Synthesis and preclinical evaluation of BOLD-100 radiolabeled with ruthenium-97 and ruthenium-103.

BOLD-100 (formerly IT-139, KP1339), a well-established chemotherapeutic agent, is currently being investigated in clinical trials for the treatment of gastric, pancreatic, colorectal, and bile duct cancer. Despite numerous studies, the exact mode of action is still the subject of discussions. Radiolabeled BOLD-100 could be a powerful tool to clarify pharmacokinetic pathways of the compound and to predict therapy responses in patients using nuclear molecular imaging prior to the therapy. In this study, the radiosyntheses of carrier-added (c.a.) [97/103Ru]BOLD-100 were performed with the two ruthenium isotopes ruthenium-103 (103Ru; ß-, γ) and ruthenium-97 (97Ru; EC, γ), of which in particular the latter isotope is suitable for imaging by single-photon emission computed tomography (SPECT). To identify the best tumor-to-background ratio for diagnostic imaging, biodistribution studies were performed with two different injected doses of c.a. [103Ru]BOLD-100 (3 and 30 mg kg-1) in Balb/c mice bearing CT26 allografts over a time period of 72 h. Additionally, ex vivo autoradiography of the tumors (24 h p.i.) was conducted. Our results indicate that the higher injected dose (30 mg kg-1) leads to more unspecific accumulation of the compound in non-targeted tissue, which is likely due to an overload of the albumin transport system. It was also shown that lower amounts of injected c.a. [103Ru]BOLD-100 resulted in a relatively higher tumor uptake and, therefore, a better tumor-to-background ratio, which are encouraging results for future imaging studies using c.a. [97Ru]BOLD-100.

Sapap3 and pathological grooming in humans: Results from the OCD collaborative genetics study.

SAP90/PSD95-associated protein (SAPAP) family proteins are post-synaptic density (PSD) components that interact with other proteins to form a key scaffolding complex at excitatory (glutamatergic) synapses. A recent study found that mice with a deletion of the Sapap3 gene groomed themselves excessively, exhibited increased anxiety-like behaviors, and had cortico-striatal synaptic defects, all of which were preventable with lentiviral-mediated expression of Sapap3 in the striatum; the behavioral abnormalities were also reversible with fluoxetine. In the current study, we sought to determine whether variation within the human Sapap3 gene was associated with grooming disorders (GDs: pathologic nail biting, pathologic skin picking, and/or trichotillomania) and/or obsessive-compulsive disorder (OCD) in 383 families thoroughly phenotyped for OCD genetic studies. We conducted family-based association analyses using the FBAT and GenAssoc statistical packages. Thirty-two percent of the 1,618 participants met criteria for a GD, and 65% met criteria for OCD. Four of six SNPs were nominally associated (P < 0.05) with at least one GD (genotypic relative risks: 1.6-3.3), and all three haplotypes were nominally associated with at least one GD (permuted P < 0.05). None of the SNPs or haplotypes were significantly associated with OCD itself. We conclude that Sapap3 is a promising functional candidate gene for human GDs, though further work is necessary to confirm this preliminary evidence of association.

High impact exercise is more beneficial than dietary calcium for building bone strength in the growing rat skeleton.

