Localization and functional roles of PMP22 in peripheral nerves of P0-deficient mice

Peripheral nerves of P0-deficient (P0(-)) mice show a severe dysmyelination and altered expression of several cell surface molecules. In the present study we investigated the subcellular localization of the peripheral myelin protein (PMP)22 in the abnormal axon-Schwann cell units of the mutants. We show by postembedding immunoelectron microscopy that PMP22 is expressed in both noncompacted and abnormally compacted myelin-like regions of P0(-) mice. By the generation of mice deficient for both P0 and PMP22 (P0(-)/PMP22(-) double mutants) we investigated the functional role(s) of PMP22 in P0(-) mice. In 4-week-old double mutants, some abnormally compacted myelin-like sheaths showed slight alterations in compaction with collapsed intraperiod lines, whereas the totally uncompacted axon-Schwann cell units displayed a more irregular cytoarchitecture owing to the presence of more cytoplasm within the loose Schwann cell loops. These findings show an only subtle impact of PMP22 on the structure of P0-deficient myelin-like sheaths. During early stages of myelin formation, peripheral nerves of P0(-)/PMP22(-) mice resembled those of PMP22(-) mutants in that they were characterized by a strongly retarded spiralling of Schwann cell processes. Thus, P0 appears to be the major determinant of myelin structure, whereas PMP22 is the predominant regulator of the timely correct initiation of myelination.     

Effect of flaxseed consumption on urinary estrogen metabolites in postmenopausal women.

Flaxseed, the richest known source of plant lignans, has been shown to have chemoprotective effects in animal and cell studies. Some of its effects may be mediated through its influence on endogenous hormone production and metabolism. Two competing pathways in estrogen metabolism involve production of the 2-hydroxylated and 16 alpha-hydroxylated metabolites. Because of the proposed differences in biological activities of these metabolites, the balance of the two pathways has been used as a biomarker for breast cancer risk. We examined the effects of flaxseed consumption on urinary estrogen metabolite excretion in postmenopausal women. Twenty-eight postmenopausal women were studied for three seven-week feeding periods in a randomized crossover design. During the feeding periods, subjects consumed their usual diets plus ground flaxseed (0, 5, or 10 g/day). Urinary excretion of the estrogen metabolites 2-hydroxyestrogen (2-OHEstrogen) and 16 alpha-hydroxyestrone (16 alpha-OHE1) as well as their ratio, 2/16 alpha-OHE1, was measured by enzyme immunoassay. Flaxseed supplementation significantly increased urinary 2-OHEstrogen excretion (p < 0.0005) and the urinary 2/16 alpha-OHE1 ratio (p < 0.05) in a linear, dose-response fashion. There were no significant differences in urinary 16 alpha-OHE1 excretion. These results suggest that flaxseed may have chemoprotective effects in postmenopausal women.     

Benzodiazepine receptor ligands. III. Synthesis and biological evaluation of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides

A new series of 2- and/or 3-substituted pyrazolo [5,1-c][benzotriazine 5-oxides and their 8-chloro derivatives were synthesized, and their benzodiazepine receptor (BZR) affinities were evaluated in vitro in comparison to lead compound 3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29) [1,2]. None of the new compounds showed significant affinity for BZR. On the basis of a pharmacophore/receptor model suggested for lead compound 29, some hypotheses to explain the inactivity of new derivatives are discussed.     

Topical prostaglandin E2 and chemo- and radio-induced oral mucositis

Oral mucositis is a frequent complication of specific antineoplastic treatments. Mouth lesions have a great impact on the quality of life of cancer patients. Current topical and systemic therapies have not yet achieved completely satisfactory results. We studied the effect of topical use of prostaglandin E2 (PGE2) 2.25 mg/day on oral mucositis of 15 chemo- or radio-treated cancer patients. Absolute mean VAS value on mouth pain decreased from 71.2 at TO, to 34.1 at T3 (p<0.001) and to 14.1 at T6 (p<0.001). Objective evaluation according to Miller scale showed significant improvement at day 3 and 6, as well. We suggest that PGE2 could be a useful additional therapeutic agent to palliate oral symptoms.     

Post-traumatic avascular necrosis of the humeral head

Summary A study of nine cases of post-traumatic avascular necrosis of the head of the humerus is presented with a review of 60 cases previously published. Onset of symptoms begins between one and two years after fracture. Pain and stiffness are the principal features. The clinical picture eventually stabilises with decreasing pain and variable loss of movement. The chief radiological changes are sclerosis and a snow-cap appearance of the head or a characteristic spanner-shaped deformity. The possible causative factors are listed and the importance of associated vascular damage emphasised. Conservative treatment is usually adequate but prosthetic replacement of the head may be indicated.

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Résumé Les auteurs analysent 60 cas de nécrose post-traumatique de la tête humérale publiés dans la littérature, auxquels ils ajoutent neuf cas personnels.Ils soulignent le rôle des facteurs combinés dans la pathogénie parmi lesquels le facteur vasculaire est le plus important. Après 1 à 2 ans de latence, les manifestations cliniques apparaissent et vont évoluer lentement vers une certaine stabilisation, en particulier des phénomènes douloureux, souvent intenses au début, mais au prix d'une raideur résiduelle quasi constante. La radiologie reconnaît deux types principaux d'image:condensation en calotte de neige;déformation en clé anglaise de la tête humérale;la glène restant très longtemps indemne.Le traitement, le plus souvent médical, devrait peut-être ressortir de la chirurgie par prothèse type Neer, qui pourrait dans les types les plus graves, être placée préventivement.

