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The Proton Improvement Plan (PIP)-II project is part of Fermilab’s upgrade of its proton accelerator complex, to provide a powerful, high-intensity proton beam to the laboratory’s upcoming research program. The project includes an 800 MeV superconducting (SC) linear accelerator (linac), with five flavours of cavities and cryomodules. The medium energy section of the linac contains two types of superconducting Single Spoke Resonator (SSR) RF cavities (SSR1 and SSR2), which are interleaved with strong solenoid focusing lenses. A unified design of the solenoid has been developed, with one solenoid design satisfying both SSR1 and SSR2 requirements. The integral focusing strength requirement of 4.5 T2m with a full width half maximum (FWHM) of 180 mm indicates the peak field strength ∼ 6.8 T in the magnet aperture, necessitating a superconducting design within the limits of NbTi as magnet wire strand. These are complex combined units that include one focusing solenoid with bucking coils to minimize fringe fields and four corrector coils each, with independent current leads to produce dipole and quadrupole fields. To simplify the current lead design and reduce complexity, the project opted conduction cooling for these magnets, thus requiring a redesign compared to previous prototype bath cooled units. Existing designs for high energy accelerators adopt bath cooled design of the solenoid focusing lenses for medium energy cryomodules. The present design explores a unique and technically superior solution for the cryomodule operation by decoupling the magnet and cavity cooling to certain extent. Reliability in cryomodule operations shall be studied after integration of magnets in the Linac beamline. Here we discuss the design requirements, challenges, electromagnetic design, superconducting wire selection and the results from magnetic measurements of the first pre-series units.

Abstract: Recently, there has been substantial interest in using rule-based modelling approaches, such as the Kappa modelling language, to attack the combinatorial intractability of many biochemical systems. These approaches have allowed several novel static analyses to be developed, which motivates broadening their expressivity. In this paper, we build upon prior work giving Kappa an SPO-rewriting semantics to add containment structure, to model the various ways in which biological mixtures are partitioned and enclosed by membranes. [Copyright &y& Elsevier]

Microsporidia are spore-forming fungal pathogens that require the intracellular environment of host cells for propagation. We have shown that spores of the genus Encephalitozoon adhere to host cell surface glycosaminoglycans (GAGs) in vitro and that this adherence serves to modulate the infection process. In this study, a spore wall protein (EnP1; Encephalitozoon cuniculi ECU01_0820) from E. cuniculi and Encephalitozoon intestinalis is found to interact with the host cell surface. Analysis of the amino acid sequence reveals multiple heparin-binding motifs, which are known to interact with extracellular matrices. Both recombinant EnP1 protein and purified EnP1 antibody inhibit spore adherence, resulting in decreased host cell infection. Furthermore, when the N-terminal heparin-binding motif is deleted by site-directed mutagenesis, inhibition of adherence is ablated. Our transmission immunoelectron microscopy reveals that EnP1 is embedded in the microsporidial endospore and exospore and is found in high abundance in the polar sac/anchoring disk region, an area from which the everting polar tube is released. Finally, by using a host cell binding assay, EnP1 is shown to bind host cell surfaces but not to those that lack surface GAGs. Collectively, these data show that given its expression in both the endospore and the exospore, EnP1 is a microsporidian cell wall protein that may function both in a structural capacity and in modulating in vitro host cell adherence and infection.

ABSTRACTMicrosporidia are spore-forming fungal pathogens that require the intracellular environment of host cells for propagation. We have shown that spores of the genus Encephalitozoonadhere to host cell surface glycosaminoglycans (GAGs) in vitro and that this adherence serves to modulate the infection process. In this study, a spore wall protein (EnP1; Encephalitozoon cuniculiECU01_0820) from E. cuniculiand Encephalitozoon intestinalisis found to interact with the host cell surface. Analysis of the amino acid sequence reveals multiple heparin-binding motifs, which are known to interact with extracellular matrices. Both recombinant EnP1 protein and purified EnP1 antibody inhibit spore adherence, resulting in decreased host cell infection. Furthermore, when the N-terminal heparin-binding motif is deleted by site-directed mutagenesis, inhibition of adherence is ablated. Our transmission immunoelectron microscopy reveals that EnP1 is embedded in the microsporidial endospore and exospore and is found in high abundance in the polar sac/anchoring disk region, an area from which the everting polar tube is released. Finally, by using a host cell binding assay, EnP1 is shown to bind host cell surfaces but not to those that lack surface GAGs. Collectively, these data show that given its expression in both the endospore and the exospore, EnP1 is a microsporidian cell wall protein that may function both in a structural capacity and in modulating in vitro host cell adherence and infection.

