γ/δ Receptor-expressing T-cell clones from a cutaneous T-cell lymphoma suppress hematopoiesis

Summary Recently we described a cutaneous T-cell lymphoma expressing the / T-cell receptor [5]. The patient suffering from this lymphoma showed low numbers of myeloid and T cells in peripheral blood, while B and NK cells were relatively increased. In vitro culture of the patient's bone marrow (BM) cells revealed a significant suppression of myeloid/monocyte colony formation (GM-CFU) compared with normal controls. This was not due to infiltration of the BM with lymphoma cells. We speculated that a soluble factor either secreted or induced by the lymphoma cells might be responsible for the marked suppression of hematopoiesis in this patient. From a skin biopsy with infiltrating / T-lymphoma cells we established T-cell clones bearing the / T-cell receptor and resembling the phenotype of the lymphoma cells. The supernatant (SN) of these / T-cell clones reduced the number of colonies in a CFU-GM assay (using normal control BM) in comparison to SN of / T-cell clones established from the same biopsy. This suppression was seen mainly on day 7 of culture and was not neutralized by the addition of placenta-CM. The main mediator of this suppression seems to be IFN-,since it was detectable in high amounts in the SN of these / T-cell tumor clones as well as in the serum of the patient. In addition, anti-IFN- antibodies can reverse the T-cell SN-mediated suppression of CFU-GM. We conclude that high serum levels of interferon-, which is secreted in high amounts from / T-cells grown from a biopsy of a cutaneous lymphoma, can suppress hematopoiesis.Abbreviations TCR T-cell receptor - IFN- interferon- - SN supernatant - placenta CM placenta conditioned medium - BM bone marrow - CFU-GM myeloid/monocyte colony formation - NK cells natural killer cells - Ab antibody M. Wilhelm was supported by theDeutsche Forschungsgemeinschaft (DFG Wi 728-2)     

Effects of Alprazolam,a Benzodiazepine,on the ACTH-, GH- and PRL-Releasing Activity of Hexarelin,a Synthetic Peptidyl GH Secretagogue (GHS), in Patients with Simple Obesity and in Patients with Cushing's Disease

GH secretagogues (GHS) possess potent GH-releasing activity but also stimulate PRL, ACTH and cortisol (F) secretion. To further clarify the endocrine activities of GHS, in 9 obese patients, 9 patients with Cushing's Disease and 14 controls we studied the ACTH, F, GH and PRL responses to hexarelin (HEX, 2.0 µg/kg i.v.), a peptidyl GHS, alone and preceeded by alprazolam (ALP, 0.02 mg/kg p.o.), a benzodiazepine. The HEX-induced ACTH response in controls was similar to that in obese patients (peak: 9.9 ± 1.9 and 24.7 ± 7.6 ng/L, respectively) and both were lower (p < 0.002) than that in Cushing's patients (peak: 210.7 ± 58.4 ng/L). The GH response to HEX in controls (peak: 58.1 ± 10.3 g/L) was higher (p < 0.001) than those in obese and Cushing's patients (18.2 ± 3.8 and 12.6 ± 5.4 /L, respectively) which, in turn, were similar. The PRL responses to HEX in controls, obese and Cushing's patients (peak: 11.9 ± 1.6, 18.0 ± 4.5 and 12.4 ± 1.4 /L, respectively) were similar. In controls the HEX-induced ACTH response was abolished by ALP (peak: 8.6 ± 2.4 vs 28.0 ± 6.7 ng/L, p < 0.03) which, on the other hand, only blunted that in obese (peak: 12.7 ± 2.1 vs 42.4 ± 8.4 ng/L, p < 0.02) and did not modify that in Cushing's patients (205.6 ± 55.4 vs 175.9 ± 47.6 ng/L). ALP blunted the GH response to HEX in controls (peak: 31.0 ± 7.1 /L, p < 0.03) while did not modify those in obese and in Cushing's patients (14.5 ± 5.3 and 13.3 ± 11.1 /L, respectively). ALP did not modify the HEX-induced PRL response in controls, obese and Cushing's patients (peak: 13.8 ± 0.9, 16.3 ± 2.4 and 19.2 ± 1.1 /L, respectively). In conclusion, alprazolam inhibits the ACTH response to hexarelin in normal and obese subjects while fails to modify the exaggerated ACTH response in Cushing's Disease suggesting that GHS activate the HPA axis via the hypothalamus in normal and obese subjects but not in patients with Cushing's disease. Alprazolam is also able to blunt the GH-releasing activity of hexarelin in normal subjects but not the low GH response to the hexapeptide in obese and Cushing's patients. The PRL-releasing activity of hexarelin in controls, obese and hypercortisolemic patients is similar and is not modified by alprazolam pretreatment.     

