The misfortunate incident of formation of a urogenital fistula remains a major challenge for surgical urologists worldwide. Such fistulae may not be a life-threatening problem, but surely the women face demoralization, social boycott and even divorce and separation. The fistula may be vaginal, recto-vaginal or a combination of the two. The World Health Organization (WHO) has estimated that in the developing nations, nearly 5 million women annually suffer severe morbidity with obstetric fistulae being the foremost on the list. The objective of our study was to enunciate the patient demography, patient profile, incidence, type of surgery, as well as the long-term outcomes encountered in the management of all types of genital fistulae at a tertiary care centre.
Materials and Methods:
50 consecutive patients, attending the outpatient department with urogenital fistulae, were studied during the period of 5 years from July 2005 to July 2009. All female patients with complaints of urinary incontinence and fecal incontinence and dribbling, patients having a history of obstructed labor, radiotherapy, instrumental delivery, foreign body or trauma and with a history of hysterectomy (abdominal/ vaginal) and lower segment caesarean section (LSCS) were included. A thorough urological examination included a dye study using methylene blue, Renal function tests, X-ray KUB and intravenous urography (IVU). Cystoscopy along with examination under anaesthesia (EUA) were done to assess the actual extent of injury. All patients were subjected to appropriate surgical interventions via the same combination of surgeons . Post operatively, prophylactic antibiotics were administered to all patients and patients were managed till discharge and followed thereafter via regular outpatient visits for a period of 3 years.
Age of patients ranged from 21 to 40 years. 64% patients hailed from rural areas, 76% were from the lower socio-economic strata, 40% illiterate and 69% were short Statured. Vesico vaginal fistulae (VVF) was seen in 64% cases of which 50% were due to obstructed labor, 19% cases post LSCS and 31% cases post total abdominal hysterectomy (TAH). 68% of urogenital fistulae were between 1 to 3 cms. We obtained a 75% cure rate in UVF, 87.5% cure rate in RVF while a 93.75% cure rate was observed in patients with VVF. 76% of all patients were cured while 8% had a recurrence, probably due to the large size of fistula.
Genital fistula is preventable, yet it remains a significant cause of morbidity among females of reproductive age group. Despite facilities available, certain conditions like physical, social, economic, illiteracy, and a very casual attitude towards maternal health and children birth practices limit utilization of services for women. It is important that the modern health care providers should be aware of these aspects, so that they can recognize services that are appropriate and acceptable to the people. Thus, one must agree that in cases of urogenital fistulae, "prevention is better than cure".
Obstructed labor; urogenital fistulae; vesico vaginal fistula
Cancer cell motility is a key phenomenon regulating invasion and metastasis. Focal adhesion kinase (FAK) plays a major role in cellular adhesion and metastasis of various cancers. The relationship between dietary supplementation of calcium and colon cancer has been extensively investigated. However, the effect of calcium (Ca2+) supplementation on calpain-FAK-motility is not clearly understood. We sought to identify the mechanism of FAK cleavage through Ca2+ bound lactate (CaLa), its downstream signaling and role in the motility of human colon cancer cells. We found that treating HCT116 and HT-29 cells with CaLa immediately increased the intracellular Ca2+ (iCa2+) levels for a prolonged period of time. Ca2+ influx induced cleavage of FAK into an N-terminal FAK (FERM domain) in a dose-dependent manner. Phosphorylated FAK (p-FAK) was also cleaved in to its p-N-terminal FAK. CaLa increased colon cancer cells motility. Calpeptin, a calpain inhibitor, reversed the effects of CaLa on FAK and pFAK cleavage in both cancer cell lines. The cleaved FAK translocates into the nucleus and modulates p53 stability through MDM2-associated ubiquitination. CaLa-induced Ca2+ influx increased the motility of colon cancer cells was mediated by calpain activity through FAK and pFAK protein destabilization. In conclusion, these results suggest that careful consideration may be given in deciding dietary Ca2+ supplementation to patient undergoing treatment for metastatic cancer.
