Transforming growth factor-β and prostate cancer

Summary This review focuses on the possible role of transforming growth factor- isoforms 1–3 (TGF) in prostate cancer. TGF1 appears to inhibit the cellular proliferation of normal prostate cells. Surprisingly, TGF1 is overexpressed in prostate cancer. To help explain this apparent paradox, it has been revealed that with tumor progression, prostate cancer cells acquire reduced sensitivity to the growth-inhibitory effects of TGF1. Aberrations of the TGF1 signaling pathway at the prereceptor, receptor, or postreceptor level may lead to prostate cancer cell resistance to TGF1 growth inhibition. Indirectly, elevated levels of TGF1 may induce host effects that may be beneficial to prostate tumor growth by suppressing the immune system, promoting angiogenesis and extracellular matrix formation, and enhancing metastatic potential. Consequently, TGF1 appears to be important in prostate carcinogenesis and tumorigenicity. TGF2 and TGF3 are only briefly presented as very little is known about their role in prostate cancer.     

Effects of urinary macromolecules on the crystallization of calcium oxalate

Summary The macromolecular fraction of urine with a molecular weight above 3,000 was isolated by dialysis. In the dialysed urine the rate of calcium oxalate (CaOx) crystallization was reduced both in the presence and absence of CaOx seed crystals. There was a clear relationship between crystallization and the relative concentration of the dialysed urine, with the highest crystallization propensity at the lowest concentration of macromolecules. Dilution of dialysed urine also affected crystal size distribution, with a predominance of small (2.8–4.5 m) crystals in 100% dialysed urine and of large (5.6–14.0 m) crystals in 5% dialysed urine. This is consistent with a macromolecular inhibition of both crystal growth and aggregation. Analysis of the crystal size distribution 120 min after supersaturation of whole urine to a level at which approximately 100 crystals in the size interval 3.5–5 m were detected in a Coulter counter surprisingly disclosed a higher mean crystal volume in urine samples from normal subjects than from stone formers. This gives support to the assumptions that macromolecules might be of importance during the initial phase of CaOx crystallization and that urine from stone formers and normal subjects might be different in this respect.     

FT-IR microscopic mappings of early mineralization in chick limb bud mesenchymal cell cultures

Summary Chick limb bud mesenchymal cells differentiate into chondrocytes and form a cartilaginous matrix in culture. In this study, the mineral formed in different areas within cultures supplemented with 4 mM inorganic phosphate, or 2.5, 5.0, and 10 mM -glycerophosphate (GP), was characterized by Fourier-transform infrared (FT-IR) microscopy. The relative mineral-to-matrix ratios, and distribution of crystal sizes at specific locations throughout the matrix were measured from day 14 to day 30. The only mineral phase detected was a poorly crystalline apatite. Cultures receiving 4 mM inorganic phosphate had smaller crystals which were less randomly distributed around the cartilage nodules than those in the GP-treated cultures. GP-induced mineral consisted of larger, more perfect apatite crystals. In cultures receiving 5 or 10 mM GP, the relative mineral-to-matrix ratios (calculated from the integrated intensities of the phosphate and amide I bands, respectively) were higher than in the cultures with 4mM inorganic phosphate or in the in vivo calcified chick cartilage.     

Premature craniosynostosis a retrospective analysis of a series of 52 cases

Summary A retrospective analysis of a consecutive series of 52 cases with premature craniosynostosis is presented.Excellent functional, cosmetic, and social results could be achieved by resection of prematurely fused sutures and the creation of artificial growth sutures. Pronounced skull deformities have been corrected using the basket handle, the visor plasty, and the T-bone techniques or a combination of several of these skull form correction techniques. The surgical correction of the skull base by the frontal advancement technique in combination with orbitotomy was only necessary in 2 of our cases and could have been considered in 2 additional cases viewed retrospectively.Our results support the hypothesis that the primary cause of skull deformity is the premature closure of vault sutures and not a primary deformity of the skull base.     

