Ophthalmic findings associated with Australian tick paralysis (holocyclotoxicity) in hospitalized domestic dogs and cats.

OBJECTIVE: To describe ophthalmic findings in hospitalized canine and feline patients with tick paralysis (TP) and investigate possible predisposing factors. ANIMALS STUDIED: Forty-seven dogs and 28 cats hospitalized with TP assessed with an ophthalmic examination performed by an ABVO resident. METHODS: Dogs and cats were hospitalized with TP from October 2021 to January 2022 and had an ophthalmic examination performed by an ABVO resident. Patient signalment data, information regarding tick number and location, hospitalization duration, medications used, and patient paralysis grades were recorded. Statistical analysis was performed to correlate findings. RESULTS: Corneal ulcers developed in up to 34.8% of dogs and up to 42.9% of cats hospitalized with TP. An absent palpebral reflex ipsilaterally increased the odds of a concurrent corneal ulcer being present by 14.7× in dogs and 20.1× in cats (p < .0001). Palpebral reflexes were absent in 38.3% of dogs and 35.7% of cats hospitalized with TP and were correlated with more severe gait paralysis (p = .01) and respiratory paralysis (p = .005) in dogs, and respiratory paralysis in cats (p = .041). STT-1 findings <10 mm/min were present in 27.7% of dogs and 57.1% of cats examined and were associated with increasing gait paralysis (p = .017) and respiratory paralysis (p = .007) in dogs, and increasing gait paralysis in cats (p = .017). CONCLUSIONS: Simple corneal ulcers, loss of a complete palpebral reflex, and reduced STT-1 scores frequently occurred in dogs and cats hospitalized for TP. The frequency of these findings increased as the degree of patient paralysis increased.

Retrospective assessment of ophthalmic disease development in domestic dogs and cats when hospitalised with tick paralysis caused by Ixodes holocyclus.

OBJECTIVE: To investigate the incidence and predisposing factors leading to the development of corneal ulcers and the loss of a palpebral reflex in hospitalised canine and feline patients with tick paralysis (TP). ANIMALS STUDIED: A total of 102 dogs and 100 cats retrospectively were assessed from previously hospitalised patients. METHODS: A retrospective cohort study was performed on 102 different canine and 100 different feline patients who were hospitalised for TP from October 2020-January 2022. Patient data were collected, and logistic regression was conducted to determine factors affecting the palpebral reflex and the development of corneal ulcers. RESULTS: Corneal ulcers occurred in 23/102 (22.5%) dogs during hospitalisation and were strongly associated with an incomplete palpebral reflex ipsilaterally during hospitalisation (P < 0.001), hospitalisation ≥3 days (P = 0.004), mechanical ventilation ≥3 days (P = 0.015) or a tick location cranial to C1 (P = 0.003). An incomplete palpebral reflex during hospitalisation was observed in 29/102 (28.4%) dogs and was significantly associated with decreasing patient weight (P = 0.018), increasing days hospitalised (P = 0.001), having a tick found cranial to C1 (P = 0.004), highest recorded GP grade (P = 0.01), highest recorded RP grade (P = 0.005), use of amoxycillin-clavulanic acid during hospitalisation (P = 0.002) and use of piperacillin/tazobactam during hospitalisation (P = 0.003). There was a significant association between the loss of a complete palpebral reflex and mortality during hospitalisation in dogs (OR = 4.5, P = 0.029). Corneal ulcers occurred in 10/100 (10.0%) cats during hospitalisation, and was significantly more likely to occur to an eye if an incomplete palpebral reflex was observed ipsilaterally during hospitalisation (OR = 20.1, P < 0.0001) and with increasing patient age (P = 0.019). The absence of a complete palpebral reflex during hospitalisation was observed in 18/10 (18.0%) cats and was significantly associated with increasing days hospitalised (P = 0.034). There was no significant association between the loss of a complete palpebral reflex and mortality during hospitalisation in cats. CONCLUSIONS: The frequency of corneal ulcers and loss of palpebral reflexes were significant in dogs and cats hospitalised by TP, with many factors contributing to the risk of these developing.

Feline distichiasis treated with cryoepilation: A retrospective study of 15 cats (27 eyes).