Microsporidia are obligate intracellular opportunistic protists that infect a wide variety of animals, including humans, via environmentally resistant spores. Infection requires that spores be in close proximity to host cells so that the hollow polar tube can pierce the cell membrane and inject the spore contents into the cell cytoplasm. Like other eukaryotic microbes, microsporidia may use specific mechanisms for adherence in order to achieve target cell proximity and increase the likelihood of successful infection. Our data show that Encephalitozoon intestinalis exploits sulfated glycans such as the cell surface glycosaminoglycans (GAGs) in selection of and attachment to host cells. When exogenous sulfated glycans are used as inhibitors in spore adherence assays, E. intestinalis spore adherence is reduced by as much as 88%. However, there is no inhibition when nonsulfated glycans are used, suggesting that E. intestinalis spores utilize sulfated host cell glycans in adherence. These studies were confirmed by exposure of host cells to xylopyranoside, which limits host cell surface GAGs, and sodium chlorate, which decreases surface sulfation. Spore adherence studies with CHO mutant cell lines that are deficient in either surface GAGs or surface heparan sulfate also confirmed the necessity of sulfated glycans. Furthermore, when spore adherence is inhibited, host cell infection is reduced, indicating a direct association between spore adherence and infectivity. These data show that E. intestinalis specifically adheres to target cells by way of sulfated host cell surface GAGs and that this mechanism serves to enhance infectivity.

ABSTRACTMicrosporidia are obligate intracellular opportunistic protists that infect a wide variety of animals, including humans, via environmentally resistant spores. Infection requires that spores be in close proximity to host cells so that the hollow polar tube can pierce the cell membrane and inject the spore contents into the cell cytoplasm. Like other eukaryotic microbes, microsporidia may use specific mechanisms for adherence in order to achieve target cell proximity and increase the likelihood of successful infection. Our data show that Encephalitozoon intestinalisexploits sulfated glycans such as the cell surface glycosaminoglycans (GAGs) in selection of and attachment to host cells. When exogenous sulfated glycans are used as inhibitors in spore adherence assays, E. intestinalisspore adherence is reduced by as much as 88%. However, there is no inhibition when nonsulfated glycans are used, suggesting that E. intestinalisspores utilize sulfated host cell glycans in adherence. These studies were confirmed by exposure of host cells to xylopyranoside, which limits host cell surface GAGs, and sodium chlorate, which decreases surface sulfation. Spore adherence studies with CHO mutant cell lines that are deficient in either surface GAGs or surface heparan sulfate also confirmed the necessity of sulfated glycans. Furthermore, when spore adherence is inhibited, host cell infection is reduced, indicating a direct association between spore adherence and infectivity. These data show that E. intestinalisspecifically adheres to target cells by way of sulfated host cell surface GAGs and that this mechanism serves to enhance infectivity.

ABSTRACTMicrosporidia are intracellular eukaryotes that infect many animals and cause opportunistic infections in AIDS patients. The disease is transmitted via environmentally resistant spores. Two spore wall constituents from the microsporidian Encephalitozoon intestinaliswere characterized. Spore wall protein 1 (SWP1), a 50-kDa glycoprotein recognized by monoclonal antibody (MAb) 11B2, was detected in developing sporonts and at low levels on the surfaces of mature spores. In contrast, SWP2, a 150-kDa glycoprotein recognized by MAb 7G7, was detected on fully formed sporonts and was more abundant on mature spores than SWP1. Nevertheless, the SWPs appeared to be complexed on the surfaces of mature spores. SWP1 and SWP2 are similar at the DNA and protein levels and have 10 conserved cysteines in the N-terminal domain, suggesting similar secondary structures. The C-terminal domain of SWP2 has a unique region containing 50 repeating 12- or 15-amino-acid units that lacks homology to known protein motifs. Antibodies from mice infected with E. intestinalisrecognized SWP1 and SWP2. The characterization of two immunogenic SWPs from E. intestinaliswill allow the study of exospore structure and function and may lead to the development of useful tools in the diagnosis and treatment of microsporidiosis.

