Muerte súbita por cetoacidosis alcohólica en etilistas crónicos: reporte de 3 casos / Sudden death by alcoholic ketoacidosis in chronic alcoholics: report of 3 cases

Resumen En Patología Forense es común estudiar cadáveres de individuos con antecedente de alcoholismo crónico, que son encontrados fallecidos y cuyo deceso no fue presenciado; por lo que en gran cantidad de autopsias la determinación de la causa de muerte es compleja. La cetoacidosis alcohólica constituye un síndrome complejo derivado de una alteración del metabolismo en el contexto de un consumo excesivo de alcohol e ingesta calórica insuficiente. Se trata de un diagnóstico diferencial importante como causa de muerte en alcohólicos crónicos que fallecen posterior a un ayuno de algunos días, secundario a molestias abdominales como gastritis inducida por etanol, usualmente asociada a vómitos. Clínicamente estas personas presentan además dolor abdominal, taquicardia y alteraciones respiratorias. El diagnóstico postmortem se confirma mediante la presencia de cuerpos cetónicos, especialmente beta-hidroxibutirato, en sangre, humor vítreo u orina. A continuación se presentan tres casos de muerte súbita por cetoacidosis alcohólica con historia de abuso crónico de bebidas etílicas; se discute su fisiopatología, hallazgos al momento de la autopsia y resultados de exámenes complementarios (análisis toxicológico y estudio histopatológico).

Abstract In the forensic pathology setting, it is frequent to study corpses of individuals that were known to be chronic alcoholics and suffered a sudden death. Therefore, many autopsies are performed, in which determining the cause of death is a complex task. Alcoholic ketoacidosis refers to a complex syndrome derived from a metabolic disarrangement, related to excessive consumption of alcohol and an insufficient caloric intake. It is an important diagnosis that should be considered in sudden deaths of chronic alcoholics with a recent history of fasting, due to abdominal complains such as gastritis induced by alcohol and usually associated with recurrent vomiting. Clinically these patients present with abdominal pain, tachycardia and respiratory anomalies. The diagnosis can be confirmed when elevated ketone bodies, especially beta-hydroxybutyrate, are found in blood, vitreous humour or urine. In this paper we present three cases of sudden death by alcoholic ketoacidosis with a history of chronic abuse of alcohol, discussing it´s pathophysiology, autopsy findings and the results of additional studies (toxicologic screening and histopathology).

Predisposition to acute pancreatitis in dogs with severe acute renal failure / Predisposição à pancreatite aguda em cães com insuficiência renal aguda grave

Patients with acute renal failure often have a negative energy balance, which promotes metabolic changes predisposing to complications. The objective of this study was to evaluate laboratory parameters of 30 dogs with severe acute renal failure, to assess their relationship with the possibility of developing acute pancreatitis due to the negative energy balance, and to correlate these findings with the degree of renal failure. Serum concentrations of urea, creatinine, beta-hydroxybutyrate, triglycerides, amylase, total lipase, and canine pancreatic lipase were compared between healthy dogs and dogs with severe acute renal failure. A greater serum concentration of beta-hydroxybutyrate and greater activity of pancreatic enzymes, particularly canine pancreatic lipase, as well as a stronger correlation between the latter and serum creatinine concentrations, were related to the occurrence of acute pancreatitis in patients with severe acute renal failure. A greater degree of renal failure implied a greater predisposition to acute pancreatitis.(AU)

O portador de insuficiência renal aguda é um paciente que, muitas vezes, encontra-se sob importante condição de balanço energético negativo, gerando alterações metabólicas que predispõem a complicações. O objetivo deste estudo foi avaliar parâmetros laboratoriais de trinta cães com insuficiência renal aguda grave, quanto a possibilidade de desenvolvimento de pancreatite aguda em função do balanço energético negativo, e relacioná-los ao grau de gravidade da insuficiência renal. As concentrações séricas de ureia, creatinina, betahidroxibutirato, triglicérides, amilase, lipase total e lipase pancreática canina foram comparadas entre o grupo de cães hígidos e o de cães doentes. Observou-se maior concentração sérica de betahidroxibutirato e maior atividade das enzimas pancreáticas, especialmente da lipase pancreática canina, além de forte correlação entre esta última e a concentração sérica de creatinina, demonstrando a ocorrência de pancreatite aguda em pacientes com insuficiência renal aguda grave. Verificou-se também que quanto mais grave é a insuficiência renal, maior é a predisposição à pancreatite aguda.(AU)