OBJECTIVE: To describe the clinical features of cats diagnosed with distichiasis and report on the outcomes following cryoepilation. ANIMALS STUDIED: Fifteen cats (27 eyes). PROCEDURES: Medical records of domestic cats with distichiasis that underwent a double freeze-thaw cycle with a -80°C cryoprobe applied to the palpebral conjunctiva, with hair then epilated were retrospectively studied. The patient signalment, distichiae locations, concurrent ocular diseases, recurrences, complications, and outcomes were recorded. RESULTS: The mean (std dev) age at the time of diagnosis and treatment was 2.2 years (2.8 years). All (15/15) cats were of the domestic shorthair (DSH) breed. Concurrent ocular findings at the initial examination were observed in 17/27 (63%) eyes, with upper lateral eyelid hypoplasia the most prevalent, present in 9/27 (33.3%) eyes. Recurrence of distichiae occurred in 8/27 (29.6%) eyes. The clinical presentation in the instances of recurrence was judged as asymptomatic and not of a clinical concern in 3/27 (11.1%) eyes, with a second procedure deemed necessary to alleviate symptoms in 5/27 (18.5%) eyes. All eyes treated with a second procedure had no recurrence of distichiae or symptoms. Complications following cryoepilation occurred in 4/27 (14.8%) eyes, with two cats developing bilateral entropion post-procedure. CONCLUSIONS: Treatment of distichiasis in cats utilizing cryoepilation was effective at alleviating symptoms, though some cats needed a second procedure. The development of post-procedural entropion was seen occasionally.

Short course of immune-suppressive doses of prednisolone, evaluated through a prospective double-masked placebo-controlled clinical trial in healthy Beagles, is associated with sustained modifications in renal, hydration, and electrolytic status.

OBJECTIVE: To investigate the effects and duration of orally administered prednisolone on renal function evaluated by glomerular filtration rate (GFR) determination and creatinine (Cr) and symmetric dimethylarginine (SDMA) concentrations as well as on urinalysis, electrolytes, and hydric status in healthy dogs. ANIMALS: 14 healthy Beagles. PROCEDURES: In this prospective double-masked placebo-controlled study, dogs were randomized after baseline evaluation to receive a 7-day course of either prednisolone (1.5 to 2.0 mg/kg, PO, q 12 h) or a placebo. A repeated-measure design was performed, each dog participating in 4 successive sampling sessions. Clinical data, systolic blood pressure, CBC, and biochemical analyses including serum SDMA concentration, GFR determination, urine output quantification, and complete urinalysis were performed for all dogs the day before (D0) and at the end of steroid administration (D7) as well as 2 weeks (D21) and 4 weeks (D35) after the end of treatment. RESULTS: At D7, when compared with baseline, GFR increased significantly in treated dogs, whereas creatinine and SDMA concentrations decreased significantly. GFR and Cr but not SDMA modifications persisted significantly at D21. None of the variables differed significantly from baseline at D35. The OR of presenting an albumin band on urine electrophoresis was 2.4 times as high in treated versus control dogs (OR, 36; 95% CI, 1.8 to 719.4; P = 0.02). CLINICAL RELEVANCE: A short-term course of immune-suppressive prednisolone treatment in healthy dogs leads to a sustained but reversible renal hyperfiltration state. Modification in electrolytic variables can affect the clinical interpretation of blood work in such patients.

Quantification of DTI in the Pediatric Spinal Cord: Application to Clinical Evaluation in a Healthy Patient Population.

BACKGROUND AND PURPOSE: The purpose of the study is to characterize diffusion tensor imaging indices in the developing spinal cord, evaluating differences based on age and cord region. Describing the progression of DTI indices in the pediatric cord increases our understanding of spinal cord development. MATERIALS AND METHODS: A retrospective analysis was performed on DTI acquired in 121 pediatric patients (mean, 8.6 years; range, 0.3-18.0 years) at Monroe Carell Jr. Children's Hospital at Vanderbilt from 2017 to 2018. Diffusion-weighted images (15 directions; b = 750 s/mm2; slice thickness, 5 mm; in-plane resolution, 1.0 × 1.0 mm2) were acquired on a 3T scanner in the cervicothoracic and/or thoracolumbar cord. Manual whole-cord segmentation was performed. Images were masked and further segmented into cervical, upper thoracic, thoracolumbar, and conus regions. Analyses of covariance were performed for each DTI-derived index to investigate how age affects diffusion across cord regions, and 95% confidence intervals were calculated across age for each derived index and region. Post hoc testing was performed to analyze regional differences. RESULTS: Analyses of covariance revealed significant correlations of age with axial diffusivity, mean diffusivity, and fractional anisotropy (all, P < .001). There were also significant differences among cord regions for axial diffusivity, radial diffusivity, mean diffusivity, and fractional anisotropy (all, P < .001). CONCLUSIONS: This research demonstrates that diffusion evolves in the pediatric spinal cord during development, dependent on both cord region and the diffusion index of interest. Future research could investigate how diffusion may be affected by common pediatric spinal pathologies.

