bluuebunny/crossref_metadata_2025 huggingface dataset:
The chitinase 3-like protein human cartilage glycoprotein 39 inhibits cellular responses to the inflammatory cytokines interleukin-1 and tumour necrosis factor-alpha
Authors: LING Hua , RECKLIES Anneliese D.
Published: June 2004

Expression of the chitinase 3-like protein HC-gp39 (human cartilage glycoprotein 39) is associated with conditions of increased matrix turnover and tissue remodelling. High levels of this protein have been found in sera and synovial fluids of patients with inflammatory and degenerative arthritis. In order to assess the role of HC-gp39 in matrix degradation induced by inflammatory cytokines, we have examined its effect on the responses of connective tissue cells to TNF-α (tumour necrosis factor-α) and IL-1 (interleukin-1) with respect to activation of signalling pathways and production of MMPs (matrix metalloproteases) and chemokines. Stimulation of human skin fibroblasts or articular chondrocytes with IL-1 or TNF-α in the presence of HC-gp39 resulted in a marked reduction of both p38 mitogen-activated protein kinase and stress-activated protein kinase/Jun N-terminal kinase phosphorylation, whereas nuclear translocation of nuclear factor κB proceeded unimpeded. HC-gp39 suppressed the cytokine-induced secretion of MMP1, MMP3 and MMP13, as well as secretion of the chemokine IL-8. The suppressive effects of HC-gp39 were dependent on phosphoinositide 3-kinase activity, and treatment of cells with HC-gp39 resulted in AKT-mediated serine/threonine phosphorylation of apoptosis signal-regulating kinase 1. This process could therefore be responsible for the down-regulation of cytokine signalling by HC-gp39. These results suggest a physiological role for HC-gp39 in limiting the catabolic effects of inflammatory cytokines.
Deuterium isotope effect on the oxidation of monophenols and o-diphenols by tyrosinase
Authors: FENOLL Lorena G. , PEÑALVER María José , RODRÍGUEZ-LÓPEZ José N. , GARCÍA-RUIZ P. A. , GARCÍA-CÁNOVAS Francisco , TUDELA José
Published: June 2004

A solvent deuterium isotope effect on the catalytic affinity (km) and catalytic constant (kcat) of tyrosinase in its action on different monophenols and o-diphenols was observed. The catalytic constant decreased in all substrates as the molar fraction of deuterated water in the medium increased, while the catalytic affinity only decreased for the o-diphenols with an R group in C-1 [-H, -CH3 and -CH(CH3)2]. In a proton inventory study of the oxidation of o-diphenols, the representation of kcatfn/kcatf0 against n (atom fractions of deuterium), where kcatfn is the catalytic constant for a molar fraction of deuterium (n) and kcatf0 is the corresponding kinetic parameter in a water solution, was linear for all substrates, indicating that only one of the four protons transferred from the hydroxy groups of the two molecules of substrate, which are oxidized in one turnover, is responsible for the isotope effects, the proton transferred from the hydroxy group of C-4 to the peroxide of the oxytyrosinase form (Eox). However, in the representation of Kmfn/Kmf0 against n, where Kmfn represents the catalytic affinity for a molar fraction of deuterium (n) and Kmf0 is the corresponding kinetic parameter in a water solution, a linear decrease was observed as n increased in the case of o-diphenols with the R group [-H, -CH3 and -CH(CH3)2], and a parabolic increase with other R groups, indicating that more than one proton is responsible for the isotope effects on substrate binding. In the case of monophenols with six protons transferred in the catalytic cycle, the isotope effect occurs in the same way as for o-diphenols. In the present paper, the fractionation factors of different monophenols and o-diphenols are described and possible mechanistic implications are discussed.
SRC-dependent outside-in signalling is a key step in the process of autoregulation of beta2 integrins in polymorphonuclear cells
Authors: PICCARDONI Paola , MANARINI Stefano , FEDERICO Lorenzo , BAGOLY Zsuzsa , PECCE Romina , MARTELLI Nicola , PICCOLI Antonio , TOTANI Licia , CERLETTI Chiara , EVANGELISTA Virgilio
Published: June 2004

