Diagnosis of Arboleda-Tham syndrome by whole-exome sequencing in an Asian girl with severe developmental delay.

OBJECTIVE: This study aims to report a severe phenotype of Arboleda-Tham syndrome in a 20-month-old girl, characterized by global developmental delay, distinct facial features, intellectual disability. Arboleda-Tham syndrome is known for its wide phenotypic spectrum and is associated with truncating variants in the KAT6A gene. METHODS: To diagnose this case, a combination of clinical phenotype assessment and whole-exome sequencing technology was employed. The genetic analysis involved whole-exome sequencing, followed by confirmation of the identified variant through Sanger sequencing. RESULTS: The whole-exome sequencing revealed a novel de novo frameshift mutation c.3048del (p.Leu1017Serfs*17) in the KAT6A gene, which is classified as likely pathogenic. This mutation was not found in the ClinVar and HGMD databases and was not present in her parents. The mutation leads to protein truncation or activation of nonsense-mediated mRNA degradation. The mutation is located within exon 16, potentially leading to protein truncation or activation of nonsense-mediated mRNA degradation. Protein modeling suggested that the de novo KAT6A mutation might alter hydrogen bonding and reduce protein stability, potentially damaging the protein structure and function. CONCLUSION: This study expands the understanding of the genetic basis of Arboleda-Tham syndrome, highlighting the importance of whole-exome sequencing in diagnosing cases with varied clinical presentations. The discovery of the novel KAT6A mutation adds to the spectrum of known pathogenic variants and underscores the significance of this gene in the syndrome's pathology.

Reaction of KHP with excess NaOH or TRIS as standard reactions for calibration of titration calorimeters from 0 to 60 °C.

Calibration of titration calorimeters is an ongoing problem, particularly with calorimeters with reaction vessel volumes < 10 mL in which an electrical calibration heater is positioned outside the calorimetric vessel. Consequently, a chemical reaction with a known enthalpy change must be used to accurately calibrate these calorimeters. This work proposes the use of standard solutions of potassium acid phthalate (KHP) titrated into solutions of excess sodium hydroxide (NaOH) or excess tris(hydroxymethyl)aminomethane (TRIS) as standard reactions to determine the collective accuracy of the relevant variables in a determination of the molar enthalpy change for a reaction. KHP is readily available in high purity, weighable for easy preparation of solutions with accurately known concentrations, stable in solution, not compromised by side reactions with common contaminants such as atmospheric CO2, and non-corrosive to materials used in calorimeter construction. Molar enthalpy changes for these reactions were calculated from 0 to 60 °C from reliable literature data for the pKa of KHP, the molar enthalpy change for protonation of TRIS, and the molar enthalpy change for ionization of water. The feasibility of using these reactions as enthalpic standards was tested in several calorimeters; a 50 mL CSC 4300, a 185 µL NanoITC, a 1.4 mL VP-ITC, and a TAM III with 1 mL reaction vessels. The results from the 50 mL CSC 4300, which was accurately calibrated with an electric heater, verified the accuracy of the calculated standard values for the molar enthalpy changes of the proposed reactions.

Fetal hepatic calcification in severe KAT6A (Arboleda-Tham) syndrome.

Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (KAT6A) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of KAT6A syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach. In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift KAT6A pathogenic variant, displaying a severe phenotype with previously unreported clinical features.

KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo truncating mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features including intellectual disability, developmental and speech delay, hypotonia and affects multiple organ systems. KAT6A is highly expressed in early development and plays a key role in cell-type specific differentiation. KAT6A is the enzymatic core of a histone-acetylation protein complex, however the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n=8) and control (n=14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23%(14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.

Impact of various buffers and weak bases on lysosomal and intracellular pH: Implications for infectivity of SARS-CoV-2.

