Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.

Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes (CREBBP, EP300) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP; RTS2: EP300), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care.

Suspected cerebral salt wasting syndrome secondary to traumatic brain injury in a dog.

OBJECTIVE: To describe a dog with suspected cerebral salt wasting syndrome (CSWS) secondary to traumatic brain injury (TBI). CASE SUMMARY: A 2-month-old intact male Chihuahua-American Pitbull Terrier mix weighing 1.94 kg presented to a veterinary teaching emergency room after suffering bite wound-penetrating trauma to the head. Treatment was initiated with hyperosmotic agents, fluid resuscitation, and analgesia. The dog's neurologic dysfunction warranted hospitalization and continuous monitoring. Within 24 hours, the dog developed hyponatremia (133 mmol/L compared to 143 mmol/L on presentation [reference interval 142-149 mmol/L]). As the dog had concurrent tachycardia, increase in urine sodium concentration, polyuria, and weight loss, a diagnosis of cerebral salt wasting was suspected. A 2% hypertonic saline constant rate infusion was administered for volume replacement, and the patient showed improvement in clinical signs and blood sodium concentration. The dog was discharged on Day 5. Recheck examination showed significant neurologic improvement with sodium just below the low end of the reference range (141 mmol/L [reference interval 142-149 mmol/L]). NEW OR UNIQUE INFORMATION PROVIDED: This is the first description of suspected CSWS in veterinary medicine. Hyponatremia is a common finding in critically ill neurologic people, including those with TBI, and is typically associated with either syndrome of inappropriate antidiuretic hormone or CSWS. As treatment recommendations for syndrome of inappropriate antidiuretic hormone and CSWS are diametrically opposed, identifying the presence of hyponatremia and distinguishing between these 2 clinical entities is critical for improving patient care for those with TBI. This case highlights the characteristics and clinical progression regarding the diagnosis and management of suspected CSWS.

Successful treatment of a severe 5-hydroxytrytophan intoxication using carbon hemoperfusion, hemodiafiltration, and mechanical ventilation in a dog.

OBJECTIVE: To describe the successful use of carbon hemoperfusion and hemodiafiltration in combination with mechanical ventilation (MV) to treat a severe intoxication of 5-hydroxytryptophan (5-HTP) in a dog. CASE SUMMARY: A dog ingested a minimum of 550 mg/kg of extended-release 5-HTP, resulting in serotonin syndrome that progressed to a comatose state and severe hypoventilation requiring MV. Extracorporeal carbon hemoperfusion coupled with hemodiafiltration was performed to remove 5-HTP from this patient. A carbon hemoperfusion cartridge was placed in series upstream in the extracorporeal circuit from the hemodialyzer. A total of 46.5 L of blood (4.89 L/kg) was processed during a 4.85-hour treatment. Serial plasma samples were obtained at 0, 60, 90, and 150 minutes during the session and 14 hours after the session. These samples were later analyzed for 5-HTP and serotonin concentrations. The extraction ratio of 5-HTP was 93.6%-98.9% through the carbon filter. The dog was weaned from MV within 8 hours after extracorporeal therapy and, after a full recovery, was successfully discharged. NEW OR UNIQUE INFORMATION PROVIDED: Despite an extensive review of the available literature, this appears to be the first reported case of using a carbon hemoperfusion, hemodiafiltration, and MV to treat severe serotonin syndrome secondary to 5-HTP intoxication in a dog. The combination of carbon hemoperfusion and hemodiafiltration can significantly reduce plasma 5-HTP concentrations after acute intoxication and may serve to decrease morbidity and mortality in patients with severe intoxication.

Survey of veterinarians in the USA to evaluate trends in the treatment approach for non-obstructive feline idiopathic cystitis.

