By U. Mitch. Virginia Intermont College.

The latter generic ponstel 250mg mastercard, ground-up approach buy discount ponstel 250 mg line, needed to win resources and support from above cheap 500mg ponstel mastercard. Their position in the field means that they can deploy resources based on expertise and local knowledge and can effective 500 mg ponstel, credibly ponstel 250mg low cost, bid for contracts from commissioners of a kind which represent new modes of service provision. These new elements may include improved access, extended hours, multidisciplinary teams and an extended range of services in community settings. Our cases revealed instances where clinical leaders within CCGs (e. In these cases, leaders could deploy the allocated resources (managerial and financial) to deliver the plan. However, given the complexity of the NHS, matters were not always quite so simple. Our cases revealed numerous examples of leadership of service redesign where the challenges were more complicated. The CCG might itself support the status quo because unpicking the tangled web of payments, contracts and systems maintenance appeared too daunting and they saw themselves as having more pressing immediate priorities. Commissioning as a platform for clinical leadership The second question asked about the extent and nature of the scope for clinical leadership and engagement in service redesign that is possible and facilitated by commissioning bodies. This question places the focus on the enabling conditions. Nor did clinicians engage in any meaningful way with these bodies. Representatives from CCGs at HWBs tended to be accountable officers and/or chairpersons. Of more direct interest was the role of the CCGs themselves. The first of these was within the CCGs: how much influence were clinicians able to exercise? The second aspect was the power and influence of CCGs as institutions: what weight did they carry among the many other players in the landscape? There were a significant number of cases where managers acted as the most influential players. However, this was by no means a universal phenomenon. Our data point to cases where GPs exercised extensive influence over the strategic direction of the CCG as a whole and significant influence within specific service areas. In some of the cases this was because influential clinical figures took up roles as chairpersons or accountable officers and steered the CCG in a particular strategic direction. The case studies which focused on reform of primary care, for example, illustrated how leading clinician managers occupying hybrid roles pursued the kinds of changes which reflected the visions set out in Liberating the NHS3 and those wanted by NHSE. The puzzle is why there were not more cases of this kind. The answer stems not only from the expected difficulties in carrying along the GP membership but, additionally, from the complex interplay of diverse institutions each with their power basis and each part of a wider web of services underpinned by payment mechanisms, which were found to be difficult to unravel. The scope for service redesign using the mechanism of these local commissioning groups was thus checked by numerous sources of inertia. Agents rooted in institutions can be expected to conform to the rules of those institutions; yet, as individual actors, they also have scope for the exercise of agency. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 87 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. DISCUSSION the various institutions (organisational and professional), as indicated by Battilana,67 and also by the orientations and values of the individual actors. Regarding the influence of CCGs as institutions in a competitive institutional landscape, the picture is again mixed. We found examples where CCGs were marginal, peripheral players. The benefits being sought from clinical leadership The third question asked about the range of benefits being targeted through different kinds of clinical engagement and leadership. The most straightforward answer to this is that there was very evident commonality in the declared objectives of the would-be service redesigners. Integration of service was the big theme and care closer to home and away from secondary care was another. The findings suggest that the creation of CCGs did, to an extent, enable and prompt increased, and more potent, clinical leadership.

