INTRODUCTION: This study examines the antibiotic prescription in dentists participated in 9th Congress of Iranian Association of Endodontists in Esfahan/2006.MATERIALS AND METHODS: A questionnaire for this cross sectional study was designed for evaluating the patterns of antibiotic prescription. It included some demographic information, clinical signs, and conditions in need for antibiotic and prophylactic prescription and their choices. Data was analyzed using Pearson’s Chi-square test.RESULTS: High percentage of responders prescribe antibiotic for fever (78.2%) and diffuse swelling (85.1%). However, some situations such as acute pulpitis, chronic periapical lesions and marginal gingivitis were irrationally prescribed.CONCLUSION: This study showed a fairly good pattern of antibiotic prescription but it was far from ideal. There are different microorganisms exist in oral cavity. In some conditions, they can enter blood via disintegrated epithelium of oral cavity causing many complications such as bacterial endocarditis. An appropriate use of antibiotics can shorten the duration of bacterial infection and decrease complications such as infection spread to adjacent anatomical spaces or systemic involvement. However, antibiotics are prescribed in different clinical situations .Antibiotics are common drugs used either for prophylaxis or as a part of the management of orofacial infections . AntimicThe survey of past studies revealed appreciable gap in knowledge with respect to rational drug use. For this reason, these researches suggest an urgent need for review of current policies and systems with the view of enhancing the drug use practices of health providers -4. TheseAlthough the findings of a recent study have shown that general practitioners prescribe therapeutic and prophylactic antibiotics, inappropriately . To our A questionnaire for this cross-sectional study was designed to investigate dental practitioners' behavior of prescribing antibiotics therapeutically and prophylactically, the both.After evaluating the validity and reliability of the questionnaire, it was given to all participants of the 9th Congress of Iranian Association of Endodontists which was hold in Esfahan, August 2006.Filled questionnaires were collected from participants. At first, the questionnaire information was sought on the gender, age, being general or specialized dentist, and record of service.Participants were asked to give answers to some clinical signs and conditions required antibiotics and their choice of medicine. Based on other studies, the following clinical signs were questioned: fever, diffuse swelling, trismus, acute pulpitis, localized periapical abscess, chronic periapical lesion, chronic marginal gingivitis, chronic periodontitis, tooth reimplantation, dry socket, before and after root canal therapy, before and after extraction, before and after dental surgery -4.Respondents were required to provide information on the preferred antibiotics and their choice of alternatives for patients who are allergic to penicillin.The next part of the questionnaire covered the patients who needed prophylactic antibiotic. Based on the recommendations of the American Heart Association, the following dental procedures were questioned: periodontal probing, scaling, supra-gingival and sub-gingival restorations, matrix band placement, tooth extraction, block and PDL injections, fluoride therapy, taking radiography, molding and root canal therapy.The collected data were computerized and processed using SPSS soft ware (version 13), and Pearson's Chi-square test was used for statistical analysis.Totally, one hundred and thirteen participants filled the questionnaires. Of these, 62.3% were general practitioners and remains (37.7%) as dental specialists.Demographic and professional characteristics of respondents are shown in The clinical signs for which the respondents would prescribe antibiotics are shown in Amongst all, amoxicillin was the most preferred antibiotic in patients who were not allergic to Penicillin followed by metronidazole. In patients who are allergic to penicillin, erythromycin and clindamycin were the most prescribed alternatives. Regarding prophylactic antibiotic prescription for patients with the risk of bacterial endocarditis data is shown in The findings of this study might reflect a fairly good pattern of antibiotic prescription but far from ideal. Results of many studies confirm it indicating that antibiotics were not always prescribed on a scientific basis ,5,7-9.A large percentage of responders would prescribe antibiotics for cases in which oral infection is accompanied by fever and evidence of diffuse swelling. Therefore, practitioners’ knowledge is well on these items. Interestingly, the data on the management of unexplained trismus, chronic periodontitis and tooth replantation showed under usage of antibiotics. About 20% would prescribe antibiotics irrationally for acute pulpitis, chronic periapical lesions, chronic marginal gingivitis, dry socket, before and after root canal therapy, before and after extraction, and before the third molar surgery in a healthy person. It is predictable that heavy work load in some of the dental centers and consequently the lack of enough time to evaluate the patient’s actual need can cause this potential abuse of the antibiotics. In other words, this abuse may be due to lack of information about the indications and side effects of antibiotics.Meanwhile, sometimes the practitioners would prescribe antibiotics for unscientific reasons like patients’ expectation to satisfy them.The proportion of practitioners who would routinely prescribe antibiotics for specific conditions varies a great deal among the presenting diseases. For example, about half of the practitioners were giving antibiotics incorrectly for chronic periapical abscess with a sinus tract, after root canal therapy, and third molar surgery. In majority of localized or diffuse infections, removal of the etiology and/or providing drainage would usually lead to a complete resolution of the problem .The incidence of infective osteitis after the minor oral surgery due to periradicular or third molar surgeries has drastically reduced with improvement of aseptic techniques and better instrumentation. Therefore, antibiotic usage is not routinely necessary in these situations -11. RameIn this study, the most frequently prescribed systemic antibiotics in dental infections were amoxicillin and penicillin, respectively. Based on the literatures -14, peniet al.  require antibiotic prophylaxis in patients at risk for infective endocarditis . EndocarWe expected that higher education would result in better antibiotic prescription pattern, but in this study it was not applicable to most of the questions. The only significant difference was observed between the level of education and antibiotic prescription pattern before and after tooth extraction and after third molar surgery. In the case of a patient who needs antibiotic after root canal therapy and is allergic to penicillin, specialists’ knowledge is statistically higher than general practitioners.The limitation of the present study, including the small number of participants should be considered and indicating the need for further work. Although more researches are needed, accumulating evidence suggests that dental practitioners’ knowledge about the use of antibiotics is far from ideal. Rational prescribing based on a thorough knowledge is an important objective. Some ways which might play the major roles to achieve this issue are dentists participating in the regularly continuing dental education courses in the field of antibiotics usage, effective communication between microbiologists and practitioners, re-evaluation and standardizing the teaching in the use of antibiotics. In addition, greater emphasis on the training of clinical students about antimicrobial agents could be beneficial in this crucial part of their work.The results of the present study have demonstrated a lack of uniformity in the rational use of antibiotic among dental practitioners in Iran.


