Comparable outcomes of outpatient remdesivir and sotrovimab among high-risk patients with mild to moderate COVID-19 during the omicron BA.1 surge.

Studies conducted prior to SARS-CoV-2 Omicron demonstrated that sotrovimab and remdesivir reduced hospitalization among high-risk outpatients with mild to moderate COVID-19. However, their effectiveness has not been directly compared. This study examined all high-risk outpatients with mild to moderate COVID-19 who received either remdesivir or sotrovimab at Mayo Clinic during the Omicron BA.1 surge from January to March 2022. COVID-19-related hospitalization or death within 28 days were compared between the two treatment groups. Among 3257 patients, 2158 received sotrovimab and 1099 received remdesivir. Patients treated with sotrovimab were younger and had lower comorbidity but were more likely to be immunocompromised than remdesivir-treated patients. The majority (89%) had received at least one dose of COVID-19 vaccine. COVID-19-related hospitalization (1.5% and 1.0% in remdesivir and sotrovimab, respectively, p = .15) and mortality within 28 days (0.4% in both groups, p = .82) were similarly low. A propensity score weighted analysis demonstrated no significant difference in the outcomes between the two groups. We demonstrated favorable outcomes that were not significantly different between patients treated with remdesivir or sotrovimab.

Changes in diet and supplement use in dogs with cancer.

BACKGROUND: Many dog owners alter their dog's nutritional regimen after a diagnosis of cancer. There are limited data as to specific changes made and reasons behind these changes. HYPOTHESIS/OBJECTIVES: To collect updated and detailed data on changes made by owners to their dog's diet and supplements after a cancer diagnosis. ANIMALS: Responses were collected from a survey of dog owners who brought their dogs to the UC Davis Veterinary Medical Teaching Hospital's Oncology Service for the first time after a cancer diagnosis. Dogs with recurrence or presenting for a second type of cancer were excluded. METHODS: Eligible owners were surveyed between December 2020 and March 2022. The survey contained 62 questions regarding diet, supplement use, and treats, and how these were altered after a cancer diagnosis. Responses were matched to medical record data. RESULTS: One hundred twenty-eight surveys were retained for analysis, including 120 respondents that completed the survey. In response to a cancer diagnosis, 54.8% (95% CI; 45.7%-63.8%) of owners altered diets or supplements or both. The most common informational resource for dog diets was veterinarians (53.9%). Usage of home-prepared foods significantly increased after a cancer diagnosis (P = .03). There was no significant difference in commercial diet usage before or after a diagnosis (P = .25). Joint support products were the most common supplements given both before (37.4%) and after (35.0%) diagnosis. CONCLUSIONS AND CLINICAL IMPORTANCE: Many dog owners alter their dog's nutritional intake after a cancer diagnosis. These owners should be provided information relating to commonly observed alterations, including home-prepared foods and supplements.

Development and Validation of a Western Blot Method to Quantify Mini-Dystrophin in Human Skeletal Muscle Biopsies.