A service excellence system for ambulatory care pharmacy services is described. An interview was designed to measure the needs, expectations, and priorities of a random sample of ambulatory care patients at a 964-bed county teaching hospital and its clinics to determine trends in patient service and satisfaction. The interviews were conducted by the same interviewers with the same script, and follow-up was continuous for two years. Information was summarized for each question and pharmacy site. In defining "service excellence" from a patient's perspective, it was determined that patients wanted a continuation of low-cost prescriptions, decreased waiting time, a friendlier, more caring staff, and environmental modifications. A service excellence system with key performance indicators was then designed and implemented. This effort included recruiting employees with behaviors that support service excellence, training employees to deliver service excellence, creating an environment that promotes patient satisfaction, and designing an ongoing monitoring system. Next, it was imperative to change the attitudes of staff and existing processes to meet or exceed patients' expectations. This phase addressed such issues as patient waiting time, staff-patient interaction, patients' environmental concerns, and staff ideas for service improvement. Finally, changes in service levels were measured. Overall patient satisfaction increased from 72% to 93% at the maincampus pharmacies. Satisfaction at the smaller sites rose from 85% to 95%, while turnaround time and number of pharmacist full-time-equivalents remained stable. A service excellence program was effective in addressing the service issues of ambulatory care patients at a large teaching hospital.

The 43 kDa inositol polyphosphate 5‐phosphatase (5‐phosphatase) hydrolyses the second messenger molecules inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5‐tetrakisphosphate [Ins(1,3,4,5)P4]. We have underexpressed the 43 kDa 5‐phosphatase by stably transfecting normal rat kidney cells with the cDNA encoding the enzyme, cloned in the antisense orientation into the tetracycline‐inducible expression vector pUHD10–3. Antisense‐transfected cells demonstrated a 45% reduction in Ins(1,4,5)P3 5‐phosphatase activity in the total cell homogenate upon withdrawal of tetracycline, and an approximately 80% reduction in the detergent‐soluble membrane fraction of the cell, as compared with antisense‐transfected cells in the presence of tetracycline. Unstimulated antisense‐transfected cells showed a concomitant 2‐fold increase in Ins(1,4,5)P3 and 4‐fold increase in Ins(1,3,4,5)P4 levels. The basal intracellular calcium concentration of antisense‐transfected cells (170 +/− 25 nM) was increased 1.9‐fold, compared with cells transfected with vector alone (90 +/− 25 nM). Cells underexpressing the 43 kDa 5‐phosphatase demonstrated a transformed phenotype. Antisense‐transfected cells grew at a 1.7‐fold faster rate, reached confluence at higher density and demonstrated increased [3H]thymidine incorporation compared with cells transfected with vector alone. Furthermore, antisense‐transfected cells formed colonies in soft agar and tumours in nude mice. These studies support the contention that a decrease in Ins(1,4,5)P3 5‐phosphatase activity is associated with cellular transformation.

The 43 kDa inositol polyphosphate 5‐phosphatase (5‐phosphatase) hydrolyses the second messenger molecules inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5‐tetrakisphosphate [Ins(1,3,4,5)P4]. We have underexpressed the 43 kDa 5‐phosphatase by stably transfecting normal rat kidney cells with the cDNA encoding the enzyme, cloned in the antisense orientation into the tetracycline‐inducible expression vector pUHD10–3. Antisense‐transfected cells demonstrated a 45% reduction in Ins(1,4,5)P3 5‐phosphatase activity in the total cell homogenate upon withdrawal of tetracycline, and an approximately 80% reduction in the detergent‐soluble membrane fraction of the cell, as compared with antisense‐transfected cells in the presence of tetracycline. Unstimulated antisense‐transfected cells showed a concomitant 2‐fold increase in Ins(1,4,5)P3 and 4‐fold increase in Ins(1,3,4,5)P4 levels. The basal intracellular calcium concentration of antisense‐transfected cells (170 +/− 25 nM) was increased 1.9‐fold, compared with cells transfected with vector alone (90 +/− 25 nM). Cells underexpressing the 43 kDa 5‐phosphatase demonstrated a transformed phenotype. Antisense‐transfected cells grew at a 1.7‐fold faster rate, reached confluence at higher density and demonstrated increased [3H]thymidine incorporation compared with cells transfected with vector alone. Furthermore, antisense‐transfected cells formed colonies in soft agar and tumours in nude mice. These studies support the contention that a decrease in Ins(1,4,5)P3 5‐phosphatase activity is associated with cellular transformation.

