Association of Chest Pain with Rate Pressure Product and ST-segment Changes after Sub Arachnoid Block in Caesarean Section.

When healthy women undergo caesarean section (CS) under sub arachnoid anaesthesia, transient electrocardiographic changes, such as ST-segment depression and T-wave abnormalities, are observed. During an elective caesarean section under sub arachnoid anaesthesia, about one-third of healthy parturient experience chest pain and ECG changes suggestive of myocardial ischemia. To assess the ST-segment and Rate Pressure Product changes with chest pain in patients with elective caesarean section under subarachnoid block. The Department of Anesthesia, Analgesia and Intensive Care Medicine at Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh was the site of this prospective observational study. The study included 86 healthy women between the ages of 20 and 35 who needed an elective caesarean section under a single shot sub arachnoid block and who visited the Department of Anesthesia, Analgesia, and Intensive Care Medicine at BSMMU in Shahbagh, Dhaka from January 2019 to June 2019. In comparison to the no chest pain group, ST-segment changes among the chest pain group at delivery, 5 minute, 10 minute after delivery and at the end of the surgery were highly significant (p=0.001). Comparatively, Rate Pressure Product changes were found to be significantly higher in the group with chest pain than in the group without chest pain (p=0.001). It is concluded that there is a substantial association of chest pain with rate pressure product and ST-segment changes after subarachroid block in caesarean section.

Dexmedetomidine as an Adjuvant to Bupivacaine in Caudal Analgesia in Children Undergoing Infra-Umbilical Surgery.

When performing infra-umbilical procedures, caudal epidural analgesia with bupivacaine is frequently used to provide both intra- and post-operative analgesia. Dexmedetomidine, an alpha 2 agonistsare extensively used in neuraxial blocks and peripheral nerve blocks to prolong the action of bupivacaine. To find out the effects of dexmedetomidine as an adjuvant to bupivacaine for caudal analgesia in children undergoing infra-umbilical surgery. This was a randomized, controlled double-blinded prospective observational study and was performed from July 2019 to December 2019. A total of 60 (Sixty) patients with different infra-umbilical surgical problems underwent different procedure under caudal anaesthesia in different operation theatre in Bangabandhu Sheikh Mujib Medical University, Dhaka were enrolled in this study. Elaborate personal history, meticulous clinical examinations and relevant laboratory investigations was done. Post-operative adverse effects also were monitored. All information from history of illness, clinical, laboratory findings, duration of analgesia and post-operative adverse effects were recorded in a preformed data sheet (Appendix-I) and statistical analysis was done by SPSS 22.0. Mean age of the children in Group A (dexmedetomidine + bupivacaine) was 5.50±2.61 years and in Group B (bupivacaine) was 5.66±2.75. Mean weight of the children in Group A was 19.22±8.58 kg and in Group B was 19.70±8.94 kg in this study. Mean duration of anaesthesia was 27.5±6.5 minute in Group A and 28.5±5.5 minute in Group B. The mean duration of analgesia was 4.32±0.54 hours for Group A and 2.12±0.32 hours in Group B. In Group A, 46.7% patients required 1 and 3.3% required 2 rescue analgesic but in Group B, 43.3% patients required single rescue analgesic and 33.3% required two rescue analgesics (p<0.05). In Group A, 6.7% patients had nausea/ vomiting and in Group B, 16.7% patients had nausea/ vomiting (p>0.05). It can be concluded that dexmedetomidine with bupivacaine for caudal analgesia in infra-umbilical surgery significantly prolongs the duration of postoperative analgesia when compared to bupivacaine alone without any side-effects.

Evaluation of Early Renal Involvement in Essential Hypertension by Measuring Urinary Biomarkers.