Acidification of the cellular lysosome is an important factor in infection of mammalian cells by SARS-CoV-2. Therefore, raising the pH of the lysosome would theoretically be beneficial in prevention or treatment of SARS-CoV-2 infection. Sodium bicarbonate, carbicarb, and THAM are buffers that can be used clinically to provide base to patients. To examine whether these bases could raise lysosomal pH and therefore be a primary or adjunctive treatment of SARS-CoV-2 infection, we measured lysosomal and intracellular pH of mammalian cells after exposure to each of these bases. Mammalian HEK293 cells expressing RpH-LAMP1-3xFLAG, a ratiometric sensor of lysosomal luminal pH, were first exposed to Hepes which was then switched to sodium bicarbonate, carbicarb, or THAM and lysosomal pH measured. In bicarbonate buffer the mean lysosomal pH was 4.3 ± 0.1 (n = 20); p = NS versus Hepes (n = 20). The mean lysosomal pH in bicarbonate/carbonate was 4.3 ± 0.1 (n = 21) versus Hepes (n = 21), p = NS. In THAM buffer the mean lysosomal pH was 4.7 ± 0.07 (n = 20) versus Hepes (4.6 ± 0.1, n = 20), p = NS. In addition, there was no statistical difference between pHi in bicarbonate, carbicarb or THAM solutions. Using the membrane permeable base NH4Cl (5 mM), lysosomal pH increased significantly to 5.9 ± 0.1 (n = 21) compared to Hepes (4.5 ± 0.07, n = 21); p < 0.0001. Similarly, exposure to 1 mM hydroxychloroquine significantly increased the lysosomal pH to (5.9 ± 0.06, n = 20) versus Hepes (4.3 ± 0.1, n = 20), p < 0.0001. Separately steady-state pHi was measured in HEK293 cells bathed in various buffers. In bicarbonate pHi was 7.29 ± 0.02 (n = 12) versus Hepes (7.45 ± 0.03, [n = 12]), p < 0.001. In cells bathed in carbicarb pHi was 7.27 ± 0.02 (n = 5) versus Hepes (7.43 ± 0.04, [n = 5]), p < 0.01. Cells bathed in THAM had a pHi of 7.25 ± 0.03 (n = 12) versus Hepes (7.44 ± 0.03 [n = 12]), p < 0.001. In addition, there was no statistical difference in pHi in bicarbonate, carbicarb or THAM solutions. The results of these studies indicate that none of the buffers designed to provide base to patients alters lysosomal pH at the concentrations used in this study and therefore would be predicted to be of no value in the treatment of SARS-CoV-2 infection. If the goal is to raise lysosomal pH to decrease the infectivity of SARS-CoV-2, utilizing lysosomal permeable buffers at the appropriate dose that is non-toxic appears to be a useful approach to explore.

What Have We Learned from Patients Who Have Arboleda-Tham Syndrome Due to a De Novo KAT6A Pathogenic Variant with Impaired Histone Acetyltransferase Function? A Precise Clinical Description May Be Critical for Genetic Testing Approach and Final Diagnosis.

Pathogenic variants in genes are involved in histone acetylation and deacetylation resulting in congenital anomalies, with most patients displaying a neurodevelopmental disorder and dysmorphism. Arboleda-Tham syndrome caused by pathogenic variants in KAT6A (Lysine Acetyltransferase 6A; OMIM 601408) has been recently described as a new neurodevelopmental disorder. Herein, we describe a patient characterized by complex phenotype subsequently diagnosed using the clinical exome sequencing (CES) with Arboleda-Tham syndrome (ARTHS; OMIM 616268). The analysis revealed the presence of de novo pathogenic variant in KAT6A gene, a nucleotide c.3385C>T substitution that introduces a premature termination codon (p.Arg1129*). The need for straight multidisciplinary collaboration and accurate clinical description findings (bowel obstruction/megacolon/intestinal malrotation) was emphasized, together with the utility of CES in establishing an etiological basis in clinical and genetical heterogeneous conditions. Therefore, considering the phenotypic characteristics, the condition's rarity and the reviewed literature, we propose additional diagnostic criteria that could help in the development of future clinical diagnostic guidelines. This was possible thanks to objective examinations performed during the long follow-up period, which permitted scrupulous registration of phenotypic changes over time to further assess this rare disorder. Finally, given that different genetic syndromes are associated with distinct genomic DNA methylation patterns used for diagnostic testing and/or as biomarker of disease, a specific episignature for ARTHS has been identified.