In human PMN (polymorphonuclear cells), challenged by P-selectin, the β2-integrin Mac-1 (macrophage antigen-1) promoted the activation of the SRC (cellular homologue of Rous sarcoma virus oncogenic protein) family members HCK (haematopoietic cell kinase) and LYN (an SRC family protein tyrosine kinase) and phosphorylation of a P-110 (110 kDa protein). SRC kinase activity in turn was necessary for macrophage antigen-1-mediated adhesion [Piccardoni, Sideri, Manarini, Piccoli, Martelli, de Gaetano, Cerletti and Evangelista (2001) Blood 98, 108–116]. This suggested that an SRC-dependent outside-in signalling strengthens the β2-integrin interaction with the ligand. To support this hypothesis further, in the present study, we used the monoclonal antibody KIM127 or manganese to lock β2 integrins in a high-affinity state, and homotypic PMN adhesion was analysed to monitor β2-integrin adhesive function. KIM127 or manganese induced PMN homotypic adhesion and P-110 phosphorylation. Both these processes were abolished by blocking antibodies against the common β2 chain, by a combination of antibodies against αL and αM or by inhibitors of SRC activity. Confocal microscopy showed that activation epitopes were expressed by β2 integrins co-localized with patches of F-actin at the adhesion sites. Blockade of SRC kinases or of actin polymerization prevented clustering of activated integrins as well as F-actin accumulation. FACS analysis showed that SRC inhibitors modified neither basal nor manganese-induced KIM127 binding. An SRC-dependent outside-in signalling initiated by β2 integrins was also required for adhesion triggered by interleukin-8. These results confirm the hypothesis that an SRC-dependent outside-in signalling triggered by high affinity and ligand binding is necessary to stabilize β2-integrin-mediated adhesion. Allowing clustering of activated integrins, SRC might link the high-affinity with the high-avidity state. Proline-rich tyrosine kinase-2 appears to be involved in this process.
Optimizing RNA interference for application in mammalian cells
Authors: MEDEMA René H.
Published: June 2004

Over the last 2 years, the scientific community has rapidly embraced novel technologies that allow gene silencing in vertebrates. Ease of application, cost effectiveness and the possibilities for genome-wide reverse genetics have quickly turned this approach into a widely accepted, almost mandatory asset for a self-respecting laboratory in life sciences. This review discusses some of the recent technological developments that allow the application of RNAi (RNA interference) in mammalian cells. In addition, the advantages of applying RNAi to study cell cycle events and the emerging approaches to perform mutational analysis by complementation in mammalian cells are evaluated. In addition, common pitfalls and drawbacks of RNAi will be reviewed, as well as the possible ways to get around these shortcomings of gene silencing by small interfering RNA.
RNase P as a tool for disruption of gene expression in maize cells
Authors: RANGARAJAN Sunita , RAJ M. L. Stephen , HERNANDEZ J. Marcela , GROTEWOLD Erich , GOPALAN Venkat
Published: June 2004

RNase P, a ribonucleoprotein responsible for the 5´ maturation of precursor tRNAs (ptRNAs) in all organisms, can be enticed to cleave any target mRNA that forms a ptRNA-like structure and sequence-specific complex when bound to an RNA, termed the EGS (external guide sequence). In the present study, F3H (flavanone 3-hydroxylase), a key enzyme in the flavonoid biosynthetic pathway that participates in the formation of red-coloured anthocyanins, was used as a target for RNase P-mediated gene disruption in maize cells. Transient expression of an EGS complementary to the F3H mRNA resulted in suppression of F3H to 29% of the control, as indicated by a reduced number of anthocyanin-accumulating cells. This decrease was not observed in experiments where a disabled mutant EGS was expressed. Our results demonstrate the potential of employing plant RNase P, in the presence of an appropriate gene-specific EGS, as a tool for targeted degradation of mRNAs.
Glycosynthase-catalysed formation of modified polysaccharide microstructures
Authors: WATTS Andrew G. , WITHERS Stephen G.
Published: June 2004

Glycosynthases are mutant glycosidases, genetically engineered to catalyse the synthesis of oligosaccharides. A study by Faijes et al. in this issue of the Biochemical Journal has expanded the ability of glycosynthases to catalyse the polymerization of carbohydrates to form unnatural oligosaccharide products that can attain unique crystalline forms. These findings reinforce the potential of glycosynthases as interesting and important tools for the enzymic synthesis of novel carbohydrates with specific and controlled structures.
Continuous positive airway pressure decreases myocardial oxygen consumption in heart failure
Authors: KAYE David M. , MANSFIELD Darren , NAUGHTON Matthew T.
Published: June 2004

The aim of the present study was to investigate the effects of CPAP (continuous positive airway pressure) support on myocardial energetics in patients with CHF (congestive heart failure). CPAP has been shown to decrease left ventricular afterload and to produce favourable short- and long-term haemodynamic and neurohormonal benefits in CHF patients. The mechanisms responsible for these actions are not completely understood. We measured the haemodynamic and myocardial metabolic response to the acute (10 min) application of CPAP in CHF patients. Myocardial VO2 (O2 consumption) and VCO2 (CO2 production) were measured by simultaneous arterial and coronary sinus blood sampling. The application of CPAP resulted in a significant decrease in left ventricular stroke work (97±12 to 83±9 g·m; P<0.05) and myocardial VO2 (0.32±0.03 to 0.25±0.01 ml of O2/beat; P<0.05). Myocardial mechanical efficiency, however, was unchanged. CPAP application decreases myocardial work and VO2. This effect on myocardial energetics could account for some of the favourable effects of CPAP in CHF patients.
Variability of inspiratory conductance quantifies flow limitation
Authors: BLOCH Konrad E. , RUSSI Erich W. , KAPLAN Vladimir
Published: June 2004

