James Artwohl

Novel, biocompatible, and disease modifying VIP nanomedicine for rheumatoid arthritis.

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Naked mole-rats: Unique opportunities and husbandry challenges

The naked mole-rat is a relative newcomer to biomedical and behavioral studies. The authors review this unusual rodents uses in research, husbandry, reproduction, and common diseases.

Endothelin-1-like immunoreactivity in a new rodent model of spontaneous hypertension

The purpose of this study was to determine plasma and tissue endothelin-1 (ET-1)-like immunoreactivity in a new rodent model of spontaneous hypertension. Plasma and tissues were procured from pentobarbital-anesthetized 16- to 18-week-old male hamsters with spontaneous hypertension and genetically/age-matched normotensive hamsters. We found that ET-1-like immunoreactivity in the plasma was similar in both groups. However, renal and cardiac ET-1-like immunoreactivity was 11- and 1.7-fold higher in spontaneously hypertensive hamsters relative to normotensive hamsters, respectively (P < .05). ET-1-like immunoreactivity was slightly, but significantly, lower in the lung and spleen of spontaneously hypertensive hamsters relative to normotensive hamsters (P < .05). ET-1-like immunoreactivity in the liver and brain was similar in both groups. We conclude that ET-1-like immunoreactivity is significantly higher in two target organs for hypertension, kidney and heart, but not in plasma or brain of adult male hamsters with spontaneous hypertension, relative to genetically/age-matched normotensive hamsters. We suggest that renal and cardiac ET-1 could play a role in the natural history of spontaneous hypertension in hamsters.

Evidence of a Steroidogenic Enzyme Gene Dose Effect on Adrenal Gene Expression in Hereditary Rabbit Congenital Adrenal Hyperplasia

ABSTRACT: We previously reported the gene deletion encoding cytochrome P-450 cholesterol side-chain cleavage enzyme (P450SCC, resulting in complete elimination of the adrenal gene expression and causing congenital adrenal hyperplasia in the rabbit. Using the rabbit congenital adrenal hyperplasia model, we investigated the wild type (wt) P-450SCC gene dose effect on gene expression in three P-450SCC genotype animals [wt/wt, wt/mutant (mt), mt/mt] identified by Southern blot analysis. Northern blots using a rabbit P-450SCC cDNA probe revealed no detectable P-450SCC mRNA in individual adrenals of animals with congenital adrenal hyperplasia (mt/mt) and approximately half or slightly less than half the levels of the mRNA in the pooled adrenals of five heterozygous (wt/mt) newborn animals compared with the mRNA levels in the pooled adrenals of five homozygous normal (wt/wt) newborn animals. Identical P-450SCC mRNA levels were found individual adrenals of adult animals with regard to the P-450SCC genotype, although at a higher expression level than in the newborn animals of the same genotype. Control Northern blots using human CPY21-B cDNA and cytoplasmic actin cDNA probes confirmed the accuracy and integrity of RNA. Western immunoblotting using antiovine P-450SCC antibody revealed decreased P-450SCC protein in the adrenals of wt/mt animals at approximately half the level of the P-450SCC protein in the adrenals of the wt/wt animals. Baseline and ACTE-stimulated serum corticosterone (B) levels in vivo were similar between the age-matched wt/mt and wt/wt animals, whereas ACTH-stimulated B levels in adult animals were higher than those in the newborn animals irrespective of P-450SCC genotype. These data demonstrated for the first time the presence of a wt steroidogenic enzyme gene dose effect on gene expression in vivo at the levels of the mRNA and enzyme protein. With age, the gene dose-related gene expression was maintained, although at higher expression levels. The normal adrenal B-producing capacity in heterozygous, wt/mt animals despite the markedly decreased P-450SCC gene expression suggests the presence of either a mechanism compensating the availability of mitochondrial cholesterol substrate to overcome the decreased P-450SCC or rate-limiting effect of P-450SCC in the conversion of excess cholesterol substrate available in the adrenal mitochondria. The greater B-producing capacity under ACTH stimulation in the adult animals compared with the newborn animal irrespective of P-450SCC genotype therefore is likely from the greater adrenal receptor capacity for ACTH rather than from the greater P-450SCC gene expression level.

A cross-sectional study of Helicobacter infection among laboratory animals and animal research workers.

O ccupational risks for Helicobacter pylori infection are not well-understood, but associations with infection have been found among certain health care workers, such as gastroenterologists, endoscopy staff, and those who work in institutions for the developmentally disabled.1,2 Some non–pylori Helicobacter species cause significant disease, such as chronic hepatitis and hepatocellular carcinoma in mice, as well as gastric disease similar to that caused by H. pylori in humans. Some non–pylori Helicobacter species, particularly species that infect cats and dogs, such as Helicobacter heilmannii and Helicobacter felis, and Helicobacter suis, common in pigs, are also known to infect humans.3,4 There are indications that zoonotic transmission of certain of these organisms is associated with human disease.5 During surveillance of the facility under investigation in this study, non–pylori Helicobacter infections were detected among mice. We hypothesized that transmission of Helicobacter pylori, non–pylori Helicobacter species, or both could occur in animal research facilities.