Acute Pancreatitis Secondary to Severe Hypertriglyceridaemia in a Patient with Type 1a Glycogen Storage Disease: Emergent Use of Plasmapheresis.

Acute pancreatitis is a well-recognised complication of hypertriglyceridaemia. High serum triglycerides may develop in the autosomal recessive disorder glycogen storage disease (GSD). Plasmapheresis has been effective in reducing triglyceride levels in pancreatitis secondary to other conditions but not previously described in GSD. We describe a 16-year-old male with type 1a GSD who presented with severe abdominal pain, tachycardia and tachypnoea. Abdominal computed tomography (CT) demonstrated acute pancreatitis. Serum triglycerides were 91.8 mM. Despite intravenous fluids and morphine sulphate, he remained seriously ill, and plasmapheresis was therefore started. After daily plasma exchange for 6 days, triglyceride levels dropped to 5 mM. This was associated with a rapid resolution of pancreatitis. Plasmapheresis is effective in rapidly reducing hypertriglyceridaemia from numerous causes, including glycogen storage disease, and may facilitate recovery from acute pancreatitis.

Sodium in feline nutrition.

High sodium levels in cat food have been controversial for a long time. Nonetheless, high sodium levels are used to enhance water intake and urine volume, with the main objective of reducing the risk of urolithiasis. This article is a review of current evidence of the putative risks and benefits of high dietary sodium levels. Its secondary aim is to report a possible safe upper limit (SUL) for sodium intake. The first part of the manuscript is dedicated to sodium physiology, with a focus on the mechanisms of sodium homeostasis. In this respect, there is only few information regarding possible interactions with other minerals. Next, the authors address how sodium intake affects sodium balance; knowledge of these effects is critical to establish recommendations for sodium feed content. The authors then review the consequences of changes in sodium intake on feline health, including urolithiasis, blood pressure changes, cardiovascular alterations and kidney disease. According to recent, long-term studies, there is no evidence of any deleterious effect of dietary sodium levels as high as 740 mg/MJ metabolizable energy, which can therefore be considered the SUL based on current knowledge.

Evaluation of Cystatin C for the Detection of Chronic Kidney Disease in Cats.

BACKGROUND: Serum cystatin C (sCysC) and urinary cystatin C (uCysC) are potential biomarkers for early detection of chronic kidney disease (CKD) in cats. An in-depth clinical validation is required. OBJECTIVES: To evaluate CysC as a marker for CKD in cats and to compare assay performance of the turbidimetric assay (PETIA) with the previously validated nephelometric assay (PENIA). ANIMALS: Ninety cats were included: 49 CKD and 41 healthy cats. METHODS: Serum CysC and uCysC concentrations were prospectively evaluated in cats with CKD and healthy cats. Based on plasma exo-iohexol clearance test (PexICT), sCysC was evaluated to distinguish normal, borderline, and low GFR. Sensitivity and specificity to detect PexICT < 1.7 mL/min/kg were calculated. Serum CysC results of PENIA and PETIA were correlated with GFR. Statistical analysis was performed using general linear modeling. RESULTS: Cats with CKD had significantly higher mean ± SD sCysC (1.4 ± 0.5 mg/L) (P < .001) and uCysC/urinary creatinine (uCr) (291 ± 411 mg/mol) (P < .001) compared to healthy cats (sCysC 1.0 ± 0.3 and uCysC/uCr 0.32 ± 0.97). UCysC was detected in 35/49 CKD cats. R(2) values between GFR and sCysC or sCr were 0.39 and 0.71, respectively (sCysC or sCr = µ + GFR + Îµ). Sensitivity and specificity were 22 and 100% for sCysC and 83 and 93% for sCr. Serum CysC could not distinguish healthy from CKD cats, nor normal from borderline or low GFR, in contrast with sCr. CONCLUSION: Serum CysC is not a reliable marker of reduced GFR in cats and uCysC could not be detected in all CKD cats.

