Molecular quantification of human beta-glucuronidase levels in a patient with Vohwinkel's syndrome

The skin must undergo the process of keratinization in order to perform its functions. During the process of differentiation, certain genes are activated while others are repressed, leading to changes in structural proteins and enzymes and in the synthesis of various lipids. An error in any of these steps can ultimately impair the process of keratinization. Vohwinkel's syndrome is the direct result of a defect in keratinization. Patients who have this epidermolytic palmoplantar keratoderma present clinically with hyperkeratosis of the stratum corneum. Hyperkeratosis has been linked to an increase in beta-glucuronidase levels. The authors studied the absolute concentration of human beta-glucuronidase in a patient with Vohwinkel's syndrome as determined through a double-antibody sandwich enzyme-linked immunosorbent assay and a Western blot assay of the blood, urine, and skin of the patient.     

Mechanism of action of angiotensin II in human isolated subcutaneous resistance arteries

1. Human isolated subcutaneous arteries were mounted in a myograph and isometric tension measured. In some experiments, intracellular calcium [Ca(2+)]i was also measured using fura-2. 2. Angiotensin II (100 pM - 1 microM) increased [Ca(2+)]i and tone in a concentration-dependent manner. The effects of angiotensin II (100 nM) were inhibited by an AT1-receptor antagonist, candesartan (100 pM). 3. Ryanodine (10 microM), had no effect on angiotensin II-induced responses, but removal of extracellular Ca(2+) abolished angiotensin II-induced rise in [Ca(2+)]i and tone. Inhibition of Ca(2+) entry by Ni(2+) (2 mM), also inhibited angiotensin II responses. The dihydropyridine, L-type calcium channel antagonist, amlodipine (10 microM), only partially attenuated angiotensin II responses. 4. Inhibition of protein kinase C (PKC) by chelerythrine (1 microM), or by overnight exposure to a phorbol ester (PDBu; 500 nM) had no effect on angiotensin II-induced contraction. 5. Genistein (10 microM), a tyrosine kinase inhibitor, inhibited angiotensin II-induced contraction, but did not inhibit the rise in [Ca(2+)]i, suggesting that at this concentration it affected the calcium sensitivity of the contractile apparatus. Genistein did not affect responses to norepinephrine (NE) or high potassium (KPSS). 6. A selective MEK inhibitor, PD98059 (30 microM), inhibited both the angiotensin II-induced contraction and rise in [Ca(2+)]i, but had no effect on responses to NE or KPSS. 7. AT1 activation causes Ca(2+) influx via L-type calcium channels and a dihydropyridine-insensitive route, but does not release Ca(2+) from intracellular sites. Activation of tyrosine kinase(s) and the ERK 1/2 pathway, but not classical or novel PKC, also play a role in angiotensin II-induced contraction in human subcutaneous resistance arteries.     

A concise review of the toxicity and carcinogenicity of dimethylarsinic acid

Dimethylarsinic acid (DMA) has been used as a herbicide (cacodylic acid) and is the major metabolite formed after exposure to tri- (arsenite) or pentavalent (arsenate) inorganic arsenic (iAs) via ingestion or inhalation in both humans and rodents. Once viewed simply as a detoxification product of iAs, evidence has accumulated in recent years indicating that DMA itself has unique toxic properties. DMA induces an organ-specific lesion — single strand breaks in DNA — in the lungs of both mice and rats and in human lung cells in vitro. Mechanistic studies have suggested that this damage is due mainly to the peroxyl radical of DMA and production of active oxygen species by pulmonary tissues. Multi-organ initiation-promotion studies have demonstrated that DMA acts as a promotor of urinary bladder, kidney, liver and thyroid gland cancers in rats and as a promotor of lung tumors in mice. Lifetime exposure to DMA in diet or drinking water also causes a dose-dependent increase in urinary bladder tumors in rats, indicating that DMA is a complete carcinogen. These data collectively suggest that DMA plays a role in the carcinogenesis of inorganic arsenic.     

In vivo evidence for K(Ca) channel opening properties of acetazolamide in the human vasculature

1. The selective carbonic anhydrase inhibitor acetazolamide is known to increase blood flow in several organs. Acetazolamide directly dilates isolated resistance arteries associated with activation of calcium-activated potassium (K(Ca)) channels. We examined both the presence and mechanism of the direct vascular action of acetazolamide in vivo in humans. 2. Forearm vasodilator responses of 30 healthy volunteers to infusion of placebo and increasing doses of acetazolamide (1-3-10 mg min(-1) dl(-1)) into the brachial artery were recorded by venous occlusion plethysmography, before and after local administration of L-NMMA (0.2 mg min(-1) dl(-1), an inhibitor of NO-synthase, n=6), indomethacin (5.0 microg min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 microg min(-1) dl(-1), an inhibitor of K(ATP) channels, n=6), tetraethylammonium (0.1 mg min(-1) dl(-1), an inhibitor of K(Ca) channels, n=6) or placebo (NaCl 0.9%, n=6). Lower dosages of acetazolamide did not affect vascular tone (n=6). 3. Acetazolamide infusions increased forearm blood flow from 2.41+/-0.17 to 2.99+/-0.18, 4.09+/-0.26 and 6.77+/-0.49 ml min(-1) dl(-1) in the infused forearm (P:<0.001), with no significant changes in the non-infused forearm, blood pressure or heart rate. Acetazolamide-induced vasodilation was not inhibited by L-NMMA, indomethacin, or glibenclamide but was significantly attenuated by TEA (vasodilation: 23+/-6, 82+/-19, 241+/-38% versus 27+/-8, 44+/-22, 42+/-35%). 4. We conclude that acetazolamide exerts a direct vasodilator effect in vivo in humans mediated by vascular K(Ca) channel activation. This makes acetazolamide the first drug known that specifically modulates this channel.     

