Impact of skin hydration on patterns of microthermal injury produced by fractional CO2 laser.

OBJECTIVES: The impact of skin hydration on patterns of thermal injury produced by ablative fractional lasers (AFLs) is insufficiently examined under standardized conditions. Using skin with three different hydration levels, this study assessed the effect of hydration status on microchannel dimensions generated by a fractional CO2 laser. METHODS: A hydration model (hyperhydrated-, dehydrated- and control) was established in ex vivo porcine skin, validated by changes in surface conductance and sample mass. After, samples underwent AFL exposure using a CO2 laser (10,600 nm) at two examined pulse energies (10 and 30 mJ/mb, fixed 10% density, six repetitions per group). Histological assessment of distinct microchannels (n = 60) determined three standardized endpoints in H&E sections: (1) depth of microthermal treatment zones (MTZs), (2) depth of microscopic ablation zones (MAZs), and (3) coagulation zone (CZ) thickness. As a supplemental in vivo assessment, the same laser settings were applied to hyperhydrated- (7-h occlusion) and normohydrated forearm skin (no pretreatment) of a human volunteer. Blinded measurement of MAZ depth (n = 30) was performed using noninvasive optical coherence tomography (OCT). RESULTS: Modest differences in microchannel dimensions were shown between hyperhydrated, dehydrated and control skin at both high and low pulse energy. Compared to controls, hyperhydration led to median reductions in MTZ and MAZ depth ranging from 5% to 8% (control vs. hyperhydrated at 30 mJ/mb; 848 vs. 797 µm (p < 0.003) (MAZ); 928 vs. 856 µm (p < 0.003) (MTZ)), while 14%-16% reductions were shown in dehydrated skin (control vs. dehydrated at 30 mJ/mb; MAZ: 848 vs. 727 µm (p < 0.003); MTZ: 928 vs. 782 µm (p < 0.003)). The impact of skin hydration on CZ thickness was in contrast limited. Corresponding with ex vivo findings, hyperhydration was similarly associated with lower ablative depth in vivo skin. Thus, median MAZ depth in hydrated skin was 10% and 14% lower than in control areas at 10 and 30 mJ/mb pulse energy, respectively (10 mJ: 210 vs. 180 µm (p < 0.001); 30 mJ: 335 vs. 300 µm (p < 0.001)). CONCLUSION: Skin hydration status can exert a minimal impact on patterns of microthermal injury produced by fractional CO2 lasers, although the clinical implication in the context of laser therapy requires further study.

Cellular brain edema induced by water intoxication in rat experimental model.

OBJECTIVES: This paper presents our own rat model of the cellular brain edema, induced by water intoxication (WI). The basic principle of the model is an osmotic imbalance in the cell membrane followed by an intracellular flow of sodium and simultaneous accumulation of water leading to the subsequent increase of BBB permeability. METHODS: The usefulness of the model was tested in precisely specified conditions whose results were clearly expressed. The procedure determined both how WI induces cellular edema as well as the disturbances caused by cellular edema. RESULTS: The evidence of existing cellular edema with increased BBB permeability was proved by intracellular accumulation of intravital dye with a large molecular size; increased brain-water content was confirmed by using the dry/wet weight method and by the decrease in CT density; the elevated intracranial pressure (ICP) due to the expanding volume was determined by continuous monitoring the ICP; the structural lesions were proved by identification of the myelin disintegration; and the impaired nervous functions was demonstrated by the of open field test method. CONCLUSION: Our experimental model can help the future studies of pathophysiology of cellular brain edema and is suitable for testing neuroprotective agents.

Neuronal excitability changes depend on the time course of cellular edema induced by water intoxication in young rats.

OBJECTIVES: The aim of the study was to determine whether the functional state of neurons is affected by the duration of the induced cellular edema and by the age of animals tested. The cellular edema was induced by water intoxication and neuronal functions were tested by the standard method of electrical stimulation of neurons of the cerebral cortex. METHODS: water intoxication was induced by standard method of fractionated hyperhydration. Excitability of cortical neurons was tested by cortical stimulation with the intensity required to induce cortical afterdischarge (AD). Animals were divided into three experimental groups (B, C, D) and three control groups (AB, AC, AD). Experimental groups differed in age of water intoxication (12 or 25 days) and age of excitability testing (25 or 35 days). Changes in the duration of AD (seconds) were statistically evaluated. RESULTS: Duration of cortical afterdischarges (AD) in the control groups was at the level literature data. In all experimental groups (B, C, D), excitability of cortical neurons was markedly inhibited. AD was possible to induce only in some of the animals and its average duration was significantly shorter than in control groups. CONCLUSION: This inhibitory effect can be explained by persistent impairment of astrocyte-to-neuron communication, which plays a key role in the process of formation of structural and functional changes during cellular edema. Some of the functional manifestations of the developing edema are influenced by the age of experimental animals. At least some events of this process are not influenced by the age of experimental animals.