In the present study, our aim was to investigate whether the variability of conductance over the course of inspiration reflects flow limitation. Pressure/flow conditions in the upper airway were modelled by a collapsible tube within a rigid chamber and a pump simulating respiration. Instantaneous conductance was estimated every 20 ms as flow/resistive pressure, and its variability during inspiration expressed as the 90th/50th percentile ratio. Accuracy of this ratio to quantify flow limitation was evaluated by observing whether it changed predictably with adjustments of model parameters. To illustrate the potential of this ratio to quantify flow limitation in a clinical setting, we recorded pneumotachographic airflow and oesophageal pressure in 11 patients with obstructive sleep apnoea during nasal continuous positive airway pressure (CPAP) ventilation, and observed changes in the 90th/50th percentile ratio of inspiratory lung conductance induced by mask pressure titration. Rising pressure surrounding the collapsible tube from subatmospheric to positive values induced progressive inspiratory collapse and increased 90th/50th percentile ratios of inspiratory conductance as predicted. Changes in flow limitation induced by other model modifications were also correctly tracked by the 90th/50th conductance percentile ratio. Increasing mask pressure during CPAP ventilation in sleep apnoea patients from subtherapeutic to therapeutic pressure levels was associated with the expected decrease in the 90th/50th percentile ratio of inspiratory lung conductance from a mean of 6.5±3.1 to 1.6±0.3 (P<0.001). We conclude that variability of inspiratory conductance quantified by the 90th/50th percentile ratio may serve as a measure of flow limitation that is independent of the absolute value of conductance.
Increase in long-chain polyunsaturated fatty acid n−6/n−3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease
Authors: ARAYA Julia , RODRIGO Ramón , VIDELA Luis A. , THIELEMANN Lilian , ORELLANA Myriam , PETTINELLI Paulina , PONIACHIK Jaime
Published: June 2004

Hepatic steatosis is a major feature associated with NAFLD (non-alcoholic fatty liver disease). The aims of the present study were to assess the levels of PUFA (polyunsaturated fatty acids) in liver total lipids, triacylglycerols (triglycerides) and phospholipids of NAFLD patients in relation to those in adipose tissue and hepatic indexes related to oxidative stress as factors contributing to hepatic steatosis. Eleven control subjects and 19 patients with NAFLD were studied. Analysis of liver and abdominal adipose tissue fatty acids was carried out by GLC. The liver content of protein carbonyl groups and malondialdehyde were taken as indexes related to oxidative stress. NAFLD patients had a depletion in LCPUFA (long-chain PUFA) of the n-6 and n-3 series in liver triacylglycerols, with decreased 20:4,n-6/18:2,n-6 and (20:5,n-3+22:6,n-3)/18:3,n-3 ratios, whereas liver phospholipids contained higher n-6 and lower n-3 LCPUFA. These findings were accompanied by an enhancement of (i) n-6/n-3 ratio in liver and adipose tissue, (ii) 18:1,n-9 trans levels in adipose tissue, and (iii) hepatic lipid peroxidation and protein oxidation indexes. It is concluded that a marked enhancement in LCPUFA n-6/n-3 ratio occurs in the liver of NAFLD patients, a condition that may favour lipid synthesis over oxidation and secretion, thereby leading to steatosis. Depletion of hepatic LCPUFA may result from both defective desaturation of PUFA, due to inadequate intake of precursors, such as 18:3,n-3, and higher intake of the 18:1,n-9 trans isomer leading to desaturase inhibition, and from an increased peroxidation of LCPUFA due to oxidative stress.
Increased high-frequency heart rate variability during insulin-induced hypoglycaemia in healthy humans
Authors: SCHÄCHINGER Hartmut , PORT Johannes , BRODY Stuart , LINDER Lilly , WILHELM Frank H. , HUBER Peter R. , COX Daniel , KELLER Ulrich
Published: June 2004

Despite causing sympathetic activation, prolonged hypoglycaemia produces little change in HR (heart rate) in healthy young adults. One explanation could be concurrent parasympathetic activation, resulting in unchanged net effects of autonomic influences. In the present study, hypoglycaemic (2.7 mmol/l) and normoglycaemic (4.7 mmol/l) hyperinsulinaemic clamp studies were performed after normoglycaemic baseline clamp periods with 15 healthy volunteers (seven male; mean age, 27 years) on two occasions in a randomized single-blind cross-over design. Non-invasive indices of cardiac autonomic activity and hormones were measured at baseline and 1 h after the beginning of hypoglycaemia or control normoglycaemia. Plasma insulin levels and mean HR were similar during both conditions. During hypoglycaemia, there was a 485% increase in plasma adrenaline (epinephrine). A shortening of the pre-ejection period by 45% suggested strong sympathetic cardiac activation. High-frequency (0.15–0.45 Hz) HRV (HR variability) increased, indicating a concomitant increase in parasympathetic tone. Thus, during hypoglycaemia-induced sympathetic cardiac activation in healthy adults, parasympathetic mechanisms are involved in stabilizing mean HR.
Combined inhibition of angiotensin II and endothelin suppresses the brain natriuretic peptide response to developing heart failure
Authors: RADEMAKER Miriam T. , CHARLES Chris J. , ESPINER Eric A. , FRAMPTON Chris M. , NICHOLLS M. Gary , RICHARDS A. Mark
Published: June 2004

Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ETA/ETB receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment (P<0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.
Cerebellar ataxia and Purkinje cell dysfunction caused by Ca
2+
-activated K
+
channel deficiency
Authors: Sausbier M. , Hu H. , Arntz C. , Feil S. , Kamm S. , Adelsberger H. , Sausbier U. , Sailer C. A. , Feil R. , Hofmann F. , Korth M. , Shipston M. J. , Knaus H.-G. , Wolfer D. P. , Pedroarena C. M. , Storm J. F. , Ruth P.
Published: June 2004

Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage- and Ca
2+
-activated K
+
channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK
-/-
) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK
-/-
mice showed a dramatic reduction in spontaneous activity of the BK
-/-
cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia.
Cardiac-specific overexpression of sarcolipin inhibits sarco(endo)plasmic reticulum Ca
2+
ATPase (SERCA2a) activity and impairs cardiac function in mice
Authors: Asahi Michio , Otsu Kinya , Nakayama Hiroyuki , Hikoso Shungo , Takeda Toshihiro , Gramolini Anthony O. , Trivieri Maria G. , Oudit Gavin Y. , Morita Takashi , Kusakari Yoichiro , Hirano Shuta , Hongo Kenichi , Hirotani Shinichi , Yamaguchi Osamu , Peterson Alan , Backx Peter H. , Kurihara Satoshi , Hori Masatsugu , MacLennan David H.
Published: June 2004

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca
2+
ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN/PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca
2+
was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca
2+
transients and peak tensions were reduced, whereas decay times of Ca
2+
transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a–PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to β-adrenergic agonists may prevent progression to heart failure.
HER-2
gene amplification can be acquired as breast cancer progresses
Authors: Meng Songdong , Tripathy Debasish , Shete Sanjay , Ashfaq Raheela , Haley Barbara , Perkins Steve , Beitsch Peter , Khan Amanullah , Euhus David , Osborne Cynthia , Frenkel Eugene , Hoover Susan , Leitch Marilyn , Clifford Edward , Vitetta Ellen , Morrison Larry , Herlyn Dorothee , Terstappen Leon W. M. M. , Fleming Timothy , Fehm Tanja , Tucker Thomas , Lane Nancy , Wang Jianqiang , Uhr Jonathan
Published: June 2004

Amplification and overexpression of the
HER-2
oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with
HER-2
-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their
HER-2
gene status by fluorescence
in situ
hybridization. The
HER-2
status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with
HER-2
-positive tumors, the
HER-2
/chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 ± 2.72 vs. 2.8 ± 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the
HER-2
gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was
HER-2
-negative each acquired
HER-2
gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8–59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.
Identification of diamino acids in the Murchison meteorite
Authors: Meierhenrich Uwe J. , Muñoz Caro Guillermo M. , Bredehöft Jan Hendrik , Jessberger Elmar K. , Thiemann Wolfram H.-P.
Published: June 2004

Amino acids identified in the Murchison chondritic meteorite by molecular and isotopic analysis are thought to have been delivered to the early Earth by asteroids, comets, and interplanetary dust particles where they may have triggered the appearance of life by assisting in the synthesis of proteins via prebiotic polycondensation reactions [Oró, J. (1961)
Nature
190, 389–390; Chyba, C. F. & Sagan, C. (1992)
Nature
355, 125–132]. We report the identification of diamino acids in the Murchison meteorite by new enantioselective GC-MS analyses.
dl
-2,3-diaminopropanoic acid,
dl
-2,4-diaminobutanoic acid, 4,4′-diaminoisopentanoic acid, 3,3′-diaminoisobutanoic acid, and 2,3-diaminobutanoic acid were detected in the parts per billion range after chemical transformation into
N,N
-diethoxycarbonyl ethyl ester derivatives. The chiral diamino acids show a racemic ratio. Laboratory data indicate that diamino acids support the formation of polypeptide structures under primitive Earth conditions [Brack, A. & Orgel, L. E. (1975)
Nature
256, 383–387] and suggest polycondensation reactions of diamino acids into early peptide nucleic acid material as one feasible pathway for the prebiotic evolution of DNA and RNA genomes [Joyce, G. F. (2002)
Nature
418, 214–221]. The results obtained in this study favor the assumption that not only amino acids (as the required monomers of proteins) form in interstellar/circumstellar environments, but also the family of diamino monocarboxylic acids, which might have been relevant in prebiotic chemistry.
'Greening the People's Home': The Formative Power of Sustainable Development Discourse in Swedish Housing
Authors: Lundqvist Lennart J.
Published: June 2004

