Deletion of aldose reductase leads to protection against cerebral ischemic injury.

Previously, we reported that transgenic mice overexpressing endothelin-1 in astrocytes showed more severe neurological deficits and increased infarct after transient focal ischemia. In those studies, we also observed increased level of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which has been implicated in osmotic and oxidative stress. To further understand the involvement of the polyol pathway, the mice with deletion of enzymes in the polyol pathway, AR, and sorbitol dehydrogenase (SD), which is the second enzyme in this pathway, were challenged with similar cerebral ischemic injury. Deletion of AR-protected animals from severe neurological deficits and large infarct, whereas similar protection was not observed in mice with SD deficiency. Most interestingly, AR(-/-) brains showed lowered expression of transferrin and transferrin receptor with less iron deposition and nitrotyrosine accumulation. The protection against oxidative stress in AR(-/-) brain was also associated with less poly(adenosine diphosphate-ribose) polymerase (PARP) and caspase-3 activation. Pharmacological inhibition of AR by Fidarestat also protected animals against cerebral ischemic injury. These findings are the first to show that AR contributes to iron- and transferrin-related oxidative stress associated with cerebral ischemic injury, suggesting that inhibition of AR but not SD may have therapeutic potential against cerebral ischemic injury.     

Carbon blacks as EPR sensors for localized measurements of tissue oxygenation.

New electron paramagnetic resonance (EPR) oximetry probes were identified in the class of carbon black materials. These compounds exhibit very high oxygen sensitivity and favorable EPR characteristics for biological applications. At low pO(2), the linewidth is particularly sensitive to changes in oxygen tension (sensitivity of 750 mG/mmHg). The application of the probes for oximetry was demonstrated in vivo: the pO(2) was measured in muscle in which the blood flow was temporarily restricted as well as in tumor-bearing mice during a carbogen breathing challenge. The responsiveness to pO(2) was stable in muscle for at least 3 months. No toxicity was observed using these materials in cellular experiments and in histological studies performed 2, 7, and 28 days after implantation. In view of their EPR characteristics (high sensitivity) as well as the well-characterized production procedure that make them available on a large scale, these probes can be considered as very promising tools for future developments in EPR oximetry.     

Infantile free sialuria without lysosomal storage

Except for two reported patients, increased free sialic acid excretion has been associated with lysosomal storage. This is a report of a child with progressive neurologic deterioration and increased excretion of free sialic acid. Although lysosomal storage was absent, nuclear invagination or inclusions were present.     

Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitizes them to the anti-proliferative effects of tamoxifen

Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFN alpha) resulted in increased expression of oestrogen receptors as measured in a whole cell binding assay. This effect was inversely proportional to dose being significant following treatment with 10-100 IU IFN ml-1 and was only observed at a low initial cell plating density. The extent of the increase in oestrogen receptor levels ranged from 1.2- to 7.2-fold following treatment with 10 IU IFN ml-1. No increase in progesterone receptor expression was observed under the same experimental conditions. Concentrations of IFN which increased oestrogen receptor levels had no effect on cell proliferation. IFN (500 IU ml-1) inhibited cell proliferation and the combination of this treatment with tamoxifen (2 microM) had a greater anti-proliferative effect than either drug alone although there was no evidence of synergism. However, a 5-day pretreatment of cells with IFN (10 IU ml-1) markedly sensitised them to the growth-inhibiting effect of a subsequent 6-day exposure to tamoxifen.     

Adequacy of the epinephrine autoinjector needle length in delivering epinephrine to the intramuscular tissues.

BACKGROUND: Epinephrine injected by an autoinjector in the anterolateral aspect of the thigh is the standard of care in the emergency self-treatment of anaphylaxis. In the United States, the autoinjector EpiPen is widely used for the self-treatment of anaphylaxis. OBJECTIVE: To investigate whether EpiPen autoinjector, with a needle length of 1.43 cm, is sufficient for intramuscular delivery of epinephrine in men and women. METHODS: The distance from skin to muscle in the anterolateral aspect of the thigh was measured in 50 men and 50 women who had undergone computed tomography of the thighs for other medical reasons. For each individual, body mass index (BMI; a measure of weight in kilograms divided by the square of height in meters) was also calculated, and the individuals were classified as underweight (BMI, < 18.5), normal (BMI, 18.5-24.9), overweight (BMI, 25.0-29.9), and obese (BMI, > or = 30.0) using standard definition. RESULTS: In the study participants the mean +/- SD distance from skin to muscle was 0.66 +/- 0.47 cm for men and 1.48 +/- 0.72 cm for women (P < .001). One man (obese at a BMI of 42.2) and 21 women (11 obese with a mean BMI of 35.2, 6 overweight with a mean BMI of 30.1, and 4 normal with a mean BMI of 24.5) had a greater distance from skin to muscle than the EpiPen needle length of 1.43 cm. CONCLUSION: The distance from skin to muscle for the anterolateral aspect of the thigh is higher in women compared with men. This difference suggests that EpiPen may not deliver epinephrine to the intramuscular tissue in many women.     

Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy: potentially serious and unappreciated complications of Roux-en-Y gastric bypass.

BACKGROUND: Neither the presence nor prevalence of enteric hyperoxaluria has been recognized after Roux-en-Y gastric bypass (RYGBP). We have noted a high rate of oxalate nephrolithiasis and even 2 patients with oxalate nephropathy in this patient population postoperatively. Our aim was to determine the frequency of the occurrence and effects of enteric hyperoxaluria after RYGBP. METHODS: Retrospective review of all patients at our institution diagnosed with calcium oxalate nephrolithiasis or oxalate nephropathy after standard (n = 14) or distal (n = 9) RYGBP. The mean postoperative follow-up was 55 months. RESULTS: A total of 23 patients (14 men and 9 women; mean age 45 years; mean preoperative body mass index 55 kg/m(2)) developed enteric hyperoxaluria after RYGBP, defined by the presence of oxalate nephropathy (n = 2) or calcium oxalate nephrolithiasis (n = 21) and increased 24-hour excretion of urinary oxalate and/or calcium oxalate supersaturation. Enteric hyperoxaluria was recognized after a mean weight loss of 46 kg at 29 months (range 2-85) after RYGBP. Two patients developed renal failure and required chronic hemodialysis. Of the 21 patients with nephrolithiasis, 14 had no history of nephrolithiasis preoperatively, and 19 of 21 required lithotripsy or other intervention. Of the 23 patients, 20 tested had increased oxalate excretion, and 14 of 15 tested had high urine calcium oxalate supersaturation. CONCLUSION: Enteric hyperoxaluria, nephrolithiasis, and oxalate nephropathy must be considered with the other risks of RYGBP. Efforts should be made to identify factors that predispose patients to developing hyperoxaluria.