The presence of parathyroid hormone-related protein (PTHrP) in the apocrine adenocarcinoma tumor line (CAC-8) derived from a hypercalcemic dog was demonstrated by western and northern blot analyses. Western blots of CAC-8 tumor extracts revealed a major protein with a molecular weight of approximately 18,000 daltons that cross-reacted with antiserum to human PTHrP. Northern blots demonstrated multiple-sized messenger RNA transcripts in CAC-8 that hybridized to a full-length cDNA probe to human PTHrP. Adenocarcinomas derived from apocrine glands of the anal sac also were stained immunohistochemically for antigens that cross-react with antiserum to human PTHrP. The tumor line (CAC-8) maintained in nude mice stained positively for PTHrP in 13 of 24 tumors. Three of ten apocrine adenocarcinomas from dogs with hypercalcemia stained for PTHrP, whereas zero of ten tumors were positive from normocalcemic dogs. Normal canine epidermal keratinocytes and areas of squamous metaplasia in a perianal gland carcinoma also were positive for PTHrP. These data demonstrated that canine tissues contained a homologue to human PTHrP that likely is important in the pathogenesis of humoral hypercalcemia of malignancy.

Mycobacterium ulcerans, the organism which causes Buruli or Bairnsdale ulcer, has never been isolated in culture from an environmental sample. Most foci of infection are in tropical regions. The authors describe the first 29 cases of M. ulcerans infection from a new focus on an island in temperate southern Australia, 1992–5. Cases were mostly elderly, had predominantly distal limb lesions and were clustered in a small region in the eastern half of the main town on the island. The authors suspected that an irrigation system which lay in the midst of the cluster was a source of infection. Limitation of irrigation was associated with a dramatic reduction in the number of new cases. These findings support the hypothesis that M. ulcerans has an aquatic reservoir and that persons may be infected directly or indirectly by mycobacteria disseminated locally by spray irrigation.

A cluster of Mycobacterium ulcerans infections has recently occurred on Phillip Island, Victoria, Australia. Previous cases of infection have generally been located around Bairnsdale in southeast Gippsland. The aim of this study was to determine the epidemiological relationship between these strains and other strains originating in Australia and Africa. The previously described plasmid pTBN12 was used as a probe with restriction enzyme-digested chromosomal DNA to differentiate the strains of M. ulcerans. The probe was able to distinguish 11 restriction fragment length polymorphisms (RFLPs). Forty-three strains originating in Victoria were divided into three types, i.e., V1, V2, and V3. The majority of strains (40) yielded a type V1 pattern, including strains from southeast Gippsland. Fourteen strains from Queensland yielded three additional RFLP types, i.e., Q1, Q2, and Q3. Five strains from Benin and seven strains from Zaire yielded five additional RFLP types. It is envisaged that molecular typing of M. ulcerans strains from around the world may have a great impact on understanding of the epidemiology of infection with this organism.

We have recently described a new serine proteinase inhibitor, proteinase inhibitor 6 (PI-6). This serpin has features that suggest it may function intracellularly, but its close resemblance to ovalbumin serpins like plasminogen activator inhibitor 2 (PAI-2) raises the possibility that it is secreted to regulate an extracellular proteinase. To determine whether PI-6 is secreted, we have examined its cellular distribution by immunohistochemistry and have attempted to induce its release from platelets and from cultured cells. We find that PI-6 is present in endothelial and epithelial cells, but it is apparently cytoplasmic and it is not released from cells in response to phorbol ester, dibutyryl cAMP or tumor necrosis factor alpha treatment. It is also not released from activated platelets. The addition of a conventional signal peptide to the amino terminus of PI-6 directed its translocation into the endoplasmic reticulum (ER), resulting in glycosylation but not secretion of the molecule. By contrast, the addition of the same signal peptide to PAI-2 markedly enhanced its translocation and secretion. Glycosylated PI-6 was sequestered in the ER and was incapable of interacting with thrombin. The failure of PI-6 to move along the secretory pathway, and the loss of inhibitory function of ER-localized PI-6, demonstrates that unlike PAI-2, PI-6 is not naturally secreted. Taken together, these results suggest that PI-6 has evolved to fulfil an intracellular role and that it represents a new type of cellular serpin.

Summary The effects of the presence or absence of calcium in the cardioplegic perfusate were studied utilizing the isolated blood perfused dog heart preparation. Hearts were subjected to two hours of arrest at 27°C followed by 90 minutes of normothermic reperfusion. Perfusates with or without 2.52 mM calcium chloride were delivered at 15 minute intervals during arrest at a perfusion pressure of 100 mm Hg.

Mycobacterium ulcerans causes extensive ulcers (Buruli ulcers) in the skin of humans. Analysis of the 3'-terminal region of the 16S rRNA gene sequence of 17 strains of M. ulcerans from Africa, the Americas, and Australia revealed three subgroups corresponding to the continent of origin, and some variable phenotypic characteristics. This sequence is useful for the rapid detection of M. ulcerans and discriminates M. marinum and M. shinshuense from M. ulcerans.