This article analyses what it takes for a new discourse to acquire formative power all the way from the formulation of ideas to the institutionalisation of new practices. Starting from seemingly contradictory propositions in the literature on housing and environmental policy discourses, and combining these with a contextual rational action approach, the empirical analysis traces the fate of the new sustainable development discourse introduced across many policy sectors in Sweden after 1996, including housing. It is found that who introduces new discursive ideas is important for their formative power; discourse introductions by government induce shifts in thoughts and talk across sectors. How this is done is even more important; metaphors and story lines of already institutionalised discourses strengthen formative power. Furthermore, using distributive measures with some strings attached is found to be an effective use of power resources to gain institutionalisation of the new discourse. However, it is found that institutionalised discourses at the local implementing level provide hindrances to formative power reaching all the way to new practices. This is furthermore accentuated by inherent contradictions in the Swedish discourse, as it built on equalising sustainable development with ecological modernisation.
THE VASCULAR CHANGES OF TUBERCULOUS MENINGITIS, ESPECIALLY THE TUBERCULOUS ENDARTERITIES
Authors: Hektoen Ludvig
Published: June 2004

1. In tuberculosis meningitis there is a tuberculosis endarteritis characterized by the formation of intimal tubercles and a diffuse subendothelial, intimal proliferation due to implantation of tubercle bacili from the blood. From the endarteritis the infiltration may spread into the muscular coat and the adventitia, and the whole wall may undergo caseous and hyaline degeneration.

2. Tuberculous proliferation in the adventitia may invade the media and the intima, and the whole wall of the arterial segment may undergo degeneration.

3. The veins are constantly the seat of more or less extensive infiltration, which always results from adjacent extravascular or arterial foci.

4. The epithelioid cells of the subendothelial, tuberculous intimal

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proliferation are most likely derived from the subendothelial layer of connective tissue and not from the endothelial lining.
THE PRODUCTION OF DIPHTHERIA TOXIN
Authors: Park W. H. , Williams A. W.
Published: June 2004

Toxin of sufficient strength to kill a 400-gramme guinea-pig in three days and a half in a dose of 0·cubic centimetre developed in suitable bouillon, contained in ordinary Erlenmeyer flasks, within a period of twenty-four hours. In such boullon the toxin reached its greatest strength in from four to seven days (0·005 cubic centimetre killing a 500-gramme guinea-pig in three days). This period of time covered that of the greatest growth of the bacilli, as shown both by the appearance of the culture and by the number of colonies developing an agar plates.

The bodies of the diphtheria bacili did not at any time contain toxin in cosiderable amounts.

The type of growth of the bacili and the rapidity and extent of the production of toxin depended more on the reaction of the bouillon than upon any other single factor.

The best results were obtained in bouillon which, after being neutralized to litmus, had about seven cubic centimetres of normal soda solution added to each litre. An excessive amount of either acid or alkali prevented the development of toxin.

Strong toxin was produced in bouillon containing peptone ranging from one to ten per cent. The strength of toxin averaged greater in the two and four-per-cent peptone solutions than in the one-percent.

When the stage of acid reaction was brief and the degree of acidity probably slight, strong toxin developed while the culture bouillon was still acid; but when the stage of acid reaction was prolonged, little if any toxin was produced until just before the fluid became alkaline.

Glucose is deleterious to the growth of the diphtheria bacillus and to the production of toxin when it is present in sufficient amounts to cause by its disintegration too great a degree of acidity in the fluid culture. When the acid resulting from decomposition of glucose is neutralized by the addition of alkali the diphtheria bacilus again grows abundantly. Glucose is not present, at least as a rule, in sufficient amounts in the meat as obtained from the New York butchers to prevent the rapid production of strong toxin if the bouillon is made sufficiently alkaline.

In our experiments, when other conditions were similar, the strength of the toxin was in proportion to the virulence and vigour of growth of the bacillus employed.
THE EFFECT OF PILOCARPINE ON THE OUTPUT OF LYMPHOCYTES THROUGH THE THORACIC DUCT
Authors: Rous F. Peyton
Published: June 2004

The intravenous injection of pilocarpine nitrate causes in the dog a rapid and considerable increase in the output of lymphocytes through the thoracic duct. The corresponding lymphocytosis induced by the drug in the blood of this animal is not profound, and increased cell-output with the lymph will explain a large part if not all of it.

Quickened lymph-flow and dyspnœic breathing are accessory in the production of the large cell-output with the lymph, but it is mainly dependent on some undetermined element. The evidence points to the mechanical nature of this element. It is probably to be sought in direct pressure from contraction of smooth muscle, as suggested by Harvey, but his observation that atropine prevents the appearance of a lymphocytosis after pilocarpine cannot be quoted in proof because atropine much slows the lymph-flow, and thus decreases cell-output.

