The age-associated alterations in late diastolic function in mice are improved by caloric restriction

Caloric restriction reduces the magnitude of many age-related changes in rodents. Cardiac function is altered with senescence in mice, rats, and healthy humans. We examined the effects of life-long caloric restriction on diastolic and systolic cardiac function in situ using Doppler techniques in ad libitum-fed 30- to 32-month-old (AL) and calorically restricted (CR) 32- to 35-month-old female B6D2-F1 hybrid mice. The heart weight to body weight ratio was similar in AL (5.74 +/- .24 mg/g) and CR (5.68 +/- .20 mg/g) mice. Two systolic functional parameters known to decrease with age in both humans and mice, peak aortic velocity and aortic acceleration, were unchanged by CR compared to AL. In contrast, diastolic function was altered by caloric restriction. Although left ventricular peak early filling velocity (E) was not different between CR and AL, peak atrial filling velocity (A) was 50% lower in CR compared to AL (p < .001). The ratio of early diastolic filling to atrial filling (E/A ratio) was 64% higher in the CR (2.74 +/- .31) than the AL (1.55 +/- .07; p = .004). The fraction of ventricular filling due to atrial systole, the atrial filling fraction, was also reduced in CR (.21 +/- .04) compared to AL (.36 +/- .02; p = .007). These changes occurred in CR without alteration in E deceleration time, which is consistent with improved diastolic function in CR. Through mechanisms that remain unknown, lifelong caloric restriction may prevent the age-related impairments in late diastolic function but does not alter the impairments in systolic or early diastolic cardiac function.     

Review of observational methods in attention deficit hyperactivity disorder (ADHD): Implications for diagnosis.

Reviewed 39 empirical studies in which direct observational methods were used to assess children in whom ADHD had been diagnosed. Classroom studies distinguished ADHD children from comparison groups better than laboratory studies. Behaviors that most consistently distinguished ADHD children from comparison groups included measures of attention, activity, and vocalization. Ways are suggested to improve the efficiency and reliability of observational research. Recommendations are made regarding the importance of classroom observations in the evaluation of ADHD children. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic thromboembolic pulmonary hypertension

Acute pulmonary hypertension has a high mortality at the onset. Patients surviving the first phase will usually recanalize the pulmonary arteries through intrinsic thrombolytic mechanisms and medical treatment. However, in some cases there is insufficient resolution of the emboli with subsequent thrombotic and fibrotic reorganization, leading to a worsening of the pulmonary obstruction. In the open pulmonary arteries the disease may lead to hypertrophy of the media and intimal proliferation, thus leading to a further increase in the pulmonary vascular resistance. This again leads to hypertrophy of the right ventricle and ultimately to right-sided heart failure. Untreated, chronic thromboembolic pulmonary hypertension has a five-year mortality approaching 100%, but extensive pulmonary thrombendarterectomy using extracorporeal circulation and deep hypothermia has been shown to lower the pulmonary vascular resistance and thereby improve the prognosis significantly. Operative treatment can now be offered in Denmark, and the purpose of this review is to draw attention to the disease, its symptoms, diagnosis and the surgical treatment.     

Aggressive limb salvage using tibio-pedal bypass grafting with free tissue transfer in a diabetic patient

Loco-regional recurrence following resection of squamous cell carcinoma of the upper aero-digestive tract is a major problem. Cells exfoliated from malignant tumours have been considered capable of implanting and giving rise to local recurrence or metastatic deposits. A prospective study was performed examining washings from the gloves and instruments used in major head and neck operations to determine if exfoliated cells were indeed present. Following removal of the main tumour specimen all surgeons washed their hands in a solution containing a cell fixative and all instruments were soaked in the solution. Samples were then centrifuged and stained using a modified PAP technique. On occasions nuclear fragments consistent with squamous cell carcinoma were present in both glove and instrument washings. We recommend that all surgeons change gloves and instruments following removal of the main tumour specimen and prior to irrigation of the operative field with a tumoricidal agent.     

A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence

BACKGROUND: Buprenorphine is a partial agonist at the mu-opioid receptor that has been proposed as an alternative to traditional full agonist maintenance therapy for the treatment of opioid addiction. We report on a clinical trial in which the relative safety and efficacy of long-term fixed-dose buprenorphine maintenance was examined in comparison to low- and high-dose methadone maintenance. METHODS: Two hundred twenty-five treatment-seeking opioid addicts (46 women, 179 men) were randomly assigned to receive, in a double-blind manner, either 8 mg/d of buprenorphine, 30 mg/d of methadone, or 80 mg/d of methadone maintenance over a 1-year period. Objective and subjective measures of efficacy (urine toxicology, retention, craving, and withdrawal symptoms) were examined at the study midpoint and at termination, and safety data were tabulated over the entire 52-week study period. RESULTS: Patients assigned to high-dose methadone maintenance performed significantly better on measures of retention, opioid use, and opioid craving than either the low-dose methadone or the buprenorphine group at both 26-week and 52-week time points. Performance on these measures was virtually identical between the latter two groups. No serious adverse health effects attributable to buprenorphine were noted. CONCLUSIONS: Buprenorphine maintenance at 8 mg/d appears to be less than optimally efficacious under the conditions of the present study. Continued research is needed to reconcile these findings with the more positive results reported by other investigative groups. There are no apparent health risks associated with long-term buprenorphine maintenance at this dosage.     

