Dietary factors and progression of diabetic nephropathy

The role of dietary factors in patients with type 1 (insulin-dependent) diabetes is reviewed by examining three different aspects: the effect of an acute protein load, the effect of dietary protein restriction on the progression of nephropathy and the metabolic effects of low-protein diets. After an acute protein load some impairment of the renal functional reserve may be observed only in patients with type 1 diabetes and overt nephropathy. However, the renal functional reserve is not able to give useful indications of the extent of renal damage and the prognosis of the disease. Both short-term and long-term dietary protein restriction are followed by a significant decrease in glomerular filtration rate (GFR) and albuminuria in type 1 diabetics with incipient nephropathy. In patients with overt nephropathy the long-term administration of a low-protein diet is followed by significant reductions in the rate of decline of GFR and in urinary protein excretion only when started at GFR values higher than 45 ml/min. The rate of functional deterioration when dietary treatment is prescribed seems critical in modulating the effects of a low-protein diet. In addition, low-protein diets may exert important metabolic and clinical effects beyond their supposed effect on progression. Clearly, an adequate dietary regimen is only part of the medical treatment in patients with diabetic nephropathy.     

Reproductive factors and breast cancer: An overview

Summary Despite extensive research, there is still uncertainty on the separate effects of parity and age at first birth on breast cancer risk. Thus, information on these variables from formal epidemiological articles published in English since 1970 is reviewed in the present article. Among 26 studies considered, one found no significant association with either variable, seven showed an association between age at first birth but not parity and breast cancer risk, six an association with parity but not age at first birth, and in twelve studies both variables appeared to be independently related with breast cancer risk. Various reasons for these apparent differences can be considered, including heterogeneity between various populations (for instance, the proportion of multiparous women in studies showing no association with parity tended to be higher than in studies finding an inverse relation with parity), criteria for selection of cases and controls, influence of age and other covariates (among which the interval between pregnancies is of particular interest) and, of course, the role of chance. The data reviewed suggest, from an aetiological viewpoint, that both parity and age at first birth have some independent effect on breast carcinogenesis. From a public health viewpoint, however, it appears that the importance of age at first birth is greater, since the trend is linear across subsequent age levels, while the protection of parity seems to be quantitatively relevant only for women with four or five births or more.

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Fortpflanzungsfaktoren und Brustkrebs: eine Übersicht

Zusammenfassung Trotz intensiver Forschung bestehen immer noch Zweifel über die einzelnen Auswirkungen von Parität und Alter bei der Erstgeburt auf das Brustkrebsrisiko. Deshalb werden in diesem Artikel die Arbeiten, welche seit 1970 in Englisch veröffentlicht worden sind, analysiert. Von den 26 berücksichtigten Studien fand eine keine eindeutige Beziehung zu diesen beiden Variablen. Sieben wiesen eine Beziehung mit dem Alter bei der Erstgeburt nach, jedoch nicht mit der Parität. Sechs fanden einen Zusammenhang mit der Parität, aber nicht mit Alter bei Erstgeburt und aus 12 Studien ging hervor, dass beide Faktoren unabhängig voneinander mit dem Brustkrebsrisiko verbunden sind. Es gibt verschiedene Hypothesen, diese Diskrepanzen zu erklären, darunter auch die Verschiedenartigkeit in den untersuchten Bevölkerungen (so lag z.B. die Proportion der Frauen mit mehreren Geburten in jenen Studien, die nicht mit Parität verbunden sind höher, als in jenen, welche eine Verbindung zur Parität fanden), die Auswahlkriterien für Fälle und Kontrollen, der Einfluss des Alters und von anderen Variablen (wobei der Zeitabstand zwischen den Schwangerschaften besonders interessant ist) und natürlich die Rolle des Zufalls. Die gesichteten Resultate deuten vom ätiologischen Sichtpunkt darauf hin, dass Parität und Alter bei der Erstgeburt unabhängig voneinander das Brustkrebsrisiko beeinflussen. Die Beziehung zwischen dem Alter bei der Erstgeburt und der Brustkrebshäufigkeit scheint, vom Standpunkt der Sozialmedizin aus, jedoch von grösserer Bedeutung zu sein, da das Risiko in jeder Altersklasse linear ansteigt. Der Schutzeffekt der Parität hingegen ist erst von der vierten oder fünften Geburt an nachzuweisen.