Strain-promoted azide-alkyne cycloaddition (SPAAC) can be used to generate artificial metalloenzymes (ArMs) from scaffold proteins containing a p-azido-L-phenylalanine (Az) residue and catalytically active bicyclononyne-substituted metal complexes. The high efficiency of this reaction allows rapid ArM formation using Az residues within the scaffold protein in the presence of cysteine residues or various reactive components of cellular lysate. In general, cofactor-based ArM formation allows the use of any desired metal complex to build unique inorganic-protein materials. SPAAC covalent linkage further decouples the native function of the scaffold from the installation process since it is not affected by native amino acid residues; as long as an Az residue can be incorporated, an ArM can be generated. We have demonstrated the scope of this method with respect to both the scaffold and cofactor components and established that the dirhodium ArMs generated can catalyze the decomposition of diazo compounds and both Si-H and olefin insertion reactions involving these carbene precursors.
artificial metalloenzyme; biocatalysis; cofactor; click chemistry; dirhodium
Pressurized metered dose inhalers (MDIs) are a long-standing method to treat diseases of the lung, such as asthma and chronic obstructive pulmonary disease. MDIs rely on the driving force of the propellant, which comprises the bulk of the MDI formulation, to atomize droplets containing drug and excipients, which ideally should deposit in the lungs. During the phase out of chlorofluorocarbon propellants and the introduction of more environmentally friendly hydrofluoroalkane propellants, many improvements were made to the methods of formulating for MDI drug delivery along with a greater understanding of formulation variables on product performance. This review presents a survey of challenges associated with formulating MDIs as solution or suspension products with one or more drugs, while considering the physicochemical properties of various excipients and how the addition of these excipients may impact overall product performance of the MDI. Propellants, volatile and nonvolatile cosolvents, surfactants, polymers, suspension stabilizers, and bulking agents are among the variety of excipients discussed in this review article. Furthermore, other formulation approaches, such as engineered excipient and drug-excipient particles, to deliver multiple drugs from a single MDI are also evaluated.
ethanol; formulation; metered dose inhaler (MDI); propellant; solubilization aids; suspending agents
The mechanisms by which IL-6 contributes to the pathogenesis of chronic inflammatory diseases and cancer are not fully understood. We previously reported that cyclooxygenase-2 (Cox-2)-dependent PGE2 synthesis regulates macrophage matrix metalloproteinase (MMP)-9 expression, an endopeptidase that participates in diverse pathologic processes. In these studies, we determined whether IL-6 regulates the Cox-2→PGE2→MMP-9 pathway in murine macrophages. IL-6 co-induced Cox-2 and microsomal prostaglandin E synthase-1 (mPGES-1), and inhibited the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), leading to increased levels of PGE2. In addition, IL-6 induced MMP-9 expression, suggesting that the observed proteinase expression was regulated by the synthesis of PGE2. However, inhibition of PGE2 synthesis partially suppressed IL-6–mediated induction of MMP-9. In the canonical model of IL-6-induced signaling, JAK activation triggers STAT and MAPKerk1/2-signaling pathways. Therefore, the ability of structural diverse JAK inhibitors to block IL-6-induced MMP-9 expression was examined. Inhibition of JAK blocked IL-6 induced phosphorylation of STAT3, but failed to block the phosphorylation of MAPKerk1/2, and unexpectedly enhanced MMP-9 expression. In contrast, MEK-1 inhibition blocked IL-6 induced phosphorylation of MAPKerk1/2 and MMP-9 expression without affecting the phosphorylation of STAT3. Thus, IL-6-induced MMP-9 expression is dependent on the activation of MAPKerk1/2 and restrained by a JAK-dependent gene product. Utilizing pharmacologic and genetic approaches, JAK-dependent induction of IL-10 was identified as a potent feedback mechanism controlling IL-6 induced MMP-9 expression. Together, these data reveal that IL-6 induces MMP-9 expression in macrophages via Cox-2-dependent and -independent mechanisms, and identifies a potential mechanism linking IL-6 to the pathogenesis of chronic inflammatory diseases and cancer.