These findings are in accord with the theory that makes mechanical factors responsible for rapidly appearing lymphocytosis. They show that there are more such factors than has been supposed. Especially do they indicate that the contribution of cells through the thoracic duct may be important in the production of lymphocytosis, and is not, as is often asserted, subsidiary to direct migration into the blood of cells from spleen, bone-marrow and the lymph-glands.
THE PULSE PRESSURE AS AN INDEX OF THE SYSTOLIC OUTPUT
Authors: Dawson Percy M. , Gorham Lemuel W.
Published: June 2004

On the basis of these facts we feel justified in making the following assertion:

Under normal conditions and during various procedures (namely, stimulation of the vagus centrally and peripherally, of the saphenus nerve centrally, and of the annulus Vieussentis, intravenous transfusion of 0.7 per cent. sodium chloride solution, intra-arterial transfusion of strong carbonate, bleeding and asphyxia) the pulse pressure is a reliable index of the systolic output.
THE ENZYMES OF FIBRINOUS EXUDATES—THE EFFECT OF ONE ENZYME UPON ANOTHER
Authors: Barker Bertha I.
Published: June 2004

By a study of the enzymes contained in fibrinous exudates produced by injection of a sterile inflammatory irritant (turpentine) conditions have been found in which each of two enzymes occurs alone. The one, leucoprotease, digests in the presence of alkali; the other, resembling lymphoprotease, digests in the presence of acid, yet both exhibit almost maximum activity in an approximately neutral medium. It is probable that both enzymes, in the body, exert their greatest activity in an approximately neutral medium, slight changes in reaction increasing digestion by the one, and suspending digestion by the other.

The enzyme digesting in acid, present in the fibrinous exudate obtained after a single injection of turpentine, disappears when repeated injection of the same irritant transforms the sero-fibrinous into a purulent exudate, and causes accumulation of leucoprotease in great quantity.
AN ANALYSIS OF FOUR HUNDRED CASES OF EPIDEMIC MENINGITIS TREATED WITH THE ANTI-MENINGITIS SERUM
Authors: Flexner Simon , Jobling James W.
Published: June 2004

It is our belief that the analyses of histories of cases of epidemic meningitis which have been presented in this article furnish convincing proof that the antimeningitis serum when used by the subdural method of injection, in suitable doses and at proper intervals, is capable of reducing the period of illness; of preventing, in large measure, the chronic lesions and types of the infection; of bringing about complete restoration to health, in all but a very small number of the recovered, thus lessening the serious, deforming, and permanent consequences of meningitis; and of greatly diminishing the fatalities due to the disease.
THE RELATION OF LESIONS OF THE ADRENAL GLAND TO CHRONIC NEPHRITIS AND TO ARTERIOSCLEROSIS; AN ANATOMICAL STUDY
Authors: Pearce Richard M.
Published: June 2004

Vaquez and Aubertin advance three theories in explanation of the adrenal hyperplasia; first, that it may not be the cause of hypertension but "an antitoxic hyperplasia" caused by the retained products of metabolism which may be responsible also for the hypertension; second, that it may be the cause of hypertension but secondary to the renal lesion; third, that it may be the cause of hypertension but may antedate the renal lesion or be entirely independent of it. They, as well as other French writers, insist that this hyperplasia is almost constantly associated with chronic nephritis of the interstitial type and it is seldom found with the parenchymatous type of nephritis, or with other lesions.

Hyperplasia of the adrenal, as far as my material enables one to judge, does not occur during the first and second decades. In the third decade it is relatively frequent in the absence of chronic arterial and renal disease but reaches the maximum in association with such disease after the fourth decade. It is an almost constant lesion in arteriosclerosis associated with chronic interstitial nephritis and left-sided heart hypertrophy, but occurs with almost equal frequency in arteriosclerosis with chronic nephritis of the parenchymatous type. It is a relatively frequent lesion of arteriosclerosis without chronic nephritis and of the latter without arteriosclerosis also. As the result of this analysis one is led to the view that while hyperplasia of the adrenal is a very frequent concomitant of chronic renal and arterial disease it is not exclusively a feature of either type of nephritis or yet of chronic vascular disease; but it probably represents the effect of some factor operating in that period of life in which chronic renal and arterial affections are most frequent.

