Adenovirus inhibition by peptidomimetic integrin antagonists

Many viruses and bacterial pathogens are capable of exploiting host cell surface integrins during their replication cycles. The ligands for many integrins contain an arginine-glycine-aspartic acid (RGD) amino acid sequence that is essential for protein-protein interaction. Human adenovirus particles contain this sequence in the penton base protein, and previous studies support a role for this RGD in integrin-dependent internalization of the virus by the cell. As synthetic peptidomimetics of RGD have been shown in other experimental systems to be antagonists of the activities of specific integrins both in vitro and in vivo, we sought to determine whether these small molecules are antagonists of adenovirus infection. Such compounds inhibited viral infection of cultured cells with similar rank order potency to that determined in assays utilizing purified extracellular matrix proteins as integrin ligands. The maximal level of inhibition achieved with the peptidomimetics was comparable to that of RGD-containing peptides, whereas no significant effects were apparent with an RGE-containing peptide. An engineered adenovirus having a mutated RGD sequence in the penton base was not susceptible to the inhibition. The results obtained with these synthetic antagonists, which have varied structures and potencies, suggest that integrins interact with adenoviral RGD in a manner similar to that of other protein ligands such as vitronectin. Furthermore, the results confirm the role of RGD in the replication cycle, and suggest peptidomimetic compounds may be useful antimicrobial agents in the treatment of a variety of diseases.     

Specific immunotherapy for severe latex allergy

We studied 4 patients (3 adult females + 13y old boy) with latex allergy. All patients had anaphylaxis related with latex and oral-latex-fruit syndrome. All 3 females had severe symptoms in the workplace. The boy had spina bifida with 9 previous surgeries and needed further surgical interventions. Positive skin prick tests (SPT), the presence of serum latex specific IgE (CAP-RAST, Pharmacia-Upjohn, Sweden- class 3 in the 3 females and class 4 in the boy) demonstrated the sensitisation. All 4 patients were treated with specific immunotherapy (SIT) with aqueous extract (ALK-ALK-ABELLO SA, Spain) administered subcutaneously at the hospital, by a modified rush schedule. A maintenance dose (MD) of 0.35_g protein was established according to the magnitude of local reactions (LRs). In one patient a higher dose induced the appearance of a systemic reaction (SR) 40 min after administration, which promptly remitted with treatment. After reaching MD, all 3 females remained assymptomatic at workplace. A challenge test with latex gloves was performed. Two months after MD was reached 2 females had no symptoms and one other had mild symptoms of rhinoconjunctivitis. The boy was subjected to a surgical intervention with no allergic reaction. We also observed a reduction on skin reactivity to latex in all patients by prick tests. We consider SIT with latex to be highly effective, safe and well tolerated provided we use this dose of the allergenic extract.     

Chemoreceptor activity is normal in mice lacking the NK1 receptor

Substance P has been proposed to be an important neurotransmitter in the carotid body with the neurokinin 1 (NK1) receptor, mediating excitation between the glomus cells and afferent nerve endings. In order to better understand the role of substance P, this study examined chemoreceptor afferent activity, in vitro, and tissue catecholamine levels and release in adult, wild-type mice and mice lacking the gene for the NK1 receptor (NK1-KO). Groups did not differ significantly in body weight, carotid body dopamine content or carotid body norepinephrine content. In wild-type mice, single unit activity increased from 0.59 +/- 0.14 Hz to 19.78 +/- 2.27 Hz during superfusion with strong hypoxia (PO2 approximately 25 Torr). Chemoreceptor activity in NK1-KO mice, increased from 0.71 +/- 0.23 to 21.50 +/- 3.62 Hz, and neither baseline or peak frequencies were significantly different from the wild-type group. Less severe hypoxia (PO2 approximately 45 torr), evoked peak activities of 12.50 +/- 1.88 and 10.64 +/- 3.72 Hz in wild-type and NK1-KO mice, which were also not significantly different. In response to severe hypoxia, free-tissue catecholamine increased to 4.92 +/- 0.85 microm in wild-type mice and 4.26 +/- 0.63 microm in NK1-KO mice, which were also not significantly different. It may therefore be concluded that loss of NK1 receptors has little effect on chemoreceptor function in the mouse, and thus they play, at best, a minor role in the hypoxic chemoreception process.     

Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections

OBJECTIVE: The purpose of this study was to evaluate the risk of cutaneous infection in patients with atopic dermatitis treated with tacrolimus ointment. METHODS: Data for 1554 patients with atopic dermatitis, treated with tacrolimus ointment in 5 clinical trials, were analyzed. RESULTS: In 3 controlled studies, the 12-week adjusted incidence of all cutaneous infections in patients treated with the vehicle, 0.03%, and 0.1% tacrolimus ointment, respectively, was 18.0%, 24.8%, and 17.7% for adult patients, and 20.9%, 19.6%, and 23.6% for pediatric patients. The incidence of any individual cutaneous infection was not significantly higher in the tacrolimus group than in the vehicle group, with the exception of folliculitis in adults. In two open-label studies, there was no evidence of an increased risk of cutaneous infections with long-term use of 0.1% tacrolimus ointment (up to 1 year), based on the incidence of adverse events, incidence by cumulative length of exposure, or hazard rates. CONCLUSION: Treatment with tacrolimus ointment (0.03% or 0.1%) does not increase the risk of cutaneous bacterial, viral, or fungal infections in patients with atopic dermatitis.     

