Comparison of in vitro and in vivo alpha/beta ratios for prostate cancer

Parallel in vitro and in vivo studies provide insight into the relationship between clinical response and intrinsic cellular radiosensitivity and may aid in the development of predictive assays. Compilations of radiosensitivity parameters from in vitro experiments can also be used to examine the potential effectiveness of alternative or new treatment plan designs until enough clinical data become available to directly estimate the requisite radiosensitivity parameters. In this work, survival data for six prostate cancer cell lines (ten datasets total) have been extracted from the literature and re-analysed using the linear-quadratic (LQ) survival model. The paired bootstrap technique for regression is used to compute 95% confidence intervals for the estimated radiosensitivity parameters. LQ radiosensitivity parameters derived from the in vitro data are then compared to radiosensitivity parameters derived from clinical data for prostate cancer. Estimates of alpha range from 0.09 to 0.35 Gy(-1) (all cell lines), and the alpha/beta ratio ranges from 1.09 to 6.29 Gy (all cell lines). Point estimates of the repair half-time (PPC-1, TSU-Pr1, PC-3 and DU-145 cell lines) range from 5.7 to 8.9 h (95% confidence interval from 0.26 h to 10.7 h). Differences in the radiosensitivity parameters determined from the data reported by different laboratories are as large as or larger than the differences in radiosensitivity parameters observed among the various prostate cell lines. The reported studies demonstrate that even seemingly small corrections for dose rate effects, such as those expected in high dose rate (HDR) experiments, can sometimes have a significant impact on estimates of alpha and alpha/beta. By neglecting dose rate effects in the analysis of HDR experiments, estimates of the alpha/beta, ratio may be too high by factors as large as 1.3 to 6.2. The half-time for repair derived from the in vitro experiments appears significantly larger (slower repair rate) than estimates derived from the clinical data. However, the prostate radiosensitivity parameters alpha and alpha/beta may be approximately the same in vitro and in vivo. Most of the in vitro data are consistent with an alpha/beta ratio for prostate cancer less than 3 or 4 Gy.     

Adeno-associated virus vector gene transfer and sarcolemmal expression of a 144 kDa micro-dystrophin effectively restores the dystrophin-associated protein complex and inhibits myofibre degeneration in nude/mdx mice

Duchenne muscular dystrophy is a severe life-threatening X-linked recessive disorder, caused by mutations in the dystrophin gene, for which currently there is no effective treatment. Because of the large size of the dystrophin cDNA (14 kb) this precluded it from being used in early adenovirus- or retrovirus-based gene therapy vectors. However, some therapeutic success has been achieved in mdx mice using adenovirus- and retrovirus-mediated transfer of a 6.3 kb recombinant mini-dystrophin cDNA. Despite this, problems with immunogenicity and inefficient transduction of mature myofibres make these vectors less than ideal for gene transfer to skeletal muscle. Adeno-associated viral (AAV) vectors overcome many of the problems associated with other vector systems. However, AAV vectors can only accommodate <5 kb of foreign DNA. For this reason we have produced a micro-dystrophin cDNA gene construct that is <3.8 kb. This construct, driven by a CMV promoter, was introduced into the skeletal muscle of 12-day-old nude/mdx mice using an AAV vector, resulting in specific sarcolemmal expression of micro-dystrophin in >50% of myofibres up to 20 weeks of age, and effective restoration of the dystrophin-associated protein (DAP) complex components. Additionally, evaluation of central nucleation indicated a significant inhibition of degenerative dystrophic muscle pathology. We have therefore shown that the current micro-dystrophin gene delivered in vivo using an AAV vector is not only capable of restoring sarcolemmal DAP complexes, but can also ameliorate dystrophic pathology at the cellular level.     

An autosomal dominant syndrome of acromegaloid facial appearance and generalised hypertrichosis terminalis.

We report a family in which a phenotype of acromegaloid facial appearance (AFA) and generalised hypertrichosis terminalis segregates through three generations. Congenital hypertrichosis terminalis and AFA have been previously reported as independent autosomal dominant traits. This is the first report to delineate an autosomal dominant transmission of the combined phenotype.     