Hypertensive kidney damage results in glomerular as well as tubular dysfunction. Albuminuria is a well-known marker of glomerular damage. On the other hand, urinary uromodulin is increasingly considered as a potential biomarker of early tubular dysfunction. The aim of the study was to assess glomerular and tubular function of the kidney by measuring urinary albumin and uromodulin excretion in hypertensive subjects. This cross-sectional study was conducted from July 2018 to June 2019 in Hypertension Clinic of Dhaka Medical College Hospital, Dhaka and Kidney Care and Research Centre, Sonargaon, Narayanganj, Bangladesh. In this study 122 hypertensive subjects with age >30 years, duration of hypertension <5 years, without accelerated or malignant BP, absence of dipstick proteinuria and eGFR >60ml/min were included. There were also 33 normotensive individuals included as healthy controls. Albumin-creatinine ratio (uACR mg/g), urine uromodulin-creatinine ratio (uUMODµg/g), urinary sodium-creatinine ratio (mEq/g) and potassium-creatinine ratio (mEq/g) were measured from single morning spot urine sample. Urinary uromodulin levels were measured by ELISA method. The hypertensive and normotensive subjects were age matched 49.0±12.0 vs. 48.0±11.0, years (p=NS). The mean uACR was 29.0±65.0 versus 5.6±2.7mg/g, (p<0.001) respectively. The median uUMOD in hypertensive subjects was 3.38 (1.73-9.06) and in normotensives 3.85(2.28-5.69) µg/g (p=non significant). Multivariate analysis showed significant inverse association between diastolic blood pressure and urinary uromodulin excretion. A uUMOD cut-off of 2.9 (25th percentile) showed eGFR, urinary sodium and potassium excretions were significantly lower at low uromodulin group. The glomerular involvement was found in 21.0% of hypertensive subjects as evidenced by albuminuria. No difference was observed in urinary uromodulin level between hypertensive and normotensive subjects. Low urinary uromodulin level was associated with lower eGFR, Na+ and K+ excretion which indicate simultaneous tubular and glomerular involvement.

Serum Leptin Correlates with Obesity But Does Not Differ Between Gestational Diabetes and Normal Glucose Tolerance during 24-28 Weeks of Gestation.

Leptin is an adipocytokine secreted by adipocytes which positively correlates with obesity. It is considered as a potential mediator for precipitating Gestational diabetes mellitus (GDM) which is more evident during 24-28 weeks of gestation. This study was conducted to see serum leptin level during 24-28 weeks of gestation in GDM at the Department of Endocrinology, BSMMU, Bangladesh from March 2019 to August 2020. Pregnant women (N=108) were challenged with 75gm oral glucose (OGTT) at 24-28 weeks of gestation and divided into GDM [n=45, age: 27.80±3.98 years, mean±SD; BMI: 27.88 (24.46-30.43) kg/m², median Interquartile range (IQR)] and normal glucose tolerance [NGT; n=62, age: 26.19±5.30 years, mean±SD; BMI: 25.80 (23.65-28.42) kg/m², median (IQR)] on basis of WHO-2013 diagnostic criteria. Fasting serum leptin and glucose were measured by ELISA and glucose oxidase method respectively. No statistically significant difference was found between GDM and NGT for leptin [26.05(16.92-50.55) vs. 23.50(14.95-38.30) median (IQR), p=0.360]. It was also not different statistically between GDM and NGT either for age groups (p=NS for all) or for Asian categories of BMI subgroups (p=NS for all). However, it was higher in subjects with BMI ≥23kg/m² than that with BMI ≤23kg/m² for both GDM [16.65 (6.39, 35.75) vs. 28.35 (19.60, 51.10) median (IQR), p=0.114] and NGT [14.65(9.19, 19.60) vs. 26.00 (17.30, 43.40) median (IQR), p=0.002]. It was also statistically similar in the GDM subgroups divided by Asian BMI cut-off (p=NS). BMI correlated with leptin in NGT (r=0.495, p<0.001) but not in GDM (r=0.177, p=0.251) and regression analysis revealed BMI (kg/m²) as predictor for high leptin (p=0.008). ROC curve analysis for leptin showed AUC for GDM was 0.553 (p=0.360) suggesting it as a poor predictor. It is concluded that fasting leptin in 24-28 weeks of gestation better relates with BMI but does not differ between GDM and NGT anddoes not seem to be a good predictor for GDM. Further study is required to make a comment on its prediction over GDM.