Endometrial stromal sarcoma (ESS) is a rare malignant tumor of the endometrium, occurring in the age group of 40–50 years. We report a case of low-grade ESS in a 39-year-old woman, presenting as rapid enlargement of a uterine fibroid polyp associated with irregular and excessive vaginal bleeding. Polypectomy followed by pan hysterectomy was performed. Histopathological examination and immunohistochemistry confirmed LGESS. As the tumor is rarely encountered, management protocols are still questionable. In our case, we tried a different post-surgical protocol and the patient is being closely followed up. Although rare, ESS should be considered in the differential diagnosis of all women who present with a rapid enlargement of a uterine leiomyoma.
Endometrial stromal sarcoma; Uterine leiomyoma; Immunohistochemistry
Juvenile nasopharyngeal angiofibroma is a locally aggressive benign vascular neoplasm, composed of vasogenic and myofibroblastic elements, accounts for 0.05–0.5% of all the head and neck neoplasms. There are very few case reports of nasopharyngeal angiofibroma involving the oral cavity; we report a case involving both the maxilla and mandible in a 17-year-old patient who reported with a large firm swelling on right side of face with recurrent epistaxis and headache. Magnetic resonance angiography revealed a large lobulated enhancing soft tissue mass, which was hypointense on T1-weighted image and heterogeneously hyperintense on T2-weighted image causing expansion of pterygopalatine fossa and sphenopalatine foramen with extension into the sphenoid sinus, ethmoid air cells, right nasal cavity, right infratemporal fossa and right maxillary sinus with remodeling of right zygomatic arch and part of body and ramus of mandible. It was supplied by the right external carotid artery. Patient was referred to the department of neurosurgery for further management. The diagnosis at an early stage is important because it is associated with high risk of morbidity, but advances in imaging, and surgical methods of treatment have changed the sites associated with high risk of morbidity.
Angiography; computed tomography; juvenile nasopharyngeal angiofibroma; magnetic resonance imaging
Pressurized metered dose inhalers (MDIs) were first introduced in the 1950s and they are currently widely prescribed as portable systems to treat pulmonary conditions. MDIs consist of a formulation containing dissolved or suspended drug and hardware needed to contain the formulation and enable efficient and consistent dose delivery to the patient. The device hardware includes a canister that is appropriately sized to contain sufficient formulation for the required number of doses, a metering valve capable of delivering a consistent amount of drug with each dose delivered, an actuator mouthpiece that atomizes the formulation and serves as a conduit to deliver the aerosol to the patient, and often an indicating mechanism that provides information to the patient on the number of doses remaining. This review focuses on the current state-of-the-art of MDI hardware and includes discussion of enhancements made to the device’s core subsystems. In addition, technologies that aid the correct use of MDIs will be discussed. These include spacers, valved holding chambers, and breath-actuated devices. Many of the improvements discussed in this article increase the ability of MDI systems to meet regulatory specifications. Innovations that enhance the functionality of MDIs continue to be balanced by the fact that a key advantage of MDI systems is their low cost per dose. The expansion of the health care market in developing countries and the increased focus on health care costs in many developed countries will ensure that MDIs remain a cost-effective crucial delivery system for treating pulmonary conditions for many years to come.
actuator; add-on devices; canister; dose counters; metering valve
Many tumors are hierarchically organized with a minority cell population that has stem-like properties and enhanced ability to initiate tumorigenesis and drive therapeutic relapse. These cancer stem cells (CSCs) are typically identified by complex combinations of cell-surface markers that differ among tumor types. Here, we developed a flexible lentiviral-based reporter system that allows direct visualization of CSCs based on functional properties. The reporter responds to the core stem cell transcription factors OCT4 and SOX2, with further selectivity and kinetic resolution coming from use of a proteasome-targeting degron. Cancer cells marked by this reporter have the expected properties of self-renewal, generation of heterogeneous offspring, high tumor- and metastasis-initiating activity, and resistance to chemotherapeutics. With this approach, the spatial distribution of CSCs can be assessed in settings that retain microenvironmental and structural cues, and CSC plasticity and response to therapeutics can be monitored in real time.
