Bulbectomy Enhances Neurogenesis and Cell Turnover of Primary Olfactory Neurons But Does Not Abolish Carnosine Expression

Primary olfactory neurons located in the olfactory neuroepithelium project to the ipsilateral olfactory bulb and undergo a continuous process of neurogenesis and differentiation. We describe, in the adult rat, the kinetics of proliferation, differentiation and survival of primary olfactory neurons either in the presence or absence of their target, the olfactory bulb. The experimental design included unilateral bulbectomy, coupled with a single bromodeoxyuridine pulse 35 days after surgery. The rate of proliferation and survival of olfactory neurons was then examined by immunohistochemistry for bromodeoxyuridine, and the differentiation status by in situ hybridization for calmodulin messenger RNA in immature and mature olfactory neurons and immunohistochemistry for the dipeptide carnosine in mature olfactory neurons. We show that primary olfactory neurons can synthesize carnosine in the absence of the olfactory bulb. However, the number of carnosine-immunopositive neurons in the absence of their target is dramatically reduced to less than one-fourth, whereas the number of olfactory neurons expressing calmodulin messenger RNA is only slightly reduced. The numeric reduction of camosine-positive neurons in the target-deprived neuroepithelium is correlated with a dramatic reduction in the survival rate of olfactory neurons, since newly generated olfactory neurons are completely lost 35 days after the bromodeoxyuridine pulse. In contrast, in the normal olfactory neuroepithelium almost one-third of newly generated olfactory neurons survive 35 days after the bromodeoxyuridine pulse. On the whole, these data indicate that most of the primary olfactory neurons have a short lifespan but that once they have connected with the olfactory bulb they may persist longer, and suggest that throughout adulthood olfactory neurons are overproduced, differentiate independently from their target, and then undergo a process of target-induced neuronal selection.     

The effects of antiinflammatory steroids on the response of the guinea-pig isolated ileum to acetylcholine,histamine, nicotine, 5-hydroxytryptamine and electrical stimulation

Summary High concentrations of antiinflammatory steroids (2.5–40 g/ml) reversibly inhibited the electrically induced contractions of the guinea-pig isolated ileum. At 40 g/ml they also reversibly inhibited contractions clicited by acetylcholine, histamine, nicotine and 5-hydroxytryptamine. PGE₁ (2.5 ng/ml), PGE₂ (2.5 ng/ml) and PGF₂ (25 ng/ml) antagonized these effects.The inhibition of contractions elicited by direct agonists were less pronounced than those elicited by indirect or partly indirect agonists. The inhibitory effect of steroids may be related to non-specific actions on biological membranes. An overall sensitization of the smooth muscle by PG's may explain their antagonism to inhibition by steroids.     

Iatrogenic Thyrotoxicosis: Causal Circumstances, Pathophysiology, and Principles of Treatment—Review of the Literature

Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones. In most instances thyrotoxicosis is due to hyperthyroidism, a term reserved for disorders characterized by overproduction of thyroid hormones by the thyroid gland. Nevertheless, thyrotoxicosis may also result from a variety of conditions other than thyroid hyperfunction. The present report focuses on the etiologies, pathophysiology, and treatment of iatrogenic thyrotoxicosis. Iatrogenic thyrotoxicosis may be caused by (1) subacute thyroiditis (a result of lymphocytic infiltration, cellular injury, trauma, irradiation) with release of preformed hormones into circulation; (2) excessive ingestion of thyroid hormones (“thyrotoxicosis factitia”); (3) iodine-induced hyperthyroidism (radiologic contrast agents, topical antiseptics, other medications). Among these causes of iatrogenic thyrotoxicosis, that induced by the iodine overload and cytotoxicity associated with amiodarone represents a significant challenge. Successful management of amiodarone-induced thyrotoxicosis requires close cooperation between endocrinologists and endocrine surgeons. Surgical treatment may have a leading yet often underestimated role in view of the potential life-threatening severity of this disease, whereas others kinds of iatrogenic thyrotoxicosis are usually treated conservatively.     

A novel conotoxin inhibiting vertebrate voltage-sensitive potassium channels.