Duchenne muscular dystrophy (DMD) is a degenerative muscular disease affecting roughly one in 5000 males at birth. The disease is often caused by inherited X-linked recessive pathogenic variants in the dystrophin gene, but may also arise from de novo mutations. Disease-causing variants include nonsense, out of frame deletions or duplications that result in loss of dystrophin protein expression. There is currently no cure for DMD and the few treatment options available aim at slowing muscle degradation. New advances in gene therapy and understanding of dystrophin (DYS) expression in other muscular dystrophies have opened new opportunities for treatment. Therefore, reliable methods are needed to monitor dystrophin expression and assess the efficacy of new therapies for muscular dystrophies such as DMD and Becker muscular dystrophy (BMD). Here, we describe the validation of a novel Western blot (WB) method for the quantitation of mini-dystrophin protein in human skeletal muscle tissues that is easy to adopt in most laboratory settings. This WB method was assessed through precision, accuracy, selectivity, dilution linearity, stability, and repeatability. Based on mini-DYS standard performance, the assay has a dynamic range of 0.5-15 ng protein (per 5 µg total protein per lane), precision of 3.3 to 25.5%, and accuracy of - 7.5 to 3.3%. Our stability assessment showed that the protein is stable after 4 F/T cycles, up to 2 h at RT and after 7 months at - 70°C. Furthermore, our WB method was compared to the results from our recently published LC-MS method. Workflow for our quantitative WB method to determine mini-dystrophin levels in muscle tissues (created in Biorender.com). Step 1 involves protein extraction from skeletal muscle tissue lysates from control, DMD, or BMD biospecimen. Step 2 measures total protein concentrations. Step 3 involves running gel electrophoresis with wild-type dystrophin (wt-DYS) from muscle tissue extracts alongside mini-dystrophin STD curve and mini-DYS and protein normalization with housekeeping GAPDH.

Human Recombinant Alkaline Phosphatase (Ilofotase Alfa) Protects Against Kidney Ischemia-Reperfusion Injury in Mice and Rats Through Adenosine Receptors.

Adenosine triphosphate (ATP) released from injured or dying cells is a potent pro-inflammatory "danger" signal. Alkaline phosphatase (AP), an endogenous enzyme that de-phosphorylates extracellular ATP, likely plays an anti-inflammatory role in immune responses. We hypothesized that ilofotase alfa, a human recombinant AP, protects kidneys from ischemia-reperfusion injury (IRI), a model of acute kidney injury (AKI), by metabolizing extracellular ATP to adenosine, which is known to activate adenosine receptors. Ilofotase alfa (iv) with or without ZM241,385 (sc), a selective adenosine A2A receptor (A2AR) antagonist, was administered 1 h before bilateral IRI in WT, A2AR KO (Adora2a-/- ) or CD73-/- mice. In additional studies recombinant alkaline phosphatase was given after IRI. In an AKI-on-chronic kidney disease (CKD) ischemic rat model, ilofotase alfa was given after the three instances of IRI and rats were followed for 56 days. Ilofotase alfa in a dose dependent manner decreased IRI in WT mice, an effect prevented by ZM241,385 and partially prevented in Adora2a-/- mice. Enzymatically inactive ilofotase alfa was not protective. Ilofotase alfa rescued CD73-/- mice, which lack a 5'-ectonucleotidase that dephosphorylates AMP to adenosine; ZM241,385 inhibited that protection. In both rats and mice ilofotase alfa ameliorated IRI when administered after injury, thus providing relevance for therapeutic dosing of ilofotase alfa following established AKI. In an AKI-on-CKD ischemic rat model, ilofotase alfa given after the third instance of IRI reduced injury. These results suggest that ilofotase alfa promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2AR-and non-A2AR-dependent signaling pathways.

Evaluation of iron, copper and zinc concentrations in commercial foods formulated for healthy cats.

OBJECTIVES: The aim of this study was to analyze iron, copper and zinc concentrations in commercial foods and compare among food formats (dry, canned, raw), foods marketed by age category (adult 1+ years and senior 7+ years) and foods intended for adult maintenance vs all life stages. METHODS: In total, 112 commercial non-therapeutic food products marketed for healthy adult and senior cats were purchased in the USA. Foods were analyzed for their proximate composition. Trace mineral concentrations were measured using inductively coupled argon plasma-optical emission spectroscopy and described on a calculated metabolizable energy basis using standard modified Atwater values. RESULTS: Measured iron (median 58.4 mg/1000 kcal [range 15.7-379.0]), copper (median 5.6 mg/1000 kcal [range 0.8-13.3]) and zinc (median 47.6 mg/1000 kcal [range 7.6-128.1]) concentrations were highly variable among cat foods. When all food products - regardless of their nutritional adequacy substantiation method - were compared with the Association of American Feed Control Officials regulatory minimums, 13/112 food products had a mineral deficiency, of which a majority (n = 11/13) were raw food products. Raw foods had significantly lower trace mineral concentrations compared with dry food products and, except for copper, canned food products. Cat foods marketed for senior cats had higher iron (P = 0.019) and zinc (P <0.0001) concentrations than foods marketed for adult cats. Foods intended for adult maintenance had higher iron (P = 0.003) and zinc concentrations than foods intended for all life stages (P <0.0001). CONCLUSIONS AND RELEVANCE: Iron, copper and zinc concentrations in commercial non-therapeutic foods for adult and senior cats are highly variable. A minority of foods - mainly raw food products - were deficient in these minerals. It is unknown if some foods with high trace mineral concentrations could have adverse effects as studies are needed to establish safe upper limits for dietary intake of trace minerals in healthy cats.

Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19.

BACKGROUNDClinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) are needed.METHODS2335 Patients who received single-dose bamlanivimab infusion between November 12, 2020, and February 17, 2021, were compared with a propensity-matched control of 2335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21, and 28.RESULTSThe median age of the population was 63 years; 47.3% of the bamlanivimab-treated cohort were 65 years or more; 49.3% were female and 50.7% were male. High-risk characteristics included hypertension (54.2%), BMI greater than or equal to 35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs. 3.5%; risk ratio [RR], 0.41), 21 (1.9% vs. 3.9%; RR, 0.49), and 28 (2.5% vs. 3.9%; RR, 0.63). Secondary exploratory outcomes included lower intensive care unit (ICU) admission rates at days 14 (0.14% vs. 1%; RR, 0.14), 21 (0.25% vs.1%; RR, 0.25), and 28 (0.56% vs.1.1%; RR. 0.51) and lower all-cause mortality at days 14 (0% vs. 0.33%), 21 (0.05% vs. 0.4%; RR,0.13), and 28 (0.11% vs. 0.44%; RR, 0.26). Adverse events were uncommon with bamlanivimab, occurring in 19 of 2355 patients, and were most commonly fever (n = 6), nausea (n = 5), and lightheadedness (n = 3).CONCLUSIONSAmong high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization, ICU admission, and mortality compared with usual care.FUNDINGMayo Clinic.

Association of Intravenous Bamlanivimab Use with Reduced Hospitalization, Intensive Care Unit Admission, and Mortality in Patients with Mild to Moderate COVID-19.

BACKGROUND: Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. METHODS: 2,335 patients who received single-dose bamlanivimab infusion between November 12, 2020 to February 17, 2021 were compared with a propensity-matched control of 2,335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21 and 28. RESULTS: The median age of the population was 63; 47.3% of the bamlanivimab-treated cohort were ≥65 years; 49.3% were female. High-risk characteristics included hypertension (54.2%), body mass index ≥35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs 3.5%; Odds Ratio [OR], 0.38), 21 (1.9% vs 3.9%; OR, 0.46), and 28 (2.5% vs 3.9%; OR, 0.61). Secondary exploratory outcomes included lower intensive care unit admission rates at days 14 (0.14% vs 1%; OR, 0.12), 21 (0.25% vs 1%; OR: 0.24) and 28 (0.56% vs 1.1%; OR: 0.52), and lower all-cause mortality at days 14 (0% vs 0.33%), 21 (0.05% vs 0.4%; OR,0.08) and 28 (0.11% vs 0.44%; OR, 0.01). Adverse events were uncommon with bamlanivimab, occurring in 19/2355, most commonly fever (n=6), nausea (n=5), and lightheadedness (n=3). CONCLUSIONS: Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization compared with usual care. FUNDING: Mayo Clinic.

Impact of storage temperature, storage duration, and deproteinization on plasma amino acid concentrations in dogs.