•A fluorescent reporter was generated that reports on the presence of SOX2 and OCT4•Breast cancer cells marked by the reporter have characteristics of cancer stem cells•The reporter identifies a therapy-resistant subpopulation of cancer cells•The reporter allows visualization of cancer stem cells in vivo and in real time
In this article, Wakefield and colleagues show that a subpopulation of cancer cells with characteristics of cancer stem cells can be identified and visualized in vitro and in vivo using a lentiviral-based fluorescent reporter that responds to the presence of the stemness master transcription factors SOX2 and OCT4.
We report a case of transient reduction in the diameter and tortuosity of an occluded vessel after intravitreal administration of 1.25 mg (0.05 ml) bevacizumab in a patient with ischaemic branch retinal vein occlusion. A 64-year-old hypertensive female presented with chief complaints of reduced vision in her right eye for 3 months. Her vision in the right eye was evaluated as counting fingers at 2 m. Fundus examination revealed superotemporal branch retinal vein occlusion. On fluorescein angiography, in the superotemporal quadrant, there was hyperfluorescence that increased in size and intensity in the late phase, suggestive of a leaking neovascular frond. In addition, there was capillary non-perfusion in the adjacent area. The patient was administered 1.25 mg (0.05 ml) of bevacizumab intravitreally in her right eye, under all aseptic precautions. After 1 week, her right eye fundus showed regression of neovascularisation. Fluorescein angiography also demonstrated regression of neovascularisation in addition to a decrease in the diameter and tortuosity of the retinal vessel.
Bevacizumab; Branch retinal vein occlusion; Retinal vessel morphology
Majority of individuals with history of visceral leishmaniasis (VL) exhibit strong immunity to re-infection, however, the mechanism of resistance is poorly understood. It is unclear whether CD8+ T cells contribute to protection against Leishmania donovani infection through cytotoxic activity. The present study aims to evaluate immunological mechanism associated with resistance to the disease in healed VL (HVL) individuals and further, the contribution of CD8+ T cells in the protective immunity.
Peripheral blood mononuclear cells (PBMCs) from VL, HVL and naive groups were exposed in vitro to total soluble Leishmania antigen (TSLA) from L. donovani. The proliferation index was determined by ELISA based lymphoproliferative assay. Cytokines and granzyme B levels were measured by CBA. Activated T-cell populations were estimated using flow cytometry.
We observed significantly higher lymphoproliferation, cytokines and granzyme B levels in HVL group compared to naive or VL group. More strikingly, we found a strong association (rs = 0.895, P < 0.0001) between proliferation index (PI) and granzyme B level, with a significant proportion of activated CD8+ T cells in HVL group.
Leishmania immune group (HVL) exhibited durable and strong cellular immune response to TSLA in terms of lymphoproliferation as well as production of Th1 cytokines and granzyme B. Additionally, the elevated level of activated CD8+ T cells and stimulation of cytotoxic activity through granzyme B production, indicated a possible role of CD8+ T cells in resistance to L. donovani infection in the HVL group.
CD8+ T cells; Granzyme B; Visceral leishmaniasis; Total soluble Leishmania antigens; Vaccine
Firmness and toughness of fruit, peel and pulp of seven different mango cultivars were studied over a ripening period of ten days to investigate the effects of harvesting stages (early, mid and late) on fruit quality. Parameters were measured at equatorial region of fruits using TA-Hdi Texture Analyzer. The textural characteristics showed a rapid decline in their behaviour until mangoes got ripened and thereafter, the decline became almost constant indicating the completion of ripening. However, the rate of decline in textural properties was found to be cultivar specific. In general, the changes in textural attributes were found to be significantly influenced by ripening period and stage of harvesting, but firmness attributes (peel, fruit and pulp) of early harvested mangoes did not differ significantly from mid harvested mangoes, while peel, fruit and pulp firmness of late harvested mangoes were found to be significantly lower than early and mid harvested mangoes.
Harvesting stage; Quality; Ripening period; Cultivar; Textural characteristics; Shelf life
This review describes the state of art in nanoparticle and nanodevice applications for medical diagnosis and disease treatment. Nanodevices, such as cantilevers, have been integrated into high-sensitivity disease marker diagnostic detectors and devices, are stable over long periods of time, and display reliable performance properties. Nanotechnology strategies have been applied to therapeutic purposes as well. For example, nanoparticle-based delivery systems have been developed to protect drugs from degradation, thereby reducing the required dose and dose frequency, improving patient comfort and convenience during treatment, and reducing treatment expenses. The main objectives for integrating nanotechnologies into diagnostic and therapeutic applications in the context of intestinal diseases are reviewed.