A history of personal violence and postpartum depression: is there a link?

Summary Background: A link between violence and depression has been shown, but not a link between violence and postpartum depression. This study sought to determine if there is an association between a history of abuse (physical, sexual, emotional as a child or adult) and postpartum depression (PPD). Method: 200 postpartum women were recruited from 6 hospitals. At 8–10 weeks postpartum, a telephone interviewer asked women about physical, emotional or sexual abuse as an adult or child and sociodemographic, obstetrical and personal medical history. PPD was assessed using the Edinburgh Postnatal Depression Scale (EPDS, score of ≥12). Abuse was determined by the Conflict Tactics Scale or the Abuse Assessment Screen. Chi-square and logistic regression were used to determine the relationship between violence and PPD. Results: 11% of women had EPDS scores of ≥12. Rates of childhood (6.5%), or adult (6.5%) physical abuse; and childhood (13%) or adult (14%) sexual abuse were reported by respondents. Emotional abuse in the current relationship (29.6%) exceeded that of childhood abuse (3.5%). Overall 43.2% of respondents had at least one form of abuse. Having a history of depression (OR = 3.3 (95% CI, 1.3–8.7)), panic attack during pregnancy (OR = 5.4 (1.6–19.0)), maternal complications (OR = 5.0 (1.7–15.1)), low social support (OR = 3.3 (1.3–8.7)) and emotional abuse (OR = 2.8 (1.1–7.4) were associated with PPD. Conclusion: Emotional abuse but not physical or sexual abuse was found to be associated with PPD. A possible explanation for this relationship may be that being in an abusive situation puts one at risk for depression and in turn, postpartum depression.     

Migraine headaches and panic attacks

Migraine headache and panic attacks are two common conditions which first occur at an early age and appear to have a number of underlying physiologic abnormalities in common. In a population-based telephone interview survey examining headache occurrence in approximately 10,000 subjects, 12-29 years old, we assessed the prevalence of panic disorder (and a less severe entity designated as panic syndrome) using an abbreviated version of the National Institute of Mental Health Diagnostic Interview Survey. Subjects with panic disorder or panic syndrome reported more frequent occurrence of headaches during the preceding week, as well as headaches of longer duration and substantially more headaches with migraine symptoms than individuals without a history of panic attack. Males with panic disorder were 7 times more likely than those without this condition to report the occurrence of a migraine headache in the previous week. In addition, 5.5% of males and 9.5% of females with panic disorder or panic syndrome reported 25% of the total migraine headaches described by all study subjects in the one-week recall period.     

Depression, APOE genotype and subjective memory impairment: a cross-sectional study in an African-Caribbean population

BACKGROUND: Subjective memory impairment (SMI) is common in older populations but its aetiology and clinical significance is uncertain. Depression has been reported to be strongly associated with SMI. Associations with objective cognitive impairment are less clear cut. Other factors suggested to be associated with SMI include poor physical health and the apolipoprotein E (APOE) epsilon4 allele. Studies of SMI have been predominantly confined to white Caucasian populations. METHOD: A community study was carried out in a UK African-Caribbean population aged 55-75, sampled from primary care lists. Twenty-three per cent were classified with SMI. Depression was defined using the 10-item Geriatric Depression Scale. Other aetiological factors investigated were education, objective cognitive function, APOE genotype, disablement and vascular disease/risk. The principal analysis was restricted to 243 participants scoring > 20 on the Mini-Mental State Examination (85%). A second analysis included all 290 participants. RESULTS: Depression, self-reported physical impairment and APOE epsilon4 were associated with SMI. The association between SMI and physical impairment was not explained by depression, vascular disease/risk, or disability/handicap. The association between epsilon4 and SMI increased as MMSE scores decreased and was particularly strong in those with depression. The epsilon4 allele was present in 69% (95% CI 41-89%) of those with depression and SMI compared with 28% (20-36%) of those with neither. CONCLUSIONS: Depression may not be a sufficient explanation for subjective memory complaints. Memory complaints in the presence of depression are associated with high prevalence of epsilon4 and therefore, presumably, a raised risk of subsequent dementia.