Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy.

BACKGROUND: Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19. METHODS: First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients' livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15ile-/-) to determine the effects of FGF15 deficiency on improving the metabolic effects. RESULTS: SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15ile-/- mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis. CONCLUSIONS: FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.

Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction.

The long non-coding RNA (lncRNA) hepatocyte nuclear factor-1 alpha (HNF1A) antisense RNA 1 (HNF1A-AS1) is an important lncRNA for liver growth, development, cell differentiation, and drug metabolism. Like many lncRNAs, HNF1A-AS1 has multiple annotated alternative transcripts in the human genome. Several fundamental biological questions are still not solved: (1) How many transcripts really exist in biological samples, such as liver samples and liver cell lines? (2) What are the expression patterns of different alternative HNF1A-AS1 transcripts at different conditions, including during cell growth and development, after exposure to xenobiotics (such as drugs), and in disease conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD) cirrhosis, and obesity? (3) Does the siRNA used in previous studies knock down one or multiple transcripts? (4) Do different transcripts have the same or different functions for gene regulation? The presented data confirm the existence of several annotated HNF1A-AS1 transcripts in liver samples and cell lines, but also identify some new transcripts, which are not annotated in the Ensembl genome database. Expression patterns of the identified HNF1A-AS1 transcripts are highly correlated with the cell differentiation of matured hepatocyte-like cells from human embryonic stem cells (hESC), growth and differentiation of HepaRG cells, in response to rifampicin induction, and in various liver disease conditions. The expression levels of the HNF1A-AS1 transcripts are also highly correlated to the expression of cytochrome P450 enzymes, such as CYP3A4, during HepaRG growth, differentiation, and in response to rifampicin induction.

Relationship between Body Composition and Serum Immunoglobulin Concentrations after Administration of Intravenous Immune Globulin-Preclinical and Clinical Evidence.

The purpose of this study was to investigate the effect of obesity on immunoglobulin G (IgG) pharmacokinetics in a rat model of obesity, and to collect clinical evidence for an association between the body composition and intravenous immune globulin (IVIG) pharmacokinetic parameters in humans. In a preclinical study, pharmacokinetics of human IgG was evaluated after intravenous (IV) and subcutaneous (SC) delivery to obese and lean rats (n = 6 in each group). Serial serum samples were analyzed using an ELISA. The animal body composition was assessed using computer tomography. Patients with primary immunodeficiency currently managed with IVIG, and at a steady state, were enrolled in the clinical study (n = 8). Serum immune globulin (Ig) concentrations were measured at baseline and immediately after the administration of two consecutive treatments, with an additional measurement at two weeks after the first administration. In addition to the patient demographic and clinical characteristics, body composition was measured using bioelectrical impedance analysis. The pharmacokinetics of human IgG was significantly different between the obese and lean rats after both the IV and SC administration of 0.5 g/kg. Furthermore, a significant difference in endogenous rat IgG was observed between the two strains. In the human study, total serum IgG and subtype (IgG1, IgG2, IgG3, IgG4) half-life negatively correlated with the body mass index and fat mass. The mean change in the total serum IgG concentration was significantly correlated to body mass index and fat mass. The results of the studies corroborated one another. In the animal study, most pharmacokinetic parameters of human IgG following IV and SC administration were significantly affected by obesity and changes in the body composition. In the clinical study, the mean serum IgG change after the IVIG administration strongly correlated to the BMI and body fat mass. Future studies are needed to establish the outcomes achieved with more frequent dosing in obese individuals with primary immunodeficiency.

Pharmacokinetics and Pharmacodynamics of Anthocyanins after Administration of Tart Cherry Juice to Individuals with Gout.