Comparing a high-dose dipyridamole SPECT imaging protocol with dobutamine and exercise stress testing protocols. Part III: Using dobutamine to determine lung-to-heart ratios, left ventricular dysfunction, and a potential viability marker

Determination of the severity of coronary artery disease (CAD) by single photon emission computed tomography (SPECT) imaging has previously been shown to have greater sensitivity, specificity, and accuracy when performed with pharmacologic stress using dobutamine than by standard dose dipyridamole (SDD) or exercise stress testing (EST) prior to SPECT imaging. The use of lung to heart (L:H) ratios has been shown to be valuable in determining the presence or absence of left main (LM) or triple vessel (3V) CAD. No such work has been previously reported for dobutamine. Twenty-one patients were studied using dobutamine (n=7) or EST (n=14). These results were compared with results from Part II of this series of studies using high-dose dipyridamole (HDD) pharmacologic stress. In this study, patients underwent L:H ratio analysis following injection of 3 mCi of Tl-201, this provides sufficient time for thallium clearance from the blood pool. Results of the L:H ratios were compared with the results of coronary arteriographic (CA) evaluation. Patients who were stressed via EST demonstrated statistically greater (p0.001) L:H ratios in patients with LM/3V CAD when compared with patients who had 0–2 significantly stenosed coronary arteries. Patients stressed with dobutamine demonstrated lower L:H ratios (p=NS) in patients with LM/3V CAD than was seen for patients with 0–2 V CAD. Patients stressed with dobutamine had statistically (p0.05) lower L:H ratios than did similar patients stressed with EST. Increased L:H ratios following EST and HDD, as shown previously in Part II of this series, provide excellent markers for LM/3V CAD following Tl-201 injection. The presence of normal L:H ratios in patients with LM/3V CAD following dobutamine stress may suggest the presence of stunned or hibernating myocardium. The presence of decreased L:H ratios following dobutamine after HDD or EST has already shown an increased L:H ratio, might suggest a marker for myocardial viability that deserves further investigation.Presented in part at the 39th Annual World Congress International College of Angiology, Istanbul, Turkey, June 1997.     

The ability of heat stress and metabolic preconditioning to protect primary rat cardiac myocytes

Primary rat cardiocytes were subjected to either thermal preconditioning for 30 min at 43°C or 20 min metabolic preconditioning (10 mM deoxyglucose, 20 mM lactate, pH 6.5). Eighteen hours later cells were analysed either for hsp 70i expression or subjected to a subsequent lethal heat stress or simulated ischaemia (10 mM deoxyglucose, 20 mM lactate, 0.75 mM sodium dithionite, 12 mM potassium chloride, pH 6.5) for 2 hours and assessed for survival by trypan blue exclusion.Hsp 70i was induced over 100 fold by thermal preconditioning and 30 fold by metabolic preconditioning (p<0.001, p<0.05), hsp 90 was induced 2.71 fold and 2.24 fold (p<0.001, p<0.001) by thermal and metabolic preconditioning respectively, while hsp 60 was not induced by either treatment. Preconditioned cultures had improved survival against subsequent lethal heat stress or simulated ischaemia: Thermal preconditioning reduced death from 69.22% to 52.46% upon subsequent lethal heat stress and from 49.13% to 36.66% upon subsequent lethal simulated ischaemia. Metabolic preconditioning reduced cell death from 51.29% to 33.8% against subsequent lethal heat stress, and from 69.09% to 55.61% upon subsequent lethal simulated ischaemia. A second marker of cell death, the release of lactate dehydrogenase activity into the culture media, was reduced to 65% and 60% of control values for thermally preconditioned cells subjected to lethal heat or lethal simulated ischaemia respectively. Metabolically preconditioned cells demonstrated lactate dehydrogenase activity of 59% and 51% that of control values, when subjected to lethal heat or lethal simulated ischaemia respectively.Abbreviations hsp heat stress protein - hsp 70i inducible 70 kDa heat stress protein - LDH lactate dehydrogenase - PBS phosphate buffered saline     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