Pharmacokinetics of Plasmid DNA in the Rat

Purpose. The pharmacokinetics of plasmid DNA after IV bolus administration in the rat by following supercoiled (SC), open circular (OC), and linear (L) pDNA forms of the plasmid.Methods. SC, OC, and L pDNA were injected at 2500, 500, 333, and 250 g doses. The concentrations in the bloodstream of OC and L pDNA were monitored.Results. SC pDNA was detectable in the bloodstream only after a 2500 g dose, and had a clearance of 390(±50) ml/min and V_d of 81(±8) ml. The pharmacokinetics of OC pDNA exhibited non-linear characteristics with clearance ranging from 8.3(±0.8) to 1.3(±0.2) ml/min and a V_d of 39(±19) ml. L pDNA was cleared at 7.6(±2.3) ml/min and had a V_d of 37(±17) ml. AUC analysis revealed that 60(±10) % of the SC was converted to the OC form, and nearly complete conversion of the OC pDNA to L pDNA. Clearance of SC pDNA was decreased after liposome complexation to 87(±30) ml/min. However the clearance of OC and L pDNA was increased relative to naked pDNA at an equivalent dose to 37(±9) ml/min and 95(±37) ml/min respectively.Conclusions. SC pDNA is rapidly metabolized and cleared from the circulation. OC pDNA displays non-linear pharmacokinetics. Linear pDNA exhibits first order kinetics. Liposome complexation protects the SC topoform, but the complexes are more rapidly cleared than the naked pDNA.     

Dose-dependent effect of dietary meat on endogenous colonic N-nitrosation

Human male volunteers were studied in a metabolic facility whilst they were fed randomized controlled diets. In eight volunteers there was a significant increase in faecal apparent total N:-nitroso compounds (ATNC) and nitrite excretion (P < 0.0001 and P = 0.046, respectively) when randomized doses of meat were increased from 0 to 60, 240 and 420 g/day over 10 day periods. Mean (+/- SE) faecal ATNC levels were 54 +/- 7 microg/day when the diets contained no meat, 52 +/- 11 microg/day when the diets contained 60 g meat/day, 159 +/- 33 microg/day with 240 g meat and 199 +/- 36 microg/day with 420 g meat. Higher concentrations of NOC were associated with longer times of transit in the gut (r = 0.55, P = 0.001) and low faecal weight (r = -0.51, P = 0.004). There was no significant decline in levels in individuals fed 420 g meat for 40 days. The exposures found on the higher meat diets were comparable with other sources of N:-nitroso compounds (NOC), such as tobacco smoke. Many NOC are known large bowel initiators and promotors in colon cancer, inducing G-->A transitions in codons 12 and 13 of K-ras. Endogenous NOC formation, combined with prolonged transit times in the gut, may explain the epidemiological associations between high meat/low fibre diets and colorectal cancer risk.     

Subacute cutaneous lupus erythematosus induced or exacerbated by terbinafine: a report of 5 cases

BACKGROUND: Subacute cutaneous lupus erythematosus is a nonscarring, non-atrophy-producing photosensitive cutaneous disorder. Half of the patients have 4 or more of the criteria for classification as systemic lupus erythematosus. In some patients, drugs induce or exacerbate the cutaneous disease. OBSERVATION: We describe 5 patients who had either an exacerbation or a new onset of subacute cutaneous lupus erythematosus while taking terbinafine for presumed onychomycosis. CONCLUSION: In general, terbinafine is a safe drug, but perhaps patients with known lupus erythematosus or photosensitivity are predisposed to drug-induced or drug-exacerbated disease.     

Acute transverse myelitis and Guillain-Barré overlap syndrome with serological evidence for mumps viraemia

Both acute transverse myelitis (ATM) and Guillain-Barré syndrome (GBS) occur as rare associations with mumps viraemia but to our knowledge, concurrent ATM and GBS related to mumps has only been reported once previously. We describe the case of a young woman presenting with confusion and collapse 2 weeks after a flu-like illness. An initial diagnosis of transverse myelitis was made on the basis of the clinical findings and radiological evidence of a swollen spinal cord with uniform high signal change on T2 weighted MRI. The patient was treated with intravenous methylprednisolone without significant recovery. The diagnosis was later revised to include GBS on the basis of worsening facial diplegia in the setting of a flaccid tetraparesis, and neurophysiological evidence of a sensorimotor axonal polyradiculoneuropathy. Acute mumps viraemia was confirmed on serological grounds. The patient made an improvement in ventilatory capacity with intravenous immunoglobulin treatment.