Reliability of canine plasma amino acid analysis depends on sample stability which can be influenced by pre-analytical handling techniques, storage temperature, storage time, and deproteinization status. Extrapolating data to dogs from research in other species is limited given discordant methodology and interspecies differences. The present study investigated the effects of deproteinization status (non-deproteinized or deproteinized) and storage temperature (at -20 °C or - 80 °C) on the concentration of 22 canine plasma amino acids during a 300-day storage period. Storage time had a significant effect (p < 0.05) of overall declining concentration of most amino acids. Compared to non-deproteinized samples, deproteinization contributed to overall higher concentrations of cyst(e)ine and glutamic acid, and consistently modified the effect of storage time and temperature on cyst(e)ine, glutamic acid, and glutamine. Compared to -20 °C, storage at -80 °C contributed to a higher concentration of cyst(e)ine and glutamic acid, and modified the effect of storage time on arginine, glutamic acid, glutamine, and tryptophan. Storage time had a consistent, significant effect on amino acid concentrations in canine plasma samples. Although sample deproteinization and low storage temperature modified the effect of storage time, these interactions were variable among analyzed amino acids. Therefore, timely sample analysis is recommended. If delayed sample analysis is inevitable, deproteinization should be performed prior to sample banking to preserve amino acid stability.

Rabbit Carcasses for Use in Feline Diets: Amino Acid Concentrations in Fresh and Frozen Carcasses With and Without Gastrointestinal Tracts.

Whole-prey diets for exotic feline species are common, and this practice has also increased in popularity for domestic cats. However, prior analyses of prey indicate possible essential amino acid inadequacy, and dilated cardiomyopathy from taurine deficiency was reported in cats fed whole ground rabbit. Crude protein, body water, and amino acid concentrations were evaluated in fresh and frozen ground rabbits with (n=10) or without (n = 10) gastrointestinal tracts. Amino acids were greater in fresh samples without gastrointestinal tracts (p < 0.05) except taurine, glycine, and cysteine. When normalized for protein content, only glutamate, alanine, methionine, isoleucine, tyrosine, lysine, histidine, and arginine were greater in fresh rabbits without gastrointestinal tracts (g/16 g N basis; p < 0.05). Freezing at -18°C for 30 days had no effect on crude protein or body water content. After freezing, only methionine was lower and only proline was higher when gastrointestinal tracts were omitted (g/16 g N basis; p < 0.05). Regardless, all essential amino acids except taurine exceeded Association of American Feed Control Officials and National Research Council nutrient recommendations for all feline life stages. In contrast, there was minimal impact of treatment on taurine concentrations. However, although feline taurine requirements for prey and other raw or fresh food diets remain undefined, none of the rabbit samples met any recommendation for taurine concentrations for commercial canned or dry extruded diets, ranging from 20 to 90% of the minimum values. Taurine supplementation is recommended when feeding rabbit to cats. Determination of taurine requirements of cats fed whole-prey diets is warranted.

Evaluation of a dry therapeutic urinary diet and concurrent administration of antimicrobials for struvite cystolith dissolution in dogs.

BACKGROUND: Struvite urolithiasis with bacterial urinary tract infection (UTI) is commonly reported in dogs; few data exist to describe successful dissolution protocols in dogs with naturally occurring disease. We hypothesized that a dry therapeutic urinary diet combined with targeted antimicrobial therapy can effectively dissolve presumptive struvite cystolithiasis in dogs with naturally occurring urease-producing bacterial UTI. RESULTS: Ten dogs with presumed infection-induced struvite cystolithiasis based on lower urinary tract signs (LUTS), radiodense cystoliths, and urease-producing bacterial UTI were enrolled. At enrollment, antimicrobials and dry therapeutic urinary diet were dispensed. In addition to lack of radiographic resolution of urolithiasis, dogs with persistent clinical signs were considered non-responders. There was no significant difference in pH between responders and non-responders; USG was significantly higher in the responder group. Recheck visits continued until radiographic dissolution or failure was documented. Five of the 10 dogs achieved radiographic dissolution of cystolithiasis within a median of 31 days (range 19-103). In the other 5 dogs, surgical urolith removal was necessary due to persistent LUTS (3 dogs within 2 weeks) or lack of continued dissolution noted radiographically (1 dog with numerous cystoliths failed at day 91; 1 dog failed by day 57 with questionable owner compliance). CONCLUSIONS: Dissolution of urinary tract infection induced struvite cystoliths can be accomplished in some dogs fed this dry therapeutic urinary diet in conjunction with antimicrobial therapy. Case selection could increase the likelihood of successful dissolution; however, if calcium phosphate is present, this could also prevent stone dissolution. If clinical signs persist despite diet and antimicrobials, stone removal is advised.

