Synthesis of ketone analogues of prolyl and pipecolyl ester FKBP12 ligands

The recently discovered small-molecule ligands for the peptidyl and prolyl isomerases (PPIase) of FKBP12 have been shown to possess powerful neuroprotective and neuroregenerative effects. Ketone analogues of the prolyl and pipecolyl esters, which mimic only the FKBP binding domain portion of FK506, are proposed and an efficient synthetic strategy is presented in this report, along with the preliminary results of in vitro and in vivo biological studies.     

Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an heritable connective tissue disorder with clinical manifestations of the ocular, dermal, and cardiovascular system. The purpose of this study was to investigate the prevalence of symptomatic intracranial aneurysms (IAs) and ischaemic stroke (IS) in PXE. METHODS: The records of 100 patients with PXE were retrieved. All patients were contacted and data on complications were collected. The literature was reviewed regarding PXE, ISs, and IAs. RESULTS: No patient with PXE had a symptomatic IA as presenting symptom. One patient presented with an IS. During follow-up of 94 of the 100 patients (mean follow-up 17.1 years, range 1-49 years), none presented a symptomatic IA (3,168 retrospective patient observation years and 1, 602 prospective patient observation years). Upper gastrointestinal haemorrhage during follow-up occurred in 17 patients, in 1 patient during aspirin use. One patient has IS as presenting symptom and a recurrence during follow-up, and 7 patients had IS during follow-up. All were caused by small-vessel disease. The relative risk of IS in PXE under 65 years compared with the general population was 3.6 (95% confidence interval 3.3-4.0). CONCLUSIONS: On the basis of the currently available data, an association between symptomatic IAs and PXE is unlikely. However, the incidence of IS, due to small-vessel disease, was increased. Antiplatelet therapy in patients with PXE may lead to a high incidence of upper gastrointestinal haemorrhages.     

Chronic radiographic lung changes in children with vertically transmitted HIV-1 infection

OBJECTIVE: We prospectively studied children with and without maternally transmitted HIV-1 infection born to mothers infected with HIV-1 to determine the incidence of chronic radiographic lung changes (CRC) and to correlate these changes with clinical assessments. SUBJECTS AND METHODS: Between 1990 and 1997, we scored 3050 chest radiographs using a standardized form. Group I children (n = 201) were HIV-1-infected at enrollment. Group II children (n = 512) were enrolled prenatally or before 28 days postpartum and subsequently subdivided into group IIa (n = 86), children identified as HIV-1-infected; and group IIb (n = 426), those who were HIV-1-uninfected. CRC were defined as parenchymal consolidations or nodular disease lasting 3 months or more or increased bronchovascular markings or reticular densities lasting 6 months or more. Morbidity was assessed by CD4 counts, viral load, the presence of low oxygen saturation, wheezing, tachypnea, crackles, and clubbing. RESULTS: The cumulative incidence of chronic radiographic lung changes in HIV-1-infected children was 32.8% by 4 years old, with increased bronchovascular markings or reticular densities being most common. Chronic changes were associated with lower CD4 cell counts and higher viral loads. Resolution of these chronic changes was associated with decreasing CD4 cell counts but not with lower rates of clinical findings, viral load, or difference in survival. CONCLUSION: With increased survival, CRC are becoming more common. The resolution of these changes may indicate immunologic deterioration rather than clinical improvement.     

High mobility group proteins 1 and 2 recognize chromium-damaged DNA

Chromium (Cr) is a human carcinogen and a potent DNA damaging agent. Incubation of DNA with CrCl3 resulted in dose-dependent binding of Cr to DNA and, at concentrations >20 microM, altered the electrophoretic mobility of a 100 bp oligonucleotide. We also demonstrate that high mobility group (HMG) proteins 1 and 2 bind Cr-damaged DNA (Cr-DNA). Protein binding was lesion density-dependent, with maximal binding to DNA treated with 100 microM CrCl3. HMG2 binds to Cr-DNA with a calculated Kd of approximately 10(-9) M. These proteins also bound DNA obtained from chromate-treated cells. These results suggest that the covalent attachment of Cr to DNA induces alterations in DNA structure which are recognized by HMG1 and HMG2. Therefore, these proteins may function as Cr-damaged DNA recognition proteins in vivo and as a consequence of binding, may play a role in directing the cellular response to Cr-DNA adduct formation.      

Sexual precocity: sex incidence and aetiology

The aetiology of 197 girls and 16 boys presenting with sexual precocity was reviewed. Ninety one girls and four boys had central precocious puberty (M:F 23:1); a cause was identified in all the boys but in only six girls. All boys with precocious puberty need detailed investigation; in girls investigation should be based on clinical findings, particularly the consonance of puberty.     

Adenocarcinoma of the esophagus: risk factors and prevention

Esophageal cancer, with an estimated number of 12,300 new cases in the year 2000, is relatively uncommon in the United States but produces a high number of annual deaths, estimated at 12,100. Moreover, the incidence of the adenocarcinoma histologic type of esophageal cancer has been rising over the past two decades. Identification of risk factors could lead to primary prevention, as well as earlier diagnosis, treatment, and increased survival. Multiple risk factors are associated with the development of esophageal adenocarcinoma. These include Barrett's esophagus, acid peptic disorders, motor disorders of the esophagus, other malignancies, medications, environmental exposures, diet, and nutrition. However, no one particular risk factor is responsible for the rising incidence of esophageal cancer. Several preventive strategies are under investigation using such agents as nonsteroidal anti-inflammatory drugs (NSAIDs), selenium, alpha-difluoromethylornithine (DFMO), and retinoids. As we gain more insight into the biology of this disease, other risk factors will hopefully be identified that will enable us to develop effective prevention strategies and, thus, reverse the current rising incidence of esophageal carcinoma.     

Reduction of sound levels with antinoise in MR imaging

A combination of active and passive techniques was used to reduce the sound levels in magnetic resonance imagers. These techniques were integrated into an existing audio system. Measurements of sound reduction varied with the protocol being used and averaged 9.9 dB with coaxial cabling and 14.2 dB with fiberoptic conduction of the feedback signal to a controller. Patient comfort and communication were improved.     

Avoidable visual impairment in The Netherlands: the project "Vision 2020 Netherlands" of the World Health Organization

In the year 2004 there were an estimated 220,000-320,000 people in The Netherlands with visual impairment. In 150,000-220,000 (70%) of them the visual impairment is either curable or could have been prevented. Those most at risk are people with intellectual disabilities, elderly people in care institutions, elderly people in general and diabetics. 'Vision 2020 Netherlands', an initiative of the World Health Organization, was launched to eliminate avoidable visual impairment in the Netherlands by the year 2020 by means of awareness campaigns, implementation of screening programmes and by expanding eye care capacity through efficient cooperation between the professional groups involved in eye care.