SCOPE: Tart cherries (TCs) contain high levels of anthocyanins that exert potent antioxidant and antiinflammatory effects and potentially benefit individuals with gout. METHODS AND RESULTS: This study aims to quantitate the major anthocyanins in TC Juice Concentrate (TCJC) and identify the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the major anthocyanin cyanidin-3-glucosylrutinoside (C3GR). A PK-PD study enrolling human subjects with a history of gout is performed. Subjects are randomized to receive either 60 or 120 mL of TCJC. Anthocyanins are quantitated using liquid chromatography-mass spectroscopy (LCMS). Antioxidant and antiinflammatory mRNA expression is measured using real-time qPCR before and after the administration of TCJC. A population PK model (popPK) is fit to the experimental data, and an indirect PD model (IDR) is constructed in Monolix. CONCLUSION: Of the bioavailable anthocyanins, C3GR achieves the highest plasma concentration in a dose-dependent manner. A popPK predicts anthocyanin exposure, and an IDR produces reasonable approximations of PD effects.

Simulated large joint fluid model for evaluating intra-articular antibiotic delivery systems: initial evaluation using antibiotic-loaded calcium sulfate beads.

Introduction: Local antimicrobial delivery via calcium sulfate (CaSO 4 ) beads is used as an adjunctive treatment for periprosthetic joint infection. There is limited clinical information describing the performance of antimicrobial-loaded CaSO 4 (ALCS) in large-scale applications. We developed a simulated large joint model to study properties of eluting ALCS. Methods: The in vitro testing platform was an adapted standardized model for tribological testing of prosthetic total hips and total knees (ASTM F732). The model was 70 mL total fluid volume, 25 % bovine serum, and 75 % phosphate-buffered saline, using ISO standard 14242-1 for human synovial fluid simulation. Four brands of CaSO 4 were evaluated. Each 10 mL of CaSO 4 was loaded with 1.2 grams (g) of tobramycin and 1 g of vancomycin powders. A 35 mL bead volume, equaling 175 beads, of each product was placed in incubated flasks. The test period was 6 weeks with scheduled interval fluid exchanges. Fluid samples were tested for antibiotic and calcium concentrations and pH. Results: Antibiotic elution showed an initial burst on Day 1, followed by a logarithmic reduction over 1 week. Tobramycin fully eluted within 2.5 weeks. Vancomycin showed sustained release over 6 weeks. Calcium ion concentrations were high, with gradual decrease after 3 weeks. All four CaSO 4 products were inherently acidic. Fluid became more acidic with the addition of antibiotics primarily driven by vancomycin. Discussion: Clinicians should be cognizant of tobramycin elution burst with ALCS in large loads. The main driver of acidic pH levels was vancomycin. We propose that joint complications may result from lowered fluid acidity, and we suggest clinical study of synovial pH.

A validated LC-MS/MS method for the quantitation of cefazolin in human adipose tissue: Application of EMR-Lipid sorbent as an efficient sample clean-up before mass spectrometric analyses.

A novel, simple, rapid, and sensitive high-performance liquid chromatography-tandem mass spectrometry method was developed to determine cefazolin concentrations in human adipose tissue. Sample preparation was performed by protein precipitation followed by using Captiva EMR-Lipid plates. The mobile phase consisted of 5 mM ammonium formate and 0.1% formic acid in water and 0.1% formic acid in ACN, and was pumped through a Synergi Fusion-RP column with a gradient elution program at a flow rate of 0.3 mL/min. The mass spectrometer was operated in a positive ion mode. Cloxacillin was used as an internal standard due to the observed cross-signal contribution between cefazolin and 13C2,15N-cefazolin. The method was validated according to the FDA and EMA guidelines and passed all the acceptance criteria. The calibration range was 0.05-50 µg/mL in adipose tissue homogenate (0.15-150 µg/g in adipose tissue), precision CV < 4.5%, accuracy within 93.1-100.4%. The carry-over was negligible, recovery of the method was high, and no significant matrix effect was present. Rat subcutaneous adipose tissue was demonstrated to be a suitable surrogate matrix for human adipose tissue. The validated method was successfully applied in a pilot pharmacokinetic study and will further be used in a large cohort of non-obese and obese patients dosed prophylactically with cefazolin before surgeries.

Fabrication of antibiotic-loaded dissolvable calcium sulfate beads: an in vitro mixing lab utilizing various antibiotic mixing formulas.