Clinical manifestations and genetic analysis of a newborn with Arboleda-Tham syndrome.

Arboleda-Tham syndrome (ARTHS) is a rare disorder first characterized in 2015 and is caused by mutations in lysine (K) acetyltransferase 6A (KAT6A, a.k.a. MOZ, MYST3). Its clinical symptoms have rarely been reported in newborns from birth up to the first few months after birth. In this study, a newborn was diagnosed with ARTHS based on the clinical symptoms and a mutation c.3937G>A (p.Asp1313Asn) in KAT6A. The clinical manifestations, diagnosis, and treatment of the newborn with ARTHS were recorded during follow-up observations. The main symptoms of the proband at birth were asphyxia, involuntary breathing, low muscle tone, early feeding, movement difficulties, weak crying, weakened muscle tone of the limbs, and embrace reflex, and facial features were not obvious at birth. There was obvious developmental delay, as well as hypotonic and oro-intestinal problems in the first few months after birth. Mouse growth factor was used to nourish the brain nerves, and touching, kneading the back, passive movements of the limbs, and audio-visual stimulation were used for rehabilitation. We hope that this study expands the phenotypic spectrum of this syndrome to newborns and the library of KAT6A mutations that lead to ARTHS. Consequently, the data can be used as a basis for genetic counseling and in clinical and prenatal diagnosis for ARTHS prevention.

DMRscaler: a scale-aware method to identify regions of differential DNA methylation spanning basepair to multi-megabase features.

BACKGROUND: Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data. RESULTS: To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearson's r = 0.94) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development. CONCLUSION: Taken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.

Speech and language development and genotype-phenotype correlation in 49 individuals with KAT6A syndrome.

Pathogenic KAT6A variants cause syndromic neurodevelopmental disability. "Speech delay" is reported, yet none have examined specific speech and language features of KAT6A syndrome. Here we phenotype the communication profile of individuals with pathogenic KAT6A variants. Medical and communication data were acquired via standardized surveys and telehealth-assessment. Forty-nine individuals (25 females; aged 1;5-31;10) were recruited, most with truncating variants (44/49). Intellectual disability/developmental delay (42/45) was common, mostly moderate/severe, alongside concerns about vision (37/48), gastrointestinal function (33/48), and sleep (31/48). One-third (10/31) had a diagnosis of autism. Seventy-three percent (36/49) were minimally-verbal, relying on nonverbal behaviors to communicate. Verbal participants (13/49) displayed complex and co-occurring speech diagnoses regarding the perception/production of speech sounds, including phonological impairment (i.e., linguistic deficits) and speech apraxia (i.e., motor planning/programming deficits), which significantly impacted intelligibility. Receptive/expressive language and adaptive functioning were also severely impaired. Truncating variants in the last two exons of KAT6A were associated with poorer communication, daily-living skills, and socialization outcomes. In conclusion, severe communication difficulties are present in KAT6A syndrome, typically on a background of significant intellectual disability, vision, feeding and motor deficits, and autism in some. Most are minimally-verbal, with apparent contributions from underlying motor deficits and cognitive-linguistic impairment. Alternative/augmentative communication (AAC) approaches are required for many into adult life. Tailored AAC options should be fostered early, to accommodate the best communication outcomes.

Shrews of the Genus Chodsigoa (Soricidae, Lipotyphla) from the Pleistocene of Vietnam.

The first finds of the fossil remains of the members of the genus Chodsigoa outside China are described from the Pleistocene of northern Vietnam. They are assigned to C. caovansunga Lunde, Musser et Son, 2003 (a maxillary fragment with A3-M3, an isolated M1, and a dentary with I1 and P4-M2) from the Middle Pleistocene of the Tham Hai cave (Lang Son Province) and C. hoffmanni Chen et al., 2017 (a maxillary fragment with P4-M2) from the Upper Pleistocene of the Lang Trang cave (Thanh Hoa Province). The described specimens are the first fossil finds of these species. They indicate that representatives of the genus Chodsigoa in Vietnam spread to the south much further in the Pleistocene than today.