Recently, we described the existence of the ubiquitin fold modifier1 (Ufm1) and its conjugation pathway in Leishmania donovani. We demonstrated the conjugation of Ufm1 to proteins such as mitochondrial trifunctional protein (MTP) that catalyzes β-oxidation of fatty acids in L. donovani. To elucidate the biological roles of the Ufm1-mediated modifications, we made an L. donovani Ufm1 null mutant (Ufm1−/−). Loss of Ufm1 and consequently absence of Ufm1 conjugation with MTP resulted in diminished acetyl-CoA, the end product of the β-oxidation in the Ufm1−/− amastigote stage. The Ufm1−/− mutants showed reduced survival in the amastigote stage in vitro and ex vivo in human macrophages. This survival was restored by re-expression of wild type Ufm1 with concomitant induction of acetyl-CoA but not by re-expressing the non-conjugatable Ufm1, indicating the essential nature of Ufm1 conjugation and β-oxidation. Both cell cycle analysis and ultrastructural studies of Ufm1−/− parasites confirmed the role of Ufm1 in amastigote growth. The defect in vitro growth of amstigotes in human macrophages was further substantiated by reduced survival. Therefore, these studies suggest the importance of Ufm1 in Leishmania pathogenesis with larger impact on other organisms and further provide an opportunity to test Ufm1−/− parasites as drug and vaccine targets.
Ubiquitin fold modifier 1; Ufm1; Ufm1mediated protein conjugation; β-oxidation; acetyl-CoA; cell division; trypanosomatid; Leishmania donovani; mitochondrial trifunctional protein; MTP
Granulosa cell tumor; Juvenile; Ovarian tumors
Background: Facial aesthetics affects how people are perceived by society and how they perceive themselves. Anterior malocclusion can have an impact on the overall facial appearance.
Aim: The aim of the study was to assess the prevalence of malocclusion and its psycho-social impact among 12 to 15 yrs old school children in Lucknow city.
Materials and Methods: The study consisted of collection of information for psychosocial assessment using a questionnaire and clinical examination of malocclusion. Data regarding psychosocial impact of dental aesthetics was collected using a Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ) given by Klages et al., (2006).
Results: 15.57% children belonged to the definite malocclusion category and 5.41% to the handicapped malocclusion category. The mean Dental self confidence score differed significantly among both male (p≤0.001) and female children (p≤0.001) across the age groups. The mean Social impact score did not differ significantly among both male (p≤0.31) and female children (p≤0.12) across the age groups.
Conclusion: The results of the present study imply that dental aesthetics had a significant impact on the psychosocial aspects of human life irrespective of the gender.
Aesthetics; Orthodontic treatment; Dental aesthetic index
Toothbrushes may play a significant role in plaque control. Toothbrushes should be correctly stored, disinfected and changed at regular intervals.
The purpose of this study was to evaluate the efficacy of 0.2% chlorhexidine (CHX) gluconate solution and ultra violet (UV) toothbrush-sanitizer for toothbrush disinfection.
Materials and Methods:
Fresh tooth brushes were distributed to fifteen study subjects, who were selected randomly and who met the study criteria. All the study participants were asked to brush their teeth with the tooth brush provided. No special instructions were given regarding the brushing techniques. Toothbrushes were collected after 7 days. All tooth brushes were randomly allocated to three groups. Tooth brushes were subjected to microbial analysis and total bacterial count was assessed. Tooth brushes allocated to Group I were soaked in 2% CHX mouthwash for 12 h, Group II were kept in UV-light toothbrush holder for 7 min, and Group III were soaked in normal saline for 12 h. All the toothbrushes were subjected for microbial analysis and mean bacterial count was determined.
There was a statistically significant difference between mean colony-forming unit count pre-sanitization and post-sanitization in all the groups, using 0.2% CHX gluconate, UV rays and normal saline (P < 0.007). However, the mean bacterial count reduced drastically after the treatment with UV rays (P = 0.001).