Predisposition to acute pancreatitis in dogs with severe acute renal failure

ABSTRACT: Patients with acute renal failure often have a negative energy balance, which promotes metabolic changes predisposing to complications. The objective of this study was to evaluate laboratory parameters of 30 dogs with severe acute renal failure, to assess their relationship with the possibility of developing acute pancreatitis due to the negative energy balance, and to correlate these findings with the degree of renal failure. Serum concentrations of urea, creatinine, beta-hydroxybutyrate, triglycerides, amylase, total lipase, and canine pancreatic lipase were compared between healthy dogs and dogs with severe acute renal failure. A greater serum concentration of beta-hydroxybutyrate and greater activity of pancreatic enzymes, particularly canine pancreatic lipase, as well as a stronger correlation between the latter and serum creatinine concentrations, were related to the occurrence of acute pancreatitis in patients with severe acute renal failure. A greater degree of renal failure implied a greater predisposition to acute pancreatitis.

RESUMO: O portador de insuficiência renal aguda é um paciente que, muitas vezes, encontra-se sob importante condição de balanço energético negativo, gerando alterações metabólicas que predispõem a complicações. O objetivo deste estudo foi avaliar parâmetros laboratoriais de trinta cães com insuficiência renal aguda grave, quanto a possibilidade de desenvolvimento de pancreatite aguda em função do balanço energético negativo, e relacioná-los ao grau de gravidade da insuficiência renal. As concentrações séricas de ureia, creatinina, betahidroxibutirato, triglicérides, amilase, lipase total e lipase pancreática canina foram comparadas entre o grupo de cães hígidos e o de cães doentes. Observou-se maior concentração sérica de betahidroxibutirato e maior atividade das enzimas pancreáticas, especialmente da lipase pancreática canina, além de forte correlação entre esta última e a concentração sérica de creatinina, demonstrando a ocorrência de pancreatite aguda em pacientes com insuficiência renal aguda grave. Verificou-se também que quanto mais grave é a insuficiência renal, maior é a predisposição à pancreatite aguda.

The effects of β-hydroxybutyrate on p75NTR mRNA and protein expression in Aβ-treated SH-SY5Y cells and mechanisms involved / 中华老年医学杂志

Objective To investigate the effect and mechanisms of β hydroxybutyrate (βOHB) regulation on p75NTR expression in Alzheimer's disease (AD) model cells.Methods First,cultured SH-SY5Y cells were exposed to Aβ (final concentrations:10,20,40,80 μmol/L) with or without 5 mmol/L βOHB pretreatment,and sham-treated cells were used as the control.At 24 h after treatment,the viability of cells was determined by the MTT assay.Secondly,cultured cells were divided into four groups.Cells in the Aβ group were exposed to Aβ (final concentration:20 μ mol/L)with or without 5 mmol/L βOHB pretreatment.Cells in the βOHB group were treated only with 5 mmol/L βOHB,and sham treated cells were used as the control.At 6 h and 24 h after treatment,the expression of p75NTR,HDAC1/2 mRNA and its protein expression,and p65 protein expression were measured by qRT-PCR or Western blot.Finally,the expression of p75NTR mRNA and protein was analyzed in cultured cells after silencing HDAC1 / 2 with siRNA.Results The viability of cells with 40 μmol/L or 80 μmol/L treatment was lower than that in the control group (P＜0.01),and there was a significant increase (P＜0.01) in cell viability of the βOHB intervention group,compared with the Aβ group.At 6 h or 24 h after treatment,the expression of p75NTR mRNA,its protein expression,and p65 protein expression were clearly increased in the βOHB group (P＜0.05) and markedly decreased (P＜0.01) in the Aβ group,compared with the control.Additionally,the expression of HDAC1 / 2 mRNA and protein was higher (P＜0.01) in the Aβ group at 6h or 24h after treatment and lower(P＜0.05 or P＜0.01)in the βOHB group at 6 h after treatment than in the control group.Compared with the Aβ group,there were significant increases (P＜0.01) observed in p75NTR mRNA,its protein expression,and p65 protein expression,and a notable decrease (P＜0.05) in HDAC1 / 2 mRNA and protein expression in cells of the βOHB intervention group at 6 h and 24 h after treatment.The expression of p75NTR mRNA and protein increased in HDAC1 knock-down cells compared with the control (P＜0.05).However,no difference was found in p75NTR expression in HDAC2 knock-down cells (P＞0.05).Conclusions βOHB up-regulates p75NTR expression by inhibiting HDAC1 of βOHB.It also activates p65 and prevents the decrease of cell viability.