Beneficial Effect of Low Dose Aspirin in Adult Patients with COVID-19: A Retrospective Observational Study in Bangladesh.

Presently Coronavirus disease 2019 is a huge human misery that is almost unstoppable with little remedy on board. The disease is predominantly associated with inflammation and thrombosis. Although aspirin exhibits excellent anti-thrombotic and anti-inflammatory properties, it is yet to be explored in treating Covid-19 patients. In this article we want to bring forth its beneficial effect in Covid-19 case management. It is a retrospective observational study. Adult Covid-19 patients either diagnosed with RT-PCR (reverse transcriptase polymerized chain reaction), or categorized as probable cases (as per World Health Organization case definition protocol) by medical doctors were enrolled as participants. Data were collected from doctors' office records for the period ranging from May 2020 to September 2020 in six districts of Bangladesh. Out of 44 participants 42 were eligible (2 children excluded) for the study. Among them 11 participants took low dose aspirin (75mg daily) during the disease process. All participants in aspirin group became cured without complication or death (RR 2.2, 95% CI 1.5-3.2, p<0.001). On the other hand, no aspirin group suffered complications and deaths. The study findings revealed that complications were significantly low among aspirin users. It documented that low dose aspirin is beneficial for Covid-19 patients. Further study is warranted with larger sample size.

Etiology of Early Renal Allograft Dysfunction and Comparison between Dysfunction and Function Group: A Single Center Study.

Over a period of two years thirty five renal allograft recipients & donors were evaluated to find out the aetiology of early renal allograft dysfunction, in the Department of Nephrology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from March 2010 to February 2012. A comparison was made between dysfunction & functioning graft group. Mean age of recipients were (36.4±9.4) years, mean age of donors were (41.7±8.3) years, with a male and female ratio of 3:1. Fifty percent recipients showed one heliotype match, ninety percent recipients were anti CMV antibody IgG positive, few were anti CMV antibody IgM positive. All kidney transplant recipients received same immunosuppressive drugs. Primary disease of the renal allograft recipients demonstrates that majority 88.58% had glomerulonephritis, 5.72% had polycystic kidney disease, 2.85% had chronic pyelonephritis and another 2.85% had diabetic nephropathy. Among 35 renal allograft recipients 23(66%) showed early graft dysfunction, 12(34%) showed normal graft function. The etiology of early graft dysfunction showed, 50% developed acute rejection, 17% acute cyclosporine toxicity, 17% acute tubular necrosis, 8% had graft thrombosis and 8% developed recurrent glomerulonephritis. Sub-clinical rejection was detected in 20% cases. Comparison of donor characteristics between dysfunctioning and functioning graft groups revealed that age and sex were identically distributed between the groups (p=0.183 and p=0.087 respectively). The mean serum creatinine of donor was significantly higher in the graft dysfunction group than that in the functioning graft group (113.5±12.6 vs. 99.6±17.3; p=0.025), as well as the mean creatinine clearance rate was significantly less in the former group than that in the later group (82.1±13.5 vs. 93.9±18.6, p=0.040). The mean cyclosporine (C2) level on 7th POD were 1593.2±320.4ng/ml in graft dysfunction group and 1439.1±199.5ng/ml in the functioning graft group which decreased to 1364.8±263.7ng/ml and 1114.2±145.1ng/ml after three months in the dysfunction and the functioning graft groups respectively. There was no significant difference in the cyclosporine level between groups on 7th POD and 14th POD, 1st and 2nd month. However, at 3rd month the level of cyclosporine was higher in the dysfunction group than that in the function group. Proteinuria on 14th POD was almost similar between dysfunction and function graft groups (p=0.704). However, higher incidence of proteinuria was observed in subsequent months in the graft dysfunction group compared to the function graft group. All the postoperative variables like systolic blood pressure, diastolic blood pressure, fever and tremor were higher in dysfunction group in comparison to functioning graft group. Per operative biopsy of donor kidney, some showed increased number of sclerotic glomeruli which is more common in dysfunction group. Among 35 recipients 2(16.7%) died due to infection in dysfunction group compared to 1(4.3%) in functioning graft group.