Reversible encapsulation allows the temporary isolation of molecules in very small spaces. There, molecular behavior is quite different than that in bulk solvent; in capsules recognition can be amplified, reactive3 into cylindrical capsule 1.1  into capsule 1.1 was revealed by the use of commercially available n-alkanes as guest probes: 1H NMR spectra of all capsular assemblies obtained. The spectra were recorded at 280 K, since all the assemblies exhibited sharp NMR peaks at that temperature. The shortest alkane leading to an extension of the original capsule 1.1 was n-tetradecane (n-C14H30), which unexpectedly gave two new assemblies , indicating a chiral extended capsule structure (this diastereotopic splitting can be observed more clearly in assembly I encapsulating n-C15H32: see D4-symmetric structure 4.11.3 (4.11.2 generated by the glycoluril 2. The latter capsule showed racemization when longer (C17–C19) n-alkane guests were inside, but those assemblies had to be heated to racemize. The faster racemization process for 4.11.3 speaks for a weaker H-bonding pattern compared to 4.11.2, perhaps as a result of the decreased angle on the concave side of 3.The insertion of propanediurea (PD) e 1.34.1  is propon-C14H30, the minor assembly II can only be observed at lower temperatures (≤280 K). The characteristic signals of the capsule host are doubled but the encapsulated guest protons are not affected this way. In addition, the guest in II appears to be in a longer assembly as the methylene signals are shifted slightly downfield . As the sample is heated, the two assemblies interconvert with coalescence at ca. 300 K  as well as the corresponding guest signals exchange, as the two different assemblies interconvert on the NMR-timescale  indicating an achiral structure for this extended capsule. Molecular modeling led to a Ch2-symmetric assembly 2.32.11.3′  orientation of the propanediurea carbonyls as shown in Ch2 symmetry is responsible for the appearance of two imide N-H signals (A and B), four different ureido N-H-resonances (1–4), three PD-bridgehead C-H signals (a–c), two different methine C-H’s (M1 and M2) and six aromatic C-H signals (Ar1–6). In addition, a majority of signals  as indicated by the appropriate exchange peaks observed in the ROESY spectrum (see Supporting There is a dynamic motion in the spacer belt of II (2.32.11.3′) was provided by encapsulation of a chiral guest. Earlier work by Waldvogel et al.,[1.1 induced local stereoselective helical folding, and we expected doubling of the enantiotopic host protons of II when a chiral magnetic environment was induced in 2.32.11.3′ by a suitable guest. This was provided by 2-heptadecanol, which upon encapsulation displayed diastereotopic signals of the guest at C3, C4 and C5 and the expected—now—diastereotopic hydrogens at the imide N-H signals of the host .What governs the structural changes in the two assemblies? Longer guests apply pressure on the two ends of the capsule and favor the propanediurea orientations that give the capsule longer dimensions (the accessible cavity length in n-octadecane (n-C18H38) resulted in the formation of yet a new assembly . It features a more relaxed guest,[2.32.11.3′) even at 340 K  was taken up by the known[8.11.2, : it was encapsulated in the congruent host III but not in the linear capsule 8.11.2  as guest, the same assembly III (2.34.11.3′) was observed and, as expected, the guest signals are shifted upfield (δ=0.5 ppm for protons at C4/C17) indicating a more compressed guest conformation. The use of n-heneicosane (n-C21H44) as guest gives rise to yet a new assembly  shown in 1H NMR data and NOE signals observed , eight different urea NH resonances (1–8), six PD-bridgehead C-H signals (a–f), two different methane C-H , and six aromatic C-H signals (Ar1–6).With mbly IV,  line 8 ispectrum  revealedobserved . Due to n-tricosane (n-C23H48), the limits of self-assembly for this system are reached. Although assembly IV is still formed, the signal-to-noise ratio is quite low even in the presence of 60 equivalents of guest . In this case the packing coefficient (PC, I is smaller than assembly II, n-C14H30 and n-C15H32 enjoy a more favorable PC inside. As can be seen in II starting with n-C16H34. By further increasing the guest length, the space inside II becomes more and more crowded, again triggering an extension of the capsule to host III with n-C19H40. A similar trend can be observed for guest n-C21H44.The structure of host ient PC,  might ex3, to form longer assemblies whenever the guest increases by only two or three carbon atoms is unusual: For glycolurils a change in host structure was observed when the guest length increased by five additional carbon atoms.[The propensity of PD on atoms. This hig1.1 with propanediurea units 3 results in the self-assembly of three new molecular capsules including the “banana”- and “S”-shaped structures III and IV. To best of our knowledge, these structures are the first examples of “bent” molecular capsules. The unique “banana” shape of host III allows the encapsulation of a complementary shaped guest that is not encapsulated in the known cylindrical capsules. These bent assemblies augur well for a richer space-shape and concomitant recognition properties for encapsulation complexes of the future.In summary, the extension of the cylindrical capsule


Nor did BLM SUMOylation inhibit binding of RPA to BLM in vitro; however, in immunoprecipitation experiments, more BLM-RPA complex formed in HU-treated SM-BLM cells, indicating that BLM SUMOylation controls the amount of BLM-RPA complex normally formed at stalled forks. Together, these results showed that BLM SUMOylation regulates the amount of ssDNA that accumulates during polymerase stalling. We conclude that BLM SUMOylation functions as a licensing mechanism that permits and regulates HR at damaged replication forks.Polymerase stalling results in uncoupling of DNA polymerase and the replicative helicase, which generates single-stranded DNA (ssDNA). After stalling, RAD51 accumulates at stalled replication forks to stabilize the fork and to repair by homologous recombination (HR) double-strand breaks (DSBs) that accumulate there. We showed recently that SUMO modification of the BLM helicase is required in order for RAD51 to accumulate at stalled forks. In order to investigate how BLM SUMOylation controls RAD51 accumulation, we characterized the function of HR proteins and ssDNA-binding protein RPA in cells that stably expressed either normal BLM (BLM+) or SUMO-mutant BLM (SM-BLM). In HU-treated SM-BLM cells, mediators BRCA2 and RAD52, which normally substitute RAD51 for RPA on ssDNA, failed to accumulate normally at stalled forks; instead, excess RPA accumulated. SM-BLM cells also exhibited higher levels of HU-induced chromatin-bound RPA than BLM+ cells did. The excess RPA did not result from excessive intrinsic BLM helicase activity, because  DNA replication is a fundamental process in all living organisms in which the genetic material is duplicated. Highly regulated checkpoint and DNA repair mechanisms ensure that the genome is faithfully replicated with each round of cell division. In mammalian cells, homologous recombination (HR) is an essential repair mechanism that stabilizes damaged DNA replication forks, repairs double-strand breaks (DSBs) that occur during DNA replication, and helps restore productive DNA synthesis following disruption or breakage of replication forks. Although HR is critical in maintaining genome integrity during replication, it is tightly regulated to avoid harmful outcomes.BLM , genome integrity is strikingly destabilized due to null mutations in the gene BS cells, which lack BLM activity, display numerous characteristics that are the consequence of excessive HR, including high rates of loss of heterozygosity  and percent unwinding was measured by electrophoresis through non-denaturing polyacrylamide gels followed by autoradiography. In both types of experiment, the percent of DNA substrate unwound over time was indistinguishable for SUMOylated compared to unSUMOylated BLM , and RPA stimulates BLM's DNA helicase activity , which generates replication-associated DSBs  in at least one Z-stack in which the fluorescence intensity was greater than the background fluorescence intensity of the nucleoplasm. The maximum number of foci that could be counted in these cells was 150. A typical immunofluorescence experiment consisted of assessment of 30–50 cells per condition. The data presented are from two to three independent experiments performed on two to three clones of each type. Immunofluorescence images for figures were created using Image J and Metamorph software (Molecular Devices).A focus was defined as a defined area of the nucleus greater than the minimum area of optical resolution /polyacrylamide gradient gels (Bio-Rad) and transferred on to polyvinylidene fluoride membranes (Bio-Rad). The membranes were blocked for 1 h at room temperature with Tris-buffered saline (Boston Bioproducts) containing 0.1% Tween 20 and 5% powdered milk (Bio-Rad), washed, and subsequently probed with appropriate primary antibodies either for 2 h at room temperature or overnight at 4°C. The membranes were then incubated with the appropriate horseradish peroxidase-linked secondary antibodies for 1 h at room temperature, washed, and incubated with Western Lightning–ECL, Enhanced Chemiluminescence reagent (Perkin Elmer) for 5 min at room temperature. Proteins labeled with antibodies on the membrane were visualized by detection on film.Chromatin preparations were made by the method of Méndez and Stillman . BrieflyCells treated with or without 5 mM HU for 6 h were harvested, washed twice in PBS buffer, and resuspended in NP-40 lysis buffer (Boston Bioproducts) containing protease inhibitors (Roche) for 30 min. Cell lysates were cleared by centrifugation . Cleared cell lysates were then incubated with 20 μl of agarose beads conjugated with anti-GFP antibodies and allowed to mix overnight at 4°C. Proteins bound to beads were separated from the supernatant by centrifugation  and washed with 5 times volume of lysis buffer. Proteins were extracted from the beads by boiling in Laemmli buffer (Boston Bioproducts) for 5 min and subsequently analyzed by immunoblot.2, 2 mM ATP, and purified recombinant proteins  using T4 polynucleotide kinase in PNK buffer at 37°C for 30 min per the manufacturer's instructions (New England Biolabs). The labeled substrate was purified using QIAquick Nucleotide Removal kit (Qiagen). The [γ−32P]ATP-labeled oligonucleotide was then annealed with a two fold excess of the unlabeled complementary oligonucleotide in annealing buffer  by heating at 95°C for 5 min and then cooling slowly to room temperature.Oligonucleotides for the fork substrate designed according to Mohaghegh et al.  were purEqual amounts of SUMOylated BLM and unSUMOylated BLM, respectively, were added to 100 μl of nickel-NTA bead slurry (Qiagen) that had been blocked in 0.5% BSA for 2 h at room temperature and then washed two times in BLM binding buffer . BLM was bound to beads for 1 h at room temperature and washed two times in BLM binding buffer. Helicase reactions were performed with 20 ng BLM in 10 mM Tris-HCl (pH 7.5), 4 mM MgCl2, 1 mM dithiothreitol, 2 mM ATP, 0.1 mg/ml BSA, and 0.3 nM of labeled helicase substrate at 37°C for either 5, 10, 15, 20, 30, 40, or 60 min. Helicase reactions were stopped by adding gel loading dye . Reaction products were analyzed by electrophoresis through pre-cast 10% non-denaturing polyacrylamide gels (Bio-Rad). The amount of substrate unwound was measured by autoradiography using a phoshorimager (Molecular Dynamics).2, 5 mM ATP, 100 μg/ml BSA, and 50 mM NaCl) for 30 min at room temperature. Beads were then washed three times in binding buffer. The amount of RPA-70 protein bound to SUMOylated BLM or unSUMOylated BLM was analyzed by immunoblot with anti-RPA/p70 antibodies.Two hundred nanograms of SUMOylated and unSUMOylated BLM, respectively, were added to 200 μl of Ni-NTA bead slurry (Qiagen) that had been previously incubated in Blocking Buffer  for 2 h at room temperature and subsequently washed three times with PBS. Increasing concentrations of purified RPA were then incubated with 20 ng of either SUMOylated BLM or unSUMOylated BLM bound to nickel-NTA beads, respectively, in binding Buffer , treatment (with and without HU), and interaction terms for cell type by treatment were treated as fixed effects. Because the foci data were not normally distributed, we used a generalized estimating equation approach that can account for non-normal correlated data with non-homogeneous variances.