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Botulinum neurotoxins (BoNTs) inhibit cholinergic synaptic transmission by specifically cleaving proteins that are crucial for neurotransmitter exocytosis. Due to the lethality of these toxins, there are elevated concerns regarding their possible use as bioterrorism agents. Moreover, their widespread use for cosmetic purposes, and as medical treatments, has increased the potential risk of accidental overdosing and environmental exposure. Hence, there is an urgent need to develop novel modalities to counter BoNT intoxication. Mammalian motoneurons are the main target of BoNTs; however, due to the difficulty and poor efficiency of the procedures required to isolate the cells, they are not suitable for high-throughput drug screening assays. Here, we explored the suitability of embryonic stem (ES) cell-derived motoneurons as a renewable, reproducible, and physiologically relevant system for BoNT studies. We found that the sensitivity of ES-derived motoneurons to BoNT/A intoxication is comparable to that of primary mouse spinal motoneurons. Additionally, we demonstrated that several BoNT/A inhibitors protected SNAP-25, the BoNT/A substrate, in the ES-derived motoneuron system. Furthermore, this system is compatible with immunofluorescence-based high-throughput studies. These data suggest that ES-derived motoneurons provide a highly sensitive system that is amenable to large-scale screenings to rapidly identify and evaluate the biological efficacies of novel therapeutics., (Published by Elsevier B.V.)

Exposure to hexavalent chromium (Cr(6+)) causes mutagenic, carcinogenic, and toxic effects, some of which have been associated with its oxidative capacity. In the kidney, Cr(6+) has been claimed to provoke necrosis of the proximal tubular cells. Our aim was to assess the functional involvement of the different segments that form the nephron in a model of acute renal failure caused by potassium dichromate and the participation of oxidative damage in this process. We also studied the possible protective effect of alpha-tocopherol (alpha-TOC) against renal damage. Wistar female rats 200g body weight (bw) received potassium dichromate (15mg/kg, sc, single dose). Lipid peroxidation and renal function were evaluated on days 0, 1, 2, 3, 7, 10, and 14. A second group received alpha-TOC (125mg/kg, by gavage) 5 days before and during dichromate exposure (same dose as for the first group), and was monitored at 0, 2, and 7 days of exposure. Creatinine clearance, glucose and sodium fractional excretions, p-aminohippurate uptake, free-water and osmolal clearances were also measured. Thiobarbituric acid-reactive substances were quantified in renal cortex. The results revealed altered proximal tubule function, decreased glomerular filtration, and distal segment dysfunction, accompanied by oxidative damage 48h after exposure to dichromate. In the alpha-TOC-treated group proximal reabsorptive and secretory functions were preserved, suggesting that oxidative damage is a participating mechanism in dichromate toxicity on these functions. In contrast alpha-TOC did not prevent glomerular or distal dysfunction, indicating selectivity of the protection afforded by this compound on the toxicity of dichromate, at the several components of the nephron.

A technique of radius opening-wedge osteotomy, bone graft, and external fixation for the treatment of symptomatic radius malunion is presented. It provides direct rigid fixation to the osteotomy components, thus maintaining the correction while allowing early wrist exercises. This technique has been effective for 7 patients in correcting deformities that averaged--20 degrees palmar tilt with radial shortening of 3.4 mm to a postoperative average palmar tilt of 5.3 degrees and -0.4 mm radial shortening. It is an alternative technique for the hand surgeon treating radius malunion and can be easily combined with adjunctive procedures.

The HIV infection primarily affects young adults, but older adults are also susceptible. The number of AIDS cases among persons aged 50 or greater is growing and is of major concern. As our awareness of the prevalence of HIV-related illnesses presenting to the emergency department improves in the younger population, we must not ignore the disease in older patients. Early recognition of HIV infection will ensure the greatest opportunity for treatment and prevention of many of the consequences of opportunistic infections. We present a case of HIV in an elderly patient in order to heighten awareness of the possibility of HIV infection in older patients presenting to the emergency department. We also review the epidemiological, diagnostic, and therapeutic aspects of AIDS in older adults.

We have tested whether toxicity and uptake of ouabain are linked phenomena in isolated guinea-pig heart. We perfused toxic dose of either ouabain, dihydroouabain (hydrophilic cardiac steroids), ouabagenin or digitoxin (hydrophobic steroids) in conditions of endocytosis inhibited. We used two schemes of inhibition of endocytosis. First, we cooled the heart at 0-4 degrees C and exposed it 60 min to either 1 X 10(-6) M ouabain or 3 X 10(-7)M digitoxin. Upon rewarming, the heart exposed to ouabain relaxed with a shorter time constant than those exposed to digitoxin. Second, we perfused four receptor mediated endocytosis (RME) inhibitors at the same time that the cardiac glycosides. RME inhibitors significantly delayed the cardiac arrest caused by ouabain and dihydroouabain but they did not modify the toxicity of 3 X 10(-7)M digitoxin or 5 X 10(-6)M ouabagenin. None of RME inhibitors modified the toxicity of 0.5 mM K+ or zero Na+ saline solution. We suggest that the protection against ouabain toxicity brought by endocytosis inhibition, is related to the Na-pump recycling. We infer that besides the sarcolemmal exposed Na-pumps, the intracellular Na-pumps pool may be of importance for the pharmacological effects of digitalis steroids.

Sarcoidosis confined to a single bone in a patient with chronic systemic sarcoidosis and seen as a soft tissue mass is exceedingly rare. The combination of lytic and sclerotic changes within one bone has not been previously reported.