Demonstration of the 5-flap technique

Summary Demonstration of the 5-flap technique which is double opposed Z-plasty and Y – V advancement is presented. A 4×4 gauze serves to demonstrate this technique.The authors dedicate this paper to the dear memory of their teacher, the late Prof. Zvi Neuman, who passed away untimely on March 22, 1977     

Transforming growth factor-beta localization during mouse prostate morphogenesis and in prostatic growth abnormalities

Summary Growth and morphogenesis of the prostate involves mesenchymal-epithelial interactions. Transforming growth factor-beta 1 (TGF-1) is one growth factor that may play a role in these paracrine interactions. We have localized TGF-1 by molecular and immunohistochemical analysis in the developing mouse prostate. Accumulations of TGF-1 protein were localized in the mesenchyme surrounding ductules in fetal and neonatal prostate. Previous studies in the mouse prostate reconstitution (MPR) model system have localized accumulations of TGF-1 to regions of oncogene-induced abnormalities. In surgically excised adult human prostate tissues, localized accumulations of TGF-1 are associated with prostate cancer and benign prostatic hyperplasia (BPH). Intracellular TGF-1 was more often associated with stromal cells in BPH and with neoplastic epithelial cells in prostate cancer. The production and accumulation of TGF-1 appears to involve interactions between mesenchymal and epithelial cells. Further experimental studies may clarify the relationships between TGF-1 and abnormal prostatic growth.     

Ultrastructure and inferred calcification of the mature and developing nacre in bivalve mollusks

Electron microscope studies of the mature nacreous layers fromBrachidontes recurvus (Rafinesque) andElliptio complanatus (Dillwyn) confirm the existence of tabular aragonite polygons interleaved with a perforate organic matrix. No evidence was found to support the concept of original component blocks orintracrystalline organic matriess. Replica studies of the immature, developing nacre reveal hollow crystals, thin crusts, subunits, and an abrupt transition to the mature shell material. A tentative explanation of some of the important features of the nacreous shell structure is offered.

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Zusammenfassung Elektronenmikroskopische Studien an reifen Perlmutterschichten desBrachidontes recurvus (Rafinesque) und desElliptio complanatus (Dillwyn) bestätigen das Vorhandensein von tubulären Aragonit-Polygonen, durchzogen von einer perforierten organischen Matrix. Der Nachweis, der die These primärer Blöcke oder intrakristalliner organischer Matrices stützen würde, konnte nicht erbracht werden. Abdruckstudien des unreifen, sich entwickelnden Perlmutters zeigten hohle Kristalle, dünne Krusten, Untereinheiten und einen abrupten Übergang zum reifen Muschelmaterial. Es wird versucht, einige wichtige Eigenschaften der Struktur des Muschelperlmutters zu erklären.

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Résumé Des études de microscopie électronique des couches nacrées adultes deBrachidontes recurvus etElliptio complanatus confirment la présence de polygones tubulaires d'aragonite en rapport avec une matrice organique aérée. Aucum argument en faveur de la théorie de blocs originaux composés ou de matrices organiques intracristallines n'a pu être trouvé. Des études par répliques de nacre jeune, en voie de développement, permettent de mettre en évidence des cristaux creux, de minces coques, des unités plus petites, et une transition abrupte aboutissant à la nacre adulte. Des hypothèses concernant certains des faits les plus importants, relatifs à la structure du nacre, sont proposées.

     

Role of TGFβ in the anti-estrogen response/resistance of human breast cancer

Transforming growth factor (TGF) has potent inhibitory effects upon epithelial proliferation and malignant progression may be associated with breakdown of the autocrine and paracrine inhibitory loops in which TGF participates. The therapeutic effects of anti-estrogens may be partially attributable to boosting of local endogenous levels of TGF. This article reviews the evidence in support of TGF being a proximate effector in mediation of the anti-neoplastic effects of anti-estrogens. Both the conventional estrogen receptor (ER)³ dependent and ER independent mechanisms of action are likely to be involved. Evidence for preferential stromal induction of TGF by anti-estrogens is emphasized, together with the therapeutic potential of this strategy for improving outcome in early breast cancer irrespective of ER status.     