Carnitine deficiency myopathy: a case of late diagnosis

Myopathies caused by lipidic metabolism alterations are very infrequent. Carnitine deficiency-associated myopathies are included in this group. Two main types of carnitine deficiency syndromes have been delineated: a predominantly myopathic form, with normal serum and low muscle carnitine levels, and a systemic form, with encephalopathy, hepatic dysfunction, muscle weakness and low muscle, liver and serum carnitine levels. Both types have typical lipid stores in muscle biopsy. We describe the case of a myopathic form of carnitine deficiency. Due to the age of the patient, this is an unusual case, with an unfavourable evolution. Therapeutic measures used in these patients have included prednisone, carnitine replacement and a low-fat with medium chain tryglycerides and high-carbohydrate diet. However, in none of the patients responding to therapy, a significative increase in muscle carnitine has been demonstrated.     

Gastroenteritis-associated Guillain-Barré syndrome on the Caribbean island Curaçao

BACKGROUND: The number of patients with Guillain-Barré syndrome (GBS) who have been observed in Cura?ao, the Netherlands Antilles, may be increasing. METHODS: Clinical and serologic data were obtained from records of patients admitted between 1987 and 1999 and fulfilling National Institute of Neurological and Communicative Disorders and Stroke criteria for GBS. When possible, serum and stool samples were collected. The results were compared with a large Dutch epidemiologic study. RESULTS: The authors identified 49 patients, an overall crude incidence rate (IR) in Cura?ao of 2.53/100,000 inhabitants (95% CI 1.87 to 3.35) (Dutch study 1.18, rate ratio (RR) of 2.14, p < 0.001). The IR in Cura?ao increased from 1.62 in 1987 to 1991 to 3.10 in 1992 to 1999, RR 5.22 (95% CI 2.48 to 10.2, p = 0.02). The IR showed a curvilinear shape within a year. In comparison with the Dutch group, patients from Cura?ao had a more severe course of the disease, with a mortality rate of 23% (3.4% in the Dutch group, p < 0.001), a higher percentage of preceding gastroenteritis (p < 0.001), and less sensory involvement (p < 0.001). In 8 of 10 serum samples, evidence was found for a recent infection with Campylobacter jejuni. CONCLUSIONS: The authors found a steady increase in incidence of GBS over the years in association with a more pronounced seasonal preponderance and a more severe course. The clinical characteristics suggest a role for C jejuni.     

HIV infection in haemophilia--a European cohort

Ten haemophilia centres in northern Europe have pooled data on 202 haemophilic children who were infected with HIV between 1979 and 1986. All cases were under 16 years of age on 1 July 1985. The age at infection ranged from 1-15 years. Thirty seven cases (18%) had progressed to AIDS by 1 July 1991 and 15 of these have died. Persistent generalised lymphadenopathy has been noted in 102 patients of whom 18 (17%) have developed AIDS. Twenty three of the remaining patients (23%) have not. CD4+ T cell counts have fallen steadily. Of 36 patients who have had shingles since seroconversion, 19 (53%) had counts below 0.2 x 10(9)/l. Thirty five out of 145 patients without shingles (24%) had similar values. The mean IgA concentration in patients with CD4+ T cell counts above 0.5 x 10(9)/l was 2.38 g/l, between 0.2 and 0.5 was 3.07 g/l, and in those with CD4+ T cell counts below 0.2 x 10(9)/l the mean IgA concentration was 4.58 g/l. Treatment patterns have altered between 1989 and 1991, with increased use of zidovudine in patients without AIDS and a marked increase in primary prophylaxis against pneumocystis pneumonia. This has been associated with a decline in the incidence of pneumocystis as an indicator disease in new AIDS cases from 56% in 1989 to 20% in 1991. These observations indicate that persistent generalised lymphadenopathy does not worsen the outlook, but shingles does. Rising IgA concentrations are markers for disease progression. Modern prophylactic regimens are delaying the onset of indicator disease, but CD4 values continue to fall steadily.     

Effect of induced uterine retroversion on bone mass in rats

OBJECTIVE: To evaluate the effect of surgical uterine retroversion on bone mass in rats. STUDY DESIGN: Forty-five female Wistar rats were assigned randomly to three groups: 15 unmanipulated rats, 15 rats that underwent uterine retroversion, and 15 rats that underwent sham uterine retroversion (exposure of the uterus to air followed by closure of the abdominal cavity). Sixty days later the rats were killed and their femurs were dissected. Femurs were weighed and measured, and femoral bone mineral content (BMC) and bone mineral density (BMD) were determined by dual energy X-ray absorptiometry. RESULTS: In the group of rats that underwent uterine retroversion, BMC, BMD, and BMC corrected for final body weight were significantly lower (P<0.001) than in the unmanipulated control and sham uterine retroversion groups. CONCLUSION: Our findings indicate that uterine retroversion induced a loss of bone mass. We could not determine the mechanism of bone loss; in our opinion, these problem merits further investigations, which currently occupy our interest.