ADMINISTRATION OF EARLY POST-PARTUM ORLAN DRENCH IN DAIRY COWS: EFFECT ON METABOLIC PROFILE / ADMINISTRACIÓN ORAL DE DRENCH EN EL POSPARTO TEMPRANO EN VACAS LECHERAS: EFECTO SOBRE EL PERFIL METABÓLICO

Some prophylactic treatments have been proposed in high-yielding dairy cattle in order to minimize the effects of negative energy balance and some disturbances such as hypocalcaemia and ketosis. The objective of this study was to evaluate the effects of two doses of Drench within 24 h after calving on the metabolic profile and prevention of ketosis. A total of 48 cows from a herd in Rio Grande do Sul state (southern Brazil) was used in the study. The animals were randomly selected and treated orally with Drench (N= 32, propylene glycol, electrolytes and choline in 40 L of water) and water (N= 16) used as control. Blood samples were collected by blood coccygeal venipuncture through a vacutainer plain system tubes. Biochemical determinations were performed in serum (albumin, urea, cholesterol, triglycerides, non-esterified fatty acids -NEFA-, calcium, phosphorus, magnesium, aspartate transaminase -AST- and gammaglutamyl-transferase -GGT-) and a cow-side determination of beta-hydroxybutyrate (BHB) was performed using the Abbot blood Precision Xtra system. All cows in the experiment had their milk production controlled. The Drench treatment produces a tendency to a better milk yield (32.5 vs 29.6 L/cow/day) and helps to prevent subclinical ketosis, as indicated by a lesser prevalence of subclinical ketosis (29.7% vs 37.2%) and mean values of BHB (1.19 vs 1.27 mmol/L) as well as a lesser lipolysis as indicated by NEFA values (509 vs 1.560 pmol/L). The other components of the metabolic profile did not have substantial effects between treatments. In short, on the conditions of the present work, the Drench treatment is an effective management tool for prevention of subclinical ketosis and severe lipolysis.

Alguns tratamentos profiláticos têm sido propostos em vacas leiteiras de alta produção a fim de minimizar os efeitos do balanço energético negativo e alguns distúrbios como hipocalcemia e cetose. Os objetivos desse estudo foram avaliar os efeitos da administração de duas doses de Drench em até 24 h depois do parto sobre o perfil metabólico e a prevenção da cetose. Um grupo de 48 vacas de um rebanho no Rio Grande do Sul foi usado no estudo. Os animais foram selecionados aleatoriamente e tratado oralmente com Drench (N= 32, propileno-glicol, eletrólitos e colina em 40 L de água) e água (N= 16) usado como controle. Amostras de sangue foram coletadas por punção venosa coccígea, através do sistema vacutainer, em tubos sem anticoagulante. Foram realizadas determinações bioquímicas no soro (albumina, ureia, colesterol, triglicerídeos, ácidos graxos não esterificados -NEFA-, cálcio, fósforo, magnésio, aspartato aminotransferase -AST- e gama-glutamil-transferase -GGT-), e na propriedade, ao pé da vaca, foi feita a determinação do beta-hidroxibutirato (BHB) no sangue com o sistema Abbot Precision Xtra. Todas as vacas do experimento tiveram sua produção leiteira controlada. O tratamento com Drench causou tendência a uma melhor produção de leite (32.5 vs 29.6 L/vaca/dia) e ajudou a prevenir a cetose subclínica, como indicou a menor prevalência (29.7% vs 37.2%) e menores médias de BHB (1.19 vs 1.27 mmol/L) bem como menor lipólise, indicado pelos valores de NE FA (509 vs 1.560 μmol/L). Os demais componentes do perfil metabólico não tiveram efeitos substanciais entre os tratamentos. Em suma, nas condições do presente trabalho, o tratamento com Drench pode ser considerado eficaz como ferramenta para a prevenção de cetose subclínica e da lipólise severa.