Vertical lengthening of the unilateral cleft lip after a triangular flap repair

Summary A triangular flap repair for unilateral cleft lip is stated to have the potential problem of creating a lip that is too long. Although preoperative measurements were performed with calipers, the gap created in the medial segment was directly measured during the procedure, in order to determine the size of the flap more precisely. Ninety patients with complete unilateral cleft lips underwent a triangular flap repair using this method. The symmetry of the Cupid's bow was evaluated at a follow-up period averaging between six years and three months. Sixty-two lips obtained symmetry and the remaining 28 cases showed a lip which was too long; none of the lips were too short. The comparison between 27 primary palate clefts (UCLA) and 63 primary and secondary palate clefts (UCLP) showed no significant difference in the surgical result. The preoperative shortness of the lip on the cleft side was significantly greater in the too long group (5.01 ± 0.95 mm) than in the symmetry group (4.40 ± 0.87 mm). The width of the flap used was significantly larger in the too long group (3.76 ± 0.79 mm) than in the symmetry group (3.42 ± 0.69 mm). The triangular flap repair with intraoperative measurements is considered to be beneficial, although preoperative measurements provide an optimal design in most cases. It is suggested that the use of a wider triangular flap results in a lip which tends to be too long in spite of the preoperative shortness on the cleft side.     

TGF-β and functional differentiation

A review of the pertinent literature suggests that TGF-1 may play a multifaceted role in functional differentiation of mammary epithelium. Evidence for the expression of TGF-1 RNA and the presence of functional TGF-1 protein in differentiating mammary epithelial cells from a pregnant mouse has been recently reported. The specific role of mammary-epithelial-cell-produced TGF-1 in the differentiating mammary gland is presently unclear. However, several possible functions are suggested from the following observations. Milk protein production is negatively regulated by exogenous TGF-1 during gestational development of the gland but not during lactation. Consistent with reports linking TGF-1 gene expression with mammary gland involution following lactation, overexpression of TGF-1 in the differentiating secretory epithelium leads to premature programmed cell death in the absence of a negative effect on secretory epithelial cell proliferation. A role for TGF-1 in cell cycle control and suppression of malignant progression independent from its inhibitory effect on epithelial cell growth has been demonstrated in keratinocytes. A similar function could provide protection against malignancy in proliferating mammary epithelium and account for TGF-1 suppression of mammary tumorigenesis in transgenic mice overexpressing transforming growth factor alpha (TGF-).³     

Comparison of anesthetic effects of epidural and intravenous administration of buprenorphine during operation

Thirty six patients were received epidural anesthesia with or without buprenorphine (BPN) during upper abdominal surgery. They were divided into three groups of 12 patients as follows; G-I received 20ml of 1% lidocaine epidurally, G-II received 20ml of 1% lidocaine epidurally and 0.6mg BPN intravenously, G-III received 20ml of 1% lidocaine with 0.6mg BPN epidurally. Additional 5ml of 1% lidocaine was given to any patient if systolic blood pressure or heart rate increased 10% compared to control value. Trachea was intubated following anesthetic induction with thiopental. The lungs were ventilated with a mixture of N₂O/O₂ (33%) and pancuronium was used for muscle relaxation. The total required doses of lidocaine in G-II and G-III were decreased 60% compared to control group (G-I) (P 0.05). The mean period of time until the first administration of pentazocine for postoperative pain was 13 ± 10hr (mean ± SD) in G-II and 19 ± 24hr in G-III compared to 5 ± 4hr in G-I (P 0.001). The dose of the administration of pentazocine that was required for pain relief during the first 48 postoperative hr in G-III was 54 ± 10mg (mean ± SD) compared to 150 ± 21mg in G-I (P 0.02) and 106 ± 28mg in G-II (P 0.05). Recovery from anesthesia in G-III was more rapid than that in G-I (P 0.05). The Pa_{CO 2} values in G-II and G-III increased 15% compared to control group at about 4hr and 8hr after administration of BPN, but any clinical treatment was not needed for them. Nonrespiratory side effects, e.g., nausea, vomiting, fatigue and headache, were comparably common in all groups. Mild hematuria associated with acute hypotension occurred in two patients in G-II (17%) immediately after the intravenous injection of 0.6mg of BPN. The results showed that 0.6mg of BPN given epidurally demonstrated better anesthetic and more potent postoperative analgesic effects and lesser side effects than 0.6mg of BPN given intravenously in patients undergoing upper abdominal surgery.(Yonemura E, Fukushima K.: Comparison of anesthetic effects of epidural and intravenous administration of buprenorphine during operation. J Anesth 4: 242–248, 1990)     