Ultrastructural Characteristics of TSH-Producing Adenomas with Special Reference to its Close Similarity to BFA-Treated Pituitary Adenoma Cells

Two of 420 patients with pituitary adenoma who underwent operation from 1989 to 1997 had thyroid stimulating hormone (TSH) producing adenoma. We investigated these TSH cell adenomas with immunohistochemical and ultrastructural methods and compared their ultrastructural features with brefeldin A (BFA, 0.5 mg/ml) treated pituitary adenoma cells. BFA-treated pituitary adenomas include a prolactin (PRL) cell adenoma, a growth hormone (GH) cell adenoma, an adrenocorticotropic hormone (ACTH) cell adenoma, a gonadotroph adenoma, and a plurihormonal adenoma. Immunohistochemical staining disclosed that one of the TSH cell adenomas produced only TSH-;bgr and that another produces both TSH-b and FSH-b. Ultrastructural analysis showed the abundance of oval-shaped dilated rough endoplasmic reticulum (rER). Within the dilated rER, the mistlike deposit or deposit along the inner margin of the rER membrane was observed. On the other hand, BFA-treated cultured pituitary adenoma cells showed the opening of the cavity of the rER cisterna and they enlarged to an oval form with time and revealed an accumulation of electron-dense deposits within the dilated rER. These ultrastructural similarities between TSH cell adenoma and BFA-treated pituitary adenoma cells indicate the functional disturbances in the secretory passage through the Golgi apparatus in TSH cell adenoma cells.     

Pyruvate carboxylase deficiencies: Complementation studies between “French” and “American” phenotypes in cultured fibroblasts

Pyruvate carboxylase (PC) deficiencies (McKusick 26615) are heterogeneous clinically and biochemically. We performed a complementation study with fibroblast strains from seven patients, (four patients with French phenotype, two patients with American phenotype, one patient with biotin responsive multiple carboxylase deficiency, MCD). The six isolated pyruvate carboxylase mutants (two cross-reacting material CRM –ve and four CRM +ve) failed to complement each other, but did complement a form of biotin responsive MCD.     

Coronary heart disease and urinary albumin excretion rate in Type 2 (non-insulin-dependent) diabetic patients

Summary Associations between overnight urinary albumin excretion rate and prevalent coronary heart disease and its major risk factors were examined in a cross-sectional study of 141 Type 2 (non-insulin-dependent) diabetic patients. Mean albumin excretion rate was higher in men (geometric mean 13.5 g/min; 95% confidence interval 10.3–17.6) than women (7.5 g/min; 5.7–9.8, p<0.01). In diabetic men and women mean albumin excretion rate was higher in those with electrocardiographic and/or symptomatic evidence of coronary heart disease than in those without (men, 23.1 g/ min; 95% confidence interval 13.7–39.0 versus 10.6 g/min; 7.9–14.2, p<0.01, women, 13.7 g/min; 8.0–23.5 versus 5.4 g/min; 4.2–6.8, p<0.01). Multiple logistic regression analysis was used to allow for confounding between variables. In the diabetic group as a whole, raised albumin excretion rate (p<0.001), gender (p<0.05) and systolic blood pressure (p=0.06) entered the best model for coronary heart disease prediction. In women, albumin excretion rate alone (p<0.01) and in men albumin excretion rate (p<0.01) and age (p=0.05) entered the best models. We conclude that albumin excretion rate is significantly associated with coronary heart disease morbidity after taking into account the confounding effects of raised blood pressure and other cardiovascular risk factors.     