An immunoperoxidase method has been developed to detect parathyroid hormone‐related protein (PTHrP) in histological specimens of tumors and of normal skin. A rabbit polyclonal antiserum against PTHrP‐(1–16) was used that did not cross‐react with PTH‐(1–34) either under radioimmunoassay conditions or at the high antiserum concentrations used in neutralizing biologic activity. PTHrP antigen was detected in the keratinocyte layer of normal skin and in 100% of 34 samples of squamous cell cancers but in only one of six breast cancers, and none of 15 other adenocarcinomata. It was also detected in four of four samples of renal cortical carcinoma and two of two of melanoma, both of which can be associated with hypercalcemia, and three of three small cell carcinomata of the lung. Immunologic detection of PTHrP could be useful in the diagnosis of tumors of squamous cell origin, particularly in the cytological differentiation of lung cancers, where it may be of value in distinguishing between squamous cell and small cell carcinoma on the one hand and poorly differentiated adenocarcinoma on the other.

The majority of tests of renal function are interpreted and their results recorded in terms of the values obtained for normal persons. Any one of them yields an estimate of the efficiency of the kidneys at a particular time, but this may be of little prognostic significance, for it is well known that in acute nephritis, acute infections, ureteral obstruction or cardiac failure renal function may be severely depressed and yet with recovery of the patient may return to normal. In chronic renal disease, however, decreasing functional values usually indicate the relentless progress of the condition.The ideal test of function would give not only an estimate of the degree of loss of renal efficiency but information as to the manner in which the normal physiologic processes have been disturbed. The processes involved in the formation of urine are so complex that no test has been devised by which it

Since the time of Bright, albuminuria has commonly been associated with disease of the kidneys. More recently the distinction has been made between non-nephritic and nephritic albuminuria. The former is most readily attributed to a transient and reversible increase in permeability of the glomerular membrane from partial asphyxia brought about by circulatory changes.1 From time to time, however, the suggestion has been made that nephritic albuminuria is the result of changes in the plasma proteins rather than any change in or damage to the kidney itself. Epstein2 saw in the albuminuria of nephrosis a disturbance of plasma protein formation; Kollert and Starlinger3 an increased tissue destruction leading to increase in fibrinogen; and Munk and his associates,4 an abnormality in the physicochemical state of the plasma colloids. The conception of extrarenal albuminuria is supported by the appearance of foreign proteins, such as egg albumin, in the urine

The multitude of substances whose “clearances”, or rate of excretion in relation to blood concentration, have been proposed as tests of kidney function indicates that a satisfactory clinical procedure is yet to be devised. The use of urea, as proposed by Moller, McIntosh and Van Slyke,1is in our experience the simplest of the more sensitive tests, since it involves only one blood sample and does not require the ingestion of the test substance. But since the rate of urea excretion is less with low urine volume than with high, function tests can be compared only as a percentage of an average empirical normal for urine volumes above or below 2 cc. per minute. There are, therefore, certain advantages in using a test substance whose excretion is independent of urine volume. Creatinine, the use of which was proposed by Rehberg,2is such a substance. This method as described3has the disadvantage of requiring ingestion of creatinine, and analysis of urine and 2 samples of blood plasma.The development by Van Slyke and Cope4of a clinical method for the determination of urea clearances suggested that a similar procedure might be devised for the creatinine clearance which, if practical, would considerably simplify the test.In the method of Van Slyke and Cope, the ratio between urine and blood urea concentrations is determined by a direct comparison, without determining the actual concentration in either. In the method here described, the same principle is applied except that creatinine is used. In order to increase the concentration of creatinine in the blood and urine, creatinine is administered to the subject by mouth, and water given at hourly intervals during the test if there is any question of the subject's ability to urinate.

Following the intravenous injection of a gum shellac solution which alters the peripheral blood picture there is an increase in the time-drop of the diluted serum. This is believed to indicate changes in the physicochemical state of the plasma. This gum shellac solution behaves as a surface-active substance; its effect on the surface tension of serum is hindered by the du Noüy phenomenon of adsorption on serum molecules.

