GH4ZD10 cells expressing rat 5-HT1A receptors coupled to adenylyl cyclase are a model for the postsynaptic receptors in the rat hippocampus.

1. Vasoactive intestinal polypeptide (VIP) stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) production by cultured GH4ZD10 cells with an EC50 value of about 7 nM. The extracellularly recovered cyclic AMP predominated, and was reduced by co-incubation with 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT), whereas dopamine (0.1-30 microM) did not reduce VIP-stimulated cyclic AMP production. 2. The responses to 5-HT and 8-OH-DPAT were blocked by (-)-alprenolol and NAN 190. The antagonism by (-)-alprenolol was competitive in nature with a pA2 value of 7.0. 3. The responsiveness of the cells to 5-HT agonists was highly dependent upon the culturing conditions used. Thus, 8-OH-DPAT inhibition of VIP (30 nM)-stimulated cyclic AMP production decreased with increasing passage number of the cells. Reduction of the zinc concentration used to promote expression of the 5-HT1A receptor gene produced a greater sensitivity of the cells to 5-HT agonists. 4. Under such conditions, the following efficacies (5-HT = 100) were found: lisuride 106, (+)-lysergic-acid diethylamide 100, 5-methoxy-N,N-dimethyltryptamine 98, RU 24949 98, 5-carboxamidotryptamine 97, (+/-)-8-OH-DPAT 90, (+)-8-OH-DPAT 87, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine 86, flesinoxan 79/88, (-)-8-OH-DPAT 62, buspirone 43/50, ipsapirone 46. Spiroxatrine and spiperone had a low intrinsic activity, but reduced the response to 5-HT. These efficacies are similar to those reported in the literature for post-synaptically localized 5-HT1A receptors in the rat hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated quantitative bone scintigraphy in patients with prostatic carcinoma treated with orchiectomy

Bone scintigraphy was performed in 16 men with newly diagnosed prostatic carcinoma before orchiectomy as well as 2 weeks and 2 months after operation. The uptake in the lower thoracic and lumbar vertebrae was registered up to 240 min after injection of ^99mTc-MDP and was then calculated for each patient and vertebra. The relative standard deviation in measured uptake due to measuring technique was estimated to be±7%. In eight patients, who had normal bone scintigraphies before orchiectomy, there were no changes in the uptake values after operation. The remaining eight patients had widespread metastatic involvement prior to treatment. Six of these patients showed a so called flare phenomenon in the abnormal vertebrae which means an initial increase in uptake after operation followed by a decreased uptake in response to therapy. One patient had a continuously increased uptake in all the abnormal vertebrae which correlated well with the clinical progression of the disease, while in another patient both reactions were seen. Thus, repeated quantitative bone scintigraphies using ^99mTc-MDP can be made in a reproducible way and can be a useful tool to follow a patient's response to treatment.     

Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21)

The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML-M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60-kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90-kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)-positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150-kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150-kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)-positive MDS/AML. Genes Chromosomes Cancer 27:229-238, 2000.     

The effect of sympathetic stimulation on proximal brachial artery mechanics in humans--differential behaviour within the length of the brachial artery?

AIMS: The mechanical properties of arteries play a major role in the regulation of blood pressure and cardiac performance. The effect of sympathetic stimulation on the mechanical properties of the proximal brachial artery was analysed in 18 healthy volunteers, nine young (25 +/- 2 years) and nine elderly (69 +/- 2 years). METHODS: A non-invasive ultrasonic echo-tracking system for measurement of systolic/diastolic variation of the proximal brachial artery diameter in combination with intra-arterial pressure measurements was used to determine wall mechanics. The pressure-diameter (P-D) relationship, distensibility coefficient (DC), compliance coefficient (CC) and stiffness(beta) were obtained at rest and during sympathetic stimulation induced by lower body negative pressure (LBNP). RESULTS: The peripheral vascular resistance increased by 100 and 72%, respectively in the young and elderly during LBNP (P < 0.001). Simultaneously, the mechanical properties of the proximal brachial artery remained unaltered, as estimated from both P-D relationship and stiffness in young (beta-index rest: 5.2 +/- 0.9, LBNP: 5.5 +/- 1.3, NS) as well as elderly (beta-index rest: 13.6 +/- 4.6, LBNP: 16.1 +/- 4.7, NS). CONCLUSIONS: LBNP-induced sympathetic activation does not change proximal brachial artery mechanics, in contrast to earlier reports on the muscular distal brachial artery. This may imply that the transition between elastic and muscular artery behaviour is within the length of the brachial artery, where the site of transition from elastic to muscular wall structure needs to be specified in future studies.     