The benefits of impact exercise and dietary calcium on bone development are controversial. We used inbred rats under highly controlled conditions to test the independent and combined effects of impact exercise and physiological levels of calcium intakes on the growing skeleton. Forty growing F-344 female rats were fed diets containing either 100% (Ca+; 0.5% Ca) or 40% (Ca(-); 0.2% Ca) of their calcium requirements. Half of each dietary group was subjected to either 10 impacts per day from 45 cm freefall drops (Impact+), or no impact (Impact(-)). All rats received a free choice of physical activity period daily. After 8 weeks, the mechanical strength, volumetric density, geometry, and microarchitecture of their ulnae were measured. Body weight and bone length did not differ among groups. On both diets, freefall impact resulted in greater bone strength, cross-sectional moments of inertia, and endosteal and periosteal circumferences in the shaft. Only Ca+ resulted in greater shaft volumetric bone mineral density (vBMD) but that did not affect shaft breaking strength. In the bone ends, both Impact+ and Ca+ positively affected density and structure of both cortical and trabecular bone but the effects of Impact+ were more pervasive. In the proximal end, Impact+ resulted in greater bone volume fraction (BV/TV) in the trabecular bone due to greater trabecular thickness, and cortical thickness was greater due to a smaller endosteal circumference. Impact+ exerted a compensatory effect on vBMD and BV/TV in Ca(-) rats at the proximal site. In Impact(-) rats only, Ca+ resulted in greater total and cortical vBMD and BV/TV in the proximal ulna. Impact+ and Ca+ exerted additive effects on cortical bone area (BA) in the proximal ulna and on total BA, periosteal circumference, and trabecular vBMD in the distal ulna. In conclusion, impact exercise was more beneficial than adequate dietary calcium to growing bones, although sufficient dietary calcium was beneficial in rats not subjected to impact exercise.

Older women track and field athletes have enhanced calcaneal stiffness.

Vigorous weight-bearing exercise is recommended to women as a method of osteoporosis prevention. This study examined older women athletes to see if they indeed were less likely to develop osteoporosis than those in the general population, and to investigate which factors could have contributed to these results. One hundred and thirty-nine women 40-88 years old, all competitors in a USA National Masters Track and Field Championships, volunteered for the study. Masters refers to competitors > or =40 years old. Their calcaneal stiffness (SI) was measured by a Lunar Achilles+ ultrasonometer. Subjects were also measured for height and weight, and completed a questionnaire on exercise history, diet, lifestyle factors, medical and menopausal issues, and use of hormone replacement therapy (HRT). The women, mean age 57.3 years, had an overall average SI of 99.5 (T-score = 0.04) which is equivalent to that of a 20-year-old woman and 20.8% higher than expected for women of their age. Their median SI remained not different from expected peak bone SI until the age of 70. For analysis, this cohort of women was divided into two groups: premenopausal and postmenopausal athletes. The SI of both groups was correlated with the earliest age at which they had first participated in sports or exercises that impart moderate to high strain rates to the lower limbs and with current participation in high impact track and field events. Variables correlated with SI in the general population, such as weight, HRT, previous fracture, hysterectomy, and current menopausal status, did not predict SI in this cohort. In conclusion, women competing in Masters track and field at the national level had calcaneal stiffness substantially higher than expected for women of their age in the general population, and their participation in vigorous sports and activities, either currently or at a younger age, was predictive of this association.

Adaptations to free-fall impact are different in the shafts and bone ends of rat forelimbs.

Impact exercise can have beneficial effects on the growing skeleton. To understand what changes it promotes in the shafts and ends of weight-bearing bones, we measured the effects of impact from repetitive free falls in growing rats. Fischer 344 female rats, 6.5 wk old, were assigned to one of three groups (n = 10 each). Controls were not dropped, whereas those subjected to impact were dropped from 30 or 60 cm. Rats in both free-fall groups were dropped 10 times per day for 8 wk. Leg bones were mechanically tested, and their cross-sectional area (CSA), cross-sectional moments of inertia, and volumetric bone mineral density (BMD) were measured by peripheral quantitative computed tomography. In the shafts of the forelimbs, but not the hindlimbs, free-fall impact resulted in greater ultimate breaking force, minimum and maximum second moments of area, and CSA but not BMD. In the bone ends of the forelimb and tibial bones, trabecular BMD increased but CSA did not. Landing from 30 and 60 cm produced peak impact forces of 12.0 and 16.7 times the standing forefoot weight for each front leg and of 4.5 and 7.7 times the standing hind foot weight for each hind foot. Overall, free-fall impact affected the forelimbs by increasing trabecular bone density in the bone ends and improving the strength at the shaft as a result of geometric improvements. These results indicate that adaptation to impact may occur by different mechanisms in bone end and shaft regions.

The activation mechanism of rat vanilloid receptor 1 by capsaicin involves the pore domain and differs from the activation by either acid or heat.