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We found that the encapsulation is first-order in basket 1 and guest 2, while the decomplexation is zeroth-order in the guest. Importantly, the interchange mechanism in which a molecule of CH3CCl3 directly displaces the entrapped CH3CCl3 was not observed. Furthermore, the examination of the additivity of free energies characterizing the encapsulation process led to us to deduce that the revolving motion of the gates and in/out trafficking of guests is synchronized, yet still a function of the affinity of the guest for occupying the basket: Specifically, the greater the affinity of the guest for occupying the basket, the less effective the gates are in “sweeping” the guest as the gates undergo their revolving motion.We used dynamic  Covalent and self-assembled molecules with a natural cavity, i.e., molecular capsules –2, emplo82 “hinges”  the process of gating is poorly synchronized with the guest exchange. The gates undergo a revolving motion to sweep the space but are concurrently less effective in enforcing the ejection of the guest from the cavity. Moreover, the results of dynamic 1H NMR measurements of CH3CCl3 (2) entering and departing basket 1  as a guest, and we hereby elaborate on the equilibrium thermodynamics of the recognition event  caused considerable 1H NMR chemical shifts of the resonances corresponding to the presence of the basket  of 1 (0.67 mM) containing CH3CCl3 (2) (1.07 mM) was in line with the formation of the 1:1 complex; note that extrapolation of the fitted line gives Ka of 86 ± 16 M−1 at 298.0 K, which is akin to the value obtained in the titration experiment. Furthermore, the van't Hoff analysis of the 1H NMR data revealed that the encapsulation is also driven by enthalpy  occupies 42% of the inner space of 1 (221 ± 9 Å3) . Accordingly, the rate of the forward reaction is given as:On the basis of the reaction stoichiometry , we initk*in describes the longitudinal magnetization of the hydrogen nuclei in CH3CCl3 transferring from the bulk solvent  can be formulated as:From k*in will be linearly proportional to the concentration of free basket 1. Indeed, when the value of k*in is plotted against the concentration of free basket 1, there is an apparent linear dependence, with the slope of the fitted curve kin = 2.1 ± 0.3 × 103 M−1·s−1  and CH3CCl3 (16–200 mM) in CD2Cl2 at 250.0 ± 0.1 K  – τ – 90° x (nonselective) – τd). Upon the integration of both signals (Iin and Iout), we subjected the data to nonlinear least-squares fitting of Iin/out versus τ using the proposed solutions of the McConnell equations ). The fitting of the data to kin from each data point would give a value of this coefficient (~2 × 103 M−1·s−1) similar to that determined in the EXSY experiment  with respect to 1 (1.65 mM) and measured k*out using the selective inversion-transfer NMR pulse sequence. Markedly, there was essentially no interdependence between k*out (21 ± 3 s−1) and the concentration of guest 2  displaces the encapsulated guest. In fact, the inspection of CPK models as well as molecular dynamics studies (see below) revealed that the departure of CH3CCl3 (93 Å3) demands (a) “opening” of at least two gates, (b) disruption of internal N–H…N hydrogen bonds, and (c) distortion of the framework of the basket. We further reason that in the case of a direct exchange of two CH3CCl3 molecules, the departure of CH3CCl3 would create an empty host, and therefore vacuum, before another guest of the same kind can take its place. Note that two large compounds  cannot simultaneously occupy the interior of 1 (~220 Å3).In accordance with this theoretical model, we increased the concentration of guest  guest 2 ; the curet/guest . The depechanism . Notably3CCl3 (2) from the interior of basket 1, we completed a series of steered molecular dynamics (SMD) simulations using the AMBER 10.0 suite of programs , 32 transients were obtained for each variable delay time (τ) with a relaxation delay (τd) of at least 5 × T1. The absolute integrals corresponding to encapsulated and free guest molecules were, at each mixing time, determined by using TopSpin software from Bruker, and the resulting data was fitted by using the two-site exchange equations described by Led et al. [k*in and k*out.eriments : A solutd et al.  to obtaiSupporting Information contains details of the computational studies.File 1Details of the computational studies.


Although tubulointerstitial nephritis with IgG4+ plasma cell (PC) infiltration is a hallmark of IgG4-related kidney disease (IgG4-RKD), only a few studies are available about the minimum number of IgG4+ PC needed for diagnosis along with IgG4+/IgG+ PC ratio in the kidney. In addition, the significance of the deposition of IgG or complement as a reflection of humoral immunity involvement is still uncertain. In this study, we analyzed 20 Japanese patients with IgG4-RKD to evaluate the number of IgG4+ PCs along with IgG4+/IgG+ PC ratio and involvement of humoral immunity. The average number of IgG4+ PCs was 43.8/hpf and the average IgG4+/IgG+ or IgG4+/CD138+ ratio was 53%. IgG and C3 granular deposits on the tubular basement membrane (TBM) were detected by immunofluorescence microscopy in 13% and 47% of patients, respectively. Nine patients had a variety of glomerular lesions, and 7 of them had immunoglobulin or complement deposition in the glomerulus. In conclusion, we confirmed that infiltrating IgG4+ PCs > 10/hpf and/or IgG4/IgG (CD138)+ PCs > 40% was appropriate as an item of the diagnostic criteria for IgG4-RKD. A relatively high frequency of diverse glomerular lesions with immunoglobulin or complement deposits and deposits in TBM may be evidence of immune complex involvement in IgG4-related disease. The main histopathological finding in the kidney of IgG4-RD is tubulointerstitial nephritis (TIN) –3, which In addition to this issue, case reports or case series of a variety of glomerular disease concurrent with TIN have been accumulated –26. ThesIn this study, we analyzed 20 Japanese patients with IgG4-RKD that were collected in our previous study aimed at establishing diagnostic criteria for IgG4-RKD , to addr Between 2004 and 2011, we found 41 patients with IgG4-RKD in Kanazawa University Hospital, Nagaoka Red Cross Hospital, Niigata University Hospital, Sapporo Medical University Hospital, and Fukuoka University Hospital, of whom 28 underwent renal biopsy. In the remaining 13 patients with IgG4-RKD without renal biopsy, 4 had only pelvic lesion and 9 had typical radiologic findings such as multiple low-density lesions on enhanced CT, high serum IgG4 levels, and other organ involvement with biopsy proven IgG4+ plasma cell infiltration. In addition, these 9 patients had radiographic improvement after successful corticosteroid treatment. Of these 28 patients, 20 who received renal needle biopsy were included in this study because they had sufficient data to determine the number of IgG4-positive cells, IgG4/IgG or IgG4/CD138 ratio, and immunofluorescence microscopy or electron microscopy. Five patients with glomerular lesions  with or without enhancement with contrast medium was performed before corticosteroid therapy to make the diagnosis of kidney involvement. Other modalities including gallium scintigraphy, magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography were also employed to identify renal and extra-renal lesions. Bouin's fluid-fixed or formalin-fixed and paraffin-embedded renal specimens of patients with IgG4-RKD were analyzed, and tubulointerstitial nephritis with or without glomerular lesions was evaluated. These specimens were stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), periodic acid methenamine silver (PAM), and Masson's trichrome for light microscopy (LM). Immunofluorescence microscopy was performed against IgG, IgA, IgM, C3, C1q, and fibrinogen. Immunostaining for infiltrating plasma cells was performed using mouse monoclonal antibody against human IgG4 , antihuman IgG , and/or antihuman CD138 . IgG4+ plasma cells were counted in five different high power fields (hpf) (×400 magnification with an eyepiece with a field number of 22) with intensive infiltration, and the average IgG4+ plasma cell count was calculated. Average of IgG4+/IgG+ or IgG4+/CD138+ plasma cell ratio of at least two different hpf (2–5 hpf) was calculated. U test or Fisher's exact probability test was employed for the statistical analyses. A value of <0.05 was considered statistically significant.  Mann-Whitney  The patients were 18 men and 2 women with an average age 64 years (range: 55 to 83). P < 0.05). Serum C3 levels of the GL group tended to be lower than those of the nonGL group (43 ± 23 versus 70 ± 27), but the difference was not statistically significant. The average number of IgG4 positive plasma cells, average IgG4+/IgG+ or IgG4+/CD138+ ratio, frequency of IgG, C3, C1q, and electron dense deposits on the TBM were not significantly different between the two groups. We analyzed 10 patients with ANCA-associated vasculitis immunohistochemically. Of these, 6 patients had more than 30/hpf plasma cell infiltration in the interstitium. Using IgG4 immunostaining, we found four patients with ANCA-associated vasculitis who fulfilled the immunohistochemical item of the diagnostic criteria of IgG4-related kidney disease Figures .  Table  In this study, we showed data about IgG4 positive plasma cell number per high power field (hpf) and IgG4+/IgG+ or IgG4+/CD138+ plasma cell ratios in the kidneys in some Japanese patients with IgG4-RKD. In addition, we compared IgG4-RKD patients with glomerular lesions with those without them clinically.  The number of IgG4+ plasma cells varies in affected organs and according to the biopsy method used  –9. As th Raissian et al. showed that 25 of 30 patients (83%) had TBM immune complex deposits by immunofluorescence microscopy (IF) or electron microscopy (EM) [Glomerular diseases sometimes concur with tubulointerstitial nephritis in patients with IgG4-related disease , 28–30.  Interestingly, the first IgG4-RKD case reported by Uchiyama-Tanaka et al. had tubulointerstitial nephritis with MGN, and subepithelial and intramembranous electron-dense deposits disappeared after successful corticosteroid therapy . In cont MGN detected during the clinical course of IgG4-RD is classified into two groups based on the presence or absence of simultaneous overlapping of TIN. Cravedi et al. reported a patient with IgG4-RD of the pancreas with salivary gland involvement who developed proteinuria after the cessation of successful steroid therapy . The ren Although case reports of Henoch-Schönlein purpura (HSP) nephritis associated with IgG4-RD are very rare and only our two cases are so far known , 29, occ In conclusion, we confirmed that infiltrating IgG4-positive plasma cells >10/hpf and/or IgG4/IgG (CD138)-positive plasma cells >40% was appropriate as an item of the diagnostic criteria for IgG4-RKD. Relatively high frequency of a variety of glomerular lesions concurrent with characteristic IgG4+ plasma-cell-rich lymphoplasmacytic infiltration with fibrosis seemed to show evidence of immune complex involvement in IgG4-related disease. However, as the number of analyzed cases in this study is small and some bias exists in case selection, worldwide study is needed to clarify the accurate frequency of the glomerular lesions in IgG4-RKD and pathophysiological significance of immune deposits in TBM and in the glomerular lesion.