B safe ponstel 250mg, O n im m unofluorescence effective 500 mg ponstel, granular capillary wall and m esangial deposits of im m unoglobulin G and com plem ent C3 are observed (starry-sky pattern) discount 250mg ponstel otc. Three pre- dom inant patterns occur depending on the location of the deposits; these include garlandlike cheap ponstel 250 mg mastercard, m esangial discount ponstel 500mg on-line, and starry-sky patterns. C, The ultrastructural findings are those of electron-dense deposits, characteristically but not solely in the subepithelial aspects of the capillary walls, in the form of large gum drop or hum p-shaped C deposits (arrow). H owever, electron-dense deposits also are found in the m esangial regions and occasionally subendothelial locations. FIGURE 4-1 (see Color Plate) Endothelial cells often are swollen, and leukocytes are not only Light, im m unofluorescent, and electron m icroscopy of poststrepto- found in the capillary lum ina but occasionally in direct contact coccal (postinfectious) glom erulonephritis. Glom erulonephritis m ay with basem ent m em branes in capillary walls with deposits. Sim ilar follow in the wake of cutaneous or pharyngeal infection with a lim - findings m ay be observed in glom erulonephritis after infectious ited num ber of “nephritogenic” serotypes of group A -hem olytic diseases other than certain strains of Streptococci. The glom erulonephritis accom panying infective endocarditis or infected ventriculoatrial shunts or other indwelling devices is that of a postinfectious glom erulonephritis or m em branoproliferative glom erulonephritis type I pattern, or both (see Fig. In reality, the changes often are a com bination of both. As shown here, this glom erulopathy is characterized by increased m esangial cellularity, with slight lobular architecture; occasionally thickened capillary walls, with double contours (arrow); and leukocytes in som e capillary lum ina. A B (focal segm ental) glom erulosclerosis with significant tubular and interstitial abnorm alities. A, In H IVAN , m any visceral epithelial cells are enlarged, coarsely vacuolated, contain protein reabsorp- tion droplets, and overlay capillaries with varying degrees of wrin- kling and collapse of the walls (arrows). B, In H IVAN , the tubules are dilated and filled with a precipitate of plasm a protein, and the tubular epithelial cells display various degenerative features (arrow). Ultrastructural findings are a com bination of those expect- ed for the glom erulopathy as well as those com m on to H IV infec- tion. Thus, the foot processes of visceral epithelial cells are effaced and often detached from the capillary basem ent m em branes. C, Com m on in H IV infection are tubuloreticular structures, m odifica- tions of the cytoplasm of endothelial cells in which clusters of m icrotubular arrays are in m any cells (arrow). Som e evidence sug- gests that H IV or viral proteins localize in renal epithelial cells and perhaps are directly or indirectly responsible for the cellular and C functional dam age. H IVAN often has a rapidly progressive down- hill course, culm inating in end-stage renal disease in as few as 4 FIGURE 4-3 (see Color Plate) m onths. H IVAN has a striking racial predilection; over 90% of H um an im m unodeficiency virus (H IV) infection. The other glom erulopathy that m ay be an integral feature of H IV Various im m une com plex–m ediated glom erulonephritides associat- infection is im m unoglobulin A nephropathy. In this setting, H IV ed with com plicating infections are known; however, several disor- antigen m ay be part of the glom erular im m une com plexes and cir- ders appear to be directly or indirectly related to H IV itself. The m orphology and clinical course Perhaps the m ore com m on of these is known as H IV-associated generally are the sam e as in im m unoglobulin A nephropathy occur- nephropathy (H IVAN ). This disease is a form of the collapsing ring in the non-H IV setting. The m ost com m on glom erulonephri- peripheral granular to confluent granular capillary wall deposits tis in patients infected with the hepatitis C virus is m em bra- of im m unoglobulin M (IgM ) and com plem ent C3; the sam e noproliferative glom erulonephritis with, in som e instances, im m une proteins are in the lum inal m asses corresponding to cryoglobulinem ia and cryoglobulin precipitates in glom erular hyaline throm bi (arrow). Thus, the m orphology is basically the sam e as in lum inal m asses (H T). D, O n electron m icroscopy the deposits m em branoproliferative glom erulonephritis type I (Fig. H epatitis C viral antigen has been docum ented in the globulin in the capillary lum ina and appearing as hyaline throm - circulating cryoglobulins. M em branous glom erulonephritis with bi (H T)are observed (arrows), often with num erous m onocytes a m esangial com ponent also has been infrequently described in in m ost capillaries. B, Im m unofluorescence m icroscopy discloses patients infected with the hepatitis C virus. H owever, m ore recent data indi- cate that this form of glom erulonephritis is a feature of hepatitis C virus infection rather than hepatitis B virus infection. In con- trast, m em branous glom erulonephritis, often with m esangial deposits and variable m esangial hypercellularity, is the glom eru- lopathy that is a com m on accom panim ent of hepatitis B virus infection. H epatitis B virus surface, core, or e antigens have been identified in the glom erular deposits. The m orphology of the glom erular capillary walls is sim ilar to the idiopathic form of m em branous glom erulonephritis.