Imaging in low-grade glioma: a guide for neurologists.

The management of low-grade glioma (LGG) is shifting as evidence has emergedthat refutes the previously commonplace imaging-based 'watch and wait' approach, in favour of early aggressive surgical resection. This coupled with the recent 2016 update to the World Health Organisation Classification of Tumours of the Central Nervous System is changing LGG imaging and management. Recently in Practical Neurology the contemporary management of low-grade glioma and the changes to this grading system were discussed in detail. 1 In this complementary article, we discuss the role of imaging in the diagnosis, surgical planning and post-treatment follow-up of LGG. We describe the principles of imaging these tumours and use several cases to highlight some difficult scenarios.

A descriptive pilot study of cytokine production following stimulation of ex-vivo whole blood with commercial therapeutic feline hydrolyzed diets in individual healthy immunotolerant cats.

BACKGROUND: Hydrolyzed diets are used in companion animals for the diagnosis and treatment of adverse food reaction. Similarly, hydrolyzed formulas are used in human infants with severe inflammatory bowel disease or milk allergy, and these must meet the standard of hypoallergenicity through rigorous testing. Unfortunately, no standards are currently applied to hydrolyzed veterinary therapeutic diets, and data for the immunogenicity of feline diets is also not available. Therefore, the main aim of this pilot study was to determine if ex-vivo whole blood stimulation assays could be used to characterize the cytokine response to hydrolyzed commercial diets in a small number of individual healthy immunotolerant cats. This approach has also been used to investigate cytokine production in response to cow milk protein in humans and currently similar studies do not exist in companion animals. Nine healthy cats previously eating the same basal diet were divided into groups and fed one of three hydrolyzed diets exclusively for 6 weeks. Heparinized whole blood was collected from each cat before and after the feeding trial. Ex-vivo whole blood stimulation assays were performed using crude extracts of the basal diet as a positive control, as this diet contained the same proteins present in the hydrolyzed diet but were intact, saline as a negative control, and each cat's respective hydrolyzed diet. Supernatants were collected and analyzed for tumor necrosis factor-alpha, interleukin-10 (IL-10), and interleukin-4 using enzyme-linked immunosorbant assay. RESULTS: Seven cats produced detectable amounts of the anti-inflammatory cytokine IL-10 upon stimulation with the basal diet. Two cats produced detectable amounts of IL-10 upon stimulation with a hydrolyzed soy-based diet and one cat produced a detectable amount of IL-10 upon stimulation with a hydrolyzed chicken-based diet (>125 pg/mL). CONCLUSIONS: Results from this pilot study suggest that in some healthy immunotolerant cats, some hydrolyzed diets may elicit a similar cytokine response compared to their basal diet, which contained the same proteins intact. Therefore, animals may be able to recognize and react to some hydrolyzed forms of tolerated proteins, and may also suggest IL-10 as a target for investigation as a potential marker for dietary tolerance in cats, however further studies would be necessary to corroborate this. Further studies are also needed to determine if this would also be the same in immunologically naïve, sensitized and clinically hypersensitized cats.

'Low grade glioma': an update for radiologists.