Die Bildungsarten,Entwicklungsstadien und Wachstumsstufen des Carcinoms am Beispiel der Epithelproliferationen der Brustdrüse

Zusammenfassung Am Beispiel früher (1937) schon beschriebener Drüsenkrebse und am Beispiel neu untersuchter Epithelproliferationen der Brustdrüse bei der Mastopathia fibrosa cystica lassen sich 2 Bildungsarten des Krebses herausstellen. Sie unterscheiden sich durch den Zeitpunkt der morphologisch erkennbaren Cancerisierung vor oder nach einer Zellproliferation. Sie stimmen darin überein, daß bei beiden Bildungsarten im Beginn ein matrizides (Rössle) Wachstum vorliegt, d. h. ein intraepithelialer Beginn im zunächst unveränderten Muttergewebe. Nach Maßgabe wissenschaftlicher Übereinkunft kann man eine zweiphasische oder eine dreiphasische Entwicklung unterscheiden. Es gibt eine intraepitheliale Zellabartung, bei der morphologisch Cancerisierung und Epithelproliferation zeitlich zusammenfallen (1. Bildungsart). Es gibt eine Zellabartung, bei der morphologisch eine gutartige Proliferation der morphologisch erfaßbaren Cancerisierung vorangeht (2. Bildungsart). Die Cancerisierung ist bei der 1. Bildungsart unabhängig von Zellzahl und Differenzierung, bei der 2. Bildungsart teilweise abhängig von der Zellzahl, aber wiederum nicht von der Differenzierung. Die Befunde bei der Mastopathia fibrosa cystica sprechen für das Vorliegen langdauernder cytostatischer Phasen der so verschiedenen Zellproliferationen und Zelldifferenzierungen.Mit 5 Textabbildungen.Herrn Prof. Dr. Dietrich in Dankbarkeit und Verehrung zum 80. Geburtstag.     

Secretory component and lactoferrin in pure pancreatic juice in chronic pancreatitis

To evaluate pathophysiological roles of proteins in pancreatic secretion, immunoreactive lactoferrin (LF) and secretory component (SC) were measured in the first fraction of the pure pancreatic juice obtained endoscopically from 17 control, 21 suspected (SCP), 14 noncalcified (NCP), and 14 calcified chronic pancreatitis (CCP) subjects. The protein and amylase tended to decrease both in concentration and output from control to CCP. LF concentration was elevated in CCP (18.0±4.9/ml) when compared with controls (2.3±0.2g/ml), and LF output in NCP (12.3±3.8 g/min) was increased from controls (3.8±0.6 g/min). The combination of high LF concentration with low protein output was observed in 10/14 in CCP but 0/14 in NCP and can be a biochemical discriminator of CCP from NCP. SC concentrations were also elevated in NCP (8.5±2.0 g/ml) and CCP (5.6±1.6 g/ml) from controls (1.2±0.2 g/ml). SC outputs in SCP (9.8±3.1 g/min) and NCP (21.1±4.8 g/min) were increased from controls (1.7±0.3 g/min), but there was no further increase in CCP. Hypersecretion of LF and SC in chronic pancreatitis is different, especially in CCP, although the mechanisms for hypersecretion are unknown.This study was supported in part by a research grant for intractable pancreatic disease from the Ministry of Health and Welfare, Japan.     

Zur Epidemiologie und Ätiologie des Oesophaguscarcinoms in China

Ohne Zusammenfassung

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The epidemiology and etiology of esophageal cancer in China

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Stipendiaten der Alexander von Humboldt-Stiftung aus der Volksrepublik China

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The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest Editorials on actual and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author.Die Zeitschrift Journal of Cancer Research and Clinical Oncology bringt in zwangsloser Folge Editorials zu aktuellen und/oder kontroversen Problemen der experimentellen und klinischen Onkologie. Diese Beiträge geben ausschließlich die persönliche Meinung des Autors wieder.     

Gastric “pseudolymphoma” with restricted light chain expression in a patient with obscure gastrointestinal blood loss

Summary We present a case report of a gastric pseudolymphoma (GL) that exhibits restricted light chain expression and, therefore, illustrates the dilemma encountered when histologically benign lesions have phenotypic abnormalities suggesting malignancy. For many years this lesion has been considered usually benign; however, recent reports such as this one demonstrate immunologic signs of monoclonality in an otherwise histologically benign lesion. This finding challenges our assumptions as to the nature of this lesion and our definition of cancer. The lesion also displays Castleman-like features (angiofollicular hyperplasia) as well as common inflammatory germinal centers. In addition we briefly review the literature.     