Assessment of brain compliance using ICP waveform analysis in water intoxication rat model.

Intracranial pressure (ICP) monitoring has been used widely for patients with intracranial hypertension. However, the data of mean ICP do not reflect various brain conditions correctly. Therefore, we performed ICP -waveform analysis to assess brain compliance. Data for ICP -waveform analysis were obtained by stereotactic intraventricle puncture. ICP waveform is expressed as a three-phase wave. Analyzed differential waveforms in a water intoxication model and continuous infusion models were evaluated respectively. In the water intoxication models, the second wave (P2) known to reflect compliance is elevated. ICP waveform analysis will be valuable for the assessment of the pathological condition of the brain.

Improved survival following cerebral edema using a novel hollow fiber-hydrogel device.

OBJECT: Cerebral edema is a significant cause of morbidity and mortality in many disease states. Current therapies of cerebral edema are often ineffective in treating severe edema. Here, the authors develop a hollow fiber-hydrogel device (HFHD) for direct surface contact-based treatment of severe cerebral edema. METHODS: Brain edema was induced in adult mice via water intoxication by intraperitoneal water administration (30% body weight). Control mice received no treatment. A distinct group of mice was treated with craniectomy but no device application (craniectomy only). A third experimental group was treated with craniectomy and HFHD application. The HFHD contained a lumen solution of 350 g/L bovine serum albumin in room-temperature artificial CSF at pH 7.4. Survival and brain water content were assessed as end points. RESULTS: Craniectomy and application of the HFHD enhanced survival in animals with severe cerebral edema. Animals treated with a craniectomy and HFHD (n = 5) survived up to 5 hours longer than animals treated with craniectomy only (n = 5) (p < 0.001) or no treatment (n = 5) (p < 0.001). Animals treated with craniectomy and HFHD (n = 5) had a survival rate of 80% within the observation period (360 minutes), whereas no animal treated with craniectomy only (n = 5) or no treatment (n = 5) survived longer than 50 and 33 minutes, respectively. Statistical significance was observed for the survival rate between the animals treated with a craniectomy + HFHD (n = 5) versus those treated with craniectomy only (n = 5) (p < 0.001), and craniectomy + HFHD versus no treatment (n = 5) (p < 0.001). Histological analysis demonstrated no significant cell loss in the cortex subjacent to HFHD application. CONCLUSIONS: Here, the authors demonstrate the feasibility of their HFHD to treat cerebral edema in this model. These results indicate that controlled water extraction from edematous brain tissue can be performed and can lead to increased survival compared with craniectomy only. Further studies remain to be performed to further optimize the HFHD and to test it in more clinically relevant models, such as traumatic brain injury.

Forensic aspects of water intoxication: four case reports and review of relevant literature.

Water intoxication (WI) is a rare condition that originates from over-consumption of water, with a potentially fatal outcome. Increased water intake (polydipsia) is followed by urination of high amount of diluted urine (polyuria) which are the main initial symptoms of WI. We present four case reports of WI. Two of them are unusual pediatric clinical cases using medical documentation and police case files, one of which is related to child abuse, and the other to a psychiatric disorder. The other two cases are fatal adult cases submitted to autopsy from a psychiatric hospital. Also, we present a diagnostic algorithm for polydipsia and polyuria before death. WI is usually seen in patients with psychiatric disorders, victims of child abuse or torture, drug abusers or it can be iatrogenically induced.

Effect of methylprednisolone on the axonal impairment accompanying cellular brain oedema induced by water intoxication in rats.

