). RESULTS: Abnormalities were detected in eight patients. Two patients had acute lymphoblastic leukaemia, and another had an anaplastic lymphoma, unsuspected prior to the WBMR. Two patients had a previously undiagnosed neuroblastoma with bone marrow metastases. Two patients had Langerhans' cell histiocytosis. Another had multiple bone lesions due to cystic angiomatosis. CONCLUSIONS: WBMR imaging may be a useful additional sequence in children in whom a systemic and especially a bone marrow abnormality is suspected.

Neuroimaging findings in glutaric aciduria type 1.

OBJECTIVE: To review the imaging features of glutaric aciduria type 1 (GA-1) in a group of 20 patients, the largest published series to date. To document the findings not previously reported and compare our findings with the imaging characteristics of GA-1 previously reported in the literature. MATERIALS AND METHODS: For 14 patients the original scans were examined and in the remaining 6, where the imaging was unavailable, the radiology reports were consulted. Nine patients had serial cranial US examinations, 13 had 18 CT scans performed and 14 patients had 39 MRI scans. RESULTS: Widening of the sylvian fissures and of the fluid spaces anterior to the temporal lobes was seen in 93% of cases. The mesencephalic cistern was also widened in 86%. Abnormal high-signal intensity on T2-weighted (T2-W) images was seen in the basal ganglia and periventricular white matter in 64% of children. Subdural collections were found in 3 patients, all of which resolved spontaneously. Four neonates followed with serial cranial US showed bilateral multiple caudothalamic cysts. Abnormal high signal on T2-W images was seen in the dentate nucleus, substantia nigra and the pontine medial lemniscus in 79, 43 and 64%, respectively. CONCLUSIONS: Widening of the sylvian fissure, mesencephalic cistern and expansion of CSF spaces anterior to the temporal lobes are cardinal signs of GA-1. If combined with abnormalities of the basal ganglia and white matter, GA-1 should be strongly suspected.

An unusual orthopaedic presentation of acute lymphoblastic leukemia.

A 3-year-old boy of Romanian origin was admitted with the inability to weight bear and pyrexia. He was investigated to rule out septic arthritis. He subsequently developed an atypical clinical picture of fleeting joint arthritis, spiking temperature with poor response to antibiotics and atypical results of investigations. The peripheral blood smear showed a normal leukocyte count, but evidence of blast cells. Bone marrow aspirate confirmed the diagnosis of acute lymphoblastic leukemia. His skeletal radiographic survey had shown evidence of symmetrical metaphyseal sclerosis in the long bones, which has not been previously described as an isolated feature of acute lymphoblastic leukemia. Following a good response to chemotherapy, partial resolution of the sclerosis occurred. This case illustrates that metaphyseal sclerosis can be one of the manifestations of acute lymphoblastic leukemia and delay in diagnosis can easily occur in the absence of classic features of the disease. An early diagnosis is a good prognostic feature of these childhood malignancies.