Absorptiometry and “osteoporosis”: problems

connecting the dots between diverse clinical and other matters and an updated bone physiology reveals relationships that could modify some ideas about the roles and uses of absorptiometry in osteoporosis work. Herein, absorptiometry means that part of clinical densitometry that depends on X-ray absorption by bone and other tissues, thus excluding ultrasound methods and magnetic resonance imaging. The modifications concern, in part, some limitations of bone mineral density data, the kinds of physiological information that absorptiometry can and cannot provide, the relative importance of bone mass and whole-bone strength, how to define and study bone health and osteoporosis, and two kinds of osteoporotic fractures. As those modifications concern important national health care issues, they deserve answers based on hard evidence. Identifying those modifications might help others to evaluate them.     

Bench test assessment of the new Raumedic Neurovent-P ICP sensor: a technical report by the BrainIT group

Summary. Background. In clinical practice, fiberberoptic and piezo-electric ICP probes are often used for measuring intracranial pressure (ICP). A number of similar technologies, although performing well in bench test studies, have been shown to exhibit unacceptable zero drift, fragility or both during trials conducted under clinical conditions. Recently, a new technology has become available, the Neurovent-P (Raumedic AG+CO, Raumedic, Germany). As a pre-requisite for a clinical trial, we have conducted and report on bench test studies to confirm the manufacturers long term zero-drift performance for this technology.Method. In a test rig static tests (recording of 20mmHg pressure) and dynamic tests, ranging from 5 to 50mmHg have been performed.Findings. 10 ICP probes have been tested for a total of 60 days. All the catheters, after the connection with the ICU monitor displayed a static pressure of 0±1mmHg and did not required pre-insertion alteration. At five days, mean zero drift was 0.6±0.9mmHg. Overall, zero drift ranged from 0 to 2mmHg. At a fixed static pressure of 20mmHg, the mean recorded value was 20.6±0.8mmHg, ranging from 19 to 23mmHg. A regression analysis of the relationship between the applied pressure and the recorded pressure during the dynamic tests of the 10 catheters yielded a correlation coefficient R² of 0.997. Applying the Altman and Bland method to assess the bias and confidence limits for the Raumedic catheter responses during the dynamic tests against the applied gold-standard hydrostatic column pressures, the average bias of –0.66±0.85mmHg, with 95% CLs of –2mmHg and 1mmHg.Conclusions. Mean zero drift, after five days, was very small and long-term continuous recording of a stable pressure was very precise. The response at dynamic tests, i.e. the changes of pressure in a wide range, was excellent. The average bias of the Raumedic catheter compared with the hydrostatic column is very small. After this bench test, the next and most critical step will be to conduct a trial of this promising technology under more demanding clinical environment.     

Der Einfluß des niederfrequenten Wechselstrom-Systems Kraus-Lechner auf das Knochenwachstum

Zusammenfassung Osteone behandelter und kontrollierter Beagle-Ulnae werden in ihrem Flächenzuwachs berechnet. Die Stimulation erfolgte über Elektronägel System Kraus-Lechner. Die Mittelwerte der therapierten Osteone übertreffen die Kontrollen. Die Grundsatzfrage, ob eine meßbare Induktion des Kno chens durch niederfrequenten Elektromagnetismus er folgt, kann mit Wahrscheinlichkeit bejaht werden.

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The influence of low-frequency DC (System Kraus-Lechner) on bone growth

Summary Osteons of Beagle-ulnae were calculated in growth. Controlled osteons were compared with osteons after therapy. Stimulation was made with electro-nails system Kraus-Lechner. The mean-values of osteons after therapy surpass control. The fundamental question, whether induction of bone growth occurs with low frequency electromagnetism will in all probability be have to answered in the affirmative.

