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.     

The prevalence of major depression or dysthymia among aged Medicare Fee-for-Service beneficiaries

RESEARCH OBJECTIVE: Estimates of the prevalence of major depression vary widely. Current estimates range from 2 to 14 % depending upon the definition and procedure for diagnosis. Further, most estimates are for special populations, either living in selected geographic areas or receiving specific types of medical care. A national survey of Medicare Fee-for-Service (FFS) beneficiaries provides an opportunity to assess the current level of major depression or dysthymia among a diverse population of older Americans. STUDY DESIGN: The Health Outcomes Survey (HOS) was administered to a national random sample of 1,000 Medicare FFS beneficiaries. We used the Mental Component Summary (MCS) measure of the SF-36 to estimate the prevalence of major depression or dysthymia. Logistic regression was used to examine associated factors. RESULTS: The response rate was 61.7%. Using an MCS score of 42 or lower, prevalence of major depression or dysthymia was estimated to be 25% for respondents age 65 years and older. Logistic regression analysis revealed that the likelihood of major depression or dysthymia was associated with years of education (Odds Ratio (OR) = 0.87), difficulties performing activities of daily living (OR = 1.72), and Medicaid enrollment (OR = 2.67). CONCLUSIONS: The results revealed that one-quarter of the respondents reported mental health problems consistent with major depression or dysthymia. This is higher than previously reported. Like previous studies, years of education, physical impairment, and poverty are strong predictors of major depression or dysthymia. The high rate of major depression or dysthymia implies there may be considerable unmet need among elderly Medicare FFS beneficiaries for diagnosing and treating mental illness.     

Effets tardifs des radiations ionisantes sur les tissus de la sphère otorhinolaryngologique

Numerous structures are included in the irradiated volume of patients presenting with head and neck cancer: skin, mucosa, bone, teeth, cartilage, muscles, salivary glands, etc. Curative intent treatment of such tumours requires aggressive approach which can lead to severe sequellae. These sequellae are in most cases dose-dependent and volume-dependent. However, an appropriate technique might decrease the severity of such sequellae. Details of these late changes are presented, including their pathophysiology, clinical syndromes, potential treatment, and prevention.     

The STR system in the human phenylalanine hydroxylase gene: true fragment length obtained with fluorescent labelled PCR primers

We present a simple, fast, non-radioactive method for the analysis of the polymorphic short tandem repeat (STR) system in the human phenylalanine hydroxylase gene. Previously, sizing of the STR marker involved radiolabelling of PCR amplified fragments and resolution on denaturing polyacrylamide gels using M13 sequencing ladder as a standard. However, this method consistently gave sizes 2 bp longer than the known sequence. The fluorescent method presented here employs internal lane standards and enables accurate sizing of the fragments. To avoid confusion, we suggest that the true fragment lengths are used as reference values in the future. The analysis of STR alleles is valuable for population genetic studies and for targeted mutation screening in phenylketonuria (PKU). It can replace RFLP-based haplotype analysis for carrier detection, and we report its use for prenatal diagnosis in a Northern Irish family with PKU. The analysis of 250 Northern Irish chromosomes, including 128 PKU alleles, showed no significant difference between normal and PKU alleles, with fragment lengths of 238 and 242 bp most common in both groups.     

Uterine contractility and placental histology in abortion by laminaria and metreurynter

Abortions by cervical dilatation with laminaria tents followed by placement of a metreurynter into the lower uterine cavity to provide a mechanical stretch (the method most often used in midterm abortions in Japan) was performed in 7 normal Japanese and American women, 19-24 weeks pregnant, to determine similarities of this process to normal term delivery. Clinical details of each case, as presented in tables, revealed intraamniotic pressure of usually less than 50 mmHg., at a frequency of 2-5 per 10 minutes with a resulting uterine activity of 100-200 Montivideo units which compares closely to contractions during normal delivery. The fetus in each case was normal. Compared to the hypertonic saline-induced abortion, this technique caused less superficial damage to the placenta and no significant ill effects to the patients were noted. It was found that laminaria dilatation alone was sufficient to induce labor without the use of the metreurynter or resorting to oxytocics. While the authors conclude with the caution that neurogenic factors cannot be ruled out, it appears that the myogenic nature of the uterus seems to be significant in abortions caused by mechanical uterine stimulation.     

Factor VIII-von Willebrand factor requires calcium for facilitation of platelet adherence

The role of divalent cations in platelet adherence to deendothelialized human arteries in flowing blood was investigated in an annular perfusion chamber. Spreading of platelets on the subendothelium was impaired below 30 microM of free Ca2+ ions (Ca2+). When Ca2+ was replaced by Mg2+, adherence was unchanged in perfusates without exogenous factor VIII-von Willebrand factor (FVIII-vWF), but the ability of FVIII-vWF to support platelet adherence was lost. Binding of FVIII-vWF to the vessel wall was independent of divalent cations, but bound FVIII-vWF was only able to mediate adherence after exposure to Ca2+. Pretreatment of FVIII-vWF with the calcium chelator EGTA (10 mM) resulted in loss of the ability to facilitate platelet adherence, while the ristocetin cofactor activity remained intact. Full restoration of the ability to mediate platelet adherence could only be obtained by prolonged dialysis against Ca2+ in the millimolar range. These data indicate that divalent cations have at least two separate roles to play in supporting platelet adherence: (1) platelet spreading on the subendothelium requires Ca2+ or Mg2+; (2) FVIII-vWF should be exposed to Ca2+ to obtain its optimal biologic activity in supporting platelet adherence.     

Neonatal subgaleal haematoma: Associated risk factors, complications and outcome

Objective : To describe the obstetric and perinatal factors, in particular the method of delivery, associated with development of a subgaleal haematoma (SGH) and to determine the outcome of survivors with this type of birth trauma. Methodology : Perinatal and obstetric data were retrospectively reviewed for 37 infants admitted to the neonatal unit of the sole tertiary paediatric referral hospital in Western Australia with an SGH, over a 24 year period from 1970 to 1993. These data were compared to data for all Western Australian births. The long-term outcome was obtained through medical and private paediatric records for 26 of these infants. Results : All except one of the neonates had instrumental deliveries; 89% had a vacuum extractor applied to the head at some stage of delivery compared to 10% of the general population of births in Western Australia. There was also a significantly increased risk of failure of attempted vacuum extraction. Of the cases where a vacuum extraction was attempted, 45% also had forceps applied to the head. Coagulopathy was associated with the severity of the SGH. There was also a high frequency of occurrence (40%) of associated head trauma such as intracranial haemorrhage, skull fracture and cerebral oedema, as well as neonatal encephalopathy (73%). The occurrence of these associated features did not correlate significantly with the severity of SGH. Minor complications of SGH included jaundice and facial bruising. There was an excess mortality associated with SGH; however, the long-term outcome for neonatal survivors with this disorder was good. None of the cases studied subsequently developed cerebral palsy or intellectual disability, and minor neurological sequelae only were documented in four infants. Conclusions : SGH is an uncommon type of birth trauma, and is associated with delivery or attempted delivery by vacuum extraction. The most commonly associated clinical problems were hypovolaemia and coagulopathy. The long-term outcome for neonates with this condition is good.