Development status of a next generation ECRIS: MARS-D at LBNL.

To demonstrate a Mixed Axial and Radial field System (MARS) as the best magnet scheme for future ECRISs, MARS-D, a demonstrative ECRIS using a NbTi MARS magnet is progressing at Lawrence Berkeley National Laboratory. An optimized MARS design can use either NbTi or Nb3Sn coils with reduced engineering complexities to construct the needed high-field magnets. The optimized magnet design could enhance MARS-D to a next generation ECRIS by producing minimum-B field maxima of 5.6 T axially and 3.2 T radially for operating frequencies up to 45 GHz. In-progress test winding has achieved a milestone demonstrating the fabrication feasibility of a MARS closed-loop coil.

Plasma exogenous creatinine clearance in clinically healthy cats: comparison with urinary exogenous creatinine clearance, tentative reference intervals and indexation to bodyweight.

Glomerular filtration rate (GFR) is considered to be the best indicator of overall kidney function. The major objectives of this study were to compare plasma exogenous creatinine clearance (PECC) with a reference method, to establish reference intervals (RIs) for PECC and to assess the effects of indexation of GFR to bodyweight (BW) in cats. PECC was compared with urinary clearance of exogenous creatinine (UECC) in six clinically healthy domestic shorthair cats (experiment 1). Tentative RIs were determined according to current guidelines and the effects of indexation to BW and of covariables on GFR were assessed in 43 clinically healthy cats of various breeds (experiment 2). PECC was 15% higher than UECC (P <0.01), but the two estimates were strongly correlated (r(2)=0.97, P = 0.001). RIs for PECC were 6.4-21.3 mL/min or 1.2-4.9 mL/min/kg. The absolute (i.e. non-indexed) GFR value was not dependent on BW. Thus, indexation of GFR to BW in cats would not standardize the GFR value, but could introduce bias in clinical interpretation. Significant effects of breed, plasma protein concentration and plasma albumin concentration on GFR were demonstrated. Plasma concentrations of urea and creatinine, when assessed separately, were also weakly correlated with GFR in healthy cats. These combined findings contribute to a better understanding of renal function assessment in cats.

Use of belatacept to maintain adequate early immunosuppression in calcineurin-mediated microangiopathic hemolysis post-renal transplant.

We report a 17-yr-old boy who developed a microangiopathic hemolytic anemia presumed secondary to tacrolimus shortly following a living-related donor renal transplant. This was initially managed by plasmapheresis. Reinstitution of calcineurin inhibition using cyclosporine led to recurrence of hemolysis, so an alternative agent was needed. He was commenced on monthly intravenous belatacept, with no further recurrence of the hemolysis, and subsequent stable graft function. Modulation via CTLA-4 offers an alternative immunosuppressive tactic if current regimens produce graft threatening adverse effects. The method of administration and frequency of dosage of belatacept also lends itself well to the high-risk period of adolescence and transition. We propose that belatacept may therefore also have utility in difficult cases complicated by poor concordance, common in the adolescent age group.

Glioma stem cells: turpis omen in nomen? (The evil in the name?).

High-grade gliomas remain incurable and lethal. Through the availability of the stem-like cells responsible for glioblastoma (GB) formation, expansion, resilience and recurrence, the discovery of glioma cancer stem cells (GCSCs) is revolutionizing this field. GCSCs provide an unprecedented opportunity to reproduce and study GB pathophysiology more accurately. This critically emphasizes our ability to unambiguously identify, isolate and investigate cells that do qualify as GCSCs, to use them as a potential model that is truly predictive of GBs and of their regulation and response to therapeutic agents. We review this concept against the background of key findings on somatic, neural and solid tumour stem cells (SCs), also taking into account the emerging phenomenon of phenotypic SC plasticity. We suggest that basic approaches in these areas can be imported into the GCSC field, so that the same functional method used to identify normal somatic SCs becomes the most appropriate to define GCSCs. This, combined with knowledge of the cellular and molecular basis of normal adult neurogenesis, promises to improve the identification of GCSCs and of selective markers, as well as the development of innovative, more specific and efficacious antiglioma strategies.