     

Stab injuries of the hand

Stab wounds of the hand should not be dismissed lightly as trifles. It may well be that deep underlying structures are destroyed even if the injury is very small, hardly visible and thus seems to be negligible. As a matter of fact, such injuries are easily overlooked particularly by the patient himself and, possibly, also by an inexperienced nurse or examiner. The most serious consequences can arise from non-diagnosed complete and incomplete injuries of tendons and nerves. The authors emphasise the importance of paying close attention to complete or partial injuries of the extensor tendons and nerves. If at all possible, these should be looked after immediately. Particular emphasis is placed by the authors on complete or partial injuries in the region of the proximal interphalangeal joints, involving the risk of a typical "buttonhole" deformity. Among the typical sequels of a stab injury are lesions of the nerves of the fingers as well as of the flexor and extensor tendons, quite apart from the general danger of an infection. Whereas injuries of the extensor tendons do not place great demands on the skill of the surgeon, injuries of the tendons and nerves in the flexor region are the domain of the hand surgeon.     

A method for estimating within-individual variability in clearance and in volume of distribution from standard bioavailability studies

Bioavailability studies are commonly undertaken, and most, because they involve subjects taking repeated doses of a drug, contain information on intraindividual variability in pharmacokinetics. However, because in such studies bioavailability itself is unknown, it is difficult to resolve which pharmacokinetic parameters vary within individuals. A mathematical model is presented which permits estimation of variability in clearance and in volume of distribution. When applied to pooled data arising from five theophylline bioavailability studies, this model has given statistical evidence that clearance of theophylline is inherently more variable within individuals (coefficient of variation, 13%) than volume of distribution (8%). As a result, use of the measurement AUC · rather than AUCas a more precise index of bioavailability is justified in studies where is measured with reasonable precision. The model could be applied to estimation of withinbatch within-person variability in bioavailability.Deceased, April 4th, 1981.     

Soluble CD40 ligand plasma levels in lung cancer.

PURPOSE: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation. EXPERIMENTAL DESIGN: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age- and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 + 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples. RESULTS: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 + 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P = 0.011) was independently related to sCD40L. CONCLUSIONS: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation.     

The outcome of liver transplantation in patients with hepatocellular carcinoma in the United States between 1988 and 2001: 5-year survival has improved significantly with time.

PURPOSE: We hypothesized that the outcome of liver transplantation in patients with hepatocellular carcinoma (HCC) has improved over the past decade because of the application of published criteria for patient selection. In this study, we compared the outcome of liver transplantation in patients with and without HCC at different time periods using the United Network for Organ Sharing data. PATIENTS AND METHODS: We excluded children, patients with multiple organ transplantation or retransplantation, and those with incomplete survival data. The study period was arbitrarily divided into three time intervals: 1987 to 1991, 1992 to 1996, and 1997 to 2001. RESULTS: During the study period, 985 patients with HCC (HCC group), and 33,339 without HCC underwent liver transplantation (control group). Kaplan-Meier patient and graft survivals were significantly lower for the HCC group compared with the control group. Cox regression analysis (after adjusting for other confounding variables) confirmed a lower patient survival in the HCC group (1-year survival, 77.0% v 86.7%; hazard ratio [HR], 1.7; 95% CI, 1.5 to 2.0; P <.0001) compared with the control group (5-year survival, 48.2% v 74.7%; HR, 2.2; 95% CI, 1.9 to 2.4; P <.0001); HCC was an independent predictor of survival. Kaplan-Meier analysis showed a significant improvement in 5-year patient survival with time in patients with HCC (1987 to 1991, 25.3%; 1992 to 1996, 46.6%; 1997 to 2001, 61.1%; P <.0001). During the same period, there was only minimal improvement in survival among the control group. CONCLUSION: Five-year survival of patients transplanted for HCC is excellent, with a steady improvement in survival over the past decade. It is possible that the published criteria for patient selection may have contributed to the better outcome.     

A registry-based study of follow-up failures in the screening experience of cervical cancer patients

Amadori A, Gentilini P, Bucchi L, Innocenti MP, Falcini F, Martini F, Fabbri M, Liverani M, Danesi S, Piantini B, Milandri C, Saragoni L, Amadori D. A registry-based study of follow-up failures in the screening experience of cervical cancer patients. Int J Gynecol Cancer 1998; 8 : 251–256.
Although all components of cervical screening are at risk of error, most studies of the previous screening experience of cervical cancer patients addressed only the false negative cytology results. Other reports showed the importance of screening failures not attributable to the Pap smear. We studied the relative frequency of all types of error observed in the screening history of 115 cervical cancer cases (median age, 60; range, 23–89) registered with the population-based Romagna Cancer Registry in Forlì (northern Italy) between 1986 and 1993. For each case, a search was made for all cytology, colposcopy, biopsy, and treatment reports issued prior to diagnosis. Eighty-one (70.4%) patients had never had a Pap smear. Eight (7.0%) were diagnosed at their first test. Twenty-six patients (22.6%) had had at least one previous smear. Among these, 10 were screened during the five years prior to diagnosis: three patients had false negative cytology results, one patient did not comply with the recommendation for an early repeat smear, two patients with positive cytology results underwent colposcopy with considerable delay (7 and 9 months), one patient had a negative colposcopy (without biopsy), and three patients had biopsies histologically reported as negative. An overview of the registry-based studies of screening histories reported so far from Italy (total number of cases 262) demonstrated that patients with serious shortcomings in follow-up after smear test, colposcopy, biopsy, clinical assessment, and treatment accounted for a substantial proportion of screening failures.