     

Masking of physicians in the Growth Failure in Children with Renal Diseases Clinical Trial

Masking — hiding identities of treatments from the patient, physician and/or statistician — is a critical element in clinical trials. Wherever possible, masking is implemented to eliminate observational bias or systematic error. In this paper, general concepts of masking in clinical trials are examined. Specific masking procedures used in the Growth Failure in Children with Renal Diseases (GFRD) Clinical Trial are described. A method to evaluate the success of this masking procedure for physicians is introduced. For each randomized patient at each clinical center, the clinic director was asked to predict which treatment (1,25-dihydroxyvitamin D₃ or dihydrotachysterol) was assigned. Results showed that 72% of responses initially indicated absolutely no idea of treatment. Additional analyses revealed that the number and percentage of correct guesses were essentially equal for the two treatment groups and that a patient's time on treatment did not affect the mask. We conclude that the mask of physicians in the GFRD Clinical Trial was well maintained.     

Enhancement of lidocaine-induced epidural anesthesia by deoxyaconitine in the rabbit

Purpose.Aconiti tuber has been used in traditional Oriental medicine to alleviate pain. The antinociceptive property of aconiti tuber is due to the action of its extracted alkaloids such as deoxyaconitine. The purpose of this study was to investigate the effect of epidural deoxyaconitine on epidural lidocaine anesthesia. Methods.Five adult rabbits were used. Three different combinations of drugs were injected into the epidural space, in the following order: first (combination A), 1.5ml of 2% lidocaine; second (combination B), 1.5ml of 2% lidocaine and 150µg deoxyaconitine; and third (combination C), 3mg nor-binaltorphimine followed by 1.5ml of 2% lidocaine and 150µg deoxyaconitine 30min later. The latency of onset and the duration of three end-points (sensory loss in the tail, loss of weight-bearing ability, and flaccid paresis of hind limb) were measured. Results.Onset times for the three end-points were not changed by deoxyaconitine or by nor-binaltorphimine. The duration of sensory loss was 27.0 ± 2.7min, the duration of loss of weight-bearing ability was 33.0 ± 2.7min, and the duration of flaccid paresis was 21.0 ± 4.2min in the combination A group. In the combination B group, deoxyaconitine extended the time of sensory loss by 80%, the time of loss of weight-bearing by 50%, and that of flaccid paresis by 60% compared with the combination A group. In the combination C group, this phenomenon was partially antagonized by pretreatment with nor-binaltorphimine, a -opioid antagonist. Conclusions.Based on our observations, deoxyaconitine enhanced epidural lidocaine anesthesia in the rabbit, and this effect seemed to be partly mediated by -opioid receptors.     

Traumatic lesion of the optic nerve

Summary This prospective study is based on 256 patients with severe brain injury. Six patients (2.3%) developed the clinical picture of inappropriate secretion of antidiuretic hormone (SIADH): 3 in the first 3 days following the injury, 3 after more than a week. Their ADH plasmatic level were measured by radio-immunoassay. In the former, many factors, largely iatrogenic, can explain the increased secretion of ADH we found and which is then definitely appropriate. It should be prevented by fluid restriction. In the latter, we found adequately low ADH levels, when the hypo-osmolarity is taken into account. Here, the aetiology seems to be a renal salt loss, eventually in relation to a natriuric factor (e.g. atrial natriuretic factor), justifying the term: Cerebral salt wasting syndrome. With the resistance to fluid restriction, the treatment still remains a problem.     

Latency and activation in the control of TGF-β

The biological activity of the transforming growth factor-'s (TGF-)³ is tightly controlled by their persistance in the extracellular compartment as latent complexes. Each of the three mammalian isoform genes encodes a product that is cleaved intracellularly to form two polypeptides, each of which dimerizes. Mature TGF-, a 24 kD homodimer, is noncovalently associated with the 80 kD latency-associated peptide (LAP). LAP is a fundamental component of TGF- that is required for its efficient secretion, prevents it from binding to ubiquitous cell surface receptors, and maintains its availability in a large extracellular reservoir that is readily accessed by activation. This latent TGF- complex (LTGF-) is secreted by all cells and is abundant both in circulating forms and bound to the extracellular matrix. Activation describes the collective events leading to the release of TGF-. Despite the importance of TGF- regulation of growth and differentiation in physiological and malignant tissue processes, remarkably little is known about the mechanisms of activationin situ. Recent studies of irradiated mammary gland reveal certain features of TGF-1 activation that may shed light on its regulation and potential roles in the normal and neoplastic mammary gland.     