Effects of Tham Nasal Alkalinization on Airway Microbial Communities: A Pilot Study in Non-CF and CF Adults.

OBJECTIVES: In cystic fibrosis (CF), loss of CFTR-mediated bicarbonate secretion reduces the airway surface liquid (ASL) pH causing airway host defense defects. Aerosolized sodium bicarbonate can reverse these defects, but its effects are short-lived. Aerosolized tromethamine (THAM) also raises the ASL pH but its effects are much longer lasting. In this pilot study, we tested the hypothesis that nasally administered THAM would alter the nasal bacterial composition in adults with and without CF. METHODS: Subjects (n = 32 total) received intranasally administered normal saline or THAM followed by a wash out period prior to receiving the other treatment. Nasal bacterial cultures were obtained prior to and after each treatment period. RESULTS: At baseline, nasal swab bacterial counts were similar between non-CF and CF subjects, but CF subjects had reduced microbial diversity. Both nasal saline and THAM were well-tolerated. In non-CF subjects, nasal airway alkalinization decreased both the total bacterial density and the gram-positive bacterial species recovered. In both non-CF and CF subjects, THAM decreased the amount of Corynebacterium accolens detected, but increased the amount of Corynebacterium pseudodiphtheriticum recovered on nasal swabs. A reduction in Staphylococcus aureus nasal colonization was also found in subjects who grew C. pseudodiphtheriticum. CONCLUSIONS: This study shows that aerosolized THAM is safe and well-tolerated and that nasal airway alkalinization alters the composition of mucosal bacterial communities. CLINICAL TRIAL REGISTRATION: NCT00928135 (https://clinicaltrials.gov/ct2/show/NCT00928135).

Identification of a novel KAT6A variant in an infant presenting with facial dysmorphism and developmental delay: a case report and literature review.

BACKGROUND: Arboleda-Tham syndrome (ARTHS), caused by a pathogenic variant of KAT6A, is an autosomal dominant inherited genetic disorder characterized by various degrees of developmental delay, dysmorphic facial appearance, cardiac anomalies, and gastrointestinal problems. CASE PRESENTATION: A baby presented multiple facial deformities including a high arched and cleft palate, with philtral ridge and vermilion indentation, a prominent nasal bridge, a thin upper lip, low-set ears, an epicanthal fold, and cardiac malformations. Whole exome sequencing (WES) revealed a heterozygous nonsense mutation in exon 8 of the KAT6A gene (c.1312C>T, p.[Arg438*]) at 2 months of age. After a diagnosis of ARTHS, an expressive language delay was observed during serial assessments of developmental milestones. CONCLUSIONS: In this study, we describe a case with a novel KAT6A variant first identified in Korea. This case broadens the scope of clinical features of ARTHS and emphasizes that WES is necessary for early diagnosis in patients with dysmorphic facial appearances, developmental delay, and other congenital abnormalities.

The US military experience with THAM.

BACKGROUND: Acidosis, a part of the lethal trauma triad, occurs frequently after major combat trauma. Tris-hydroxymethyl aminomethane (THAM) has been used to effectively treat acidosis in injured casualties. No research has been conducted assessing the safety of THAM in the military combat setting. We sought to describe the US military experience with THAM administration to battlefield injury subjects. METHODS: We conducted a retrospective descriptive cohort study reviewing the trauma data from the Department of Defense Trauma Registry. US military personnel with an injury severity score greater than 15, between September 2001 and December 2014, were analyzed. Our primary outcome was the 30-day all-cause mortality among cohort treated with THAM versus those who were not. Differences between the cohort were examined using a student t-test (continuous variables), Wilcoxon Rank Sum test (ordinal variables), and chi-squared test (nominal variables). RESULTS: 4558 subjects met the inclusion criteria. 69 received THAM and 4489 did not. Casualties receiving THAM had higher mean ISS scores (33 vs. 27, p < 0.001), and required significantly higher amounts of packed red blood cells (RBCs, 37 vs. 10, p < 0.001). THAM cohort had longer ventilator and intensive care unit (ICU) days with an overall lower survival to hospital discharge. On univariable analysis, THAM was associated with lower odds of survival (OR 0.18, 95% CI 0.11-0.31) but on multivariable analysis, when controlling for confounders, THAM use was not associated with a worse odds of survival (OR 0.83, 95% CI 0.21-3.24). CONCLUSIONS: Within our combat trauma population, we were unable to detect worse 30 day mortality associated with THAM administration. Prospective investigations are needed to validate its use in critically injured combat casualties.