Identification of a commonly amplified 4.3 Mb region with overexpression of C8FW, but not MYC in MYC-containing double minutes in myeloid malignancies

Double minutes (dmin), the cytogenetic hallmark of genomic amplification, are found in approximately 1% of karyotypically abnormal acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS). The MYC gene at 8q24 has been reported to be amplified in the majority of the cases, and generally it has been assumed that MYC is the target gene. However, only a few studies have focused on the extent of the amplicon or on the expression patterns of the amplified genes. We have studied six cases (five AML and one MDS) with MYC-containing dmin. Detailed fluorescence in situ hybridization analyses identified a common 4.3 Mb amplicon, with clustered proximal and distal breakpoints, harboring eight known genes (C8FW, NSE2, POU5FLC20, MYC, PVT1, AK093424, MGC27434 and MLZE). The corresponding region was deleted in one of the chromosome 8 homologues in five of the six cases, suggesting that the dmin originated through extra replication (or loop-formation)--excision--amplification. Northern blot analysis revealed that MYC was not overexpressed. Instead, the C8FW gene, encoding a phosphoprotein regulated by mitogenic pathways, displayed increased expression. These results exclude MYC as the target gene and indicate that overexpression of C8FW may be the functionally important consequence of 8q24 amplicons in AML and MDS.     

The effect of local cold application on intramuscular blood flow at rest and after running

Local blood flow was measured with 133Xe clearance technique in eight male distance runners, where one leg was cooled for 20 min by applying two "instant cold packs" on the quadriceps muscle. An initial cooling period after resting was followed by a second cooling period 10 min after running. Skin temperature was maximally reduced after 4.5 min of cooling, both at rest and after running, by 15 degrees C and 14.9 degrees C, respectively. During the first 5 min of cooling no reduction of blood flow was seen. After 10 min of cooling blood flow was significantly reduced in the cooled compared to the control leg by 49% (P less than 0.05) after resting and 34% (P less than 0.05) after running. A maximum reduction of blood flow by 66 and 69% (P less than 0.01), respectively, was seen 10 min after the cooling period. In the event of an acute injury, this delayed reaction of cryotherapy on intramuscular blood flow should be carefully considered.     

Lead in finger-bone analysed in vivo in active and retired lead workers

In 75 active lead workers the median lead level in finger-bone (bone-Pb), as determined in vivo by an X-ray fluorescence method, was 43 micrograms/g (range less than 20-122). In 32 retired workers the median level was even higher, 59 micrograms/g (range less than 20-135), which indicates a slow turnover rate of lead in finger-bone. This was confirmed in 18 of the "active" workers, in whom bone-Pb was studied in connection with an exposure-free period. In spite of a significant decrease in blood-lead levels (B-Pb), no systematic change of bone-Pb occurred. There was an increase of bone-Pb with time of employment, but with a large interindividual variation. No association was found between bone-Pb and present B-Pb in the active lead workers. However, in the retired ones, B-Pb rose with increasing bone-Pb. The bone-lead pool thus causes an "internal" lead exposure.     

Community-based injury prevention: effects on health care utilization.

BACKGROUND: Worldwide, an estimated 78 million people are disabled each year because of unintentional injuries and about 3 million die. The WHO Safe Community model is a framework for community-based injury prevention programmes. The aim of this study is to evaluate the outcome on health care utilization of a Safe Community programme. METHODS: The incidence of injuries treated at health care facilities in an intervention municipality (pop. 41,000) was compared to the injury incidence in a control municipality (pop. 26,000). The incidence was recorded immediately before and one year after programme implementation from registrations made during all first-contact health care visits and from examination of hospital discharge registers. RESULTS: The incidence of health care treated injuries in the intervention area had decreased by 13% (95% CI: 9-16%) from 119 (95% CI: 115-122) per 1000 population-years to 104 (95% CI: 101-107). In the control area, the corresponding injury incidences were 104 (95% CI: 100-108) and 106 (95% CI: 102-109). The hospital-treated injuries in the intervention area decreased by 15% (95% CI: 7-24%) from 19 (95% CI: 17-20) per 1000 population-years to 16 (95% CI: 15-17), while in the control area, the incidences remained at 13 (95% CI: 11-14) per 1000 population-years. Utilization of acute care in the intervention area for reasons other than injuries increased by 8% (95% CI: 6-10%), while in the control area, the number of visits did not show significant change. CONCLUSION: This first controlled evaluation showed that an injury prevention programme based on local action groups can significantly reduce injuries requiring health care in a community. Local prevention can provide a complement to national level campaigns.