Worthy of special emphasis is the observation that the characteristic lesion of an adrenal, the seat of local arteriosclerosis, is of the type of the chronic productive inflammation seen in arteriosclerosis of the pancreas and kidney; that is, thickening of the vessels, increase of connective tissue and round cell infiltration. Associated with these changes is a hyperplasia which is very constant, and which may be, in part, of the nature of a compensatory hyperplasia similar to that seen in the liver of cirrhosis and acute yellow atrophy. A hyperplasia of this type, as has been shown, may occur in destructive lesions of the gland. This, however, does not explain hyperplasia in the absence of local vascular changes which fact is, possibly, as suggested by Landau, evidence, not of a correlation between kidney and adrenal, but of a vicarious hypertrophy depending upon lesions of some other organ of the body than the kidney, possibly some other ductless gland, affected by arteriosclerosis or other disease.
A STUDY OF EXPERIMENTAL REDUCTION OF KIDNEY TISSUE WITH SPECIAL REFERENCE TO THE CHANGES IN THAT REMAINING
Authors: Sampson John A. , Pearce Richard M.
Published: June 2004

The immediate effect of the operation on the portion of the kidney remaining is an infarcation of the tissue compressed by the sutures. This area of necrosis extends but a short distance into the adjacent kidney tissue. The infarcated tissue gradually becomes replaced by fibrous tissue and in three to four week's time the necrotic tissue entirely disappears. The amount of fibrous tissue in time becomes so slight and the healing so perfect that it is difficult to detect the site of the operation. The renal elements sometimes persist in the infarcated area and the glomeruli apparently are more resistant than the tubules. The tubules in the infarcated area sometimes become calcified and bone formation beneath the epithelium of the pelvis is of very frequent occurrence. The pelvic epithelium usually shows marked proliferation and may invade the field of operation in alveolar masses. Calculi may form in the pelvis of the kidney. Sutures penetrating the pelvis as well as the necrotic tissue resulting from the compression of the sutures probably furnish the nuclei for the calculi.

Removal of approximately half of one kidney did not alter either the remaining portion of that kidney or the size of the opposite kidney in two animals of this series. These experiments were terminated on the thirty-fourth and forty-seventh days. In a similar experiment of twenty-one day's duration there was slight but definite atrophy of the remaining tissue of the kidney operated upon.

Removal of approximately half of each kidney at one operation did not alter the remaining kidney tissue in two animals of the second group. The longest period of observtaion was fifty-four days. On the other hand in a similar experiment where 164 days elapsed, the remaining portions of each kidney had increased markedly in size.

Removal of one kidney and approximately half of the other did not alter the remaining kidney tissue in six animals in which from five to fifty-six days elapsed before termination of the experiment.

In six experiments in which one kidney was removed and approximately half of the other, three of the animals died as a result of the operation on the sixth, seventh and tenth days. The probable cause of death was renal insufficiency: the animals refused food, vomited persistently and lost strength and weight. The other three animals recovered and were killed at periods varying from five to eight weeks. The reduction of the kidney tissue to one quarter of its original amount at one operation was attained with danger but was not necessarily fatal.

In every experiment there was a loss of weight varying from four to twenty-four per cent. To what extent this loss in weight is due to the reduction of kidney substance and to what extent it is due to diet and confinement it is impossible to say, as we made no control experiments to elucidate these points.
FATAL SEPTICEMIA IN MACACUS RHESUS CAUSED BY A STREPTOCOCCUS DECOLORIZED BY GRAM'S METHOD
Authors: Lamar R. V.
Published: June 2004

A Gram-negative streptococcus is associated with one form of fatal septicemia arising naturally in Macacus rhesus confined in laboratories.

This streptococcus differs from Streptococcus pyogenes in its behavior to Gram's method of staining; in its slight fermentative powers; in the persistence of vitality for a very long time in its cultures; in its high degree of pathogenicity for certain lower animals; and in the preservation of its virulence undiminished for many months when cultivated upon artificial media.

In the present state of our knowledge this streptococcus must be considered as not identical with any streptococcus heretofore described.
AUTO- AND ISOTRANSPLANTATION, IN DOGS, OF THE PARATHYROID GLANDULES
Authors: Halsted W. S.
Published: June 2004

1. The autotransplantation of parathyroid glandules into the thyroid gland and behind the musculus rectus abdominis has been successful in sixty-one per cent. of the cases in which a deficiency greater than one-half has been created.

2. In no instance has the autotransplantation succeeded without the creation of such deficiency.

3. Isotransplantation has been uniformly unsuccessful.

4. Parathyroid tissue transplanted in excess of what is urgently required by the organism has not lived.

5. One parathyroid autograft may suffice to maintain the animal in good health and spirits for many months and possibly for years.

6. Excised or deprived of their blood supply in the course of operation upon the human subject, parathyroid glands should, in the present state of our knowledge, be grafted, and probably into the thyroid gland.

7. Complete excision of the thyroid lobes in dogs may be well borne for a year or more. The myxœdema which usually has manifested itself within a few weeks has not increased after the first few months. May it subsequently diminish with the hypertrophy of accessory thyroids?

8. Parathyroid tissue is essential to the life of dogs, as has been conclusively proved by the result of excision of the sole, sustaining graft.