Rapid molecular characterization of mutations leading to unstable hemoglobin β-chain variants

Summary Characterization of unstable hemoglobins by protein analysis is often difficult. However, it is facilitated by DNA analysis, especially in the case of hyperunstable -chain variants, which produce a -thalassemia phenotype. We have applied an efficient strategy to the detection of such variants at the DNA level, based on computer-designed denaturing gradient gel electrophoresis (DGGE) of amplified DNA fragments. This approach makes it possible to detect any anomaly in the -globin gene. We describe the use of the DGGE method for rapid characterization of -chain variants and report a new missense mutation in the -globin gene third exon, 127 CAG-CGG/Gln-Arg, which is responsible for the synthesis of a highly unstable hemoglobin.     

Uptake and metabolism of radiolabelled GM1-ganglioside in skin fibroblasts from controls and patients with GM1-gangliosidosis

Summary The uptake and metabolism of [3-³H-sphingosine]GM1-ganglioside was measured in cultured skin fibroblasts from controls and patients with infantile, juvenile and adult GM1-gangliosidosis. When dissolved in medium with phosphatidylserine, GM1-ganglioside was efficiently taken up by cultured skin fibroblasts and transferred into lysosomes. A linear increase in GM1-ganglioside endocytosis was shown with phosphatidylserine concentrations of up to 40m/ml. A pulse-chase study revealed that [³H]GM1-ganglioside was metabolized to GM2-ganglioside, GM3-ganglioside, ceramide dihexoside, ceramide monohexoside, ceramide and sphingosine. Sphingosine was recycled to sphingomyelin. In a 20-h pulse study, cell lines from patients with GM1-gangliosidosis of infantile, juvenile and adult types hydrolysed 2–5%, 20–44% and 54–58% of the total endocytosed GM1-ganglioside respectively. These values were lower than in control cells (64.17 ± 5.43% (n=10)). The hydrolysis rates of exogenous [³H]GM1-ganglioside in cultured fibroblasts from patients with various types of GM1-gangliosidosis closely reflected the clinical severity.Abbreviations GM1 Gal13GalNAc14(NeuAc23)Gal14Galc-1-ceramide - GM2 GalNAc14(NeuAc23)Gal14Glc-1-ceramide - GM3 NeuAc23Gal14Glc-1-ceramide - CDH Gal14Glc-1-ceramide     

Efficacy of mizoribine treatment in patients with SjÖgren’s syndrome: an open pilot trial

The aim of this study was to evaluate the efficacy and safety of mizoribine in patients with SjÖgrens syndrome. Forty patients with sicca syndrome, whose conditions were definitely diagnosed as SjÖgrens syndrome, were given mizoribine orally at a dosage of 150mg/day for 12 months. The percentage change in salivary secretion after 3, 6, and 12 months of the therapy increased to +112.2% (P 0.001), +119.9% (P 0.01), and +147.3% (P 0.001), respectively, compared with the baseline. Serum IgG levels decreased significantly throughout the study, and the level was 1969.4 ± 620.0mg/dl after treatment for 12 months compared with the pretreatment value of 2094.3 ± 746.6mg/dl (P 0.05). The patients assessment of clinical signs and symptoms on a 10-cm visual analog scale improved significantly from 7.2 ± 2.3cm at the start of the treatment to 5.0 ± 1.9cm after 12 months (P 0.001). There was a similar improvement in the physicians assessment using the 10-cm visual analog scale: 7.1 ± 1.6cm at the start of the treatment and 5.2 ± 1.9cm after 12 months (P 0.001). With regard to safety, no serious adverse reactions were observed. Although a controlled study would be required to clarify the efficacy of mizoribine, these preliminary observations indicate its efficacy for ameliorating glandular symptoms through improvements in immune abnormalities in patients with SjÖgrens syndrome.     

