Teriparatide Treatment of Severe Osteoporosis Reduces the Risk of Vertebral Fractures Compared with Standard Care in Routine Clinical Practice

Teriparatide (TPTD) is often used for the treatment of patients with severe osteoporosis, but its effectiveness in this patient group has not been specifically studied. Here, we report upon the results of an observational study involving 323 patients with severe osteoporosis (bone density T-score of ?4 or less) who were treated at a specialist osteoporosis clinic with TPTD (n = 217) or standard care (n = 106) over a 5.5-year period. The standard care group did not receive TPTD because they declined to self-inject (59.4 %), had a contraindication (7.5 %), or were already stabilized on oral bisphosphonates (33 %). The two groups were matched for the severity of osteoporosis, fracture risk, and most other clinical variables. The annual percentage change in lumbar spine bone mineral density (BMD) was greater in the TPTD group (8.2 ± 6.0 vs. 5.0 ± 8.4, p = 0.002), but there was no difference in response of hip BMD. During follow-up, 3/217 (1.38 %) TPTD-treated patients had new vertebral fractures compared with 7/106 (6.6 %) receiving standard care (p = 0.011), but there was no difference between the groups in the rate of nonvertebral fractures (11.1 vs. 8.5 %, p = 0.47). Logistic regression analysis adjusting for baseline characteristics showed that the risk of vertebral fractures in TPTD-treated patients was significantly reduced compared with standard care (odds ratio = 0.12, 95 % confidence interval 0.03–0.55, p = 0.007). Treatment of severe spinal osteoporosis with TPTD substantially reduces the risk of vertebral fractures compared with standard care and may be the preferred treatment in this patient group.     

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.     

Book review of The Neuropsychiatry of Epilepsy. Edited by Michael Trimble and Bettina Schmitz (Cambridge,UK: Cambridge University Press, 2002). [Pp. 350]. ISBN 0521005167 (pbk). £39.95.

Bimanual co-ordination is a field that has generated much research interest. It is clear that when hands move simultaneously there is a tendency for such movements to be synchronized. This phenomenon has also been observed in individuals with congenital brain damage, such as cerebral palsy. This paper provides an overview of past and current work in the area of bimanual co-ordination looking at the nature of the coupling and the underlying control of such movements. Work on ‘non-disabled’ individuals and unimanual reaching and grasping is included, but the main emphasis is bimanual co-ordination in children with hemiparetic cerebral palsy. The direction for future research is discussed and consideration given to the therapeutic implications of such work.     

Identification of 1-hydroxypyrene glucuronide as a major pyrene metabolite in human urine by synchronous fluorescence spectroscopy and gas chromatography-mass spectrometry

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs)from various occupational, environmental, medicinal and dietarysources. The measurement of specific PAH metabolites, particularly1-hydroxypyrene, in human urine treated with deconjugating enzymes(e.g. ß-glucuronidase) has been extensively used asa means of assessing recent exposure to PAHs. We have examinedpyrene metabolites in human urine prior to enzymatic deconjugationin order to determine the relative proportions of conjugatedand unconjugated pyrene metabolites. The analytical method utilizedimmuno-affinity chromatography, high performance liquid chromatography(HPLC) and the complementary techniques of synchronous fluorescencespectroscopy (SFS) and gas chromatography-mass spectrometry(GC-MS) to measure pyrene-containing metabolites. SFS analysisof immunoaffinity-purified urine samples showed fluorescencespectra characteristic of the pyrene moiety (using wavelengthdifferences of 34 nm, 54 nm and 102 nm). These spectra are producedby several PAHs containing the pyrene moiety. HPLC analysiswith fluorescence detection indicated that the major fluorescentmetabolite in immunoaffinity-purified urine was much more polarthan simple hydroxylated metabolites of pyrene (1-hydroxypyrene)or benzo[a]pyrene (benzofa] pyrene-diols or -tetrols). Followingdigestion with ß-glucuronidase, this metabolite co-chromatographedwith authentic 1-hydroxypyrene and exhibited fluorescence spectracharacteristic of 1-hydroxypyrene, suggesting that the majormetabolite was a glucuronide conjugate of 1-hydroxypyrene. Thiswas subsequently confirmed by GC-MS analysis of trimethylsilylderivatives of the major metabolite; both 1-hydroxypyrene andglucuronic acid were detected independently as derivatized products.Since 1-hydroxypyrene glucuronide is approximately 5-fold morefluorescent than 1-hydroxypyrene, it may provide a more sensitivebiomarker for assessing exposure to pyrene in mixtures of PAHs.     