The spread and perpetuation of the HIV/AIDS epidemic in South Africa has hindered the country's social and economic growth after apartheid. This paper documents my experiences while working with the Projects Abroad Human Rights Office and specifically my interactions with the Treatment Action Campaign (TAC), an organization which has taken a multi-dimensional approach in order to educate people about HIV/AIDS and attempt to provide access to medicines for millions of South Africans afflicted with the disease. I discuss how TAC has used both traditional and non-traditional methods of advocacy to combat the epidemic and equate access to health care to a social justice issue by empowering marginalized communities. The paper's dual purpose is to applaud TAC's continuous success in combating HIV/AIDS with such a multi-dimensional approach and illustrate how other organizations can utilize such an approach in order to affect social change. To illustrate TAC's approach, I utilize Lucie White's three dimensions of lawyering and equate TAC to a single cause lawyer, signifying that White's characterization of multi-dimensional activism is not limited to individuals, but can rather be applied at the firm level. White's three dimensions include: (a) advocacy through litigation, (b) advocacy in stimulating progressive change, and (c) advocacy as a pedagogic process. From this analysis, I conclude that TAC's multi-dimensional approach and specifically its inherent practice of White's three dimensions has been the root of its success in educating millions about the virus and advocating for access to medicines for those who have contracted HIV. TAC's innovative advocacy has also mobilized a new generation of South African activists who have helped TAC grow into a vibrant and integral organization within the country's post-apartheid culture. Such an example can serve as a framework for future organizations who wish to tackle other challenges that face the country. As we passed the Groote Schuur hospital, the teaching hospital for the University of Cape Town's faculty of medicine , served as a liaison connecting me with various HIV/AIDS organizations actively working to eradicate the almost 20-year long epidemic plaguing South Africa and killing approximately 300,000 people per year in the country, a rate of approximately 900 deaths per day . We had scheduled a meeting at the Treatment Action Campaign (TAC)  field office to discuss the organization's work and possible assistance with surveys assessing Khayelitsha residents’ current access to anti-retroviral (ARV) treatment  and general viewpoints regarding the government's role in combating HIV/AIDS. We were scheduled to meet with a TAC employee and activist who worked to co-ordinate initiatives between health clinics in Khayelitsha and TAC's regional office. This particular TAC employee had valuable contacts within Khayelitsha's healthcare community, an essential requirement if we were going to be granted allowance to conduct surveys in clinics, a privilege that would otherwise require a lengthy authorization process taking several weeks or even months.We were heading to Khayelitsha, Cape Town's largest township and home to over 1.25 million residents, composed of both native South Africans and refugees from neighbouring African countries such as Botswana, Namibia and Zimbabwe  office housed in the same building, my pre-conceived notions of a setting with all the luxuries befitting the bureaucracy and privilege to which I was accustomed quickly faded. I soon realized that I was about to be introduced to the organization that had mobilized a new generation of South African AIDS activists to attempt ending the epidemic that had claimed so many of their generation.Upon arriving in Khayelitsha, in a crowded marketplace filled with minibus taxis and blaring reggae and rap music, overshadowing sporadic cries in Xhosa and dialectical English, I spotted the TAC emblem signifying the office's entrance. As we climbed the stairs, passing the As our contact at TAC was running behind schedule, our PAHRO guide, another PAHRO volunteer and I waited patiently in the crammed common area while gazing at volunteers hurrying throughout the office and simultaneously speaking about current initiatives and the day's activities in a non-chalante, jovial demeanour not unknown to indigenous South Africans. In those fifteen minutes while waiting for the TAC employee, I learned what so many visitors from around the world had recognized about TAC. The organization's inimitability stemmed from its grassroots mobilization efforts and ability to utilize local talent to educate the traditionally marginalized black South African community about HIV/AIDS. TAC has sustained this endeavour by going beyond the traditional spheres of advocacy and using innovative approaches to enable social change. It has employed a nurturing approach centred on sympathy and compassion rather than judgment and antagonism.This paper will discuss how TAC has used both traditional and non-traditional methods of advocacy in South Africa to combat the HIV epidemic and equate access to health care to a social justice issue by empowering marginalized communities. TAC, in endeavouring to raise the social conscience of South Africans in understanding the destructive nature of the HIV/AIDS epidemic, has used but has not limited itself to the county's legal and political institutions. One purpose of this paper is simply to describe and applaud TAC's continuous success in combating the spread of HIV/AIDS and the organization's growing influence in post-apartheid South Africa. Another purpose though is to delineate TAC's multi-dimensional approach and how other similar organizations within South Africa and abroad can utilize such a model in order to affect social change. To illustrate TAC's successful strategy of promoting social change, I will employ Lucie White's three dimensions of lawyering  and dischttp://www.pbs.org/newshour), a figure that had reached 5.2 million by mid-year 2009. Just as the number of South Africans living with HIV swelled, so too did TAC's numbers, which as of March 2007 had almost reached 20,000 volunteers and workers throughout the country with six provincial, nine district and 200 branch offices . Due to TAC's activism in challenging what was then the government's policy and the court's subsequent decision to order South African hospitals to provide nevirapine to expecting and new mothers, innumerable children who would otherwise have been afflicted with paediatric HIV have not inherited the virus from their mothers.TAC has utilized the established legal and political avenues in South Africa to disseminate its message about the HIV epidemic and challenge injustices that limit access to treatment, particularly for the marginalized poor. TAC's 2002 claim against South Africa's Minister of Health was an example of White's first dimension of lawyering . ChaskalAnother example of TAC's utilization of White's first dimension of lawyering is its 2009 lawsuit against the Department of Correctional Services (DCS) demanding access to treatment for HIV infected prisoners  challenged the government's right pursuant to the e system .In this instance, TAC utilized established institutions for more than simply a legal victory. TAC's role as amicus curiae and advocate for affordable medicines elaborated upon social issues throughout the campaign that were brought to light by Christopher Moraka's death. One salient issue was the inequality in the two-tiered South African healthcare system in which the private sector accounted for 75% of public expenditures on health care while serving only 20% of the population. Visiting numerous public and private clinics in addition to state run hospitals, I became accustomed to this ubiquitous reality. Hundreds of patients waiting to see one rotating physician at eight o'clock in the morning in an old, cramped public clinic far overdue for repairs became a normal sight. Conversely, I witnessed nearly empty waiting rooms serviced by sometimes five to six physicians working in a private clinic. Upon asking one private practitioner about the apparent disparity between sectors in his profession, he responded by acknowledging grave deficiencies, but then immediately remarked that if he were to transfer his practice to the public sector he would have to work longer hours, arrive at his luxury home in Green Point  after dinnertime and not be able to send his ‘princesses’ to a superior private school. Judged through the lens of South African law, the private practitioner cannot be faulted. His aloofness to the crisis signifies a greater social crisis that TAC was attempting to illuminate through the Defiance Campaign, namely the superiority of private health care in South Africa, which attracts more doctors and public funding to sustain advanced facilities that cater to the wealthy and, most often, minority white and coloured populations . Both the NSP and RHC's goals exemplify TAC's role as an intermediary institution as they simultaneously attempt to improve access to treatment by lobbying the government to change its policies regarding access to ARVs and educate disenfranchised groups such as black youth, women and township dwellers about the importance of safe sexual practices that will inevitably decrease the annual HIV prevalence rate by 50%. Thus, TAC's multi-dimensional and methodical grassroots approach that appreciates the ethnic sensitivities of the past is crossing conventional political boundaries by waging battles both at the governmental level and in the streets.An example of TAC's promotion of the first form of citizenship is its Resource for Health Campaign (RHC), which is interfacing the government with HIV patients lacking access to treatment. The RHC's focus is on meeting the National Strategic Plan (NSP) goals set by the government of South Africa in 2007, namely to reduce the rate of new HIV infections