Dimensions of impulsive behavior in obese, overweight, and healthy-weight adolescents.

Impulsivity is a multidimensional construct that has been linked with obesity. To explore profiles of impulsive behavior potentially associated with adolescent weight status, we measured multiple dimensions of impulsivity (delay discounting, sustained attention, and behavioral disinhibition) using laboratory behavioral tasks in a sample of adolescents (N=61). For comparison purposes, we also assessed self-reported impulsive behavior with the BIS-11-A. Participants differed in body mass index: obese (n=21), overweight (n=20), and healthy-weight (n=20). Obese and overweight adolescents were more impulsive on the measure of delay discounting than healthy-weight adolescents, but no difference was found between obese and overweight adolescents on this measure. Obese adolescents also were more impulsive on the measure of inattention compared to overweight and healthy-weight adolescents, who did not differ on this measure. Behavioral disinhibition had no association with weight status, nor did the self-report measure of impulsivity. The additive pattern of these findings for certain laboratory behavioral measures indicates that obese adolescents are more impulsive than their healthy-weight counterparts on two dimensions of behavior, whereas overweight adolescents are more impulsive on only one dimension. Consequently, adolescents who are impulsive on two dimensions of behavior (i.e., delay discounting and sustained attention) may be at greater risk of becoming obese rather than overweight compared to adolescents who are impulsive on only one dimension of behavior (i.e., delay discounting).

Upwind impacts of ammonia from an intensive poultry unit.

This study investigated potential ammonia impacts on a sand dune nature reserve 600 m upwind of an intensive poultry unit. Ammonia concentrations and total nitrogen deposition were measured over a calendar year. A series of ammonia and nitrogen exposure experiments using dune grassland species were conducted in controlled manipulations and in the field. Ammonia emissions from the intensive poultry unit were detected up to 2.8 km upwind, contributing to exceedance of critical levels of ammonia 800 m upwind and exceedance of critical loads of nitrogen 2.8 km upwind. Emissions contributed 30% of the total N load in parts of the upwind conservation site. In the nitrogen exposure experiments, plants showed elevated tissue nitrogen contents, and responded to ammonia concentrations and nitrogen deposition loads observed in the conservation site by increasing biomass. Estimated long-term impacts suggest an increase in the soil carbon pool of 9% over a 50-year timescale.

Effects of dietary salt intake on renal function: a 2-year study in healthy aged cats.

BACKGROUND: Increasing salt intake to promote diuresis has been suggested in the management of feline lower urinary tract disease. However, high dietary salt intake might adversely affect blood pressure and renal function. OBJECTIVES: The objective of this study was to assess the long-term effects of increased salt intake on renal function in healthy aged cats. METHODS: This study was controlled, randomized, and blinded. Twenty healthy neutered cats (10.1 ± 2.4 years) were randomly allocated into 2 matched groups. One group was fed a high salt diet (3.1 g/Mcal sodium, 5.5 g/Mcal chloride) and the other a control diet of same composition except for salt content (1.0 g/Mcal sodium, 2.2 g/Mcal chloride). Clinical examination, glomerular filtration rate, blood pressure measurement, cardiac and kidney ultrasonography, and urinary and blood tests were performed before and over 24 months after diet implementation. Statistics were performed using a general linear model. RESULTS: Sixteen cats completed the 2 year study. The only variables affected by dietary salt intake were plasma aldosterone and urinary sodium/creatinine ratio, respectively, higher and lower in the control group all over the study period and urinary specific gravity, lower in the high salt diet group at 3 months. CONCLUSIONS AND CLINICAL IMPORTANCE: Glomerular filtration rate (GFR), blood pressure, and other routine clinical pathological variables in healthy aged cats were not affected by dietary salt content. The results of this 2 year study do not support the suggestion that chronic increases in dietary salt intake are harmful to renal function in older cats.

Deep brain stimulation and the role of astrocytes.

Deep brain stimulation (DBS) has emerged as a powerful surgical therapy for the management of treatment-resistant movement disorders, epilepsy and neuropsychiatric disorders. Although DBS may be clinically effective in many cases, its mode of action is still elusive. It is unclear which neural cell types are involved in the mechanism of DBS, and how high-frequency stimulation of these cells may lead to alleviation of the clinical symptoms. Neurons have commonly been a main focus in the many theories explaining the working mechanism of DBS. Recent data, however, demonstrates that astrocytes may be active players in the DBS mechanism of action. In this review article, we will discuss the potential role of reactive and neurogenic astrocytes (neural progenitors) in DBS.