Responses of oral-microflora-exposed dental pulp to capping with a triple antibiotic paste or calcium hydroxide cement in mouse molars.

INTRODUCTION: Responses of oral-microflora-exposed dental pulp to a triple antibiotic paste (TAP), a mixture of ciprofloxacin, metronidazole, and minocycline in ointment with macrogol and propylene glycol, remain to be fully clarified at the cellular level. This study aimed to elucidate responses of oral-microflora-exposed dental pulp to capping with TAP in mouse molars. METHODS: A cavity was prepared on the first molars of 6-week-old mice to expose the dental pulp for 24 h. The exposed pulp was capped with TAP (TAP group) or calcium hydroxide cement (CH group), in addition to the combination of macrogol (M) and propylene glycol (P) (MP, control group), followed by a glass ionomer cement filling. The samples were collected at intervals of 1, 2, and 3 weeks, and immunohistochemistry for nestin and Ki-67 and deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL) assay were performed in addition to quantitative real-time polymerase chain reaction (qRT-PCR) analyses. RESULTS: The highest occurrence rate of pulp necrosis was found in the control group followed by the CH group at Weeks 2 and 3, whereas the highest occurrence rate of healed areas in the dental pulp was observed in the TAP group at each time point. Tertiary dentin formation was first observed in the dental pulp of the TAP group at Week 2. In contrast, bone-like and/or fibrous tissues were frequently observed in the CH group. qRT-PCR analyses clarified that TAP activated the stem and dendritic cells at Weeks 1 and 2, respectively. CONCLUSIONS: The use of TAP as a pulp-capping agent improved the healing process of oral-microflora-exposed dental pulp in mouse molars.

Hydrogen bond-assisted synthesis of MoS2/reduced graphene oxide composite with excellent electrochemical performances for lithium and sodium storage.

MoS2/reduced graphene oxide composites (MoS2/rGO) were successfully prepared by a designed tris(hydroxymethyl)methyl aminomethane (named THAM)-assisted hydrothermal method, which involves the modification of THAM on the surfaces of graphene oxide via hydrogen bonds and then the adsorption of MoO42- on the decorated surfaces due to the electrostatic attraction. The three-dimensional framework of interconnected rGO nanosheets provides good electronic conductivity and facile strain release during the electrochemical reaction, thus enhancing the overall performance of the MoS2-based electrode. Herein, the composite delivers high specific capacity, excellent cycling stability and rate performance for lithium- and sodium- ions batteries (LIBs and SIBs). The MoS2/rGO anode exhibits capacities of 880 mAh g-1 at 1 A g-1 after 200 cycles and 396 mAh g-1 even at 2 A g-1 after 2000 cycles for LIBs. As to SIBs, the reversible capacities of 485 mAh g-1 and 339 mAh g-1 can be retained at 0.1 A g-1 after 60 cycles and 0.5 A g-1 after 300 cycles, respectively. Our results demonstrate that the MoS2/rGO anode is one of the attractive anodes for LIBs and SIBs. Furthermore, the facile method can be extended to biosensing, catalytic, and biomedical applications.

Liquid extracorporeal carbon dioxide removal: use of THAM (tris-hydroxymethyl aminomethane) coupled to hemofiltration to control hypercapnic acidosis in a porcine model of protective mechanical ventilation.