Determining the Cause of Natural Death: A Case of Previously Unknown Sturge-Weber Syndrome / 대한법의학회지

In some cases, it is difficult to determine a single cause of death even after conducting full autopsy and additional tests. A 49-year-old man, reportedly having diabetes mellitus, was found unconscious by his mother and revealed to be dead. He had several contusions all over his body, including the right periocular area, but they did not appear fatal. A focal area of polymicrogyria and cortical dysplasia was found on the right preoccipital notch, accompanied with dystrophic calcification and leptomeningeal angiomatosis. These findings were considered indicative of Sturge-Weber syndrome, a rare neurocutaneous disorder, of atypical type without facial lesions. Blood level of beta-hydroxybutyrate was 859 microg/mL, implying that he also had diabetic ketoacidosis. His ketoacidosis may not have been corrected appropriately because of status epilepticus in association with brain lesion, resulting in his death, but neither direct evidence nor statement was obtained. In cases with several apparent causes of death, the examiner's assumption should be based not on imagination but on evidence, and logic should not be overlooked. It is more helpful for the investigators or the bereaved to obtain more detailed information rather than come to a hasty conclusion.

Effect of beta-Hydroxybutyrate on Flurothyl-Induced Seizure Susceptibility / 대한소아신경학회지

PURPOSE: The ketogenic diet (KD) remains a therapy in search of explanation although it is an established treatment for patients with intractable seizures. It was designed to mimic the biochemical changes seen upon fasting, specifically the formation of ketone bodies: acetoacetate (ACA), beta-hydroxybutyrate (BHB), and to a lesser extent, acetone. The present study was designed to investigate the protective effect of BHB on flurothyl-induced seizures in rats. METHODS: Thirty-four male Sprague-Dawley rats were divided into two equal groups. Experimental rats (n=17) were injected intraperitoneally with BHB (20 mmol/kg), while control animals (n=17) with normal saline. Fifteen minutes later, seizures were chemically induced by flurothyl infusion (40 mL/min). Seizure susceptibility was defined as the latency from the start of flurothyl infusion to the onset of a generalized seizure. Shorter latencies reflected greater seizure susceptibility. RESULTS: The mean (+/- SEM) latency to the onset of a generalized seizure in the experimental animals treated with BHB was 476.5 +/- 13.9 seconds, which was significantly longer (P < 0.05) than the control (438.0 +/- 10.5 seconds). CONCLUSION: This study demonstrated the significant decrease in flurothyl-induced seizure susceptibility in rats treated with BHB. Our results suggest that BHB may be directly anticonvulsant.

A Study on the Age-Dependent Ketosis Induced by the Ketogenic Diet / 대한간질학회지

PURPOSE: Ketogenic diet (KD) remains a therapy in search of explanation although it is an established treatment for patients with intractable epilepsy. It has been clinically proven more efficacious at younger ages, presumably because of the enhanced ability of the immature brain to extract and utilize ketone bodies. The study was designed to investigate whether ketosis induced by the KD is age-dependent. METHODS: A KD ([fat]:[protein+carbohydrate] ratio of 4.3:1) was administered to male Sprague-Dawley rats for 3 weeks, while control animals were fed a standard rodent chow. Dietary treatment was initiated at either postnatal 3 or 12 weeks. Blood beta-hydroxybutyrate (BHB) levels were assayed from blood obtained via the tail vein with the Keto-SiteTM reflectance meter and test cards on treatment day 21. RESULTS: Blood BHB levels in the KD-treated group were significantly higher than those in the control group in 3 week-old rats (4.18+/-0.62 [n=30] vs. 0.27+/-0.02 [n=30] mM, respectively; p0.05). CONCLUSIONS: The present study demonstrates that the KD induces more severe ketosis in younger rats. Age-dependent differences in the degree of ketosis induced by the KD may explain that the diet is clinically more efficacious at younger ages.