OBJECTIVES: Our previous experiments proved that methylprednisolone (MP) can significantly reduce axonal impairment accompanying extracellular oedema induced by the osmotic challenge (load) on the blood-brain barrier (BBB). The aim of the present work was to identify whether MP can affect myelin impairment accompanying intracellular oedema induced by water intoxication. METHODS: For induction of cellular brain oedema, the standard model of water intoxication was chosen. Animals received distilled water in amount corresponding to 15% of the animal's body weight. The volume was divided into three parts and administered intraperitoneally in 8 hours interval. Axonal changes were recognized as signs of myelin disintegration (oedematous distensions, axonal swelling, vesicles, varicosities) at histological sections stained with Black Gold and classified into four grades of myelin degradation. Hippocampal CA1 and CA3 areas and the dentate gyrus were selected for the study. Methylprednisolone was administered either intraperitoneally or intracarotically. Its effect was studied in two different time intervals: in the acute group (30 minutes after hyperhydration and MP application) and in chronic one (1 week after hyperhydration and MP application). RESULTS: In both the acute and chronic groups, cellular oedema induced by water intoxication brought about apparent damage of myelin (compared to control animals p<0.0001). Intracarotic injection of MP was not able to influence myelin integrity changes either in the acute or in chronic group. However, intraperitoneal administration of MP increased the level of myelin deterioration in the acute group (p 0.05), but improved myelin changes in the chronic group (p<0.005). CONCLUSION: The effect of MP on axonal impairment during cellular brain oedema induced by water intoxication differs from that during the extracellular osmotic oedema. In the extracellular oedema, cellular metabolism is not significantly affected and myelin changes can be influenced by the neuroprotective effect of MP. The primary cause of cellular oedema is a disorder of cellular metabolism and myelin impairment is one of the structural consequences of such disorder. That is why the myelin changes are not affected by MP administration in a consistent and specific manner.

Astrocyte ERK phosphorylation precedes K(+)-induced swelling but follows hypotonicity-induced swelling.

Hypotonicity following water intoxication and/or salt loss leads to mainly astrocytic brain swelling. Astrocytic swelling also occurs following brain trauma or ischemia, together with an increase in extracellular K(+) ([K(+)](o)), stimulating a bumetanide/furosemide/ethacrynic acid-inhibitable cotransporter, NKCC1, that accumulates Na(+) and K(+) together with 2 Cl(-) and osmotically obliged water. Either type of swelling may become fatal and is associated with phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2)). Only the swelling associated with elevated [K(+)](o), leads to an increase in astrocytic proliferation and in expression of the astrocytic marker, glial fibrillary acidic protein. These differences prompted us to investigate key aspects of the molecular pathways between hypotonicity-induced and high-K(+)-mediated swelling in primary cultures of mouse astrocytes. In the latter Ca(2+)-mediated, AG1478-inhibitable transactivation of the epidermal growth factor (EGF) receptor leads, via bumetanide-inhibitable activation of the mitogen activated protein (MAP) kinase pathway to ERK phosphorylation and to NKCC1-mediated swelling. In the former, inhibition of the MAP kinase pathway, but not of EGF receptor activation, abolishes ERK phosphorylation, but has no effect on swelling, indicating that activation of ERK is a result, not a cause, of the swelling.

Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling.

Aquaporin-4 (AQP4) is a water transport protein expressed in glial cell plasma membranes, including glial cell foot processes lining the blood-brain barrier. AQP4 deletion in mice reduces cytotoxic brain edema produced by different pathologies. To determine whether AQP4 is rate-limiting for brain water accumulation and whether altered AQP4 expression, as occurs in various pathologies, could have functional importance, we generated mice that overexpressed AQP4 in brain glial cells by a transgenic approach using the glial fibrillary acid protein promoter. Overexpression of AQP4 protein in brain by approximately 2.3-fold did not affect mouse survival, appearance, or behavior, nor did it affect brain anatomy or intracranial pressure (ICP). However, following acute water intoxication produced by intraperitoneal water injection, AQP4-overexpressing mice had an accelerated progression of cytotoxic brain swelling, with ICP elevation of 20 +/- 2 mmHg at 10 min, often producing brain herniation and death. In contrast, ICP elevation was 14 +/- 2 mmHg at 10 min in control mice and 9.8 +/- 2 mmHg in AQP4 knock-out mice. The deduced increase in brain water content correlated linearly with brain AQP4 protein expression. We conclude that AQP4 expression is rate-limiting for brain water accumulation, and thus, that altered AQP4 expression can be functionally significant.

Reduced anterior hippocampal formation volume in hyponatremic schizophrenic patients.