Indications for and outcome of primary repair compared with faecal diversion in the management of traumatic colon injury.

AIM: Injuries of the colon are a serious sequel of abdominal trauma owing to the associated morbidity and mortality. This study aims to assess postoperative outcome and complications of faecal diversion and primary repair of colon injuries when applied according to established guidelines for the management of colon injuries. METHOD: This retrospective study was conducted on 110 patients with colon injuries. Guided by estimation of risk factors, patients were managed either by primary repair alone, repair with proximal diversion or diversion alone. RESULTS: There were 102 (92.7%) male patients and 8 (7.3%) female patients of median age 38 years. Thirty-seven were managed by primary repair and 73 by faecal diversion. Colon injuries were caused by penetrating abdominal trauma in 65 and blunt trauma in 45 patients. Forty-three patients were in shock on admission, and were all managed by faecal diversion. Forty patients developed 84 complications after surgery. Primary repair had a significantly lower complication rate than faecal diversion (P = 0.037). Wound infection was the commonest complication. The overall mortality rate was 3.6%. CONCLUSION: Primary repair, when employed properly, resulted in a significantly lower complication rate than faecal diversion. Significant predictive factors associated with a higher complication rate were faecal diversion, severe faecal contamination, multiple colon injuries, an interval of more than 12 h after colon injury and shock.

Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds.

We have developed a strategy for synthesizing passively permeable peptidomimetic macrocycles. The cyclization chemistry centers on using aziridine aldehydes in a multicomponent reaction with peptides and isocyanides. The linker region in the resulting product contains an exocyclic amide positioned α to the peptide backbone, an arrangement that is not found among natural amino acids. This amide provides structural rigidity within the cyclic peptidomimetic and promotes the creation of a stabilizing intramolecular hydrogen bonding network. This exocyclic control element also contributes to the increased membrane permeability exhibited by multicomponent-derived macrocycles with respect to their homodetic counterparts. The exocyclic control element is employed along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which contain multiple polar residues. This strategy should be applicable in the pursuit of synthesizing therapeutically relevant macrocycles.

Zika virus, an emerging flavivirus, as a cause of fever and rash in a traveller returning from Central America.

Fever in a returning traveller is a common clinical scenario for physicians in primary and acute care. Differential diagnoses for these patients are generated based on presenting clinical symptoms, travel destinations, potential exposure activities as well as the incubation period of common etiologic agents. In a case of fever and rash in a woman returning to Canada from El Salvador in November 2015, measles, dengue and chikungunya viral infections were queried as possible causes. Subsequent molecular testing using amplification of conserved regions of the flavivirus genome from nasopharyngeal and urine samples was positive, suggesting an active flavivirus infection. Sequencing was significant for the identification of Zika virus, a flavivirus that has only recently become endemic to Brazil and is now emerging throughout Central America. Zika virus should now be included in the differential diagnosis for travelers returning from Central and South America with a febrile illness and rash. To our knowledge this is the first reported case of Zika virus in Canada related to the most recent outbreak in Central America, South America and the Caribbean.

Thrombotic Thrombocytopenic Purpura: Issues in Diagnosis and Treatment.

Thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency fatal without prompt treatment. Plasma exchange (PEX), the treatment of choice for TTP, is not readily available and has major complications. We report seven cases of TTP, both acquired immune and secondary. Two patients had TTP secondary to malignancy and one secondary to SLE. Male to female ratio was 1:3 and median age at presentation 38 years. Six patients had moderate to very high level of LDH while one primary TTP had only mild elevation. Median haemoglobin and platelet at presentation were 6.3 gm/dL and 38 k/UL respectively. Median LDH value was 4595 u/L. All patients were treated with plasma exchange (PEX) except the two cases secondary to malignancy. One patient died of cardiac arrest during plasma exchange. None of the patients treated with PEX had relapsed over a median follow up of 18 months.