OBJECTIVES: The goal of this study was to gather information on treatment approaches and trends for the treatment of non-obstructive feline idiopathic cystitis (FIC). METHODS: An internet-based survey of veterinarians was conducted focusing on outpatient treatment approaches for cats that are stable, not obstructed and that exhibit lower urinary signs suspected to be due to FIC, where other causes (eg, urolithiasis, urinary tract infection, other) have been ruled out. RESULTS: A total of 606 veterinarians submitted complete surveys for inclusion. Respondents reported that when obtaining patient histories, in ⩾75% of client interactions they gathered information about feline stressors (542/606, 89%), resource set-up (eg, number of litter boxes; 466/606, 77%) and diet (552/606, 91%). Only 31% (187/606) of respondents reported that they gathered information about daily human/cat interaction in ⩾75% of client interactions, with 69% (419/606) of veterinarians inquiring about this information 50% of the time or less. Top treatments selected for acute presentations of FIC were analgesics (537/606, 89%), modified litter box management (435/606, 72%) and synthetic feline pheromones (422/606, 70%). Top treatments selected for chronic FIC management were prescription diets (519/606, 86%), modified litter box management (508/606, 84%) and environmental enhancements (493/606, 81%). Challenges with owner compliance and expectations were selected as barriers to achieving a positive treatment outcome by 81% (486/599) and 62% (372/599) of respondents, respectively. Rehoming or euthanasia were recommended by 37% (224/606) and 10% (59/606) of veterinarians, respectively, due to difficulties managing FIC. CONCLUSIONS AND RELEVANCE: The treatment approach for non-obstructive FIC appears to be multimodal and recommendations vary between acute and chronic presentations. An area of opportunity is client communication and education, which may improve owner compliance and help set appropriate expectations. The importance of human/cat interaction as a management strategy appears under-emphasized.

Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment.

While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n â€‹= â€‹1) or G239S variant (n â€‹= â€‹2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 â€‹mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.

Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy.

KCNQ2 variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and KCNQ2 G256W heterozygosity. Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path. Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells. Ezogabine partly reversed this suppression. G256W/+ mice have epilepsy leading to premature deaths. Hippocampal CA1 pyramidal cells from G256W/+ brain slices showed hyperexcitability. G256W/+ pyramidal cell KCNQ2 and KCNQ3 immunolabeling was significantly shifted from axon initial segments to neuronal somata. Despite normal mRNA levels, G256W/+ mouse KCNQ2 protein levels were reduced by about 50%. Our findings indicate that G256W pathogenicity results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of KCNQ2 encephalopathy. Our results, spanning structure to behavior, may be broadly applicable because the majority of KCNQ2 encephalopathy patients share variants near the selectivity filter.

Trends in admission and case fatality for acute malnutrition: Kingston 1892-1991

The case fatality ratio (CFR) in acute protein-energy malnutrition (PEM) achieved in the Tropical Metabolism Research Unit (TMRU) was compared with that of other tertiary care facilities in Kingston. Trends in admission and fatality rates, case severity and complications were also examined. From ward admission registers for Bustamante Hospital for Children (BHC), the University Hospital of the West Indies (UHWI), children's wards and the TMRU all cases of PEM admitted from 1982 through 1991 were enumerated and there was a docket search for random subsamples. Ten-year mean CFR percent for BHC was 8.8 (n=1974); for UHWI wards 5.5 (n=658); for TMRU 7.1 (n=662). BHC has the least restrictions on admission and showed most clearly that the peak time in Kingston for admission of PEM was around 1985, falling to a minimum in 1988 - 1990 and rising again in 1991; however, the other sites also showed similar trends. BHC had a range of CFR precent p.a. of 20.0 to 3.0, with a striking fall in the second half of the decade. There was no temporal CFR trend for the UHWI or TMRU. The latter institution had the highest proportion of admissions with marasmic-kwashiorkor and the lowest proportion with recorded infection. The annual variation in numbers of PEM deaths at BHC was best accounted for by (a) percentage change in consumer price index and (b) percentage change in the US$ value of the Jamaican $, in the preceding year, and (c) annual number of admissions, together. Generally, our findings suggest a minor role for expert in-patient management in reducing deaths from PEM

Biochemical markers in gastrointestinal malignancies

E discutido o papel dos marcadores bioquímicos no diagnóstico dos tumores do aparelho digestivo. Sua importância para estratificar pacientes quanto a probabilidade de sobrevida, detectar recorrência e monitorizar o tratamento é analisada

The level of cancer markers in relation to certain biological characteristics of the gastrointestinal tumors

Niveis de marcadores de cancer circulantes sao considerados dependentes da natureza biologica das celulas neoplasicas. A producao de CEA em resposta a uma lesao gastrointestinal maligna variou de acordo com a localizacao e estadiamento patologico do tumor primario, enquanto que o grau histologico nao interferiu com os niveis do antigeno. Carcinomas do estomago pareceram sintetizar menos CEA do que aqueles do intestino grosso. A atividade enzimatica dos tumores malignos do colon e do reto, determinada pelos ensaios da gama-GT e PHI revelou estar associada com a progressao tumoral, enquanto que o grau histologico nao foi um fator importante na determinacao dos niveis destes mercadores...