A promising approach to facilitate protective mechanical ventilation is the use of extracorporeal CO2 removal techniques. Several strategies based on membrane gas exchangers have been developed. However, these techniques are still poorly available. The goal of this study was to assess the efficacy and safety of THAM infusion coupled to hemofiltration for the management of hypercapnic acidosis. A severe respiratory acidosis was induced in seven anesthetized pigs. Five of them were treated with THAM 8-mmol·kg(-1)·h(-1) coupled to hemofiltration (THAM+HF group) at 100 mL·kg(-1)·h(-1). After 18-hours of treatment the THAM infusion was stopped but hemofiltration was kept on until 24-hours. The 2 other animals were treated with THAM but without hemofiltration. After 1-hour of treatment in THAM+HF, PaCO2 rapidly decreased from a median of 89.0 (IQR) (80.0, 98.0) to 71.3 (65.8, 82.0) mmHg (P<0.05), while pH increased from 7.12 (7.01, 7.15) to 7.29 (7.27, 7.30) (P<0.05). Thereafter PaCO2 remained stable between 60-70 mmHg, while pH increased above 7.4. After stopping THAM at 18 hours of treatment a profound rebound effect was observed with severe hypercapnic acidosis. The most important side effect we observed was hyperosmolality, which reached a maximum of 330 (328, 332) mOsm·kg H2O(-1) at T18. The animals treated only with THAM developed severe hypercapnia, despite the fact that pH returned to normal values, and died after 12 hours. Control-group had an uneven evolution until the end of the experiment. A combined treatment with THAM coupled to hemofiltration may be an effective treatment to control severe hypercapnic acidosis.

Lactic Acidosis: Current Treatments and Future Directions.

Mortality rates associated with severe lactic acidosis (blood pH<7.2) due to sepsis or low-flow states are high. Eliminating the triggering conditions remains the most effective therapy. Although recommended by some, administration of sodium bicarbonate does not improve cardiovascular function or reduce mortality. This failure has been attributed to both reduction in serum calcium concentration and generation of excess carbon dioxide with intracellular acidification. In animal studies, hyperventilation and infusion of calcium during sodium bicarbonate administration improves cardiovascular function, suggesting that this approach could allow expression of the positive aspects of sodium bicarbonate. Other buffers, such as THAM or Carbicarb, or dialysis might also provide base with fewer untoward effects. Examination of these therapies in humans is warranted. The cellular injury associated with lactic acidosis is partly due to activation of NHE1, a cell-membrane Na(+)/H(+) exchanger. In animal studies, selective NHE1 inhibitors improve cardiovascular function, ameliorate lactic acidosis, and reduce mortality, supporting future research into their possible use in humans. Two main mechanisms contribute to lactic acid accumulation in sepsis and low-flow states: tissue hypoxia and epinephrine-induced stimulation of aerobic glycolysis. Targeting these mechanisms could allow for more specific therapy. This Acid-Base and Electrolyte Teaching Case presents a patient with acute lactic acidosis and describes current and future approaches to treatment.

Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca(2+) influx through transient receptor potential V1 (TRPV1) channels.

Non-selective transient receptor potential vanilloid (TRPV) cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM) is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1) and the Ca(2+)-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 µM) and pH 6.5 buffer elicited steep increases in the intracellular Ca(2+) concentration ([Ca(2+)]i), while treatment with THAM (pH 8.5) alone had no effect. However, treatment with THAM (pH 8.5) following capsaicin application elicited a profound, long-lasting increase in [Ca(2+)]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre-activation is required to provoke enhanced, THAM-induced [Ca(2+)]i increases, which could be a mechanism underlying pain induced by basic pH.

Enthalpies of Reaction of Tris(hydroxymethyl)aminomethane in HCl(aq) and in NaOH(aq).

The enthalpy of reaction of tris(hydroxymethyl)aminomethane, NBS Standard Reference Material 724a, measured in an adiabatic solution calorimeter at 298.15 K in 0.1 N HCl solution is -245.76 ±0.26 J · g-1, and in 0.0500 N NaOH solution is 141.80 ± 0.19 J · g-1. The conditions applicable and the factors included in the overall uncertainties are discussed in detail. For the reaction in 0.1 N HCl in the range, 293 to 303 K, ΔCp = 1.435 ± 0.023 J · g-1 · K-1, and in 0.0500 N NaOH in the range, 295 to 303 K, ΔCp = 1.025 ± 0.025 J · g-1 · K-1. Possible sources of error in measurements of the reactions are discussed. A summary of other enthalpy measurements of the reaction in 0.1 N HCl is given.