annually by 50% and provide ARVs to 80% of those requiring them by 2011. As Tempelman and Vermeer remark, the NSP, despite being ambitious, is a clear strategy attempting to address salient issues posed by HIV and AIDS to the social, cultural and economic development, progress and stability of all sectors within South Africa . DespiteMSF to mobilize the poor and assist the government in its claim against the PMA. Upon discontinuing its case, the PMA remarked on the impetus for the withdrawal by pointing to the adverse publicity received against it and the multinational pharmaceutical companies which it represents as a result of TAC's accusations that corporate greed was triumphing over public health. Never before in recent history had a South African grassroots organization proven so successful in its lobbying strategy against a financially superior entity. TAC had mobilized those directly affected by the HIV virus to protest in large numbers against an injustice denying the poor access to essential medicines that would prolong their lives with HIV. TAC was able to mobilize various groups spanning the socio-economic spectrum to support the government's right to lower the price of essential medicines. In pursuing such an endeavour, TAC exemplified its role in promoting a novel form of South African citizenship centred upon activism and responsible government. Moreover, TAC played the role of a catalyst in intervening between the government and marginalized communities who were seeking increased access to treatment.The Christopher Moraka Defiance Campaign, introduced above, is another example of the TAC's promotion of participatory citizenship by acting as an intermediary between the State and the poor. TAC instituted a stellar media campaign to educate poor South Africans about the injustices of generic drug price increases. Additionally, TAC held multi-racial, multi-class demonstrations and workshops in collaboration with international NGOs such as Subsequent to the Defiance Campaign, but also keeping in line with TAC's role as an intermediary institution, its December 2001 appearance before the High Court of South Africa claimed that the government had a positive obligation, subsequent to Section 27(2) of the South African Constitution, to promote access to health care and thus access to HIV/AIDS drug treatment. TAC lawyers emphasized citizen rights to health care and the socio-economic consequences of not recognizing the government's positive obligation in Section 27(2). In addition to agreeing that Section 27(2) elicits such an obligation, the court addressed the continuing scientific debate looming in South Africa at the time about the legitimacy of the causation between HIV and AIDS, concluding that an interrelationship does exist. TAC's activism eventually led to the 2003 National ARV Treatment Programme, at which time ARV treatment became fully subsidized by the government in the public healthcare system.From the above examples, TAC bridged the gap between established state apparatuses and traditionally disenfranchised South Africans empowering the latter to fully realize their rights in the post-apartheid system.The second form of citizenship TAC has promoted is non-institutional and created by marginalized people themselves. In this light, TAC has successfully mirrored previous social movements centred on health issues; a concept now termed ‘biological citizenship’ . Michel Another example of TAC's promotion of non-institutional mobilization of marginalized groups is its support of the Thatnusizo Support Group in Inanda, Durban. The group originally began with only three people, all of whom had lost children to AIDS. Empowered by TAC workshops and educational material combating the stigma behind HIV/AIDS, the group grew by knocking on doors and spreading information to neighbours. As one TAC volunteer noted about TAC's role in transforming people from passive subjects into active participants, ‘We were a top-down organization but now our members are showing a potential to lead. Branch members used to just keep quiet in meetings, but are beginning to participate actively – it started small but then it grew’ . In thisDuring my time in Cape Town, I read about TAC's intermediary role in bridging the gap between the impoverished majority and State institutions. However, it was the second form of participatory citizenship, namely the promotion of non-institutionalized forms of public engagement that I witnessed for myself. TAC representatives from its Literacy and Treatment Program (LTP) visited Khayelitsha clinics, which were no more than modest building structures with usually one or two healthcare workers and rarely a physician, three times weekly to give presentations to the long line of patients waiting for their clinical appointments about the importance of safe sexual practices and regular adherence to treatment schedules. The LTP volunteers, themselves residents of Khayelitsha, achieved an immediate legitimacy when speaking with patients and residents after their presentations about personal, social and health-related matters. This legitimacy, rooted in a cultural and historical congruency, would be difficult to attain for an outsider such as myself seeking to further understand the myriad of socio-economic issues pertaining to the HIV/AIDS epidemic. TAC's grassroots strategy has empowered their volunteers to consider their work with a sense of responsibility and ownership that inevitably will lead to greater prosperity for the volunteers' own communities. Whereas the government and external international organizations have failed to gain this respect and legitimacy due to a history of mistrust and adversarial approaches, TAC has sought to personalize the HIV/AIDS virus to the marginalized communities which it afflicts. Due to this approach, TAC is invigorating the next generation of activists to seek a better future for South Africa while breaking the shackles of the past.By simultaneously promoting both forms of the citizenship discussed above, TAC has engaged White's pedagogical process by encouraging public health care consumers originating from marginalized communities to reflect upon their circumstances and seek to improve their lives through organized and dedicated action. Likewise, TAC has revived such marginalized groups from Lukes' third level of subordination which manifests in the form of fatalism and psychological withdrawal by educating the masses about their newfound position in the post-apartheid framework in which they can compete on an equal basis despite ethnic and racial differences. Although much work is required in the future for full emancipation and equality, TAC's approach, which allows communities to forge solutions for themselves rather than relying on external and, often times, dominating forces, is promoting sustainable social progress already manifesting in greater mobilization, confidence, entrepreneurship and higher standards of living.The foregoing discussion illustrated how TAC's grassroots approach has exemplified Lucie White's three dimensions of lawyering. Throughout its history TAC has approached advocacy through litigation, by attempting to stimulate social change and by engaging in a pedagogical process. In this process, TAC has acknowledged the deeply ingrained sense of subordination among South Africa's majority black population, which remained suppressed through government policies and legislation during apartheid. Although the formal era of apartheid has ended, a symbolic apartheid continues to exist in which there is unequal access to essential resources, especially health care. HIV continues to ravage the South African population with approximately 17% of 15–49 year olds being HIV positive. I witnessed the effects of such a statistic firsthand upon visiting an HIV orphanage in Masiphumelele, a rural township approximately 45 minutes outside of Cape Town. As I conversed and played with the children, full of life, laughter and hope far beyond the expectations of an external observer viewing their circumstances, the orphanage's director informed me that many of the children had contracted HIV through MTCT. However, she followed her statement by remarking that all of the children were completely healthy due to sufficient access to ARV treatments. As we sat in the director's office afterwards, energized by our foregoing activities with the children, I felt invigorated by the possibilities available to all South African HIV patients upon the realization of the 2011 NSP goals. This realization of goals would raise hope for South Africans to realize a better future for itself based on the opening provision of its constitution which states that, ‘The Republic of South Africa is one, sovereign, democratic state founded on the … values [of] human dignity, the achievement of equality and the advancement of human rights and freedoms.’ Although the normative provisions of the South African Constitution stand in contrast to omnipresent social and economic realities, TAC's innovative advocacy throughout the past decade has mobilized a new generation of South Africans to participate fully in all aspects of society to combat injustices perpetuating the HIV epidemic. TAC's effect on society spans further than health care and challenges the legitimacy upon which the apartheid regime was constructed. Its multi-dimensional approach, illustrated in this paper through White's dimensions of lawyering, has demonstrated the law's ability to transform society when viewed through the goal of social progress. Invigorated by the possibilities open to the Rainbow Nation, I walked out of the director's office with a greater sense of purpose in my own practice of law to facilitate social change. From this feeling, as I left the orphanage, I could not help but recite the lyrics from the theme song of the 2010 Soccer World Cup, ‘When I get older, I will be stronger, they'll call me freedom, just like a waving flag …’ .