Chronic periprosthetic joint infection (PJI) is a devastating complication that requires an aggressive eradication protocol. Local antimicrobial delivery via dissolvable calcium sulfate (CaSO 4 ) using small-sized beads (3-8 mm) has been utilized as an adjunctive treatment combined with implant exchange, radical debridement, and antimicrobial loaded acrylic spacers. The non-exothermic setting of CaSO 4 theoretically allows for any antimicrobial agent to be used, so long as mixing methods provide a consistent fabrication within a reasonable set time. This study performed the first in vitro mixing study, in which various antimicrobial agents, used singularly and in combination, were mixed with a synthetic CaSO 4 product to observe and document their interactions. The study was performed in a simulated operating room environment. We report a standard mix formula with set times, testing 22 different antimicrobial agents, combinations, and doses. For some antimicrobials and combinations, set times using the standard formula were either too fast or exceedingly slow. For these 14 antimicrobial agents and combinations, we were able to arrive at individualized mixing methods. We present all mixing formulas and set times. In all, we were able to establish mixing methods that incorporate all antimicrobial agents and combinations that we have seen utilized via surgeon-directed use.

Difficult Revision Total Hip Arthroplasty Cases Treated with an Offset Head Center Acetabular Shell.

Acetabular bone loss is common during revision total hip arthroplasty (THA). A new acetabular shell was developed with a goal of maintaining native hip center-of-rotation (COR) while achieving good fixation with standard instrumentation and technique. Previous radiographic studies have demonstrated the efficacy of this shell in lowering hip COR. In this case series, we demonstrate the use of this shell in patients undergoing difficult revision THAs. Based on these cases, we have presented how this offset COR acetabular shell may help bring down the hip COR in patients who undergo revision total hip arthroplasty with severe bone loss.

Use of an offset head center acetabular shell in difficult primary total hip arthroplasties.

Several conditions may predispose patients to development of antero-lateral acetabular bone deficiency, including developmental dysplasia of the hip, osteonecrosis, or septic arthritis, among others. This may compromise the ability to gain acetabular component stability and impair reliable fixation. Large acetabular shells have often been used to achieve adequate fixation in scenarios of severe bone loss, however, these techniques have been shown to elevate the center of rotation (COR) of the hip and alter hip biomechanics. Recently, a new acetabular shell was developed with a goal of maintaining the native hip COR while achieving good fixation with standard instrumentation and technique. Previous radiographic studies have demonstrated the efficacy of this shell in lowering hip COR. In this case series, we demonstrate the use of this shell in patients with difficult hip pathologies. We have demonstrated how this offset COR acetabular shell may help bring down the COR of the hip in these quite challenging cases utilizing conventional techniques.

Pharmacokinetics, Pharmacodynamics, and PKPD Modeling of Curcumin in Regulating Antioxidant and Epigenetic Gene Expression in Healthy Human Volunteers.

Curcumin is a major component of the spice turmeric ( Curcuma longa), often used in food or as a dietary supplement. Many preclinical studies on curcumin suggest health benefits in many diseases due to its antioxidant/anti-inflammatory and epigenetic effects. The few human studies and curcumin's unfavorable pharmacokinetics (PK) have limited its potential, leading researchers to study and develop formulations to improve its PK. The purpose of this clinical study is to describe the acute pharmacokinetics and pharmacodynamics (PK/PD) of commercially marketed curcumin in normal, healthy human volunteers. Twelve volunteers received a 4 g dose of curcumin capsules with a standard breakfast. Plasma samples were collected at specified time points and analyzed for curcumin and its glucuronide levels. RNA was extracted from leukocytes and analyzed for expression of select antioxidant and epigenetic histone deacetylase (HDAC) genes. Plasma levels of parent curcumin were below the detection limit by HPLC-ITMS/MS/MS. However, curcumin-O-glucuronide (COG), a major metabolite of curcumin, was detected as soon as 30 min. These observations of little to no curcumin and some levels of metabolite are in line with previous studies. PD marker antioxidant genes NRF2, HO-1, and NQO1 and epigenetic genes HDAC1, HDAC2, HDAC3, and HDAC4 were quantified by qPCR. COG PK is well-described by a one-compartment model, and the PK/PD of COG and its effect on antioxidant and epigenetic gene expression are captured by an indirect response model (IDR). A structural population PK model was sequentially established using a nonlinear mixed-effect model program (Monolix Lixoft, Orsay, France). Physiologically based pharmacokinetic modeling (PBPK) and simulation using Simcyp correlated well with the observed data. Taken together, these results show that the bioavailability of the parent curcumin compound is low, and oral administration of curcumin can still deliver detectable levels of curcumin glucuronide metabolite. But most importantly, it elicits antioxidant and epigenetic effects which could contribute to the overall health beneficial effects of curcumin.