Parathyroid Carcinoma in a 10 Years Old Female Child.

Parathyroid carcinoma (PC) is a rare cause of hypercalcaemia in children. Only 7 cases of PC have been reported so far in the world journal. The authors report the 8th case of parathyroid carcinoma in children less than 16 years of age. A 10 year old girl presented with difficulty in walking, dorsiflexion and ulnar deviation of both wrist joints and occasional pain in the central abdomen of about two years duration. Biochemical investigations revealed serum calcium 12.2 mg/dL (normal 9-11 mg/dL), serum alkaline phosphate 4992 U/L (normal 50-136 U/L), PTH (parathyroid hormone) 2217 pg/ml (normal 9-80 pg/ml). Parathyroid scintigraphy localized the lesion in the left parathyroid gland. X-ray showed bilateral coxa vera, genu valgus deformity and multiple stress fractures in both wrist joints. Histopathology confirmed PC with capsular and vascular invasion.

Basophils exhibit antibacterial activity through extracellular trap formation.

Basophils are primarily associated with immunomodulatory functions in allergic diseases and parasitic infections. Recently, it has been demonstrated that both activated human and mouse basophils can form extracellular DNA traps (BETs) containing mitochondrial DNA and granule proteins. In this report, we provide evidence that, in spite of an apparent lack of phagocytic activity, basophils can kill bacteria through BET formation.

Enteropathogenic Escherichia coli (EPEC): Does it have a role in colorectal tumourigenesis? A Prospective Cohort Study.

BACKGROUND: Despite the characterization of many aetiologic genetic changes. The specific causative factors in the development of sporadic colorectal cancer remain unclear. This study was performed to detect the possible role of Enteropathogenic Escherichia coli (EPEC) in developing colorectal carcinoma. PATIENTS AND METHOD: Fresh biopsy specimens have been obtained from the colonic mucosa overlying the colorectal cancer as well as from the colon of the healthy controls. Culture, genotyping and virulence of EPEC were done using (nutrient broth culture, and PCR). Strains biochemically identified as Escherichia coli were selected from the surface of a MacConkey's plate and were serogrouped by slide agglutination tests. RESULTS: From January 2011 to June 2014, 213 colorectal cancer patients (Group 1) and 248 healthy controls (Group 2) were prospectively enrolled in this study. EPEC was positive in 108 (50.7%) in group 1 and 51 (20.6%) in group 2 (P = 0.0001). A significant difference between both groups was observed regarding serotyping, genotyping (eae gene) and virulence category (P = 0.0001). A significant difference between the 2 subgroups of colorectal cancer cases was observed regarding genotyping (eae, bfb genes) and virulence category. CONCLUSION: The incidence EPEC was higher significantly in patients with colorectal cancer. E. coli in patients with colorectal cancer significantly differed serotypically and genotypically from the E. coli in normal population. E. coli colonization of the colonic mucosa may be a cause colorectal cancer.

Epitope-based peptide vaccine design and target site depiction against Ebola viruses: an immunoinformatics study.

Ebola viruses (EBOVs) have been identified as an emerging threat in recent year as it causes severe haemorrhagic fever in human. Epitope-based vaccine design for EBOVs remains a top priority because a mere progress has been made in this regard. Another reason is the lack of antiviral drug and licensed vaccine although there is a severe outbreak in Central Africa. In this study, we aimed to design an epitope-based vaccine that can trigger a significant immune response as well as to prognosticate inhibitor that can bind with potential drug target sites using various immunoinformatics and docking simulation tools. The capacity to induce both humoral and cell-mediated immunity by T cell and B cell was checked for the selected protein. The peptide region spanning 9 amino acids from 42 to 50 and the sequence TLASIGTAF were found as the most potential B and T cell epitopes, respectively. This peptide could interact with 12 HLAs and showed high population coverage up to 80.99%. Using molecular docking, the epitope was further appraised for binding against HLA molecules to verify the binding cleft interaction. In addition with this, the allergenicity of the epitopes was also evaluated. In the post-therapeutic strategy, docking study of predicted 3D structure identified suitable therapeutic inhibitor against targeted protein. However, this computational epitope-based peptide vaccine designing and target site prediction against EBOVs open up a new horizon which may be the prospective way in Ebola viruses research; the results require validation by in vitro and in vivo experiments.