Despite massive scale up of funds from global health initiatives including the Global Fund to Fight AIDS, Tuberculosis and Malaria  and other donors, the ambitious target agreed by G8 leaders in 2005 in Gleneagles to achieve universal access to HIV/AIDS treatment by 2010 has not been reached. Significant barriers to access remain in former Soviet Union (FSU) countries, a region now recognised as a priority area by policymakers. There have been few empirical studies of access to HIV/AIDS services in FSU countries, resulting in limited understanding and implementation of accessible HIV/AIDS interventions. This paper explores the multiple access barriers to HIV/AIDS services experienced by a key risk group-injecting drug users (IDUs).Semi-structured interviews were conducted in two FSU countries-Ukraine and Kyrgyzstan-with clients receiving Global Fund-supported services , service providers  and a purposive sample of national and subnational stakeholders . Systematic thematic analysis of these qualitative data was conducted by country teams, and a comparative synthesis of findings undertaken by the authors.Stigmatisation of HIV/AIDS and drug use was an important barrier to IDUs accessing HIV/AIDS services in both countries. Other connected barriers included:criminalisation of drug use; discriminatory practices among government service providers; limited knowledge of HIV/AIDS, services and entitlements; shortages of commodities and human resources; and organisational, economic and geographical barriers.Approaches to thinking about universal access frequently assume increased availability of services means increased accessibility of services. Our study demonstrates that while there is greater availability of HIV/AIDS services in Ukraine and Kyrgyzstan, this does not equate with greater accessibility because of multiple, complex, and interrelated barriers to HIV/AIDS service utilisation at the service delivery level. Factors external to, as well as within, the health sector are key to understanding the access deficit in the FSU where low or concentrated HIV/AIDS epidemics are prevalent. Funders of HIV/AIDS programmes need to consider how best to tackle key structural and systemic drivers of access including prohibitionist legislation on drugs use, limited transparency and low staff salaries within the health sector. I was arrested last year...'; '...they start beating at once and force you into the car...'; '...there is an example when heroin was planted to one of the guys, and he was on methadone; finally he was imprisoned'.Service providers in both countries reported that the militia (police) also regularly apprehended outreach workers, many of whom were former drug users known to the authorities. An NGO needle/syringe exchange worker in Ukraine explained that outreach workers did not visit places according to a set pattern, to avoid militia harassment, but this made it difficult for clients to know where to access their services. Service providers, stakeholders and clients also reported that police often detained IDUs using OST services when they entered or left government premises, although the frequency had reduced. A Kyrgyz client of an NGO drugs service explained that the militia regularly examined his arms to check whether he had injected recently and if so demanded bribes. He sometimes travelled to the service by taxi, at considerable expense, to avoid being stopped. Clients of substitution therapy services were required to carry a certificate stating that their methadone had been supplied legally; however, often people did not have this documentation. Several Kyrgyz clients using a range of NGO and government services commented on these problems: 'a whistler is settled in the drop-in centre, he whistles [when he sees] police men...and nobody will visit this centre'.IDUs using different government and NGO-run HIV/AIDS services indicated that they had developed ways to reduce the chance of being harassed or arrested by the militia. A client using an AIDS Centre in Kyrgyzstan explained: '...Some HIV/AIDS control activities financed by the Global Fund and other donors in Ukraine and Kyrgyzstan aimed to address the problems stemming from the criminalisation of drugs use both at national and local levels. NGO advocacy programmes in both countries had fostered some changes in the implementation of drugs laws in many parts of the country: new guidelines had been introduced on how militia should deal with IDUs, and programmes were launched to inform clients about their legal rights. In an attempt to promote greater understanding and tolerance, a Kyrgyz NGO provided information for clinical staff, militia and policymakers including seminars on drugs, harm reduction and HIV/AIDS with the aim of promoting greater understanding and tolerance among service providers. Furthermore, stakeholders and service providers in both countries collected data from sex workers and disseminated their findings at police forums. The challenge, however, was persuading the Ministry of Interior which, as one Kyrgyz service provider noted, 'does not recognise the existence of the problem'.Previous studies have suggested that stigmatisation of vulnerable groups and the criminalisation of drug use in the region exacerbated risky behaviour and increased vulnerability to police human rights abuses ,5,54,66.The study revealed discriminatory practices among HIV/AIDS service providers-especially government services-to be an important barrier to their use. Ukrainian and Kyrgyz clients indicated that government staff were often less tolerant than those of nongovernmental staff, a finding also noted by a civil society perspective report from the Open Society Institute . IDU intI am scared to go to a hospital, probably, someone would recognize me, here [at this HIV/AIDS service] nobody knows me; I come here'. In Kyrgyzstan diversity of ethnic/language groups in some areas exacerbated the difficulties clients experienced in developing effective relationships with government staff. For example a stakeholder reported that in Jalalabad in southern Kyrgyzstan-a region that has a complex ethnic/linguistic mix of Kyrgyz, Russian, Uzbek and Kazakh speakers-government service providers were often unable to communicate with clients.Indeed, HIV-positive clients suggested this was indicative of experiences when using general state-run healthcare services. Some had been refused hospitalisation or, having learnt that they were HIV-positive, were discharged by health workers. Potential service users avoided approaching general medical services because they were usually required to show documents including medical cards stamped to show they were HIV-positive, and there was no guarantee of confidentiality. A Ukrainian client said: 'first impression is very important for drug users; there should be such qualities as patience, tolerance'. Similarly Ukrainian clients said: 'Nongovernmental organisations are more tolerant...more flexible and are not bound by various norms' and: 'Here I feel safer than anywhere else...I do not feel any negative attitudes or prejudices against me. I was never refused help here'.Clients commented that the acceptability of different NGO and government-run HIV/AIDS services could depend upon staff attitudes. NGOs were seen as being more accessible than government services in this respect. For example a Kyrgyz service provider suggested: '...informal and confiding atmosphere' and the way staff were attentive, sympathetic and non-discriminating. The maintenance of confidentiality was important since most IDUs tried to conceal their drug dependence. If users believed that an NGO or government-run HIV/AIDS would not respect their confidentiality, then they would be unlikely to return. Illustrating this point a Kyrgyz client said: 'I don't want to see this outreach worker again, and will never go there again. Why did she tell my mom that I take syringes?'.A Ukrainian NGO drugs worker explained that client numbers increased as trust was built over time and people became more aware of HIV/AIDS services that were tolerant. The interviewee knew most clients by name and emphasized the importance of talking to clients so as to learn where drugs were being sold, enabling the service to more effectively target interventions. Ukrainian and Kyrgyz clients said they valued the absence of bureaucracy in accessing different NGO services. A Ukrainian client described an '...as a former injecting drug user and being HIV positive, with a wife and children, I don't want someone else to suffer...'. A Kyrgyz NGO manager said: '...their work is based on the "peer to peer" principle. So, these people know the problem from inside and it is easier for them to work, they understand more, deeper, better and they have more trust of the clients.Global Fund-supported Ukrainian and Kyrgyz NGO services targeting IDUs commonly recruited former IDUs as staff or volunteers, including former clients who were seen as having good knowledge of current clients' perspectives, thereby enabling them to build trust and provide move effective interventions. Ukrainian and Kyrgyz clients said they valued this 'peer-to-peer' principle. For example, a former client and volunteer in Ukraine explained: '...Nevertheless problems were reported: a high rate of staff turnover among NGO harm reduction outreach-workers existed, with many leaving after receiving training and experience for better paid or more secure positions. Some former IDUs had reverted to drug use through coming into regular contact with current users. NGO service providers in both countries reported that the problems of staff retention were also exacerbated by the uncertainties inherent in receiving regular tranches of Global Fund grants (discussed below).Our study found that Ukrainian and Kyrgyz clients' access to HIV/AIDS government and NGO-run services was affected by their limited knowledge of risk factors, what HIV/AIDS services were available, and the eligibility criteria for accessing the available services. In Kyrgyzstan in particular the fact that it was possible to be tested for HIV/AIDS anonymously and free of charge was not widely known by potential clients. Kyrgyz stakeholders indicated that the level of knowledge about HIV/AIDS among the general population, particularly in rural areas, remained low.Despite the introduction of information/educational programmes that had been supported by Global Fund HIV/AIDS programmes and other donors in Ukraine and Kyrgyzstan, clients, service providers and stakeholders agreed that many people remained unaware of the ways in which HIV was transmitted. In both countries Global Fund and other donor grants had been used to support some mass media health promotion, leaflets and other materials produced and distributed by sub-recipients, posters displayed in public spaces, and HIV/AIDS awareness lessons in some schools. In Ukraine during the 1990s media reporting of HIV/AIDS had the effect of instilling fear in society rather than providing informative commentary  Intervie... TV spots talk about danger, rather than about prevention; hence people start reacting to HIV with fear, and the whole situation is further aggravated. These spots should be modified somehow. Yes, this disease is frightening...