Complex role of tumor cell transforming growth factor (TGF)-βs on breast carcinoma progression

Growth inhibition by the TGF-s has been extensively studied in both normal and transformed mammary epithelial cells. It has been proposed that loss of autocrine TGF- mediated growth regulation is a critical event in breast tumorigenesis and several lines ofin vitro andin vivo data support this hypothesis. However, a positive association between the expression of TGF-s by tumor cells and the progression or maintenance of breast cancinoma cells has been observed in many studies inin vivo tumor models. Possible mechanisms for these growth enhancing effects of TGF- include immunosuppression mediated by tumor TGF-s, enhanced angiogenesis, increased peritumoral stroma formation, and cell adhesion. The net effect of tumor cell TGF- on the biology of breast carcinogenesis would depend on the balance between autocrine growth inhibition of mammary epithelial cells and these growth enhancing effects.     

Zur Entwicklung der Hüftluxationsbehandlung im Laufe der Medizingeschichte

Zusammenfassung Die historische Entwicklung der ärztlichen Heilmaßnahmen zur Hüftgelenksreposition bei der typischen angeborenen Verrenkung ist ein interessantes Spiegelbild der gesamten Medizingeschichte und der Orthopädie im besonderen. Schon Hippokrates hat auf Grund recht guter pathologisch-anatomischer Sachkenntnis in seinem bedeutenden Werk i — über die Einrichtung der Gelenke — ein ebenso einfaches wie zweckmäßiges Extensionsverfahren am luxierten Bein dargestellt. Nach einer auffallend langen Zeitspanne resignierter Beschränkung auf rein palliative Therapie folgte eine radikal-aktive Ära der operativ-chirurgischen Reposition der kongenitalen Hüftluxation — vor allem repräsentiert durch die blutige Einrenkungsmethode von Hoffa und Lorenz. Erst die klinischen Mißerfolge dieses heroischen Vorgehens mit seiner Möglichkeit eines genauen bioptischen Studiums der weichgewebigen und artikulären Skeletsituation schufen die Grundlage zur Entwicklung der klassischen unblutigen Repositionsmethode, um deren Primat zwischen dem Italiener Paci und Adolf Lorenz eine heftige Kontroverse entstand. Zur stabilen Retention der eingerenkten Luxationshüfte wurden in der Folgezeit sehr verschiedenartige Gipsfixationen und Spreizapparate empfohlen — am bekanntesten die Lorenzprimärstellung, die weniger forcierte Langeposition und das geniale Schedelaufrad. Die moderne Orthopädie hat für die operative Korrektur unblutig nicht zu reponierender Hüftluxationen, etwa beim Vorliegen eines weichgewebigen Interpositums, oder bei unbefriedigendem Behandlungsergebnis eine ganze Reihe chirurgischer Hilfsoperationen — jeweils mit ganz spezieller Indikation — zur Verfügung: Die blutige Einrenkung, die Pfannendachplastik bei mangelhafter knöcherner Formsicherung des Acetabulums, die Femurosteotomie bei bestehender Oberschenkeldeformität im Sinne einer Coxa valga oder pathologischer Antetorsion des proximalen Femurendes — schließlich die Arthroplastik mit oder ohne Endoprothese bei schmerzhaft-kontrakten Spätzuständen. Als ultima ratio kann in besonders schweren Fällen ein stabiles beschwerdefreies Standbein durch Arthrodese geschaffen werden. Selbstverständlich werden heute auch sämtliche bewährten sonstigen physikalischen Hilfsmittel und Heilverfahren — aktive und passive Gymnastik, temporäre Gamaschenextension und Apparatentlastung, Massage und Bäderbehandlung — zur Verbesserung von Form und Funktion der Luxationshüften in den großen Kreis therapeutischer Möglichkeiten einbezogen.Die Arbeit wurde auf die Initiative und unter der Leitung von Herrn Prof. Dr. Rupprecht Bernbeck, München, verfaßt.