Anticoagulant activity of enoxaparin and unfractionated heparin for venous thromboembolism prophylaxis in obese patients undergoing sleeve gastrectomy.

BACKGROUND: One risk of bariatric surgery is venous thromboembolism and the optimal strategy to reduce risk requires further clarification. OBJECTIVES: The objectives of this study were to identify antiXa goal attainment with the institutional standard chemoprophylaxis, analyze discordance between antiXa and thrombin generation assay (TGA) in terms of adequacy of anticoagulation, and to identify correlations between patient characteristics or covariates and markers of coagulation status. SETTING: Large academic medical center in Northeastern United States. METHODS: A total of 60 sleeve gastrectomy patients were enrolled in this institutional review board-approved, prospective cohort study. Patients received the institutional standard prophylactic therapy (subcutaneous enoxaparin 40 mg twice daily or unfractionated heparin [UFH]). The UFH dose was weight based, 5000 units (<120 kg) or 7500 units (≥120 kg) every 8 hours. Various measures of coagulation status were measured at or near steady state. RESULTS: Patients receiving enoxaparin achieved goal antiXa more frequently compared with the UFH group, and statistical significance was demonstrated (93.8 % versus 4.5%, respectively; P < .0001). Target endogenous thrombin potential reduction from baseline was more frequently obtained in the enoxaparin group versus UFH (50% versus 27.7%, respectively; P = .12). AntiXa was below the limit of detection for the majority of UFH patients; while TGA suggested patients did experience anticoagulation at some level of effectiveness. Endogenous thrombin potential change in the enoxaparin group was correlated to several measures of body composition. CONCLUSIONS: Patients receiving enoxaparin achieved goal antiXa more often versus UFH. There was discordance between antiXa and TGA-based assessment of coagulation status. TGA may provide a more robust assessment of the adequacy of chemoprophylaxis.

Indications, complications and outcomes of inferior vena cava filters: A retrospective study.

INTRODUCTION: Inferior vena cava filters are used to prevent embolization of a lower extremity deep vein thrombosis when the risk of pulmonary embolism is thought to be high. However, evidence is lacking for their benefit and guidelines differ on the recommended indications for filter insertion. The study aim was to determine the reasons for inferior vena cava filter placement and subsequent complication rate. MATERIALS AND METHODS: A retrospective cohort of patients receiving inferior vena cava filters in Edmonton, Alberta, Canada from 2007 to 2011. Main outcome was the indication of inferior vena cava filter insertion. Other measures include baseline demographic and medical history of patients, clinical outcomes and filter retrieval rates. RESULTS: 464 patients received inferior vena cava filters. An acute deep vein thrombosis with a contraindication to anticoagulation was the indication for 206 (44.4%) filter insertions. No contraindication to anticoagulation could be identified in 20.7% of filter placements. 30.6% were placed in those with active cancer, in which mortality was significantly higher. Only 38.9% of retrievable filters were successfully retrieved. CONCLUSIONS: Inferior vena cava filters were placed frequently in patients with weak or no guideline-supported indications for filter placement and in up to 20% of patients with no contraindication to anticoagulation. The high rates of cancer and the high mortality rate of the cohort raise the possibility that some filters are placed inappropriately in end of life settings.