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy

PURPOSE: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. METHODS: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the beta 2 subunit of CHRN. RESULTS: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. CONCLUSIONS: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.     

Detection of malondialdehyde DNA adducts in human colorectal mucosa: relationship with diet and the presence of adenomas.

Colorectal biopsies from normal mucosa of participants in the United Kingdom Flexible Sigmoidoscopy Trial and European Prospective Investigation on Cancer (EPIC; n = 162) were analyzed for the presence of malondialdehyde-deoxyguanosine (M(1)-dG), a DNA adduct derived from lipid peroxidation. The aim was to investigate whether dietary factors can modulate M(1)-dG levels and whether M(1)-dG in normal mucosa is a risk factor for colorectal adenomas. Samples were analyzed using a sensitive immunoblot blot assay. This study has shown for the first time that M(1)-dG is present in human colorectal tissue. M(1)-dG levels ranged from undetectable (n = 13) to 12.23 per 10(7) total bases. Mean levels were 4.3 +/- 3 and 4.6 +/- 2.9 per 10(7) total bases in men and women, respectively. In men, there were positive associations of adduct levels with height and age, and inverse associations with body mass index. Legumes, fruit, salad, and whole meal bread were inversely associated with M(1)-dG adducts, whereas consumption of offal, white meat, beer, and alcohol were positively associated with elevated levels. In women, there was an inverse association of the adduct with the ratio of polyunsaturated:saturated fatty acids (P = 0.019) and a weak positive correlation with saturated fat (P < 0.061). When levels of adducts were compared in individuals with and without adenomas, there was a trend for higher levels in individuals presenting with adenomas especially in the highest category of M(1)-dG adducts (P < 0.005).     

Blood pressure and urinary sodium in men and women: the Norfolk Cohort of the European Prospective Investigation into Cancer (EPIC-Norfolk)

BACKGROUND: Abundant evidence indicates that a high sodium intake is causally related to high blood pressure, but debate over recommendations to reduce dietary sodium in the general population continues. A key issue is whether differences in usual sodium intake within the range feasible in free-living populations have clinical or public health relevance. OBJECTIVE: We examined the relation between blood pressure and urinary sodium as a marker of dietary intake. DESIGN: This was a study of 23104 community-living adults aged 45-79 y. RESULTS: Mean systolic and diastolic blood pressure increased as the ratio of urinary sodium to creatinine increased (as estimated from a casual urine sample), with differences of 7.2 mm Hg for systolic blood pressure and 3.0 mm Hg for diastolic blood pressure (P < 0.0001) between the top and bottom quintiles. This trend was independent of age, body mass index, urinary potassium:creatinine, and smoking and was consistent by sex and history of hypertension. The prevalence of those with systolic blood pressure >/= 160 mm Hg halved from 12% in the top quintile to 6% in the bottom quintile; the odds ratio for having systolic blood pressure >/= 160 mm Hg was 2.48 (95% CI: 1.90, 3.22) for men and 2.67 (95% CI: 2.08, 3.43) for women in the top compared with the bottom quintile of urinary sodium. Estimated mean sodium intakes in the lowest and highest quintiles were approximately 80 and 220 mmol/d, respectively. CONCLUSIONS: Within the usual range found in a free-living population, differences in urinary sodium, an indicator of dietary sodium intake, are associated with blood pressure differences of clinical and public health relevance. Our findings reinforce recommendations to lower average sodium intakes in the general population.