Diminished hippocampal volume occurs in the anterior segment of some schizophrenic patients, and in the posterior segment in others. The significance of hippocampal pathology in general and these segmental differences in specific is not known. Several lines of evidence suggest anterior hippocampal pathology underlies the life-threatening hyponatremia seen in a subgroup of patients with schizophrenia; therefore our goal was to determine if this region was preferentially diminished in hyponatremic patients. We studied seven polydipsic hyponatremic, ten polydipsic normonatremic, and nine nonpolydipsic normonatremic schizophrenic inpatients, as well as 12 healthy controls. All underwent structural scanning on a high resolution (3.0 T) magnetic resonance imaging (MRI) scanner. Hippocampal formation, amygdala, and third ventricle volumes were manually traced in each subject. The hippocampus was divided at the posterior extent of the uncus, and all structural volumes were corrected for whole brain volume and other significant recognized factors (i.e., age, gender, height, parental education). Despite being overhydrated, anterior hippocampal formation volume was diminished in those with polydipsia and hyponatremia relative to each of the other three groups. Third ventricle volume was larger in this group than in healthy controls but similar to the two patient groups. Posterior hippocampal and amygdala volumes did not differ between groups. Other potential confounds (e.g., water imbalance) either had no effect or accentuated these differences. We conclude the anterior hippocampal formation is smaller in hyponatremic schizophrenic patients, thereby linking an important and objective clinical feature of schizophrenia to a neural pathway that can be investigated in animal models. The findings strengthen the hypothesis that anterior hippocampal formation pathology disrupts functional connectivity with other limbic structures in schizophrenia.

Aquaporin-4 and brain edema.

Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.

Thyroid transcription factor-1 facilitates cerebrospinal fluid formation by regulating aquaporin-1 synthesis in the brain.

In the brain, aquaporin-1 (AQP-1), a water channel for high osmotic water permeability, is mainly expressed in the apical membrane of the ventricular choroid plexus and regulates formation of cerebrospinal fluid (CSF). Although the physiology of AQP-1 has been the subject of several publications, much less is known about the trans-acting factors involved in the control of AQP-1 gene expression. Here we report that TTF-1, a homeodomain-containing transcriptional regulator, is coexpressed with AQP-1 in the rat brain choroid plexus and enhances AQP-1 gene transcription by binding to conserved core TTF-1-binding motifs in the 5'-flanking region of the AQP-1 gene. Intracerebroventricular administration of an antisense TTF-1 oligodeoxynucleotide significantly decreased AQP-1 synthesis and reduced CSF formation. In addition, blockade of TTF-1 synthesis increased survival of the animals following acute water intoxication-induced brain edema. These results suggest that TTF-1 is physiologically involved in the transcriptional control of AQP-1, which is required for CSF formation.

Bilobalide prevents ischemia-induced edema formation in vitro and in vivo.

EGb761, a standardized extract of Ginkgo biloba, has neuroprotective properties in animal models of ischemia, an activity that is partially attributed to its constituent, bilobalide. EGb761 has also been reported to inhibit edema formation induced by toxins such as triethyltin. The goal of this study was to test the activity of pure bilobalide to prevent edema formation in models of ischemia. Oxygen-glucose deprivation (OGD) in rat hippocampal slices served as a model of in vitro-ischemia. OGD caused cellular edema formation as indicated by an increase of slice water contents in 30 min. Bilobalide (1-10 microM) reduced slice water contents in ischemic slices in a concentration-dependent manner. As a model of in vivo-ischemia, we performed middle cerebral artery occlusion (MCAO) in mice. Permanent MCAO caused cell death and swelling of the ischemic hemisphere within 24 h. Pretreatment of the mice with bilobalide (10 mg/kg i.p.) reduced infarct area by 43% (as judged by 2,3,5-triphenyl-tetrazolium chloride (TTC) staining) and edema formation by 70% (as judged by hemispheric enlargement). In parallel experiments, pretreatment with bilobalide also reduced forebrain water contents in the ischemic hemisphere by 57%. As an alternative model of brain edema formation, we used water intoxication to increase brain water content; bilobalide, was, however, inactive in this model. We conclude that bilobalide strongly and specifically attenuates edema formation in models of brain ischemia in vitro and in vivo. Bilobalide may be therapeutically effective in brain edema which occurs secondarily to large hemispheric stroke and traumatic brain injury in humans.

Three distinct roles of aquaporin-4 in brain function revealed by knockout mice.