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Les facteurs reproductifs et le cancer du sein: un résumé

Résumé Malgré des recherches approfondies, des doutes subsistent quant aux effets de parité et d'âge à la première naissance sur le risque du cancer du sein. Différents travaux parus en anglais depuis 1970 sont analysés dans cet article. Des 26 études analysées, une seule ne démontrait pas d'association. Sept ont montré une association avec l'âge à la première naissance mais pas avec la parité. Six ont démontré une association avec la parité mais non avec l'âge à la première naissance et 12 études ont montré une influence indépendante de ces deux facteurs sur le risque de cancer du sein. Différentes hypothèses peuvent être considérées pour ces différences apparentes, y compris l'hétérogénéité entre les populations étudiées (par exemple la proportion de femmes multipares est plus élevée dans les études démontrant une association avec la parité que dans celles avec une relation inverse), la sélection des cas et des témoins, la structure de l'âge, ainsi que d'autres facteurs comme par exemple l'intervalle entre les grossesses et bien sûr le hasard. Ces données laissent apparaître que la parité, ainsi que l'âge à la première naissance, peuvent influencer d'une manière indépendante le risque du cancer du sein. La corrélation entre l'âge à la première naissance et le cancer du sein est très importante pour la santé publique, étant donné que le risque augmente avec chaque classe d'âge, tandis que la parité n'a un effet protecteur qu'à partir de la quatrième ou de la cinquième naissance.

     

Human isolated small intestine: motor responses of the longitudinal muscle to field stimulation and exogenous neuropeptides

Summary (1) Longitudinal muscle strips from the human small intestine (jejunum/ileum) responded to electrical field stimulation (1–50 Hz) with frequency-related primary contractions which were largely atropine- (3 M) sensitive. When the tone was raised by addition of galanin (0.3 – 1 M), prostaglandin (PG) E₂ (1–10 M) or neurokinin A (NKA, 0.1 M), a frequency-related relaxation was evident which was potentiated by atropine. All the responses to field stimulation were abolished by tetrodotoxin (1 M), thus indicating their neural origin. (2) The atropine-sensitive primary contraction to field stimulation was virtually abolished by omega conotoxin fraction GVIA (CTX, 0.1–0.3 M) while the relaxations were CTX-resistant. The field stimulation-induced relaxations, which were observed in the presence of atropine and guanethidine (3 M), were also unaffected by apamin (0.1 M). (3) NKA and substance P (SP) produced a concentration- (1 nM–1 M for both peptides) related contraction, NKA being about 53 times more potent than SP. [Pro⁹]SP sulphone and [MePhe⁷]-NKB, selective agonists of the NK-1 and NK-3 receptor, respectively, were barely effective. On the other hand, [\Ala⁸]NKA(4–10), a selective NK-2 receptor agonist, had a potent contractile activity, similar to that of NKA. (4) Galanin (1 nM–1M) produced an atropine- and tetrodotoxin-resistant concentration-related contraction of longitudinal muscle of human isolated small intestine. The response to galanin did not show any sign of fading and was particularly suitable to study the evoked relaxations. (5) Calcitonin gene-related peptide (CGRP) (10–100 nM) consistently inhibited the nerve-mediated contractions of strips from the ileum while the effect on the jejunum was less pronounced. Vasoactive intestinal polypeptide (VIP, 0.1–1 M) inhibited nerve-mediated contractions both in the ileum and the jejunum. (6) These experiments indicate that both cholinergic excitatory and non-adrenergic non-cholinergic nerves affect motility of the longitudinal muscle of the human small intestine. Furthermore, several neuropeptides produce potent motor effects, the contractile response to tachykinins being apparently mediated by activation of NK-2 receptors.     

Rapid leukocyte integrin activation by chemokines

Summary: Chemokines control selective targeting of circulating leukocytes to the microvasculature by triggering inside-out signal transduction pathways leading to integrin-dependent adhesion. Integrin activation by chemokines is very rapid, is downmodulated within minutes and appears to involve both enhanced heterodimer lateral mobility on the plasma membrane, facilitating encounters with dispersed ligand, as well as induction of a high-affinity state. These two modalities of integrin activation by chemokines involve distinct signaling pathways in the cell, yet complement each other functionally, allowing binding of rolling cells under conditions of low as well as high ligand density. Recent data show that chemokines generate both pro- and anti-adhesive intracellular signaling events, whose equilibrium is likely to be relevant to the kinetics of adhesion and de-adhesion, and to cell movement during diapedesis and chemotaxis. Importantly, chemokines utilize different signaling mechanisms to modulate the activity of distinct integrin subtypes. These recent advances suggest that chemokines may regulate adhesive responses of immune cells based not only on patterns of chemokine receptor expression, but also on variable signaling pathways that can modulate the pro-adhesive responses of leukocytes as a function of their differentiated state, and of the local microenvironment.     

Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis

T lymphocytes from patients with multiple sclerosis (MS) recognize multiple myelin basic protein (MBP) epitopes. This situation complicates the design of specific immunotherapies. We investigated to which extent the T cell response to MBP is heterogeneous in single subjects in terms of preferentially recognized regions of the molecule, major histocompatibility complex (MHC) restriction, and stability over time. From each of nine patients with MS, a minimum of six MBP-specific T lymphocyte lines (TLL) were assayed for the proliferative response to a panel of overlapping peptides, encompassing the whole MBP. Predominant Tcell recognitions of distinct MBP regions were present in three patients, all HLA-DR2⁺, independently of the clinical features of their disease. Tcell reactivity was preferentially directed to residues 16-38 in one patient. In this case the response was also stable over time, during different phases of the disease. Predominant reactivity to residues 86-99 was detected in the two other DR2⁺ patients. In each of the patients with other HLA-DR haplotypes (DR2^?), as well as in three DR2⁺ non-MS donors, the Tcell response to MBP appeared to be considerably more heterogeneous. The HLA restriction element varied among TLL recognizing the same MBP region, even when raised from the same individual. The genomic HLA typing, performed on the DRB1 and DRB5 genes in the DR2⁺ subjects, showed no obvious correspondence between preferential responses to regions of MBP and HLA-DR2 subtypes. In this context, a simple, new method for the genomic typing of the HLA-DRB1 gene in individuals with the HLA-DR2 serological specificity is also described. We conclude that predominant and stable T cell responses to a single MBP region can be detected in some patients with MS. In these individuals, the MHC restriction of the T cell recognition of predominant regions appears to be variable. Polymorphisms of the HLA-DR2 gene products alone do not account for the selection of the dominant MBP Tcell epitope.     

MEG Characterization of Spontaneous Alpha Rhythm in the Human Brain

The present piece of research studied the spontaneous alpha rhythm of the human brain by combining the use of a whole-cortex neuromagnetometer and Magnetic Resonance Imaging. Single trials of spontaneous brain activity were recorded from ten human subjects asked to rest, with their eyes either closed or open, in relaxed wakefulness. MEG measurements were conducted over a period of one and a half years. The replicability of the results was confirmed for eight subjects out of ten. For three subjects, the alpha rhythm did not show any reductions due to the opening of the eyes. Both field map pattern and location of the estimated source were persistently stationary during each of the bursts of oscillations of the alpha rhythm. Dipoles were concentrated in clusters, indicating the existence of several spatially distributed sources. The calcarine fissure, the parieto-occipital sulcus and the surrounding occipital and parieto-occipital areas were identified as cortical sites of the brain where the alpha rhythm may originate. For four subjects, the majority of the sources were located near or in the calcarine fissure, while for five subjects, they were located near or in the parieto-occipital sulcus and for the remaining subject they were equally divided between the two generation sites.     

Pregnancy: Alcohol and risk of spontaneous abortion

The objective of this study was to assess the association betweenalcohol drinking before and during pregnancy and the risk ofspontaneous abortion using data from a case-control study conductedin Milan, Italy. A total of 462 women (median age 30 years)were admitted for spontaneous abortion (within the 12th weekof gestation) to a network of obstetrics departments in thegreater Milan area. Of these, 148 (32%) were between the fourthand the eighth week of gestation and 314 (68%) between the ninthand the 12th week. A control group was made up of 814 women(median age 29 years) who gave birth at term (>37 weeks gestation)to healthy infants (Apgar 5th minute 8, weight 3000 g) on randomlyselected days at the same hospitals where cases had been identified.A total of 212 cases (46%) and 355 controls (47%) reported alcoholdrinking before conception. Considering non-drinkers as thereference category, the relative risks (RR) of spontaneous abortionwere 1.2 (95% confidence interval (CI), 0.9–1.6] and 0.8(95% CI, 0.6–1.1), respectively, in drinkers of one toseven and more than seven drinks per week before conception.No association emerged between the duration of alcohol drinkingand the risk of spontaneous abortion. A total of 166 cases (35.9%)and 263 (32.3%) controls reported any alcohol drinking duringthe first trimester of pregnancy. The corresponding relativerisk was 1.1 (95% CI, 0.9–1.4) and no relationship emergedbetween the number of drinks per week and the risk of abortion.Likewise, maternal wine and beer drinking in the first trimesterof pregnancy was not associated with the risk of spontaneousabortion. Evidence available from this and previous studies,although partially controversial, indicates that moderate (oneor two drinks per day) alcohol consumption does not increasemarkedly the risk of miscarriage.