Three-Dimensional and Conventional Carotid Ultrasound for Assessment of Carotid Plaque in a Stroke Patient: A Simple Way to Validate Findings.

Single-sweep automated 3-D ultrasound is a new imaging modality for the assessment of carotid plaque. Its most important application is the measurement of the plaque volume. To our knowledge, to date there is not a widely accepted "gold standard" to validate 3-D plaque volume measurement. We compared the findings of 2-dimensional and 3-D carotid ultrasound imaging with those of postsurgical plaque specimen using a simple method.

Novel oral anticoagulant management issues for the stroke clinician.

BACKGROUND: Four nonvitamin K antagonist oral anticoagulants (NOACs) are approved for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). AIMS: In this review, we assemble available evidence for the best management of ischemic and hemorrhagic stroke patients in the context of NOAC use. SUMMARY OF REVIEW: NOACs provide predictable anticoagulation with fixed dosages. The direct thrombin inhibitor dabigatran and direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban are all noninferior to warfarin for the prevention of ischemic stroke and systemic embolism and are associated with reduced incidence of intracranial hemorrhage. While these agents offer treatment options for NVAF patients, they also present challenges specific to the clinician managing cerebrovascular disease patients. CONCLUSIONS: We summarize available evidence and current approaches to the initiation, dosing, monitoring and potential reversal of NOACs in stroke patients.

Concomitant Posterior Hip Dislocation, Ipsilateral Intertrochanteric- and Proximal Tibial- Fractures with Popliteal Artery Injury: A Challenging Trauma Mélange.

Constellation of ipsilateral posterior hip dislocation, intertrochanteric- and proximal tibial fracture with popliteal artery injury is rare. Management of this presentation is challenging. A motor vehicle accident victim presented with these injuries, but without any initial signs of vascular compromise. Popliteal artery injury was diagnosed intra-operatively and repaired. This was followed by external fixation of tibial fracture, open reduction of dislocated hip and internal fixation of intertrochanteric fracture. Patient regained bilateral complete weight bearing and returned to pre-accident activity level. Apt surgical management including early repair of vascular injury in such a trauma mélange allows for a positive postoperative outcome.

Does femoral neck to cup impingement affect metal ion levels in hip resurfacing?

BACKGROUND: Impingement of the femoral neck with the acetabular component after metal-on-metal hip resurfacing arthroplasty (HRA) is a possible cause of edge loading and accelerated bearing wear. No attempt has been made to correlate radiographic impingement signs and blood metal ion levels. QUESTIONS/PURPOSES: We (1) compared serum cobalt (CoS) and chromium (CrS) concentrations between patients with and without radiographic impingement signs treated with unilateral HRA, (2) determined whether divot depth on the femoral neck correlated with CoS and CrS, and (3) assessed the predictive value of radiographic impingement signs for high levels of CoS and CrS. METHODS: A retrospective radiographic review of 141 patients with CoS and CrS analyses yielded 21 patients with and 120 without radiographic impingement signs (controls). Radiographic measurements included divot depth and orientation of the acetabular component to compute the contact patch to rim distance, a measure of functional head coverage. We defined a patient as having radiographic impingement signs if a remodeling of the femoral neck cortex showed a depression matching the predicted path of an impinging acetabular component. CoS and CrS were analyzed by inductively coupled plasma mass spectrometry and the radiographs were taken within 12 months of the last blood draw. RESULTS: Median CoS and CrS were greater in the impingement group than in controls in patients with less than 10-mm contact patch to rim distances. Divot depth did not correlate with CoS or CrS. In predicting elevated ion levels (≥ 7 µg/L), the presence of a radiographic impingement sign showed a sensitivity of 50% for CoS and 33% for CrS and a specificity of 87% for both CoS and CrS. CONCLUSIONS: Radiographic impingement signs influenced CoS and CrS only when the functional head coverage was insufficient due to poor socket positioning. Radiographic impingement signs alone were not a good predictor of elevated metal ion levels.