The recently cloned rat vanilloid receptor, VR1, can be activated by capsaicin, acid, and heat. To determine the molecular mechanisms facilitating channel opening in response to these stimuli, VR1 and six channels containing charge neutralization point mutations surrounding the putative channel pore domain were expressed and characterized in Xenopus laevis oocytes. Steady-state dose-response relationships, current-voltage relationships, ionic selectivities, and single-channel properties were recorded using voltage-clamp techniques. Three of the mutant channels are significantly more sensitive to capsaicin than is wild-type VR1, whereas none differed in their activation by acidic pH or temperature. Furthermore, one of the mutants has lost all positive cooperativity for capsaicin activation (Hill coefficient congruent with 1, VR1 congruent with 2), is much more selective for Ca(2+), and exhibits a lower efficacy for acid than for capsaicin activation. Single-channel recordings show that capsaicin- and acid-activated channels have the same conductance, that the three mutants with increased capsaicin sensitivity exhibit higher open probabilities at submaximal capsaicin concentrations, and that the gating properties of capsaicin activation differ from those of acid activation. These data indicate that VR1 undergoes conformational changes upon capsaicin binding that it does not undergo in response to activation by protons or thermal stimuli. Furthermore, these structural rearrangements include the putative pore domain and reveal the location of an intracellular domain that contributes to the positive cooperativity seen for capsaicin activation.

Different responses to repeated applications of zingerone in behavioral studies, recordings from intact and cultured TG neurons, and from VR1 receptors.

When applied repetitively to the cornea, capsaicin, the pungent compound in hot pepper, causes an initial eye-wiping response that diminishes upon repeated exposure (tachyphylaxis). This diminution, however, is not observed upon repetitive application of its pungent analogue, zingerone, to the cornea or tongue. In addition, compared with capsaicin, the lingual application of zingerone produces a gustatory response with a shorter latency and duration. Because both the tongue and the cornea are innervated by the trigeminal nerve, and because zingerone and capsaicin are structurally related, it is not evident why the responses to these compounds should give such different behavioral and psychophysical endpoints. We have addressed this issue by measuring the neural responses from rat trigeminal ganglion neurons (TG) to repeated applications of zingerone applied to the cornea, from cultured rat TG neurons, and from cloned capsaicin receptors (VR1) expressed in Xenopus oocytes and then comparing these effects to those evoked by capsaicin. Extracellular recordings from the trigeminal ganglion revealed that the responses to repeated corneal applications of 30 mM zingerone show desensitization. Cultured TG neurons, and oocytes expressing VR1 receptors, were also desensitized by repeated applications of zingerone. Electrophysiological recordings revealed that these two vanilloids could activate the same receptor (VR1), currents in the same neuron, and crossdesensitize. The more rapid onset and shorter duration responses seen with zingerone (compared with capsaicin) provides a rationalization for its more rapid onset and shorter duration gustatory response. We attribute the different behavioral responses to periodic applications of these two agonists to two competing effects: one leading to sensitization, and the other to tachyphylaxis. Which of these dominates depends on the concentration, exposure time, and interstimulus interval. Consequently, whether or not zingerone will exhibit tachyphylaxis depends critically on the experimental conditions.

The development of a community-based family HIV service.

This paper describes the development of a community-based family HIV clinic in south London, an area with one of the highest rates of HIV seroprevalence in the UK. The King's family clinic was developed by broadening existing interdisciplinary services for women with HIV, utilizing the strengths of community-based paediatric care as well as integrating paediatric support from acute hospital-based services. Different models of care for children infected or affected by HIV and problems encountered in developing the service, including ethical dilemmas, and current activity are discussed.

What is vestibular papillomatosis? A study of its prevalence, aetiology and natural history.