The results of thirteen control experiments, designed to show the number of glomeruli in the rabbit's kidney open to the circulation under the chosen experimental conditions without intentional interference, indicate the "normal" range to be from 42 to 100 per cent. Since ten of the thirteen results fall within the figures 56 and 89 per cent, we may take these figures as the chief basis for our discussion. Three experiments only were made in which renal vasodilatation was produced by caffeine and salt. The percentage of open glomeruli found was in every case higher than any control except one. The results show without ambiguity that in rabbits, as in frogs, renal vasodilatation by caffeine is accompanied by increase in number of patent glomeruli. Our prime interest lay in the general question rather than in the action of individual substances in the group of vasodilators; hence this series was not extended further. Among the experiments designed to test the effects of renal vasoconstriction are to be found nine in which adrenalin was injected, two in which CO2 was inhaled, two in which the splanchnic nerve was stimulated, and four in which hemorrhage was induced. Not all are of equal value for our present purpose, inasmuch as the degree of certainty with which we can assume that renal vasoconstriction was actually produced is not the same in all. Enough experience with the action of adrenalin on the kidney of the anesthetized rabbit is available to permit the assertion that the dosages used in the nine adrenalin experiments were sufficient to insure constriction of renal vessels. Similar certainty exists in the experiment in which high concentration of CO2 was used; less in the case of 10 per cent CO2. Stimulation of the splanchnic nerve in rabbits so frequently fails to produce results typical of direct constriction of renal vessels that we may regard the production of this effect in the two experiments in which this was done as doubtful. In the perfusion experiments by Richards and Plant (7) the reactions of the renal vessels to stimulation of the splanchnic nerve resembled those to intravenously injected adrenalin rather than to the direct excitation of constrictor fibers. In six rabbits in which Livingston subjected the nerve to varying degrees of electrical stimulation, in one only was distinct constriction of the renal vessels produced, and in this a latent period of 45 seconds occurred between the beginning of stimulation and the production of effect. In one of our experiments a rabbit was used in which the superior cervical sympathetic ganglion on the left side had been extirpated months before. During the stimulation of the splanchnic nerve the left pupil was observed to dilate, showing increased adrenalin secretion. Hence, we are inclined to regard the two attempts to produce vasoconstriction by this means as having been largely unsuccessful. In one experiment only of the four in which hemorrhage was induced was there unmistakable evidence of compensatory vasoconstriction which may have involved the renal vessels. The blood pressure curve of this animal showed rhythmically occurring waves of the Traube-Hering type and dyspnea was noted. In this the estimate of open glomeruli was 28 per cent. In the other three experiments no such change occurred and no dyspnea was seen. In pithed frogs, hemorrhage alone of moderate extent is less apt to lessen the number of patent glomeruli than are any of the other constrictor agencies tried by Richards and Schmidt. In this discussion, therefore, we lay little weight on the results obtained in the two experiments in which the splanchnic nerve was stimulated and on those of the first three hemorrhage experiments. The chief conclusion to be drawn from these experiments is that which was anticipated from the observations of Richards and Schmidt on frogs, and of Khanolkar on rabbits; viz., that in the rabbit, renal vasodilatation and renal vasoconstriction are usually associated with increase and decrease respectively in number of glomeruli through which blood flows (see Text-fig. 1). Analogous changes apparently occur in the capillary pathway in individual glomeruli. Hence renal function in mammals may be altered by changes in the extent of glomerular filtration surface to which the blood has access. Other conditions remaining the same, it is obvious that changes in extent of filtration surface must result in proportionate changes in urinary output. The figures for rate of urine elimination at the time of injection of the dye in these experiments are in substantial agreement with these statements (see Text-fig. 2). Exceptions to our chief conclusion as stated have been encountered. In Experiment 57,86 per cent of the glomeruli were open in a constricted kidney which was excreting no urine: in Experiment 30, 16 per cent were open in the kidney which was eliminating seven drops per minute: the outputs of the kidneys in the caffeine experiments were far higher than those of control kidneys in which comparable numbers of glomeruli were open. In considering these exceptions, account must be taken of the fact that other conditions do not commonly remain constant. When a renal vasodilator is introduced we conceive not only of possible increase in extent of accessible glomerular surface, but also of increase in glomerular pressure and increased rate of renewal of fluid in contact with glomerular membranes. Hence the response is greater than can be accounted for by any one factor alone. A basis of experiment exists in support of the belief that usually sufficient differences in physiological state exist among the small arteries and arterioles of the kidney so that a constrictor influence, exerted equally upon all, elicits various degrees of response (1). Closure of some, continuing patency of others, results. Blood flow and blood pressure in the glomeruli which are supplied by the vessels which remain open may be decreased, increased, or unchanged according See PDF for Structure. to the relation between the degree of reaction in those vessels and the height of arterial blood pressure. It is not to be expected that urinary outputs will uniformly vary with the number of glomeruli remaining open. Rapid blood flow and high glomerular pressure in relatively few glomeruli may result in more urine than slow flow and low pressure in many. This argument is implicit in Hermann's original statement and is completely in harmony with the result of direct observation in the frog. It is supported by the data of Experiment 30. In Experiment 57, however, urine was suppressed by adrenalin when 86 per cent of the glomeruli remained open. The kidney in this experiment was highly diuretic before the adrenalin injection. We may, therefore, assume that all or nearly all of the glomeruli were open and that intermittent contractions of the arterioles were minimal; hence, that the physiological state of the vessels concerned was more nearly uniform than is conceived to be the case when only a fraction of the glomeruli are open and in which intermittent contractions and relaxations must be pronounced. Thus a relatively uniform constriction was produced in all of such degree as to lessen materially glomerular pressure and blood flow, but insufficient to actually close more than a few afferent arterioles. In Experiment 33, the dosage of adrenalin was such as to permit the possibility that constrictor action may have been largely confined to efferent vessels (8). While the exceptional results have been discussed at greater length than has been devoted to the majority of experiments, we believe that they do not constitute adequate ground for criticism of the chief conclusion as stated.