[but] we need more explanatory information, and this information should be shared in a different manner.Similar problems were noted as part of the Kyrgyz Global Fund programme. A manager of a Kyrgyz NGO commented:The policy of prevention using fear was not right...We cultivated stigma ourselves, inspired fear...One ought to...use all resources, starting with mass media, so that people know about ways of transmission.some information videos are not acceptable for our population, they show naked bodies-too explicit...'. Hence, materials failed to reach and effectively engage marginalized groups. Another Kyrgyz stakeholder reported that providing women with information on HIV/AIDS-related issues in rural Kyrgyz communities was particularly problematic.Kyrgyz clients, service providers and stakeholders were critical of Global Fund-supported HIV/AIDS information programmes. A Kyrgyz stakeholder, for example, explained that social marketing for HIV/AIDS was ineffective since messages lacked cultural sensitivity outside the capital Bishkek. Often leaflets were too long, they used overly professional language, and films and posters depicted modern lifestyles and dress codes that challenged conservative views: '...Clients, service providers and stakeholders suggested that peer education and referrals were important means by which communities improved their knowledge of HIV/AIDS and government and NGO HIV/AIDS services: most Ukrainian and Kyrgyz clients said that they had learned about services they were using from their peers. Kyrgyz clients using drugs services emphasised the importance of networks of drug users in delivering messages to communities. In both countries many government and NGO providers promoted peer education and referrals as ways of extending coverage. Ukrainian clients indicated that their knowledge of HIV/AIDS had improved substantially since using different NGO harm reduction services.Our study suggests that shortages of medicines, commodities (including needles/syringes) and equipment (including laboratory equipment), and low quality and inappropriate commodities, were important barriers to clients receiving both government and NGO-run HIV/AIDS services. The majority of stakeholders and government and NGO service providers suggested that, while Global Fund support had allowed services to expand significantly, shortages of commodities remained a critical barrier to delivery, with reports of NGOs in Ukraine having to borrow equipment to maintain coverage. In Kyrgyzstan, clients and some stakeholders criticised the inappropriateness of some supplies procured as part of the Global Fund programme, such as the size and bore of needles and syringes supplied to service providers, which did not correspond to clients' needs . This reduced client demand for these commodities.ad hoc observations and client interviews. Stakeholders suggested that corruption was less widespread among Ukrainian HIV/AIDS services, although the practice of government health staff selling drugs such as painkillers and other supplies to drug dealers leading to shortages was still practiced.Discriminatory practices and limited transparency among services impacted on access to commodities among clients. In addition to the loss of Global Fund-financed needles and syringes intended for free distribution through sale in markets, Ukrainian and Kyrgyz stakeholders also acknowledged that some government and nongovernmental organisations employed corrupt working practices, such as inaccurate record-keeping, to conceal poor levels of performance and misuse of commodities and other resources. They described an institutionalized lack of transparency among some government and NGO service providers in both countries, and underdeveloped monitoring and evaluation systems. Indeed, the monitoring and evaluation system employed by the Kyrgyz Global Fund Principal Implementing Unit (PIU) had limited means to verify activity levels reported by sub-recipients. There were infrequent or absent spot checks by PIU staff to check records, and limited A high proportion of Ukrainian clients perceived staff shortages as an important barrier to receiving both government and NGO HIV/AIDS services, and stakeholders in both countries indicated that low government salaries resulted in low levels of motivation, and exacerbated problems of staff retention, including international and rural-urban labour migration. Previous studies have also reported acute health worker shortages in Central Asia due to international labour migration . In bothQuantitative data collected as part of this study showed that while staff numbers among NGO HIV/AIDS services had risen, they had remained static among government services -16. StakThey leave for another place of work or go to Russia. When a break is too long, they just don't come back. But, to recruit new people is the same as starting again'. These problems meant clients did not receive these services or were forced to rely on services funded by alternative donors to receive needles/syringes.Kyrgyz NGO service providers reported that Global Fund funding interruptions were frequently experienced by their organisations, that the problem was getting increasingly common, and that this had disrupted service delivery. In many cases this was caused by difficulties submitting quarterly monitoring reports by NGO sub-recipients on time. Most NGOs delivering needle/syringe exchange services did not stop work when financing breaks occurred, and relied on unpaid volunteers to provide services. A number of NGOs continued to distribute syringes using their own channels, violating rules in doing so. However, long interruptions in 2007-2008 forced several organisations to suspend activities, and breaks in payment of salaries forced many NGO staff to seek employment elsewhere. One interviewee explained: 'The economic transition in FSU countries in the last ten years has been traumatic. Studies have reported increased poverty and unemployment, weakened social welfare, increased domestic violence, alcoholism, intravenous drug use and sex work. These factors fuelled the HIV/AIDS epidemic and created severe financial shortfalls in the healthcare system, reducing coverage and increased out-of-pocket payments ,7,8. FacWhilst notionally free to users, Ukrainian and Kyrgyz clients interviewed suggested that they frequently made additional and/or informal payments to receive commodities from government HIV/AIDS services including medicines and surgical gloves which they found expensive. The costs of obtaining necessary official documents required by government services also constituted a substantial economic barrier to using these services. Such problems were not reported by Ukrainian and Kyrgyz clients as a significant problem in utilising NGO-run services. However, observations of transactions in the markets, which were conducted as part of the Kyrgyz study, revealed that Global Fund-financed needles/syringes intended for free distribution by NGO HIV/AIDS services and some government providers were very widely available for purchase. Many clients reported that service providers, both NGO and government employees, appeared to exercise considerable discretion over whether or not to give them resources-including needles/syringes. Clients were often uncertain whether or not staff sold commodities for personal profit, or if staff were attempting to extract informal payments for commodities.The study revealed that there were substantial variations in geographical accessibility to HIV/AIDS services in the two focus countries. Ukrainian and Kyrgyz clients and stakeholders agreed that the main problems of geographical accessibility stemmed from the uneven distribution of both government and NGO-run HIV/AIDS services. Notable was the limited services outside larger towns/cities, but also the uneven distribution within the larger cities where the study took place. While it was beyond the study's scope to systematically interview clients living outside larger towns/cities, qualitative data point to substantial local variations in geographical accessibility. For example, clients living outside Odessa and Osh explained that distance was a substantial barrier to using both government and NGO HIV/AIDS services, exacerbated by poor public transport. Government AIDS Centres were located on the edge of built up areas in Kyiv and Odessa, reflecting the stigmatisation of HIV/AIDS, and these were poorly served by public transport in Odessa. Stakeholders and service providers reported that within larger cities such as Kyiv, Odessa and Osh, the distribution of NGOs receiving Global Fund grants was uneven: most had a history of operating within specific neighbourhoods, building trust among a small local client base but leaving many areas badly served. Clients stated that they were sometimes disinclined to travel for free needles/syringes since buying them through local retailers was less expensive than travel costs.To address some of these problems many Global Fund-supported Ukrainian and Kyrgyz NGOs supported by the Global Fund and other donors ran outreach health promotion and needle/syringe distribution services. Basic government HIV/AIDS services had also been extended to primary and secondary government healthcare outlets in both countries where services included blood sampling for sending to AIDS Centre laboratories for HIV testing, administering antiretroviral drugs; and in some cases distributing needles and syringes. Nevertheless, clients reported that problems remained: many said they preferred to receive care through specialist government or NGO HIV/AIDS services rather than at local government clinics as it was easier to conceal their HIV/AIDS status in the former.Clients reported that they experienced substantial organisational and bureaucratic barriers to using government HIV/AIDS services in both focus countries. They often lacked information on procedures for using these services, which varied between different providers since there appeared to be substantial discretion among individual staff, making service use unpredictable. Ukrainian clients in particular described the procedure for accessing government HIV/AIDS and indeed other government health services as complex and bureaucratic, often resulting in unanticipated costs including travelling to several different healthcare outlets, unanticipated delays and difficulties making appointments. For example a Ukrainian client explained that she was refused care by a government HIV/AIDS service because she was registered as living in another region, and the procedure of obtaining new permanent registration was lengthy and complex.in order to become a client of substitution therapy programs you need to have an HIV-positive status'  and '...to go through rehabilitation for drug users for free, you've got to wait for 2-3 months because there is a waiting list'. While relatively few clients in both countries felt that problems of referral between services acted as a barrier and