Manganese in the upper Severn mid-Wales.

The concentrations of manganese (Mn) in the Upper River Severn (the Plynlimon catchments) are examined in relation to rainfall, cloud water, throughfall, stemflow and stream water concentrations where there is over 20 years of monitoring data available. Manganese concentrations are particularly low in rainfall and cloud water, with maximum concentrations occurring under low volumes of catch due to atmospheric "washout" of contaminants and dry deposition. There is strong Mn enrichment in throughfall and stemflow and this is probably linked to cycling through the vegetation. Manganese in the streams and groundwaters are primarily supplied from within-catchment sources. The highest concentrations occur within the tree canopy probably due to element cycling and in groundwaters due to mobilisation from the rock. Manganese concentrations in streams are at their lowest during spring and summer following long dry spells, with rapid increases following subsequent rain. There is no clear long-term trend in Mn concentration in the streams although there are increases in Mn concentrations for years when there is extensive felling of spruce plantation forest and in 1995 following a more extensive dry period. New high resolution monitoring picks up the effects of the rising limb of the hydrograph when concentrations rapidly increase, diurnal patterns during summer low-flow periods and contrasting dynamics between moorland and forested catchments.

Grazing intensity is a poor indicator of waterborne Escherichia coli O157 activity.

Contamination of watercourses with fecal matter represents a significant risk to public health due to the associated risk from human pathogens (e.g. Escherichia coli O157, norovirus). In addition, water contamination may also perpetuate the re-infection cycle of human pathogens within domesticated and wild animal populations. While diffuse pollution from agricultural fields has been identified as a major source of these pathogens, the relationship between livestock grazing intensity and subsequent pathogen persistence in water is not well established. Our aim was to critically evaluate the importance of land use management on the activity of E. coli O157 in freshwaters collected from a livestock dominated catchment in the UK. We inoculated replicate batches of both filter-sterilised and non-sterile freshwaters with a chromosomally lux-marked E. coli O157 and monitored pathogen survival and activity over a 5 d period. Our results indicate that the greatest risk for pathogens entering freshwater is probably associated with high intensity livestock areas, although their subsequent survival is greatest in waters from low intensity livestock areas. We ascribe this enhanced persistence in the latter to reduced competition and predation within these aquatic environments. These results have serious implications for the reliability of pathogen risk exposure maps which are based on grazing intensity alone.

A phase II trial of huperzine A in mild to moderate Alzheimer disease.

OBJECTIVE: Huperzine A is a natural cholinesterase inhibitor derived from the Chinese herb Huperzia serrata that may compare favorably in symptomatic efficacy to cholinesterase inhibitors currently in use for Alzheimer disease (AD). METHODS: We assessed the safety, tolerability, and efficacy of huperzine A in mild to moderate AD in a multicenter trial in which 210 individuals were randomized to receive placebo (n = 70) or huperzine A (200 µg BID [n = 70] or 400 µg BID [n = 70]), for at least 16 weeks, with 177 subjects completing the treatment phase. The primary analysis assessed the cognitive effects of huperzine A 200 µg BID (change in Alzheimer's Disease Assessment Scale-cognitive subscale [ADAS-Cog] at week 16 at 200 µg BID compared to placebo). Secondary analyses assessed the effect of huperzine A 400 µg BID, as well as effect on other outcomes including Mini-Mental State Examination, Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scale, Alzheimer's Disease Cooperative Study Activities of Daily Living scale, and Neuropsychiatric Inventory (NPI). RESULTS: Huperzine A 200 µg BID did not influence change in ADAS-Cog at 16 weeks. In secondary analyses, huperzine A 400 µg BID showed a 2.27-point improvement in ADAS-Cog at 11 weeks vs 0.29-point decline in the placebo group (p = 0.001), and a 1.92-point improvement vs 0.34-point improvement in the placebo arm (p = 0.07) at week 16. Changes in clinical global impression of change, NPI, and activities of daily living were not significant at either dose. CONCLUSION: The primary efficacy analysis did not show cognitive benefit with huperzine A 200 µg BID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that huperzine A 200 µg BID has no demonstrable cognitive effect in patients with mild to moderate AD.