Effect of the Ketogenic Diet on Flurothyl-Induced Seizure Susceptibility / 대한간질학회지

PURPOSE: Despite decades of clinical experience with the ketogenic diet (KD), its efficacy and mechanisms of action have been examined in few animal studies. The present study was designed to investigate the effect of a KD on flurothyl-induced seizure susceptibility in rats. METHODS: Twenty male Sprague-Dawley rats were divided into two equal groups. Dietary treatment was initiated at P39. The experimental group was fasted for a day and then fed a KD consisting of [fat] : [protein + carbohydrate] ratio of 4.3 : 1, while the control group was fed a standard rodent chow. On treatment day 21, blood beta-hydroxybutyrate (BHB) levels were assayed and seizures were chemically induced by flurothyl (40 micro l/min). Seizure susceptibility was defined as the latency from the start of flurothyl infusion to the onset of a generalized seizure (loss of posture with bilateral hindlimb tonic extension). Shorter latencies reflect greater seizure susceptibility. RESULTS: Blood BHB levels in the KD-treated group were significantly higher than those of the control group (4.75+/-0.38 [n=10] vs. 0.19+/-0.02 [n=10] mM, respectively ; p<0.01). The latencies to the onset of a generalized seizure were 673.2+/-32.95 [n=10] and 523.0+/-31.11 [n=10] seconds for the KD-treated and control groups, respectively (p<0.01). CONCLUSION: This study demonstrates the significant decrease in the susceptibility of flurothyl-induced seizure in the KD-treated rats. Furthermore, we have established a working animal model from which future mechanistic studies can be based.

Effects of the Ketogenic Diet on Pentylenetetrazole-Induced Seizure / 대한소아신경학회지

PURPOSE: Despite decades of clinical experience with the ketogenic diet(KD), its efficacy and mechanisms of action have been examined in few animal studies. The present study was designed to investigate the effects of the KD on pentylenetetrazole(PTZ)-induced seizure severity in rats. METHODS: Thirty-eight male Sprague-Dawley rats were divided into two equal groups. Dietary treatment was initiated at P22. The KD group was fasted for a day and then fed a KD consisting of a [fat] : [protein+carbohydrate] ratio of 4.3 : 1 for 26 days, while the control group was fed a standard rodent chow. Blood beta-hydroxybutyrate(beta-OHB) levels were assayed on treatment days 0, 20, and 24. Seizures were chemically induced by intraperitoneal injection of PTZ(60mg/kg of body weight) between treatment days 22 and 27. Seizure severity was evaluated by using a scoring system of seizure behaviors : 0, no seizure; 0.5, abnormal behavior; 1, myoclonic jerk; 2, myoclonic jerk with jumping; 3, forelimb clonus with preserving righting reflex; 4, generalized clonic seizure with brief loss of righting reflex; 5, generalized tonic clonic seizure; 6, expire. A greater score represents a more severe seizure. RESULTS: Blood levels of beta-OHB were low(<0.3mM) and showed no significant differences in both groups on day 0. Rats fed the KD developed an increased level of ketosis that was significantly above the levels found in the control group on days 20 and 24 (p<0.001). The KD group(2.37+/-0.27) exhibited significantly(p<0.05) lower seizure score than the control group(3.37+/-0.35). CONCLUSION: The KD was previously reported to increase PTZ-induced seizure thresholds in rats. In our study, rats fed the KD exhibited significantly decreased PTZ-induced seizure scores relative to controls. This suggests that the KD can not only increase the resistance to seizure but also decrease the severity of seizure induced by PTZ.

FABRICATION OF BONE WITH POLY-BETA-HYDROXYBUTYRATE AND BONE MARROW STROMAL CELL EMPLOYING THE METHOD OF TISSUE ENGINEERING / 解放军医学杂志

To investigate the feasibility of using poly-beta-hydroxybutyrate as scaffolds for bone tissue engineering. Marrow stromal cells were harvested from New Zealand rabbit′s iliac bone. After being cultured and multiplied in vitro,with the use of dexamethasone to promote the osteoblastic phenotype of the cells, the cells were seeded into poly-beta-hydroxybutyrate. The cells/ poly-beta-hydroxybutyrate construction was implanted subcutaneously in nude mice. In control animals, poly-beta-hydroxybutyrate alone was implanted. Osteogenesis was assessed by histological and roentgenographic analysis. Four weeks after implantation, osteoid tissue had been observed in the specimens of the composite; 8 weeks after implantation, large amount of new bone had been found, and lamellar bone had been observed also. In the control, only fibrous tissue had been found. It suggested that poly-beta-hydroxybutyrate can be used as a scaffold material for bone tissue engineering.