OBJECTIVES: To clarify the prevalence, aetiology, symptoms and natural history of vestibular papillomatosis. DESIGN: Study in two parts: 1. prevalence assessed by colposcopic examination of the vulva of unselected patients by one doctor (J.M.W.); 2. patients selected by clinical appearance as having vestibular papillomatosis (by J.M.W. and other doctors) assessed in a research clinic. SETTING: Outpatient genitourinary medicine clinic in South London. SUBJECTS: Part 1 study: 295 female clinic attenders; part 2 study: 18 women with clinical vestibular papillomatosis. MAIN OUTCOME MEASURES: Part 1 study: number of unselected patients found to have vestibular papillomatosis. Part 2 study: associated symptoms, histology, DNA hybridisation and polymerase chain reaction on vulval biopsies. Clinical regression of lesions. Cervical cytology and colposcopy. RESULTS: Part 1 study: Vestibular papillomatosis was identified by colposcopic examination of the vulva in 3/295 (1%) of women. Part 2 study: 9/18 (50%) women with vestibular papillomatosis were asymptomatic; the other nine had intermittent mild symptoms. Thirteen (72%) had a history of genital warts. Vulval biopsies had features suggestive of wart virus infection on histology in 17/18 (94%) and HPV16 was found by DNA hybridisation studies or polymerase chain reaction in 7/18 (39%). On follow up (mean duration 9 months) the vulval lesions had regressed in 9/12 patients. Ten patients had cervical wart virus infection or intraepithelial neoplasia (CIN), or both, and five needed laser treatment for this. CONCLUSIONS: In this study vestibular papillomatosis was associated with human papillomavirus (HPV) infection. This study suggests that vestibular papillomatosis need not be treated, but patients with it may be at increased risk for CIN.

Parvovirus infection and anaemia in a patient with AIDS: case report.

Opportunistic infections such as Pneumocystis carinii pneumonia are well-recognised in patients with the acquired immune deficiency syndrome (AIDS). Anaemia due to a variety of causes also occurs in AIDS. Persistent infection with parvovirus (B19) causing severe anaemia has been reported in patients with leukaemia and congenital immunodeficiency. A case is now reported of parvovirus infection and anaemia, in an adult with AIDS, which responded dramatically to immunoglobulin therapy.

Maternal rubella at St Thomas' Hospital in 1978 and 1986: support for augmenting the rubella vaccination programme.

The effects of the rubella epidemics in 1978 and 1986 among patients attending antenatal clinics at St Thomas' Hospital were compared. Although many pregnant women who had been exposed to rubella-like illnesses were investigated in both 1978 (269) and 1986 (160), the number of cases of maternal rubella was substantially lower in 1986 (1) than in 1978 (17). Rubella vaccination of 11-14-year-old girls was introduced in the United Kingdom in 1970, but 10% of our patients were susceptible and only 36% gave a definite history of vaccination. Despite the smaller number of maternal rubella cases, substantial resources were expended on assessing patients who had been exposed to or who presented with rubella-like illnesses. In 1978 an intensification of the selective rubella vaccination campaign was recommended, but experience in the 1986 epidemic supports the view that the programme should be augmented by vaccination of preschool children with a combined measles, mumps, and rubella vaccine, with a view to rubella eradication.

Continuous vindesine infusion in advanced head and neck cancer.

Sixteen patients with advanced squamous cell carcinoma of the head and neck were treated with a 48-hour I.V. vindesine infusion. The dosage was 3 mg/m2/48 hours every 2 weeks. Toxicity consisted of leukopenia, paresthesias, and phlebitis. Major objective responses were seen in four patients (one CR, three PR), with a median duration of 4 months.

Linitis plastica caused by metastatic lobular carcinoma of the breast.

We describe herein the syndrome of linitis plastica caused by metastatic lobular carcinoma of the breast. In 14 of our 31 patients, gastric involvement, alone or concurrent with other metastasis, provided the first sign of tumor dissemination. The distinction of primary and secondary gastric malignancies in patients with a history of breast cancer is most important for successful management of patients. At a time when primary gastric carcinoma is decreasing nationally, an awareness of the association of lobular breast tumors with linitis plastica due to metastases may modify diagnostic evaluation and treatment planning in patients who present with symptoms of this syndrome.