CHX, UV rays and normal saline are effective in a reduction of bacterial count on toothbrushes. UV rays treatment was more effective, when compared to CHX and normal saline.
Chlorhexidine gluconate; disinfectant; toothbrush contamination; ultra violet radiation
Changes in the peripheral distribution and amount of condensed chromatin are observed in a number of diseases linked to mutations in the lamin A protein of the nuclear envelope. We postulated that lamin A interactions with nuclear envelope transmembrane proteins (NETs) that affect chromatin structure might be altered in these diseases and so screened thirty-one NETs for those that promote chromatin compaction as determined by an increase in the number of chromatin clusters of high pixel intensity. One of these, NET23 (also called STING, MITA, MPYS, ERIS, Tmem173), strongly promoted chromatin compaction. A correlation between chromatin compaction and endogenous levels of NET23/STING was observed for a number of human cell lines, suggesting that NET23/STING may contribute generally to chromatin condensation. NET23/STING has separately been found to be involved in innate immune response signaling. Upon infection cells make a choice to either apoptose or to alter chromatin architecture to support focused expression of interferon genes and other response factors. We postulate that the chromatin compaction induced by NET23/STING may contribute to this choice because the cells expressing NET23/STING eventually apoptose, but the chromatin compaction effect is separate from this as the condensation was still observed when cells were treated with Z-VAD to block apoptosis. NET23/STING-induced compacted chromatin revealed changes in epigenetic marks including changes in histone methylation and acetylation. This indicates a previously uncharacterized nuclear role for NET23/STING potentially in both innate immune signaling and general chromatin architecture.
Leishmania donovani is the causative agent of the potentially fatal disease visceral leishmaniasis (VL). Chemotherapeutic options available to treat VL are limited and often face parasite resistance, inconsistent efficacy, and toxic side effects. Paromomycin (PMM) was recently introduced to treat VL as a monotherapy and in combination therapy. It is vital to understand the mechanisms of PMM resistance to safeguard the drug. In the present study, we utilized experimentally generated PMM-resistant L. donovani to elucidate the mechanisms of resistance and parasite biology. We found increased membrane fluidity accompanied by decreased intracellular drug accumulation in the PMM-resistant parasites. There were marked increases in gene expression of ATP-binding cassette (ABC) transporters (MDR1 and MRPA) and protein phosphatase 2A that evince increased drug efflux. Further, evaluation of parasite tolerance toward host leishmanicidal mechanisms revealed PMM-resistant parasites as being more tolerant to nitrosative stress at the promastigote and amastigote stages. The PMM-resistant parasites also predicted a better survival capacity, as indicated by resistance to complement-mediated lysis and increased stimulation of host interleukin-10 (IL-10) expression. The susceptibilities of PMM-resistant isolates to other antileishmanial agents (sodium antimony gluconate and miltefosine) remained unchanged. The data implicated the roles of altered membrane fluidity, decreased drug accumulation, increased expression of ABC transporters, and greater tolerance of parasites to host defense mechanisms in conferring PMM resistance in Leishmania.
A 50-day-old female child presented with asymptomatic skin colored raised lesion on the dorsal aspect of the left wrist since the age of 10 days. The diagnosis of cutaneous mastocytoma was made based upon clinical and histopathological features.
Asymptomatic mastocytoma; solitary Darier's sign
AIM: To determine the expression of membrane-bound mucins and glycan side chain sialic acids in Helicobacter pylori (H. pylori)-associated, non-steroidal inflammatory drug (NSAID)-associated and idiopathic-gastric ulcers.
METHODS: We studied a cohort of randomly selected patients with H. pylori (group 1, n = 30), NSAID (group 2, n = 18), combined H. pylori and NSAID associated gastric ulcers (group 3, n = 24), and patients with idiopathic gastric ulcers (group 4, n = 20). Immunohistochemistry for MUC1, MUC4, MUC17, and staining for Erythrina cristagalli agglutinin and Sambucus nigra agglutinin (SNA) lectins was performed on sections from the ulcer margins.