In 20 post-mortem dissections, the subvesical bile duct of Luschka was noted in six specimens. Microscopic examination of ten other post-mortem gallbladders revealed small bile ducts on the gallbladder surface in five. Four cases of injury to the duct of Luschka during cholecystectomy are described and illustrated with cholangiographic and histological evidence. Post-cholecystectomy bile leaks from the drain tube, which closed spontaneously without sequelae, were noted in 9 per cent of 204 randomly selected cases and were regarded, at least in some, as being caused by a divided duct of Luschka. The practical significance of this duct during cholecystectomy is to keep close to the gallbladder wall during removal of the gallbladder, and to ligate a divided bile duct of Luschka if recognized at surgery.

In 5 patients with hematuria due to acute or subacute nephritis, the administration of ascorbic acid in massive doses over a period of 6 to 10 days sufficient to saturate the body stores had no significant effect on the amount of hematuria or albuminuria. In one case there was a definite decrease but coincidental spontaneous improvement could not be excluded.

The effect of partial or complete obstruction of the renal vein on the secretion of urine and the histology of the kidney has been investigated repeatedly. Conflicting results reported in the literature have been reviewed by Rowntree, Fitz and Geraghty,1Orofino,2and Nicastro.3Little has been added to the histological description of such kidneys since Buchwald and Litten's4report. The outstanding feature is degeneration and atrophy of the tubules with apparently relatively normal glomeruli. Other studies have been concerned with the development of an adequate collateral circulation to maintain the functional capacity of the kidney. This is apparently much better in dogs than in either cats or rabbits, and Alesandri,5Rown-tree, Fitz and Geraghty were able to maintain dogs in excellent condition for a time even when one kidney had been removed and the other renal vein ligated. Usually, however, even in the dog when the renal vein has been ligated a progressive atrophy of the kidney follows with decrease and finally cessation of all urinary secretion. In cats and rabbits this is the constant finding.Orofino found that from 5 to 20 days after ligation of one renal vein in dogs, the urine from that kidney was decreased in amount, and contained lower concentrations of urea and chloride but more albumin than the urine from the normal kidney. Dicker and Demoor6found the volume of urine from the ligated kidney greater (2 to 3 times) than from the normal side 6 to 8 weeks after operation, while the concentration of urea was reduced, that of chloride was increased. These experiments suggested that the effect of temporary obstruction to the renal vein and the resulting anemia of the kidney produces its greatest effect on the highly specialized epithelium of the renal tubules.

In this article, the author reflects on the biggest change he expects to see in the independent software vendors (ISVs), value-added resellers (VARs), and channel resellers in 2011.

The article focuses on the mobile strategies that should be employed by value-added resellers (VARs) to take advantage on the increasing smartphone usage. It states that VARs can build applications internally if they can manage software development, formulate specifications, and are financially stable. It suggests extending the applications using firms that provide canned solutions, which extend an existing web reporting to a mobile device.