Toxins from cone snail (Conus species) venoms are multiple disulfide bonded peptides. Based on their pharmacological target (ion channels, receptors) and their disulfide pattern, they have been classified into several toxin families and superfamilies. Here, we report a new conotoxin, which is the first member of a structurally new superfamily of Conus peptides and the first conotoxin affecting vertebrate K+ channels. The new toxin, designated conotoxin ViTx, has been isolated from the venom of Conus virgo and comprises a single chain of 35 amino acids cross-linked by four disulfide bridges. Its amino acid sequence (SRCFPPGIYCTSYLPCCWGICCSTCRNVCHLRIGK) was partially determined by Edman degradation and deduced from the nucleotide sequence of the toxin cDNA. Nucleic acid sequencing also revealed a prepropeptide comprising 67 amino acid residues and demonstrated a posttranslational modification of the protein by releasing a six-residue peptide from the C-terminal. Voltage clamp studies on various ion channels indicated that the toxin inhibits the vertebrate K+ channels Kv1.1 and Kv1.3 but not Kv1.2. The chemically synthesized product exhibited the same physiological activity and identical molecular mass (3933.7 Da) as the native toxin.     

Characterization of gastrin-induced proangiogenic effects in vivo in orthotopic U373 experimental human glioblastomas and in vitro in human umbilical vein endothelial cells.

PURPOSE: This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo. EXPERIMENTAL DESIGN: The influences of G17 and G17 receptor antagonists were characterized in vitro in terms of angiogenesis on human umbilical vein endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo with respect to U373 orthotopic glioma xenografts. The influence of phosphatidylinositol 3'-kinase, protein kinase C, and nuclear factor-kappaB inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis. G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced modifications in nuclear factor-kappaB DNA binding activity were characterized by means of specific enzyme-linked immunosorbent assays. The influence of G17 on E- and P-selectin expression was determined by means of computer-assisted microscopy, whereas the influence of E- and P-selectin on HUVEC migration was approached by means of antisense oligonucleotides. The chemotactic influence of G17 and IL-8 on HUVEC migration was characterized by means of computer-assisted videomicroscopy with Dunn chambers. RESULTS: Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were present in HUVECs and microvessels dissected from a human glioblastoma. Whereas G17 significantly increased the levels of angiogenesis in vivo in the U373 experimental glioma model and in vitro in the HUVECs, the CCKB receptor antagonist L365,260 significantly counteracted the G17-mediated proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do so. IL-8 receptor alpha (CXCR1) and IL-8 receptor beta (CXCR2) mRNAs were not detected in these endothelial cells. Gastrin significantly (but only transiently) decreased the level of expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin significantly decreased HUVEC tubulogenesis processes in vitro on Matrigel. CONCLUSIONS: The present study shows that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs.     

Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study.

PURPOSE: Bone metastases are associated with severe and sometimes intractable pain, compromising patient quality of life (QOL). This open-label pilot study investigated the effects of short-term intensive treatment with intravenous (i.v.) ibandronate on opioid-resistant bone pain in patients with skeletal metastases. PATIENTS AND METHODS: Eighteen patients with advanced tumors and metastatic bone disease received nonstandard treatment with 4 mg of ibandronate administered i.v. (2-hour infusion) for 4 consecutive days (16-mg total dose). Baseline opioid analgesic use was equivalent to 400 mg/d of morphine. Patients were assessed for 6 weeks or until death. Changes from baseline were determined for bone pain, opioid consumption, patient functioning, QOL, performance status, and biochemical markers of calcium metabolism and bone turnover. Renal function was assessed by serum urea and creatinine measurement. RESULTS: Short-term, intensive ibandronate treatment significantly reduced bone pain scores within 7 days (P <.001). Pain reductions were sustained over the study period. Ibandronate significantly improved QOL, patient functioning, and performance status (P <.05). Mean values of the urinary cross-links pyridinoline and deoxypyridinoline tended to increase after day 21, returning close to baseline values by day 42. There was no correlation between the change in crosslinks values and the change in pain scores after ibandronate treatment. Ibandronate was well tolerated, with no evidence of renal toxicity. CONCLUSION: Nonstandard, intensive treatment with i.v. ibandronate seems to have a marked analgesic effect in patients with opioid-resistant bone pain from metastatic bone disease. Further investigation is warranted.     

How to optimize physicians' communication skills in cancer care: results of a randomized study assessing the usefulness of posttraining consolidation workshops.