Late-onset radial nerve palsy associated with conservatively managed humeral fracture. A case report and suggested classification system.

Radial nerve palsy can occur with humerus fracture, either at the time of injury (primary) or during reduction (secondary). Late-onset radial nerve palsy (not immediately related to injury or reduction) has been very seldom reported in the English literature. We describe a case of late-onset radial nerve palsy, which developed 9 weeks after an attempted closed management of a midshaft humerus fracture. Exploration of the nerve was performed. The radial nerve was found to be stretched over the ends of the fracture. Open reduction and external fixation of the fracture with mobilization of the nerve from the fracture site lead to complete return of radial nerve function occurring by 3 months. We recommend exploration of cases of late-onset radial nerve palsy in contrast to primary or secondary radial nerve palsy, which can be treated conservatively. Our experience suggests that the cause of the palsy is a continuous ongoing pathology and not a single time event as in primary or secondary cases. Radial nerve palsies associated with humeral fracture should be classified as either primary (at the time of injury), secondary (at the time of reduction), or late onset (not related to either injury or reduction).

Computed tomography of normal distal tibiofibular syndesmosis.

OBJECTIVE: The purpose of this study was to determine the shape and measurements of the normal distal tibiofibular syndesmosis on computed tomographic scans and to identify features that could aid in the diagnosis of syndesmotic diastasis using computed tomography (CT). MATERIALS AND METHODS: CT scans of 100 patients with normal distal tibiofibular syndesmoses were reviewed retrospectively. In 67% the incisura fibularis was deep, giving the syndesmosis a crescent shape. In 33% the incisura fibularis was shallow, giving the syndesmosis a rectangular shape. The measurements of both types were taken using the same reference points. RESULTS: The mean age of the patients was 40 years, and there were 53 men and 47 women. The mean width of the distal tibiofibular syndesmosis anteriorly between the tip of the anterior tibial tubercle and the nearest point of the fibula was 2 mm. The mean width of the distal tibiofibular syndesmosis posteriorly between the medial border of the fibula and the nearest point of the lateral border of the posterior tibial tubercle was 4 mm. In men the mean width of the distal tibiofibular syndesmosis, anterior and posterior, was 2 mm and 5 mm, respectively, and in women it was 2 mm and 4 mm, respectively. CONCLUSION: This study provides measurements of the normal tibiofibular syndesmosis to aid in the diagnosis of occult diastasis.

D-Lactic acid-induced neurotoxicity in a calf model.

Lactic acidosis (DAC) occurs as a complication of short-bowel syndrome in humans and in a variety of other gastrointestinal disorders in monogastrics and ruminants. DAC is associated with signs of impaired central nervous system (CNS) function including ataxia and coma. The objective of this experiment was to determine whether either acidification of nervous tissue or d-lactic acid is responsible for decreased neurological function. Eight Holstein calves (32 +/- 11 days, 70 +/- 10 kg) were surgically catheterized with indwelling intravenous jugular and atlanto-occipital space cerebrospinal fluid (CSF) catheters and infused for 6 h in random order with isomolar dl-lactic acid (dl-LA), l-lactic acid (l-LA), hydrochloric acid (HCl), or saline. dl-LA induced ataxia after 4 h of infusion and produced the greatest obtunding of CNS function (at 7 h, score 8.0 +/- 0.4), whereas the other infusions caused neither ataxia nor scores over 1.5 (P < 0.01 from dl-LA). dl-LA induced significantly less acidemia than HCl (at 6 h pH 7.13 +/- 0.06 and 7.00 +/- 0.04, base excess -16 +/- 1 and -23 +/- 3 mmol/l, bicarbonate 11 +/- 1 and 8 +/- 1 mmol/l respectively, all P < 0.01) but greater than l-LA and saline (P < 0.01). CSF changes followed a similar but less pronounced pattern. Although HCl infusion produced a severe acidemia and CSF acidosis, only minor effects on neurological function were evident suggesting that d-lactate has a direct neurotoxic effect that is independent of acidosis. Conversely, l-LA produced only minor neurological changes.