Dopamine-ß-Hydroxylase Activity and Levels of Its Cofactors and Other Biochemical Parameters in the Serum of Arsenicosis Patients of Bangladesh.

Dopamine-ß-hydroxylase (DBH) is a neurotransmitter (catecholamine)-mediating enzyme, which catalyzes the formation of norepinephrine from dopamine. The levels of DBH activity, its coenzyme (ascorbic acid) and cofactor (Cu(++)) and other biochemical parameters were measured in the serum of 32 arsenicosis patients of Bangladesh at three different age groups, namely, group 1 (10-18 years, 9 patients), group 2 (19-40 years, 14 patients) and group 3 (41-70 years, 9 patients) of the locality of Stadium Para of Meherpur district of Bangladesh. The values were compared with the same number of age-matched normal healthy individuals of the respective group. DBH activity was markedly decreased in the patients of group 1 as compared to that of the normal healthy people. The activities of DBH were decreased to lesser extents for the other two age groups. The total protein contents in the serum of arsenicosis patients were also significantly low as compared to that in the age-matched control groups. The levels of ascorbic acid and copper were found to be decreased in the serum of arsenicosis patients. The serum glucose levels were elevated in arsenicosis patients, as compared to that of the respective healthy controls. Other parameters, such as zinc and vitamin A levels were also decreased in the serum of arsenicosis patients. It was evident from the results of drinking of the arsenic contaminated water of shallow tube wells that the levels of DBH activity decreased significantly as compared to the control healthy persons. The levels of proteins, ascorbic acid, copper, zinc and vitamin A were decreased in the serum of people drinking the arsenic contaminated tube wells water as compared to that in the control healthy people with the exception that the levels of glucose were elevated in the serum of these patients. The pathophysiological significance of the results could be correlated with the decreased in proteins and that in DBH activities as DBH deficiency is characterized by lack of sympathetic noradrenergic function.The general physiologic findings of autonomic function indicate that complete DBH deficiency include minimal or absent plasma norepinephrine and epinephrine.

Rearrangement of 4-amino-3-halo-pyridines by nucleophilic aromatic substitution.

The reaction of 3-halo-4-aminopyridines with acyl chlorides and triethylamine is described. The pyridin-4-yl α-substituted acetamide products were obtained in moderate to high yields. The presented rearrangement reaction, in which the presumed N-acylated intermediate reacts intramolecularly via nucleophilic aromatic substitution, results in a formal two-carbon insertion.

A case of Conn's syndrome presenting with painfull muscular weakness.

We present a case of 30-year-old lady presenting with gradual difficulty in standing up from sitting position for 6 months, pain in arms and thighs, tingling sensation and numbness in palms and soles, increased fluid intake and increased frequency of micturition for the same duration. She was hypertensive for 12 years. On general examination patient seemed depressed and on nervous system examination her power of muscles in both upper and lower limb of both side was 3/5. Plasma sodium at the upper normal range 144mmol/l (normal range 135-146), lower level of serum potassium 1.7mmol/L (normal range 3.5-5.0), high urinary potassium 26.7mmol/l (normal range 1-10), very high serum CPK 4269U/L (for female normal range 10-79), low normal plasma rennin 1.58mg/ml/hr (normal range standing 0.40-8.80, supine 0.30-3.0), high serum aldosterone 1326.39pg/ml (normal range 25-315), high pH 7.45 (normal range 7.36-7.44) and on imaging evidence of an adrenal adenoma on left side was found and the patient was diagnosed as a case of Conn's syndrome.

Otitis interna induced by Cryptococcus neoformans var. grubii in a cat.

