Studies with two investigational interventions: a simple model to assess their effects and interaction

The paper presents a simple way to design and analyse studies on pharmacodynamic food-interaction and drug-interaction studies. The study design includes two distinct interventions--the drug or control against eating, or fasting, and allows an analysis of variance. It provides a model for a more analytical approach in the conduct and analysis of pharmacodynamic interaction studies and pharmacotherapeutic combination trials.     

Effects of L-5HTP with and without carbidopa on plasma ß-endorphin and pain perception

L-Tryptophan (L-TP) has been used in migraine and other pain conditions. The mechanism underlying the analgesic effect is still partly undefined. In this study the effects of subchronic administration of L-5-hydroxy-tryptophan (L-5HTP) (with and without carbidopa) on plasma beta-endorphin (beta-EP) levels and subjective pain threshold and tolerance were investigated in seven healthy volunteers. To measure also an objective indicator for pain, the nociceptive flexion reflex threshold was studied. L-5HTP treatment with and without carbidopa administration increased beta-EP levels significantly (p less than 0.05). L-5HTP plus carbidopa induced an increase in beta-EP significantly (p less than 0.05) higher than that after L-5HTP alone. Neither subjective pain threshold and tolerance nor RIII threshold was modified by either treatment. Our data seem to point to the existence of a complex linkage between plasma opioid levels and pain perception.     

Viewpoints on the problem of subspecialization in internal medicine

There is no doubt that the specialisations which were performed during the last two to three decades in the field of internal medicine decisively furthered the scientific progress also in this subject. From the more and more detailed insights into the pathological process connected with this and the opening of more and more far-reaching therapeutic possibilities, however, resulted also with regard to the patients' care an increasingly organ-related medicine, which lost sight of the patient as a subject and personality. It has been omitted that the purely natural-scientifically orientated way of consideration is only one side of medical activity and that for recognition of all aspects of the homo patients internal medicine has to make use also of comprehensions and experiences of arts and social sciences. The synthesis of the two roots, connected with a subspecialization restricted to the necessary measure and its integration into a patient-orientated total concept of internal medicine should be able to reasonably coordinate scientifically explored facts, technical achievements, ethical things and things expected by the patient.     

Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy

The diagnostic value of biphasic radiographic examination of the stomach and duodenum was compared with that of fiberoptic endoscopy in a prospective, blinded study of 385 patients with dyspepsia. This investigation was directed at gastric malignancies and peptic ulcers. Methodologically there is no absolute standard for a study of this kind because histologic examination is useful for detection of cancer but inadequate for ulcers. As an alternative, kappa indexes and the sensitivity and specificity, as derived by Hui and Walter, were calculated and compared. For the detection of gastric carcinoma, radiographic and endoscopic findings had almost perfect agreement beyond chance. For gastric ulcers, radiography and endoscopy had substantial agreement, which became perfect if small ulcers (less than 5 mm) were excluded. For duodenal ulcers, radiography had a lower sensitivity than endoscopy; this disagreement disappeared if small ulcers were excluded. Both methods have equal merit; choice of the initial diagnostic procedure will therefore depend on cost, discomfort to the patient, and risk of complications.     

Pressure but not angiotensin II-induced increases in wall mass or tone influences static and dynamic aortic mechanics.

OBJECTIVE: To distinguish between static (due to slow changes in pressure) and dynamic (due to pressure pulsatility) components of aortic compliance over a large pressure range in vivo and to examine the effects of increased vascular mass and smooth muscle tone on these components. METHODS: Using ultrasound wall tracking, aortic lumen area-pressure curves were generated in anaesthetized rats over a broad range of pressures by altering blood volume. The compliance coefficient calculated at each mean pressure was considered the dynamic compliance at that pressure; the slope of the diastolic lumen area-pressure curve represents static compliance. Experiments were performed in control rats and rats treated with angiotensin II (ANG II) acutely (500 ng/kg per min intravenously) to modify vascular tone or chronically (250 ng/kg per min subcutaneously for 2 weeks) to modify vascular mass. RESULTS: The dynamic compliance-pressure curve approximated a parabola. Maximal dynamic compliance (0.272+/-0.026 mm2/kPa in control rats) was achieved at near-normotensive pressure (+/-105 mm Hg). The diastolic lumen area-pressure curve showed an exponential relationship within a physiological range (30-130 mm Hg). ANG II-induced increases in aortic wall mass or smooth muscle tone did not modify the relationship between static or dynamic compliance and pressure. CONCLUSIONS: These findings demonstrate that static and dynamic mechanics of the rat thoracic aorta depend differently on blood pressure. Static compliance increases slightly with pressure in a physiological range, while dynamic compliance is auto-regulated around normotensive pressures. Neither static nor dynamic compliance of the rat thoracic aorta are influenced by ANG II-induced increases in aortic wall mass or smooth muscle tone.     

Treatment of palatal fistula by expansion

Treatment of a large anterior fistula of the hard palate remains a problem. A new approach is presented by expansion of the palatal mucosa by custom-made implants, allowing closure in two layers without tension or extensive undermining.     

Smooth muscle relaxing, acute and long-term blood pressure lowering effects of atriopeptins. Structure-activity relationship

The relationship between the arterial relaxing, acute and long-term blood pressure lowering effects of atriopeptins were analyzed. We therefore evaluated effects of atriopeptin (103-126), i.e., atriopeptin III, and compared them to those of selected analogs. Atriopeptin (103-126) relaxed isolated aortas (1-30 nM) and lowered systolic blood pressure in conscious spontaneously hypertensive rats when high doses (4-400 nmol/kg i.v.) were administered acutely or low doses (0.4-4.0 nmol/kg/hr i.v.) were administered chronically. The relaxing effect was not affected by amino-terminal extension with up to four amino acids and by carboxy-terminal deletion of one amino acid. Further deletions lowered the relaxing potency. The observed maximal amplitude of the acute blood pressure lowering was reduced drastically by carboxy-terminal deletion of even one amino acid. This was prevented by substitution of the carboxy-terminal acid by an amide. Although not affecting the amplitude, amino-terminal extension with Arg or Arg-Arg prolonged markedly the duration of action of the acute effect. Chronic administration of atriopeptin (103-126), (103-125) and (103-123) affected blood pressure similarly. These findings illustrate different structure-activity relationships for the smooth muscle relaxing, acute and long-term antihypertensive activities of atriopeptins. From this it is suggested that the carboxy-terminal amino acids modulate differently the biological activities of atriopeptins, that amino-terminal amino acids modulate the duration of action of the acute in vivo effects and that the long-term antihypertensive effects of atriopeptins are not related directly to their arterial smooth muscle relaxing and acute blood pressure lowering effects.     

Telomerase in human tumors: molecular diagnosis and clinical significance

Shortening of structures known as telomeres, which cap the ends of chromosomes, is postulated to limit the lifespan of human cells. Activation of telomerase, an enzyme that synthesizes telomeric DNA, is an essential step in cell immortalization. Telomerase is ordinarily inactive in most somatic cells, but can be detected in nearly all tumors. The activation of telomerase in malignant cancers seems to be an important step in tumorigenesis, whereby the cell gains the ability of indefinite proliferation. Due to the association between telomerase expression and malignancy, the enzyme is expected to be a useful tumor marker and a new anticancer therapeutic target. However, recent results scale down to some extent the initial enthusiastic expectations for telomerase as the ideal malignancy marker.