With the recent publication of a new World Health Organization brain tumour classification that reflects increased understanding of glioma tumour genetics, there is a need for radiologists to understand the changes and their implications for patient management. There has also been an increasing trend for adopting earlier, more aggressive surgical approaches to low-grade glioma (LGG) treatment. We will summarize these changes, give some context to the increased role of tumour genetics and discuss the associated implications of their adoption for radiologists. We will discuss the earlier and more radical surgical resection of LGG and what it means for patients undergoing imaging.

Risk of obesity in the neutered cat.

Surgical neutering is one of the most common procedures performed on pets in the USA among other countries. There are known effects of neutering on the physiology and behavior of the cat that predispose to obesity, which is the most significant sequela from a nutritional perspective. Increased food intake is the most likely factor influencing weight gain in the neutered cat. Proactively addressing these changes with nutritional management strategies can help prevent weight gain and associated negative consequences.

Assessment of protein and amino acid concentrations and labeling adequacy of commercial vegetarian diets formulated for dogs and cats.

OBJECTIVE: To determine measured crude protein (CP) and amino acid (AA) concentrations and assess labeling adequacy of vegetarian diets formulated for dogs and cats. DESIGN: Cross-sectional study. SAMPLE: 13 dry and 11 canned vegetarian diets for dogs and cats. PROCEDURES: Concentrations of CP and AAs were determined for each diet. Values were compared with the Association of American Feed Control Officials (AAFCO) Dog and Cat Food Nutrient Profiles. Product labels were assessed for compliance with AAFCO regulations. RESULTS: CP concentration (dry-matter basis) ranged from 19.2% to 40.3% (median, 29.8%). Minimum CP concentrations for the specified species and life stage were met by 23 diets; the remaining diet passed appropriate AAFCO feeding trials. Six diets did not meet all AA minimums, compared with the AAFCO nutrient profiles. Of these 6 diets, 1 was below AAFCO minimum requirements in 4 AAs (leucine, methionine, methionine-cystine, and taurine), 2 were below in 3 AAs (methionine, methionine-cystine, and taurine), 2 were below in 2 AAs (lysine and tryptophan), and 1 was below in 1 AA (tryptophan). Only 3 and 8 diets (with and without a statement of calorie content as a requirement, respectively) were compliant with all pet food label regulations established by the AAFCO. CONCLUSION AND CLINICAL RELEVANCE: Most diets assessed in this study were not compliant with AAFCO labeling regulations, and there were concerns regarding adequacy of AA content. Manufacturers should ensure regulatory compliance and nutritional adequacy of all diets, and pets fed commercially available vegetarian diets should be monitored and assessed routinely.

Management of the hospitalized transplant patient.

Significant hyperglycemia is commonly observed immediately after solid organ and bone marrow transplant as well as with subsequent hospitalizations. Surgery and procedures are well known to cause pain and stress leading to secretion of cytokines and other hormones known to aggravate insulin action. Immunosuppression required for transplant and preexisting risk are also major factors. Glucose control improves outcomes for all hospitalized patients, including transplant patients, but is often more challenging to achieve because of frequent and sometimes unpredictable changes in immunosuppression doses, renal function, and nutrition. As a result, risk of hypoglycemia can be greater in this patient group when trying to achieve glucose control goals for hospitalized patients. Key to successful management of hyperglycemia is regular communication between the members of the care team as well as anticipating and rapidly implementing a new treatment paradigm in response to changes in immunosuppression, nutrition, renal function, or evidence of changing insulin resistance.

Approach to the hospitalized patient with severe insulin resistance.