most Ukrainian and Kyrgyz clients said that they had been referred between NGO and government services, interviewees explained that client referrals were in practice inconsistently applied and frequently consisted of informal signposting rather than formalised referral across government and NGO providers.Ukrainian clients had experienced various other problems. For example: '...Previous research has shown how global HIV/AIDS initiatives, including the Global Fund, have contributed to achieving international access goals by funding dramatic scale up of HIV/AIDS prevention, treatment and care services, encouraged political commitment to a highly stigmatized disease, improved linkages between government and NGO-run HIV/AIDS services, supported advocacy, and provided training . Attemptessential that debates surrounding universal access acknowledge that access is not simply determined by commodity delivery and service coverage, which represent the more easily measured performance indicators.While HIV/AIDS service scale-up has been significant in Ukraine and Kyrgyzstan, increased service availability has not always resulted in and does not equate with increased accessibility for the populations in need of these services. Our study confirms previous work examining problems faced by IDUs in Eastern Europe and Central Asia -66. ThosIn this paper we explore the specific barriers to access experienced by IDUs using HIV/AIDS services in the counties in which the study was set. These differ substantially from experiences in high-income countries where laws relating to drug use tend to be less repressive, and in generalised HIV/AIDS epidemic settings where the main mode of HIV transmission tends not to be through injecting drug use ,24,31-51within the health sector that influenced or determined access, whereas our study shows that critical barriers to accessing HIV/AIDS services in Ukraine and Kyrgyzstan stem from outside the health sector. These include prohibitionist and punitive drug laws and their implementation, and the multiple stigmatisations-by officialdom, communities and even their families-of those with HIV/AIDS and of those who used illicit drugs. HIV/AIDS programmes must acknowledge and address both health service-specific and external political and societal factors if they are to be effective.What our study shows is that the analytical frameworks currently being employed in studies of access to general healthcare are of limited utility for understanding the complex and specific access issues facing marginalised groups such as IDUs seeking HIV/AIDS services in countries with low/concentrated epidemics. For example, earlier access studies reviewed earlier in this paper -26,31-52In countries where the HIV/AIDS epidemic is fuelled by injecting drug use, legislation and policing practices have undermined the effectiveness of Global Fund HIV/AIDS programmes. While attempts to reduce repressive police practices, some of which have been supported by the Global Fund, have made some progress, this remains a substantial problem highlighting the need for more sustained advocacy programmes at all levels, including training police officers to work more sensitively with IDUs. Ultimately, however, it is about political will. Hence, it is essential firstly to promote more effective engagement between government ministries including health, education and the interior in multi-sectoral decision making processes; and secondly to support sustained, coherent social marketing programmes aimed at reducing stigmatisation of high-risk behaviours and HIV/AIDS within society as a whole. If new funding opportunities are not used to tackle these structural and systemic drivers of the HIV epidemic, the scale of the epidemic will outstrip these countries' capacity to control it.Another limitation of previous access studies -26,31-51This study had a number of methodological limitations: firstly, individuals not using HIV/AIDS services were not interviewed due to considerable difficulties engaging with those groups, which constituted a sampling bias. Secondly, because sampling was limited to urban areas in the two countries, the perceptions of clients and service providers in other cities and smaller towns and rural areas were not collected. Indeed, it is a reasonable assumption that the problems of accessibility outside large cities would be greater to those experienced within them. Thirdly while our data suggest that there are some regional differences, for example particular problems experienced in Western Ukraine and Southern Kyrgyzstan and geographical variations with cities, the study did not systematically explore differences between different regions of the two focus countries. Fourthly, this study reports findings based on data collection carried out in 2007 and 2008: it therefore represents a snapshot in time in a changing policy environment in the two focus countries. Finally, while the data suggest that a similar range of access barriers are experienced in both focus countries, one should not generalise the conclusions of this study beyond Ukraine and Kyrgyzstan.If internationally agreed targets are designed to spur action, then the goal of universal access to treatment by 2010 has been moderately successful. Since 2005, scale up of additional funding from global health and HIV initiatives such as the Global Fund has made HIV/AIDS treatment and prevention available to many more people. However, as our study shows, availability of services does not equate with accessibility of services. This is a serious limitation in the policy response to HIV/AIDS services that requires immediate attention.Our analysis shows that in at least two countries from the FSU region there are clear barriers to access facing the most vulnerable members of society. New global initiatives, such as the Global Fund, have created an opportunity for governments and NGOs to acknowledge, and respond to the rapidly growing HIV epidemic. However, HIV/AIDS remains highly stigmatised in these two countries from the FSU region, with clients reporting stigma and discrimination from families, law enforcement agencies, and notably from providers of some government health services.Our study has contributed to the literature on HIV/AIDS in the FSU region ,8,53-56 not using services, to compare problems of HIV/AIDS service access in urban and rural areas and between different regions of the two countries, and to compare the experience of Ukraine and Kyrgyzstan to those of other countries of the FSU region.While this study has started to build an understanding of the problems of accessing HIV/AIDS services in two FSU countries further research is required in order to deepen our knowledge of these problems and to help inform the development of future HIV/AIDS programmes. Large scale quantitative client surveys would be valuable in order to assess the scale of different access problems, while further qualitative research could help to better understand the health systems and structural drivers of the access problems experienced at the service delivery level. Studies are needed to explore the perspectives of people The authors declare that they have no competing interests.NS led on drafting this article. NS, DB, RB, GM and TS all participated in the conception, design and execution of the study and analysis and interpretation of data. AH contributed substantially to the analysis and interpretation of data. All authors participated in manuscript writing and have read and approved the final manuscript.


Unnecessary long-term use of broad-spectrum antibiotics is linked to the emergence and selection of resistant bacteria, prolonged hospitalisation and increased costs. Several clinical trials indicate that the biomarker procalcitonin (PCT) can guide antibiotic therapy. Some of these trials have shown a promising reduction in the number of antibiotic prescriptions, duration of antibiotic therapy and even length of stay in the ICU, although their size and selection criteria limit their external validity. The objectives of the Stop Antibiotics on guidance of Procalcitonin Study (SAPS) are to evaluate whether daily PCT can improve “real-life” antibiotic use in Dutch ICU’s by reduction of the duration of antibiotic treatment without an increase of recurrent infections and mortality.Multicenter randomised controlled intervention trial. Powered for superiority of the primary efficacy endpoint and non-inferiority on the primary safety endpoints (non-inferiority margin is set on 8%).Inclusion criteria: (1) ICU-patients aged ≥18 years and (2) receiving antibiotics for a presumed or proven infection and (3) signed informed consent. Exclusion criteria: (1) patients who require prolonged antibiotic therapy, (2) suffer from Mycobacterium tuberculosis, (3) cystic fibrosis, (4) viral or parasitic infections and (5) those that are severely immunocompromised or (6) moribund.The intervention consists solely of an advice to discontinue antibiotic treatment in case PCT has decreased by more than 80% of its peak level (relative stopping threshold) or decrease below a value of 0.5 ng/ml (absolute stopping threshold).The study hypothesis is that PCT-guided therapy is non-inferior to standard care based on implemented guidelines and local expertise, whilst reducing antibiotic usage. Computerised 1:1 randomisation will allocate 908 patients per arm. Arm 1: standard of care. Arm 2: procalcitonin-guided therapy. The primary efficacy endpoint is consumption of antibiotics expressed as the defined daily dosage and duration of antibiotic therapy expressed in days of therapy. This trial is designed to shorten antibiotics safely, therefore the primary safety endpoint is mortality measured at 28 day and 1 year.This will be the largest procalcitonin-guided antibiotic intervention trial in ICU setting thus far. Currently 1600 of the planned 1816 patients are randomised (November 2012). The first interim analysis has passed without any safety or futility issues.http://www.clinicaltrials.gov: Id. Nr. NCT01139489, at http://www.trialregister.nl: Id.nr. NTR1861.Trial registration number at  Resistance to antimicrobial drugs is an increasing threat to public health. Each year, about 25.000 people die in the EU from an infection with multidrug-resistant bacteria. In the EU infections due to such bacteria result in extra healthcare costs of over 1.5 billion Euros each year University Medical Center Utrecht, Utrecht [D. de Lange]St. Elisabeth Hospital, Tilburg [J. van Oers]St. Lucas Andreas Hospital Amsterdam [M. van den Elsen]Isala Clinics, Zwolle [H. Kieft]Diakonessenhuis, Utrecht Martini Hospital, Groningen [B. Loef]Atrium Medical Center, Heerlen [T. Dormans]Medical Center Haaglanden, Den Haag [G. Admiraal]Bronovo Hospital, Den Haag [J. Streefkerk]WestFriesGasthuis, Hoorn [A. Tacx]Slotervaart Ziekenhuis, Amsterdam (G. Kluge, H. Biermann]University Medical Center Groningen, Groningen [M.N. Nijsten]Medisch Spectrum Twente, Enschede [A. Beishuizen]Wilhelmina Ziekenhuis, Assen [J. Lutisan]Canisius-Wilhelmina Ziekenhuis, Nijmegen [J. Schouten]The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/13/178/prepub