PURPOSE: Although there is wide recognition of the usefulness of improving physicians' communication skills, no studies have yet assessed the efficacy of post-training consolidation workshops. This study aims to assess the efficacy of six 3-hour consolidation workshops conducted after a 2.5-day basic training program. METHODS: Physicians, after attending the basic training program, were randomly assigned to consolidation workshops or to a waiting list. Training efficacy was assessed through simulated and actual patient interviews that were audiotaped at baseline and after consolidation workshops for the consolidation-workshop group, and approximately 5 months after the end of basic training for the waiting-list group. Communication skills were assessed according to the Cancer Research Campaign Workshop Evaluation Manual. Patients' perceptions of communication skills improvement were assessed using a 14-item questionnaire. RESULTS: Sixty-three physicians completed the training program. Communication skills improved significantly more in the consolidation-workshop group compared with the waiting-list group. In simulated interviews, group-by-time repeated measures analysis of variance showed a significant increase in open and open directive questions (P =.014) and utterances alerting patients to reality (P =.049), as well as a significant decrease in premature reassurance (P =.042). In actual patient interviews, results revealed a significant increase in acknowledgements (P =.022) and empathic statements (P =.009), in educated guesses (P =.041), and in negotiations (P =.008). Patients interacting with physicians who benefited from consolidation workshops reported higher scores concerning their physicians' understanding of their disease (P =.004). CONCLUSION: Consolidation workshops further improve a communication skills training program's efficacy and facilitate the transfer of acquired skills to clinical practice.     

Incidence of non-AIDS-defining cancers before and during the highly active antiretroviral therapy era in a cohort of human immunodeficiency virus-infected patients.

PURPOSE: To determine incidence of non-AIDS-defining cancers (NADC) in HIV-infected patients before (P1) and during (P2) the use of highly active antiretroviral therapy (HAART) relative to that observed in the French general population (FGP) of the same age and sex. PATIENTS AND METHODS: Sex- and age-adjusted NADC standardized incidence ratios (SIR), with FGP as reference, were estimated in 1992 to 1995 (P1) and in 1996 to 1999 (P2) in a French Hospital Database on HIV prospective hospital cohort study. RESULTS: NADCs were diagnosed in 260 patients during P1 and 391 patients during P2 among the 77,025 patients included in the database between January 1, 1992, and December 31, 1999. Estimated incidence of all cancers was higher in HIV-infected men than in FGP during both periods (P1 SIR = 2.36 and P2 SIR = 1.91). No excess of cancers was observed among HIV-infected women in either period. Incidence of all cancers did not change from P1 to P2 in either sex (SIR = 0.96 for men and 1.00 for women). In contrast, incidence of Hodgkin's disease (HD) was higher than in FGP in both sexes and both periods and increased in P2 as compared with P1; incidence of lung cancer was higher in both sexes during P2. CONCLUSION: Relative to FGP, the overall incidence of NADCs was increased in HIV-infected men but not in women and did not differ between P1 and P2. Only HD was much more common in HIV infection, and the potential role of HAART on HD cannot be excluded.     

Safety profile of different low-molecular weight heparins used at therapeutic dose.

Low-molecular weight heparins (LMWHs) have been shown to be as safe and effective as unfractionated heparin (UFH) for the treatment of acute venous thrombosis and non-life-threatening pulmonary embolism. Different reports have shown that LMWHs may also be used to treat patients with unstable angina or non-Q-wave infarction. The safety of LMWHs used at therapeutic dose has been widely studied in pivotal clinical trials and analysed in several meta-analyses. However, despite the wide development and use of LMWHs, several issues regarding the safety and optimal use of LMWHs remain unanswered. The main adverse effect of LMWHs is bleeding and it is uncertain whether a weight-adjusted dosage regimen without laboratory monitoring can be used in patients with a high risk of bleeding, such as patients with renal failure, elderly patients, obese patients or pregnant women. These patients are usually excluded from clinical trials and only a few studies, not sufficiently powered to estimate efficacy and safety, have been carried out in these special populations. Most of the available data comes from pharmacokinetic or population pharmacodynamic studies or clinical reports. Results in patients with renal impairment who are not undergoing haemodialysis suggest that a reduction in calculated creatinine clearance levels is associated with an increased risk of accumulation of anti-Xa activity, the extent of which differs depending on the individual LMWH and the extent to which the compound is cleared by the kidney. The limited data available regarding the use of therapeutic doses of LMWHs in obese patients suggest that there is no need to cap the dose at a maximal allowable dose. Long-term (3-month) treatment with LMWHs appears to be as effective and safe as oral anticoagulant therapy for the treatment of venous thromboembolism. It appears that each LMWH is a distinct compound with unique pharmacokinetic and pharmacodynamic profiles. Until more data are available regarding these special populations, periodic monitoring of anti-Xa activity levels may be recommended to detect accumulation and/or an overdose and minimise the bleeding risk. The non-haemorrhagic adverse effects of the LMWHs include heparin-induced thrombocytopenia (HIT) and osteoporosis. The incidence of HIT appears to be lower with LMWHs than with UFH; there is currently not enough data to compare the frequency of HIT between the various LMWHs. LMWHs also appear to carry a lower risk of causing osteoporosis than UFH. In conclusion, studies that include special population patients are required to make conclusive recommendations concerning the safety and monitoring of the different LMWHs.