RESULTS: Staining intensity of MUC17 was higher in H. pylori ulcers (group 1) than in idiopathic ulcers (group 4), 11.05 ± 3.67 vs 6.93 ± 4.00 for foveola cells, and 10.29 ± 4.67 vs 8.00 ± 3.48 for gland cells, respectively (P < 0.0001). In contrast, MUC1 expression was higher in group 4 compared group 1, 9.89 ± 4.17 vs 2.93 ± 5.13 in foveola cells and 7.63 ± 4.60 vs 2.57± 4.50 for glands, respectively (P < 0.0001). SNA lectin staining was increased in group 4, in parallel to elevated MUC1 expression, indicating more abundant α2-6 sialylation in that group.
CONCLUSION: Cytoplasmic MUC17 staining was significantly decreased in the cases with idiopathic ulcer. The opposite was observed for both MUC1 and SNA lectin. This observation may reflect important pathogenic mechanisms, since different mucins with altered sialylation patterns may differ in their protection efficiency against acid and pepsin.
Mucin; Idiopathic ulcer; Helicobacter pylori; Glycosylation; Peptic ulcer disease; Mucosal cytoprotection
Promastigote miltefosine (MIL) susceptibility was performed on Leishmania donovani isolates from Indian patients with visceral leishmaniasis treated with MIL. Isolates that were obtained before the onset of MIL treatment, after completion of treatment (29th day), or at the time of treatment failure, were screened using in vitro promastigote assay. The MIL susceptibility of the pre-treatment isolates (N = 24, mean IC50 ± SEM = 3.74 ± 0.38 μM) was significantly higher than that of the post-treatment group (N = 26, mean IC50 ± SEM = 6.15 ± 0.52 μM; P = 0.0006) but was similar in the cured patients (N = 22, mean IC50 ± SEM = 5.58 ± 0.56 μM) and those who failed treatment (N = 28, mean IC50 ± SEM = 4.53 ± 0.47 μM). The pre/post-treatment results thus showed a 2-fold difference, whereas isolated from cured versus failed patients showed a similar susceptibility, suggesting that this higher tolerance is not responsible for MIL-treatment failure. Our work highlights the need for careful monitoring of MIL susceptibility for implementation in national VL elimination programs.
Non-selective positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) are known to impair anterograde memory. The role of the various GABAAR subtypes in the memory-impairing effects of non-selective GABAAR PAMs has not been fully elucidated. The current study assessed, in rhesus monkeys, effects of modulation of α1, α2/3, and α5GABAARs on visual recognition and spatial working memory using delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) procedures, respectively. The DMTS procedure (n=8) involved selecting a previously presented ‘sample' image from a set of multiple images presented after a delay. The SOSS procedure (n=6) involved touching a number of boxes without repeats. The non-selective GABAAR PAM triazolam and the α1GABAA preferential PAMS zolpidem and zaleplon reduced accuracy in both procedures, whereas the α5GABAA preferential PAMs SH-053-2′F-R-CH3 and SH-053-2′F-S-CH3, and the α2/3GABAA preferential PAM TPA023B were without effects on accuracy or trial completion. The low-efficacy α5GABAAR negative allosteric modulator (NAM) PWZ-029 slightly increased only DMTS accuracy, whereas the high-efficacy α5GABAAR NAMs RY-23 and RY-24 did not affect accuracy under either procedure. Finally, the slopes of the accuracy dose-effect curves for triazolam, zolpidem, and zaleplon increased with box number in the SOSS procedure, but were equivalent across DMTS delays. The present results suggest that (1) α1GABAARs, compared with α2/3 and α5GABAARs, are primarily involved in the impairment, by non-selective GABAAR PAMs, of visual recognition and visuospatial working memory in nonhuman primates; and (2) relative cognitive impairment produced by positive modulation of GABAARs increases with number of locations to be remembered, but not with the delay for remembering.
CANTAB; Cognition; delayed matching-to-sample; GABA; GABAA receptor; Learning & Memory; Psychopharmacology; Rhesus monkey; self-ordered spatial search; GABAA receptor; cognition; delayed-matching-to-sample; self-ordered spatial search; benzodiazepine; rhesus monkey