Ancient Views on the Hypothalamic-Pituitary-Thyroid Axis: An Historical and Epistemological Perspective

The modern views on the anatomical and physiological interactions between the hypothalamus, pituitary and thyroid gland have emerged only in the last fifty years, although their historical roots may be found in a number of ancient and still poorly known ideas and observations. The regulation of energy body stores and temperature by the hypothalamic-pituitary-thyroid axis, for example, is a classical case of fixitèe du mileu interieur in the sense originally suggested by Claude Bernard in the late 1800s, i.e. a homeostatic mechanism, but already 2100 year before Aristotle had stated that the brain was necessary for the maintenance of body integrity by regulating food intake and behavior in relation to body temperature, the latter primarily determined by the heat of the circulating blood. Five hundred years later Galen of Pergamon reported fundamental discoveries in the anatomy of the third ventricle region, including the location of the pituitary gland inside the sella turcica embodied in a vascular network, the rete mirabilis, and observed nerves adjoining the soft flesh in the neck, i.e. the thyroid gland. He first proposed that the energy of the body (the vital spirit) was carryed through the arteries at the level of the rete mirabilis, where it was transformed into nerve inpulse (the animal spirit), eventually tranferred by the nerves to the periphery of the body, glands included, raising implicitly the possibility for a nervous influence over the thyroid activity. The Galenic model remained virtually unaltered up to the beginning of the 14^th century, when the mediaeval anatomist Mondino de' Liuzzi put forth the idea that the thyroid gland interacted with the heat of the blood circulating in the internal carotid arteries due to their anatomical relation with the thyroid. This interaction enriched the vital spirit, i.e. the energy of the body, prior to its pituitary transformation into animal spirit, i.e. to nerve inpulse directed to the periphery of the body. In addition, Mondino envisaged the possibility that the third ventricle was implicated in the regulation of the animal behavior by processing sensory, cognitive and emotional informations. No trace of these Mondino's ideas can be found throughout the Renaissance, despite the leading anatomical work of the period, the Fabrica by Andreas Vesalius, remained apparently prone to the Galenic dogma of the rete mirabilis. After Vesalius, the Galenic anatomy and physiology of the infundibular region survived for at least two more centuries, and we owe Luigi Galvani, the discoverer of animal electricity, the first detailed anatomical observation that in humans the nasal secretions were not a drainage waste of the brain ventricles, as postulated by Galen, but the product of nasal mucous glands. From an epistemological standpoint, Aristotle anticipated the possibility that the set point for energy intake and behavioral adaptation was determined by the interplay between the brain activity and a thermogenic principle present in the circulating blood, in a manner very close to a circuitry devoted to maintain the energetic and thermic stady state of the living organism (homeostasis). The Galenic modelling of brain-thyroid interaction is an evolution of the Aristotelian one, since it postulates an anatomical and functional loop linking the transport of body energy to the brain through the arteries, and the transformation of this energy into neural output directed to the peripheral glands, thyroid included, by the mediation of the pituitary gland. Finally, the proposal by Mondino de' Liuzzi provides a scheme of brain-thyroid interaction that merges together the homeostatic Aristotelian with the pituitary/autonomic Galenic models, suggesting that the thyroid plays a thermoregulatory role linked to the control of body energy. This remarkable set of ideas has never been credited to Mondino by the modern historical critique, possibly due to the impact that the methodological reform of anatomy by Vesalius, resulting in the denial of much Galenic tradition, had on the way to interpret Mondino's work from the late Renaissance up to the 20^th century. The current concepts of the regulation by peripheral nerves of the thyroid blood flow and/or secretion seems to have been anticipated by anecdotal observations in the Egyptian and Roman times. In the second half of the 18^th century the belief by Luigi Galvani that the peripheral nerves were carrying electrical impulses can be considered the first theoretical statement derived from an empirical evidence, i.e. the animal electricity, supporting the Galenic idea that autonomic fibers might influence the secretion of humors from peripheral glands, thyroid included. However, only during the last century and first half of the present one it is possible to recognize anatomical and physiological observations that, although controversial like those of W.B. Cannon on experimental hyperthyroidism, opened the way to the current evidence of an autonomic control of the thyroid function.     