Neuropsychological dysfunction in depression: the relationship to regional cerebral blood flow

The relationship between neuropsychological test performance and regional cerebral blood flow (rCBF) was examined in 29 patients meeting Research Diagnostic Criteria (RDC) for major depression. Following a comprehensive neuropsychological assessment two subsets of tests, comprising tests that discriminated between patients and controls or between patients with varying degrees of global cognitive impairment, were selected. These subtests were entered into a principal components analysis (PCA) which generated a two-factor solution, accounting for 50% of the overall variance in test scores. Individual patient loadings on each of these factors were subsequently correlated with regional cerebral blood flow (rCBF), as measured by positron emission tomography (PET). Both factors demonstrated significant correlations with rCBF in the medial prefrontal cortex and frontal polar cortex while for each factor there were also unique patterns of correlations with posterior brain regions. The findings provide additional evidence that neuropsychological deficits in depression are associated with abnormalities in regional brain function and in particular with the function of the medial prefrontal cortex.     

Inhibition of alanine:glyoxylate aminotransferase 1 dimerization is a prerequisite for its peroxisome-to-mitochondrion mistargeting in primary hyperoxaluria type 1

Peroxisome-to-mitochondrion mistargeting of the homodimeric enzyme alanine:glyoxylate aminotransferase 1 (AGT) in the autosomal recessive disease primary hyperoxaluria type 1 (PH1) is associated with the combined presence of a normally occurring Pro(11)Leu polymorphism and a PH1-specific Gly170Arg mutation. The former leads to the formation of a novel NH2-terminal mitochondrial targeting sequence (MTS), which although sufficient to direct the import of in vitro-translated AGT into isolated mitochondria, requires the additional presence of the Gly170Arg mutation to function efficiently in whole cells. The role of this mutation in the mistargeting phenomenon has remained elusive. It does not interfere with the peroxisomal targeting or import of AGT. In the present study, we have investigated the role of the Gly170Arg mutation in AGT mistargeting. In addition, our studies have led us to examine the relationship between the oligomeric status of AGT and the peroxisomal and mitochondrial import processes. The results obtained show that in vitro-translated AGT rapidly forms dimers that do not readily exchange subunits. Although the presence of the Pro(11)Leu or Gly170Arg substitutions alone had no effect on dimerization, their combined presence abolished homodimerization in vitro. However, AGT containing both substitutions was still able to form heterodimers in vitro with either normal AGT or AGT containing either substitution alone. Expression of various combinations of normal and mutant, as well as epitope-tagged and untagged forms of AGT in whole cells showed that normal AGT rapidly dimerizes in the cytosol and is imported into peroxisomes as a dimer. This dimerization prevents mitochondrial import, even when the AGT possesses an MTS generated by the Pro(11)Leu substitution. The additional presence of the Gly170Arg substitution impairs dimerization sufficiently to allow mitochondrial import. Pharmacological inhibition of mitochondrial import allows AGT containing both substitutions to be imported into peroxisomes efficiently, showing that AGT dimerization is not a prerequisite for peroxisomal import.     

The detection of intrathecal synthesis of anti-herpes simplex IgG antibodies: comparison between an antigen-mediated immunoblotting technique and antibody index calculations. European Union Concerted Action on Virus Meningitis and Encephalitis

The detection of intrathecal antibody synthesis was compared by the calculation of antibody indices (AI) derived from ELISA techniques with the detection of virus-specific oligoclonal IgGs by an antigen-mediated capillary blot technique. Twenty-seven paired serum and cerebrospinal fluid (CSF) samples were examined from 15 immunocompetent patients with herpes simplex virus encephalitis (HSE) diagnosed by PCR on early CSF samples. These techniques were also applied to paired samples from 20 multiple sclerosis (MS) patients, 10 patients with other inflammatory neurological diseases and 10 patients with non inflammatory neurological disorders. There was a good correlation between the results obtained by AI and those obtained by immunoblotting, especially in HSE (2 discordant results out of 27). Discrepancies were more frequent (25%) in MS patients where a "polyspecific" reaction characterized by low affinity antibodies is known to occur. Some of the discrepancies could, in part, be due to serological cross-reaction with varicella zoster virus.     

Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism

The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.     

Condom use by Dutch men with commercial heterosexual contacts: determinants and considerations

We report responses from 559 clients of female prostitutes, with a view to determining to what extent previously identified factors play a part in condom use. To increase the response rate to advertisements in daily and weekly newspapers, interviews were held by phone. This procedure had the advantage of ensuring the anonymity many clients demanded. Of those clients having vaginal or anal contact (91%), 14% had not always used condoms in the previous year. Compared with consistent condom users, these men were less highly educated, had twice as many commercial contacts, and had more contacts with "steady" prostitutes. They were either more emotionally motivated to visit prostitutes than were consistent condom users or exhibited a stronger need for sexual variation. They showed a more compulsive attitude toward visiting prostitutes, had a more negative attitude toward prostitution in general, evaluated condoms more negatively, had a higher personal efficacy to achieve unsafe contacts, and had a higher general risk assessment, commensurate with their behavior. Men with only safe contacts had either an intrinsic or an extrinsic motivation for condom use. Among extrinsically motivated men, their behavior change was more recent and had not yet taken root: They still envisioned unsafe commercial sex to be possible in the future. Education aimed at the small group of men practicing unsafe contacts will not easily and directly lead to behavior change. But these educational activities may support prostitutes to persist in (consistent) condom use, regardless of clients' pressure to do otherwise.