The article presents the views of J. Alan Hayman, co-founder of XCO Software, on the outlook of the point-of-sale systems industry. He states that cellular telephones will replace the utility of microcomputers as primary source of information. He adds that all telephone companies will offer mobile strategies through the use of solutions that provide flexibility and integration capabilities. Further, he says value-added resellers will become strategic partners in implementing mobile strategy.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. TGF-β is a myelosuppressive cytokine that has been indirectly linked to the pathogenesis of some subsets of MDS and acute leukemias. We demonstrate by immunohistochemistry that smad2, a component of the TGF-β signaling pathway, is constitutively activated in MDS bone marrows. This activation was seen in both low and high grade cases of MDS when compared to anemic controls and provides the first direct evidence of activation of TGF-β signaling in MDS. To demonstrate the functional role of TGF-β signaling in MDS, a GFP expressing lentiviral siRNA construct was designed to knockdown TGF receptor I (TBRI) expression. Stable expression of this lentivirus in a variety of hematopoietic cells resulted in >70% inhibition of TBRI mRNA by qPCR. Lentiviral siRNA Knockdown of TBRI in primary CD34+ cells resulted in an increase in GFP+ erythroid colony formation, indicating an inhibitory role of TGF-β in human hematopoiesis. To further test the efficacy of TBRI inhibition in stimulating hematopoiesis, we used a specific and potent inhibitor of TBRI (ALK5) kinase, SD-208. SD-208 was effectively able to inhibit TGF-β mediated activation of smad-2 and potently inhibit TGF-β mediated gene expression in bone marrow stromal cells. SD-208 treatment also led to reversal of TGF-β induced inhibition of primary CD34 cell proliferation and both erythroid and myeloid colony formation in short term assays. Most importantly, treatment with SD-208 led to significant dose dependent increases in erythroid and myeloid colony formation from primary MDS bone marrow derived hematopoietic progenitors. Furthermore, we tested the efficacy and specificity of SD-208 in a TGF-overexpressing transgenic mouse. This mouse constitutively expresses TGF-β through an albumin promoter, develops progressive anemia and dysplasia and thus serves as a novel model of human bone marrow failure. Treatment with SD-208 by oral lavage at 30mg/kg/d for two weeks led to significant increases in both myeloid and erythroid colony formation from murine bone marrows and led to a trend of increasing hemoglobin and hematocrit. Taken together, these studies demonstrate a role of TBRI inhibition in stimulating hematopoiesis in human bone marrow failure and should lead to future studies with SD-208 and other inhibitors of TGF signaling pathways in MDS.

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis that leads to peripheral cytopenias. TGF-β is a myelosuppressive cytokine that has been indirectly linked to the pathogenesis of some subsets of MDS and acute leukemias. We demonstrate by immunohistochemistry that smad2, a component of the TGF-β signaling pathway, is constitutively activated in MDS bone marrows. This activation was seen in both low and high grade cases of MDS when compared to anemic controls and provides the first direct evidence of activation of TGF-β signaling in MDS. To demonstrate the functional role of TGF-β signaling in MDS, a GFP expressing lentiviral siRNA construct was designed to knockdown TGF receptor I (TBRI) expression. Stable expression of this lentivirus in a variety of hematopoietic cells resulted in >70% inhibition of TBRI mRNA by qPCR. Lentiviral siRNA Knockdown of TBRI in primary CD34+ cells resulted in an increase in GFP+ erythroid colony formation, indicating an inhibitory role of TGF-β in human hematopoiesis. To further test the efficacy of TBRI inhibition in stimulating hematopoiesis, we used a specific and potent inhibitor of TBRI (ALK5) kinase, SD-208. SD-208 was effectively able to inhibit TGF-β mediated activation of smad-2 and potently inhibit TGF-β mediated gene expression in bone marrow stromal cells. SD-208 treatment also led to reversal of TGF-β induced inhibition of primary CD34 cell proliferation and both erythroid and myeloid colony formation in short term assays. Most importantly, treatment with SD-208 led to significant dose dependent increases in erythroid and myeloid colony formation from primary MDS bone marrow derived hematopoietic progenitors. Furthermore, we tested the efficacy and specificity of SD-208 in a TGF-overexpressing transgenic mouse. This mouse constitutively expresses TGF-β through an albumin promoter, develops progressive anemia and dysplasia and thus serves as a novel model of human bone marrow failure. Treatment with SD-208 by oral lavage at 30mg/kg/d for two weeks led to significant increases in both myeloid and erythroid colony formation from murine bone marrows and led to a trend of increasing hemoglobin and hematocrit. Taken together, these studies demonstrate a role of TBRI inhibition in stimulating hematopoiesis in human bone marrow failure and should lead to future studies with SD-208 and other inhibitors of TGF signaling pathways in MDS.