Cryptococcus neoformans var. grubii was identified at necropsy in a case of bilateral otitis interna in a 7-year-old, female, domestic shorthair cat with a 9-day history of acute onset of vestibular disease. Gross examination, including that of the middle and inner ears, was unremarkable. Histologically, the auricular vestibuli, cochleae, and semicircular canals were bilaterally affected by granulomatous inflammation with extracellular and intrahistiocytic yeasts. The yeasts and associated inflammation obstructed and disrupted perilymphatic and endolymphatic spaces of the inner ears. Disruption of the saccular and utricular maculae, cristae ampularis, and organ of Corti, as well as changes in the endolymphatic and perilymphatic fluids, probably impaired the vestibular and auditory functions of this cat. The route of infection was most likely hematogenous.

Thymic stromal lymphopoietin stimulates the formation of eosinophil extracellular traps.

BACKGROUND: Thymic stromal lymphopoietin (TSLP) that is released by epithelial cells upon certain environmental triggers activates cells of the innate and adaptive immune system resulting in a preferential T helper 2 immune response. By releasing eosinophil extracellular traps (EETs), eosinophils achieve an efficient extracellular bacterial killing. Eosinophil extracellular traps release, however, has been observed in both infectious and noninfectious eosinophilic diseases. Here, we aim to investigate whether eosinophils generate functional EETs as a direct response to TSLP, and further to study the extra- and intracellular mechanisms involved in this process as well as TSLP receptor (TSLPR) expression by eosinophils in vitro and in vivo. METHODS: Thymic stromal lymphopoietin receptor expression on blood and tissue eosinophils was assessed by immunoblotting, flow cytometry, and immunofluorescence staining. Purified eosinophils were stimulated with recombinant human TSLP. The release of extracellular DNA in association with eosinophilic cationic protein (ECP) was detected by fluorescence staining techniques and confocal microscopy. In addition, cell survival, cell adhesion, production of reactive oxygen species (ROS), and the inhibition of bacterial growth by TSLP-stimulated eosinophils were measured. RESULTS: Thymic stromal lymphopoietin receptor was observed on peripheral blood eosinophils as well as on tissue infiltrating eosinophils in skin diseases. TSLP did not affect eosinophil survival, but induced the formation of EETs consisting of mitochondrial DNA in association with ECP in a concentration- and time-dependent manner. Eosinophil extracellular trap release could be inhibited by blocking either cell adhesion or ROS production. While eosinophils prevented the growth of both Staphylococcus aureus and Staphylococcus epidermidis, the latter were unable to elicit EET formation and eosinophils required additional TSLP stimulation to achieve this antibacterial activity. CONCLUSIONS: thymic stromal lymphopoietin directly stimulates eosinophils to produce EETs. Our observations link epithelial TSLP expression triggered by environmental factors with pathogen defense mechanisms involving eosinophils.

Design and synthesis of novel bone-targeting dual-action pro-drugs for the treatment and reversal of osteoporosis.

There is an important medical need for effective therapies to redress the general bone loss associated with advanced osteoporosis. Prostaglandin E(2) and related EP4 receptor agonists have been shown to stimulate bone regrowth but their use has been limited by systemic side effects. Herein is described the design and synthesis of novel dual-action bone-targeting conjugate pro-drugs where two classes of active agents, a bone growth stimulating prostaglandin E(2) EP4 receptor subtype agonist (5 or 6) and a bone resorption inhibitor bisphosphonate, alendronic acid (1), are coupled using metabolically labile carbamate or 4-hydroxyphenylacetic acid based linkers. Radiolabelled conjugates 9, 11a/b and 25 were synthesized and evaluated in vivo in rats for uptake of the conjugate into bone and subsequent release of the EP4 agonists over time. While conjugate 11a/b was taken up (9.0% of initial dose) but not released over two weeks, conjugates 9 and 25 were absorbed at 9.4% and 5.9% uptake of the initial dose and slowly released with half-lives of approximately 2 weeks and 5 days respectively. These conjugates were well tolerated and offer potential for sustained release and dual synergistic activity through their selective bone targeting and local release of the complimentary active components.