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These investigations have added substantial insight into the molecular mechanisms involved in renal solute transport and the molecular pathogenesis of inherited renal tubular disorders buy cheap ponstel 250mg. This chapter focuses on the inherited renal tubular disorders generic 250mg ponstel overnight delivery, highlights their molecular defects buy 500 mg ponstel otc, and discusses models to explain their under- lying pathogenesis cheap ponstel 250mg. For m any of Inherited disorder Transmission mode Defective protein these disorders buy ponstel 500 mg mastercard, the identification of the disease-susceptibility gene and its associated Renal glucosuria? AR, AD Sodium-glucose transporter 2 defective protein product has begun to pro- Glucose-galactose malabsorption syndrome AR Sodium-glucose transporter 1 vide insight into the m olecular pathogenesis Acidic aminoaciduria AR Sodium-potassium–dependent of the disorder. Blue diaper syndrome AR Kidney-specific tryptophan transporter Neutral aminoacidurias: AR? Methioninuria Iminoglycinuria Glycinuria Hereditary hypophosphatemic rickets AR? Urate transporter AD— autosomal dominant; AR— autosomal recessive; ClC-K2— renal chloride channel; NCCT— thiazide-sensitive cotransporter; NKCC2— bumetanide-sensitive cotransporter; ROMK— inwardly rectified. Under Tmax norm al physiologic conditions, filtered glucose is alm ost entirely Observed curve reabsorbed in the proxim al tubule by way of two distinct sodium - coupled glucose transport system s. In the S1 and S2 segm ents, bulk Threshold reabsorption of glucose load occurs by way of a kidney-specific 200 high-capacity transporter, the sodium -glucose transporter-2 (SGLT2). The residual glucose is rem oved from the filtrate in the S3 seg- m ent by way of the high-affinity sodium -glucose transporter-1 (SGLT1). This transporter also is present in the sm all intestine. As are all m em brane transport system s, glucose transporters are saturable. The top panel shows that increasing the glucose concen- 0 tration in the tubular fluid accelerates the transport rate of the 0 200 400 600 glucose transporters until a m axim al rate is achieved. The term 400 threshold applies to the point that glucose first appears in the urine. The m axim al overall rate of glucose transport by the proxi- Normal m al tubule SGLT1 and SGLT2 is term ed the Tm ax. Glucose is detected in urine either when the filtered load is increased (as in Type B renal glucosuria diabetes m ellitus) or, as shown in the bottom panel, when a defect occurs in tubular reabsorption (as in renal glucosuria). Kinetic 200 studies have dem onstrated two types of glucosuria caused by either reduced m axim al transport velocity (type A) or reduced affinity of Type A renal glucosuria the transporter for glucose (type B). M utations in the gene encoding SGLT1 cause glucose-galactose m alabsorption syndrom e, a severe autosom al recessive intestinal disorder associated with 0 m ild renal glucosuria (type B). Defects in SGLT2 result in a com - 0 200 400 600 paratively m ore severe renal glucosuria (type A). H owever, this dis- Filtered glucose load, mg/min 1. Am ong m em bers of the basolateral glu- cose transporter (GLUT) fam ily, only GLUT1 and GLUT2 are rele- vant to renal physiology. Clinical disorders associated with m utations in the genes encoding these transporters have yet to be described. FIGURE 12-3 O ver 95% of the filtered am ino acid load is norm ally reabsorbed in Cystine actually is a neutral am ino acid that shares a com m on the proxim al tubule. The term am inoaciduria is applied when m ore carrier with the dibasic am ino acids lysine, arginine, and ornithine. Am inoaciduria The transport of all four am ino acids is disrupted in cystinuria. The can occur in the context of m etabolic defects, which elevate plasm a rarer disorder, lysinuric protein intolerance, results from defects in am ino acid concentrations and thus increase the glom erular filtered the basolateral transport of dibasic am ino acids but not cystine. In addition, am inoaciduria can arise from genetic defects in consequent hyperam m onem ia. Three distinct groups of inherited am inoacidurias are distin- H artnup disease, blue diaper syndrom e, m ethioninuria, im inogly- guished based on the net charge of the target am ino acids at neutral cinuria, and glycinuria. Several neutral am ino acid transporters pH : acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. H artnup disease involves a neutral am ino acid transport system Acidic am inoaciduria involves the transport of glutam ate and in both the kidney and intestine, whereas blue diaper syndrom e aspartate and results from a defect in the high-affinity sodium - involves a kidney-specific tryptophan transporter. M ethioninuria potassium –dependent glutam ate transporter. It is a clinically appears to involve a separate m ethionine transport system in the benign disorder.