Aquaporin-4 (AQP4) is expressed in astrocytes throughout the central nervous system, particularly at the blood-brain and brain-cerebrospinal fluid barriers. Phenotype analysis of transgenic mice lacking AQP4 has provided compelling evidence for involvement of AQP4 in cerebral water balance, astrocyte migration, and neural signal transduction. AQP4-null mice have reduced brain swelling and improved neurological outcome in models of (cellular) cytotoxic cerebral edema including water intoxication, focal cerebral ischemia, and bacterial meningitis. However, brain swelling and clinical outcome are worse in AQP4-null mice in models of vasogenic (fluid leak) edema including cortical freeze-injury, brain tumor, brain abscess and hydrocephalus, probably due to impaired AQP4-dependent brain water clearance. AQP4 deficiency or knock-down slows astrocyte migration in response to a chemotactic stimulus in vitro, and AQP4 deletion impairs glial scar progression following injury in vivo. AQP4-null mice also manifest reduced sound- and light-evoked potentials, and increased threshold and prolonged duration of induced seizures. Impaired K+ reuptake by astrocytes in AQP4 deficiency may account for the neural signal transduction phenotype. Based on these findings, we propose modulation of AQP4 expression or function as a novel therapeutic strategy for a variety of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury.

Rabdomiolisis de origen multifactorial en paciente con intoxicación acuosa / Rhabdomyolysis due to multifactorial causes in water intoxication patient

La rabdomiolisis es un síndrome caracterizado por necrosis muscular y liberación del contenido de las células musculares al torrente sanguíneo que presenta etiologías muy diversas, algunas sólo parcialmente explicadas. En la práctica clínica es preciso iniciar un rápido diagnóstico en aras de prevenir complicaciones tan severas como el fallo renal agudo. A continuación presentamos un caso de rabdomiolisis relacionada con el tratamiento con olanzapina (AU)

Rhabdomyolysis is a syndrome caused by injury to skeletal muscle and involves leakage of the intracellular contents into plasma. Rhabdomyolysis has many causes, some of them are more easily understood than others. The physician must be alert to the diagnosis of rhabdomyolysis and to its subtle presentation to prevent the most severe complication of acute renal failure. We report one case of rhabdomyolysis induced by treatment with olanzapine (AU)

Fatal water intoxication in a schizophrenic patient--an autopsy case.

We report a case of fatal water intoxication due to polydipsia. A 69-year-old schizophrenic male was found dead at his room of the hospital in which he had been admitted. Medico-legal autopsy was carried out to determine the cause of his death. The autopsy revealed no severe trauma leading him to the death. Internally, it was noticed that the stomach was vigorously expanded, including fluid contents. Intracardiac blood, being dark-red in color, seemed to be diluted. The both lungs ballooned aqueously, showing apparently edema. However, there was neither macroscopic nor histopathological lesion, being responsible for his death. Postmortem biochemical analyses revealed severe hyponatremia of 92 mEq/ml. In cases with short postmortem interval, serum sodium level almost similarly reflected antemortem level. According to his psychiatric doctor, he had been diagnosed as water intoxication due to polydipsia. Moreover, at 2 h before the discovery of his body, he had been found to drink much running water. It was concluded the cause of his death as fatal water intoxication.

Efficacy of clozapine in a non-schizophrenic patient with psychogenic polydipsia and central pontine myelinolysis.

Clozapine is an atypical antipsychotic drug that has been demonstrated to be a highly effective treatment for polydipsia in schizophrenic patients. The authors report the first case of a non-schizophrenic patient affected by polydipsia and central pontine myelinolysis who was successfully treated with clozapine.

Water intoxication in cattle.

Water intoxication is a condition that is common in cattle, and has also been reported in other domestic animals and man. A comprehensive description of the condition is lacking. For a better understanding of the condition, this paper reviews work that has been reported previously by various authors.

Pathological changes in calves that died from experimental water intoxication.

The pathology of calves that died from experimental water intoxication was investigated. Oedema of the brain and urinary bladder, and renal damage were significant pathological findings in these calves. The findings were attributed to positive water balance in calves suffering from water intoxication.

[Water intoxication in pulmonary tuberculosis complicated by aspergillosis]. / Vízmérgezés aspergillosissal szövödött tüdötuberculosisban.

The authors found a serum sodium level of 113 mmol/l in a 70 year old confused male patient with cachexia and fever, which level rised to 125 mmol/l as a result of hypertonic sodium chloride and furosemide therapy, resulting in improving sensorium. At the same time the urine osmolality (235 mOsm/kg) was high compared to the serum osmolality (258 mOsm/kg). The physical and radiological examination showed bilateral pneumonia. The patient died in acute circulatory insufficiency. At the autopsy miliary pulmonary tuberculosis with superinfection by aspergillosis was proved. The authors discuss the possible mechanisms of water intoxication occurring with lung diseases and the difficulties regarding the diagnosis and therapy of aspergillosis.