Involvement of α2-Adrenoceptors in mechanism of intragastric nicotine protection against ethanol injury in rat stomach

To elucidate the role of - and -adrenoceptors in the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury, the following studies were performed. At 0.5-hr prior to the injury study, rats were pretreated with: subcutaneous control, prazosin (0.5 mg/kg) or yohimbine (5 mg/kg) to block ₁- or ₂-adrenoceptors; or intraperitoneal control, metoprolol (2 mg/kg) or butoxamine (4 mg/kg) to block ₁- or ₂-adrenoceptors, respectively. At 1-hr intervals, rats received intragastric vehicle or nicotine (4 mg/kg) and 40% ethanol (10 ml/kg). Total lengths of the linear gastric corpus mucosal lesions were measured by an unbiased observer using a caliper. In a separate study, 0.5-hr after subcutaneous control or yohimbine (5 mg/kg), rats were treated with intragastric vehicle or nicotine (4 mg/kg). One hour later, gastric mucus volume, gastric juice volume and pH, and titratable acid in the gastric juice were measured. In the rat stomach, the intragastric nicotine protection against 40% ethanol-induced mucosal injury was not blocked by selective ₁-(prazosin), ₁-(metoprolol), or ₂-(butoxamine) adrenoceptor antagonists. The protection was significantly reduced although not completely abolished by selective ₂-(yohimbine) adrenoceptor antagonist. Yohimbine also significantly reduced basal and nicotine-stimulated increase in gastric mucus volume. These data suggest that ₂-adrenoceptors are involved in the protective effect of intragastric nicotine against 40% ethanol-induced gastric mucosal injury possibly by a mucus-dependent mechanism.Supported by Veternas Administration Medical Research Funds, and in part by research grants (0162-01, 02, and 291-01) from the Smokeless Tobacco Research Council, Inc., and by funds (1RT 80) provided by the Cigarette and Tobacco Surtax Fund of the State of California through the Tobacco-Related Disease Research Program of the University of California to F.W.L. Dr. Endoh is a recipient of the University of California Tobacco-Related Disease Research Program Research Fellowship Award (FT 37).     

The treatment of hypertension: New lamps for old?

Summary Meta-analysis of clinical trials does not help the clinician to treat individual patients. A general conclusion that the reduction of high blood pressure is beneficial has to be matched by specific information about the level of blood pressure that is acceptable and about the effect of particular doses of specific drugs. Results obtained from trials of old-fashioned antihypertensive drugs cannot confidently be extrapolated to modern agents. Sufficient data do not exist to encourage universal drug treatment for patients with mild hypertension.     

Extrarenal nephroblastomas

Summary The cases of extrarenal nephroblastoma published in the world literature have been tabulated and reviewed, and are discussed from a historical point of view.The Journal of Cancer Research and Clinical Oncology publishes in loose succession Editorials and Guest editorials on current and/or controversial problems in experimental and clinical oncology. These contributions represent exclusively the personal opinion of the author     

Immunoglobulin production and secretion in bence jones protein myeloma and “nonsecretory” myeloma

Summary Using our electron microscopic method for polysome analysis and an immunofluorescent technique we studied Ig production and secretion by tumor cells in seven BJP myeloma patients and seven nonsecretory myeloma patients.In BJP myeloma Ig production and secretion is of three types: Type 1, only L-chains are synthesized and secreted; Type 2, the myeloma cells show fluorescence for H-chains, but upon polysome analysis there is no peak at polysomes corresponding to H-chain production; Type 3, the myeloma cells show fluorescence for H-chains, and polysome analysis shows two peaks corresponding to L- and H-chain production.Polysome analysis of nonsecretory myelomas show the presence of only very few membrane-bound polysomes and their distribution curves are entirely different from those of ordinary myeloma. Furthermore, the distribution patterns vary among seven cases. Results obtained by polysome analysis and immunofluorescent technique suggest that the nonsecretory myeloma could be divided into several subtypes.Supported in part by grants-in-aid for scientific Research (748103, 867050, 167092, 267108, 777124) from the Ministry of Education, Science and Culture of Japan