There may be found, perhaps, in our experiments, explanation of the fact observed by others (Enderlen, Payr) that, when transplanted, thyroid preserves its integrity less well than parathyroid tissue. In the instances recorded the amount of thyroid gland excised may have been insufficient to make possible the fullest success of the transplantation; and particularly so when we consider the extent of the hypertrophy of which the thyroid gland seems capable.
A STUDY OF THE PATHOLOGICAL ANATOMY OF THE PANCREAS IN NINETY CASES OF DIABETES MELLITUS
Authors: Cecil Russell L.
Published: June 2004

1. Anatomical lesions of the pancreas occur in more than seven-eighths of all cases of diabetes mellitus.

2. In diabetes associated with lesions of the pancreas, the islands of Langerhans constantly show pathological changes (sclerosis, hyaline degeneration, infiltration with leucocytes and hypertrophy).

3. In some cases of pancreatic diabetes (twelve of ninety cases) the lesion of the pancreas is limited to the islands of Langerhans.

4. In sixteen cases of diabetes associated with hyaline degeneration of the islands of Langerhans the average duration of the disease has been three and a half years; in forty-six cases with sclerosis of these bodies, three years and eleven months. In six cases of diabetes associated with an infiltration of leucocytes about the islands of Langerhans the average duration has been eleven months.

5. Destructive lesions of the islands of Langerhans may be associated with compensatory hypertrophy of other interacinar islands.

6. Peculiar adenoma-like hypertrophy of the islands of Langerhans occurs in a small proportion of cases (seven of ninety) and may be associated with adenomata of the thyroid gland (two cases) and of the pituitary body (one case).

7. Diabetes mellitus occurring in association with hæmochromatosis (bronzed diabetes) is referable to pigmentation and destruction of the islands of Langerhans.

8. The pancreas is found to exhibit no pathological changes in twelve per cent. of cases. In approximately one-half of these cases it has been noted that the size of the gland or the number of islands is much less than normal.

9. Fifty per cent. of cases of diabetes mellitus occurring before the age of thirty years are associated with lesions of the pancreas; seventy-five per cent. of all cases of diabetes in which the pancreas is normal occur before the age of thirty years. Ninety-seven per cent. of cases of diabetes occurring after the age of thirty years are associated with lesions of the pancreas; and eighty-six per cent. occur in association with chronic interacinar pancreatitis accompanying arteriosclerosis.

10. Interacinar pancreatitis which occurs in seventy-three per cent. of all cases of diabetes is almost constantly associated with arteriosclerosis: gangrene of the extremities, which occurs with one-fourth of all cases of interacinar pancreatitis, is doubtless referable to the same cause.

11. Chronic interlobular pancreatitis, when associated with diabetes, is accompanied by sclerosis or hyaline degeneration of the islands of Langerhans.

12. Diabetes in association with myxœdema or with exophthalmic goiter may be referable to a lesion of the pancreas, namely, chronic interacinar inflammation with sclerosis of the islands of Langerhans; diabetes in association with acromegaly may be referable to a lesion of the islands of Langerhans, namely, sclerosis and hyaline degeneration with adenoma-like hypertrophy.
STUDIES IN EDEMA
Authors: Fleisher Moyer S. , Hoyt Daniel M. , Loeb Leo
Published: June 2004

1. The secretion of urine and the elimination of fluid through the intestinal canal which are caused by the intravenous injection of solution of 0.85 per cent. sodium chloride are decreased by the addition of calcium chloride to the sodium chloride solution. The secretion of urine is more markedly inhibited than is the elimination of fluid through the intestines.

2. In contradistinction to the decreased elimination of fluid through the kidneys and intestines, addition of calcium chloride to the sodium chloride solution increases markedly the transudation of fluid into the peritoneal cavity. To a certain degree the urine and ascites may be said to increase in an inverse proportion.

3. Although calcium chloride inhibits both absorption from and secretion into the intestines it seems to decrease the secretion more markedly than the absorption.

4. The action of calcium chloride in increasing the ascitic fluid is a double one: first, by diminishing the amount of urine secreted: secondly, by increasing the ascites independently of its action on the kidneys. The latter may be a direct action on the endothelial cells of the peritoneal cavity: this, however, must be determined by further investigations.

5. Addition of calcium chloride to the infused fluids increases the tendency to the occurrence of edema of the lungs.

6. Infusion of large quantities of fluid into animals dilutes the blood, but this dilution seems to be carried only to a certain degree— about 30 per cent.—and to be independent of the chemical character of the solution and of the function of the kidneys.

7. The presence or absence of the kidneys has a marked influence on the intestinal and ascitic fluids. When the averages of ascitic and intestinal fluids per 1,000 c.c. of retained fluid in non-nephrectomized animals and these fluids per 1,000 c.c. of infused fluid in nephrectomized animals are compared, more fluid is found in the case of the nephrectomized animals. This fact can only be explained in part by the shorter time necessary for the same amount of fluid to be retained in the case of the nephrectomized animals. Nephrectomy causes an increase of the ascites and the intestinal fluids through a mechanism which will have to be investigated by means of further experiments.