Glucose control improves outcomes in the hospitalized patient, particularly patients on prolonged ventilator support, after acute myocardial infarction or after coronary artery bypass surgery. An iv insulin algorithm is the standard of care for initial treatment of significant hyperglycemia in the hospitalized patient, and it can be transitioned to periodic sc insulin once the patient is more stable. However, illness, medications, the endocrine and inflammatory response to stress, and pain can all contribute to insulin resistance and further aggravate preexisting insulin resistance caused by obesity. Glucose treatment goals have been established to guide the rapy, but achieving those goals can be more challenging in the presence of severe insulin resistance. When target glucose values are not achieved with established insulin algorithms, the practitioner should evaluate for potential causes of insulin resistance from technical factors that cause "pseudo-insulin resistance" as well as other modifiable factors, such as electrolyte disorders, parenteral and enteral nutrition, or other medications. Published glucose guidelines provide glucose "goals" to guide changes in the insulin algorithm, but these goals may be difficult to achieve in all individuals. We propose a stepwise approach to evaluate and treat severe insulin resistance in the hospitalized patient in order to achieve glucose goals in a timely fashion.

Tacrolimus and sirolimus induce reproductive abnormalities in female rats.

BACKGROUND: Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities. METHODS: We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested. RESULTS: TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls. CONCLUSION: In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Body mass index percentile more sensitive than acanthosis nigricans for screening Native American children for diabetes risk.

BACKGROUND: Many Native American tribes use acanthosis nigricans to screen for type 2 diabetes risk. We hypothesized that acanthosis nigricans misses many children at risk for type 2 diabetes. METHODS: We evaluated 5- to 18-year-old Native American children and youth to assess the sensitivity and specificity of acanthosis nigricans as a marker for insulin resistance. RESULTS: In a cohort of 161 youth (72 males/89 females), mean age was 10.7 years + 3.9. Mean body mass index (BMI) percentile was 76.8 +/- 23.3, and 54% had a BMI at or above the 85th percentile. Acanthosis nigricans was present in 21.7% of the participants and was more common in 12-to 18-year-olds than in 5 to 11-year-olds (p = .02). Of those with acanthosis nigricans, 82.4% had insulin resistance (homeostatic model assessment of insulin resistance >4), but only 48.3% of those with insulin resistance had acanthosis nigricans. In contrast, BMI at or above the 85th percentile had a high sensitivity (74%) for insulin resistance, even though its specificity was lower (58%). CONCLUSIONS: The presence of acanthosis nigricans alone was a specific, but not a sensitive, screening tool for identifying youth with insulin resistance. BMI at or above the 85th percentile was a more sensitive screening tool than acanthosis nigricans alone, or acanthosis nigricans and BMI together for identifying children and youth with IR who are at increased risk for type 2 diabetes.

Diazepam delays the death of hippocampal CA1 neurons following global ischemia.

Although diazepam provides limited long term neuroprotection, it may be useful for expanding the therapeutic time window after stroke by delaying neuronal death. However, it is not known to what extent diazepam maintains normal cellular structure and function in the first few days after ischemia. We used histological, immunohistochemical and electrophysiological endpoints to address this question. Gerbils underwent 5 min of global ischemia followed by 10 mg/kg diazepam (D) given 30 and 90 min later. Other animals were subjected to sham surgery, normothermic ischemia (I) or ischemia at 32 degrees C (Hypo). Postischemic brain temperature was regulated at approximately 37 degrees C for 24 h. Gerbils in the D and I groups were sacrificed 1, 2 and 3 days after ischemia. Sham and Hypo gerbils were sacrificed on day 3. CA1 cell counts, MAP2 staining and CA1 field potentials were performed at each survival time. Hypothermia prevented CA1 necrosis, preserved MAP2 integrity and maintained CA1 field potential amplitude. Ischemic gerbils showed a significant reduction in these 3 outcome measures by day 3. Diazepam-treated gerbils exhibited near normal levels of CA1 neurons and MAP2 staining. Most importantly, CA1 field potentials were similar to sham values and significantly preserved relative to non-treated ischemic gerbils. Diazepam maintains near normal structural and functional integrity up to 3 days after a global ischemic insult. As such, this drug may be useful for extending the therapeutic time window after cardiac arrest, stroke and related disorders.