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These promoter or enhancer gions in contact with each other buy 500mg ponstel with visa. An important effect of many phosphorylation events is to alter the ability of the phospho- protein to interact with other proteins cheap ponstel 250mg free shipping. This is illustrated by CREB generic ponstel 500 mg on line, which can activate transcription only when phos- phorylated on a particular serine residue (ser133)(12) discount ponstel 250mg mastercard. As seen later cheap 250mg ponstel otc, phosphorylation of ser133 permits CREB to in- teract with an adapter protein, CBP (CREB-binding pro- tein), which, in turn, contacts and activates the basal tran- scription apparatus (13). REGULATION OF GENE EXPRESSION BY EXTRACELLULAR SIGNALS Transcription Factors: Targets of Signaling Pathways Most genes probably contain response elements that confer responsiveness to physiologic signals. Response elements work by binding transcription factors that are activated (or inhibited)by specific physiologic signals, of which the most common is phosphorylation. Two general mechanisms of transcriptional regulation by extracellular signals are illus- FIGURE 17. Schemeof intracellular pathwaysunderlying regu- trated Fig. In one mechanism, transcription fac- lation of gene expression. Activation of neurotransmitter, hor- tors that are present at significant levels in cells under basal mone, or neurotrophic factor receptors leads to the activation of conditions are rapidly activated by signaling cascades to acti- specific second messenger and protein phosphorylation path- ways, which produce multiple effects on neuronal function vate or repress transcription of responsive target genes. In through the phosphorylation of numerous proteins. Among the the other major mechanism, transcription factors that are effects of these intracellular pathways on neuronal function is expressed at very low levels under basal conditions are them- the regulation of gene expression. This can be accomplished by two basic types of mechanisms. In one case, transcription factors, selves induced by a physiologic signal, after which they can already in the nucleus, are phosphorylated by protein kinases; regulate expression of a series of additional genes. CREBis an example of a transcription factor that functions in this manner. Among the sion is the transduction of signals from the cell membrane target genes for CREBfamily transcription factors are those for to the nucleus; this can be accomplished by several different other transcription factors, for example, Fos and Jun family pro- types of mechanisms. IncreasedexpressionofFosand Junthenleadstoalterations in the expression of additional target genes. One example is provided by the steroid hormone receptor transcription fac- tors, discussed at length later. Another example is the tran- scription factor nuclear factor- B (NF- B)(15). This tran- scription factor is retained in the cytoplasm by its binding elements termed cAMP-response elements (CREs)(Fig. Signal-regulated phosphorylation of I Bby tion step in CREB activation involves not the transcription protein kinase C leads to dissociation of NF- B, which per- factor itself, but activated protein kinases (cAMP-dependent mits it to enter the nucleus, where it can bind DNA; I B protein kinase; also called protein kinase A)that, on entering is then proteolyzed within the cytoplasm. Alternatively, CREB ac- Other transcription factors must be directly phosphory- tivation can involve the nuclear translocation of second mes- sengers, such as Ca2 bound to calmodulin, which, on en- lated or dephosphorylated to bind DNA. For example, phosphorylation of STATs (signal transducers and activa- tering the nucleus activate protein kinases that then tors of transcription)by protein tyrosine kinases in the cyto- phosphorylate CREB (Fig. As stated earlier, phos- plasm permits their multimerization, which, in turn, per- phorylation converts CREB into a transcriptional activator mits nuclear translocation and construction of an effective by permitting it to recruit CBP into the transcription com- DNA binding site within the multimer (16). Still other transcription factors are already bound to their The remainder of this chapter provides a more in-depth cognate cis-regulatory elements in the nucleus under basal discussion of several transcription factor families that have conditions and are converted into transcriptional activators received a great deal of attention as mediators of neural and by phosphorylation. CREB, for example, is bound to DNA behavioral plasticity in the adult. Chapter 17: Regulation of Gene Expression 221 nervous system, including those encoding neuropeptides (e. The consensus CRE sequence illustrates an important principle, the palindromic nature of many tran- scription factor–binding sites. Examining the sequence TGACGTCA, it can be readily observed that the sequence on the two complementary DNA strands, which run in opposite directions, is identical. Many regulatory elements are perfect or approximate palindromes because many tran- scription factors bind DNA as dimers, with each member of the dimer recognizing one of the half-sites. CREB binds to a CRE as a homodimer, with a higher affinity for palindromic than for asymmetric CREs.

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