Synthesis and biological evaluation of orally active anti-Trypanosoma agents.

In previous studies, we developed anti-trypanosome tubulin inhibitors with promising in vitro selectivity and activity against Human African Trypanosomiasis (HAT). However, for such agents, oral activity is crucial. This study focused on further optimizing these compounds to enhance their ligand efficiency, aiming to reduce bulkiness and hydrophobicity, which should improve solubility and, consequently, oral bioavailability. Using Trypanosoma brucei brucei cells as the parasite model and human normal kidney cells and mouse macrophage cells as the host model, we evaluated 30 new analogs synthesized through combinatorial chemistry. These analogs have fewer aromatic moieties and lower molecular weights than their predecessors. Several new analogs demonstrated IC50s in the low micromolar range, effectively inhibiting trypanosome cell growth without harming mammalian cells at the same concentration. We conducted a detailed structure-activity relationship (SAR) analysis and a docking study to assess the compounds' binding affinity to trypanosome tubulin homolog. The results revealed a correlation between binding energy and anti-Trypanosoma activity. Importantly, compound 7 displayed significant oral activity, effectively inhibiting trypanosome cell proliferation in mice.

Dysfunction of Thyroid Hormones Following Acute Coronary Syndrome in a Tertiary Care Hospital in Dhaka City.

In cardiovascular homeostasis thyroid hormone plays an important role. We planned to study the changes in thyroid hormone profile in acute coronary syndrome patients admitted in the coronary care unit and compare them between two groups: unstable angina/non-ST elevated Myocardial infarction (UA/NSTEMI) and ST elevated Myocardial infarction (STEMI). This study was a hospital based descriptive cross sectional study which was conducted from 01 March 2018 to 01 February 2019 in Coronary Care Unit of Bangladesh Medical College Hospital and laboratory tests were done in Microbiology Department of Bangladesh Medical College, Dhaka, Bangladesh. Eighty three cases of acute coronary syndromes were taken for the study. Troponin-I was measured as cardiac marker, Electrocardiogram, Complete blood count, blood glucose level, Blood urea, serum creatinine, serum electrolytes, Fasting lipid profile, Thyroid profile, Echocardiography 2D were done. Most of the respondents were distributed in age group 46-60 years where 34(64.15%) male and 19(35.85%) female. Out of 83 Acute Coronary Syndrome (ACS) patients, 27(32.53%) hypertensive, 22(26.50%) diabetic and 16(19.27%) were Chronic kidney disease (CKD). Abnormal lipid profile was present in 30(43.47%) patients. Among total 52 male and 31 female 9(17.30%) male and 6(19.35%) female had abnormal thyroid function. We further elaborated abnormal thyroid function tests in STEMI group and UA/Non STEMI group of ACS patients. We found 10 patients in STEMI group and 5 patients in UA/Non STEMI group with abnormal thyroid function 29.41% and 10.20% respectively which was not statistically significant (p=0.025). This study depicts abnormality in thyroid hormone profile in 18.07% patients of ACS. Abnormal thyroid function increases risk of coronary artery disease. TSH level of ACS patients on hospital admission could be helpful to evaluate further prognosis of the disease.

Pattern and Predictors of Infection Among Patients With Rheumatological Disease on Immunosuppressive Medications: A Retrospective Study in a Tertiary Care Hospital in Bangladesh.

Background Immunomodulatory therapy for chronic rheumatic disease carries a risk for infectious complications. In Bangladesh, there is limited information regarding patterns and factors associated with infections among patients receiving immunosuppressive medications. Objective The present study aimed to find out patterns and predictors associated with infection among patients who were on different immunosuppressive medications due to chronic rheumatological disease. Methodology This was a retrospective study; all confirmed cases of (new and old) different rheumatological diseases on disease-modifying agents attended at the rheumatology clinic of Dhaka Medical College Hospital from January 2019 to December 2021 were enrolled. Result Among 489 cases, 90 (18.4%) patients had documented infections. The most common rheumatological diseases were systemic lupus erythematosus (28, 31.1%), ankylosing spondylitis (26, 28.8%), and rheumatoid arthritis (20, 22.2%). COVID-19 (28, 31.1%) was the most commonly occurring infection followed by urinary tract infection (14, 15.6%), fungal infection (12, 13.3%), herpes zoster (10, 11.1%), pulmonary tuberculosis (TB) (eight, 8.8%), latent TB (seven, 7.7%), community-acquired pneumonia (six, 6.6%), and sepsis (three, 3.3%). Infection was most prevalent among patients who received steroids of more than 10 mg per day (17, 18.8%) than those less than 10 mg steroid per day (six, 6.7%), Factors associated with infections were (odds ratio, 95% CI, p-value) underweight (2.3, [1.3-2.7], 0.001), anemia (1.8, [1.1-5.7], 0.01), neutropenia (1.6, [1.1-2.9], <0.002), hypoalbuminemia (3.1, [1.6-4.9], 0.001), hypovitaminosis D (1.9, [1.3-4.5], 0.001), high blood sugar (1.5, [1.1-5.3], 0.02), inadequate counseling of steroid side effect (1.7, [1.1-3.9], 0.03), prednisolone >10mg/day (2.2, [1.19-4.10], 0.001). Conclusion COVID-19 pneumonia, urinary tract infections, fungal infection, tuberculosis, herpes zoster, and community-acquired pneumonia were commonly occurring infections among patients receiving different immunosuppressive medications. Factors like poor nutritional status, presence of anemia, leucopenia, hypoalbuminemia, hyperglycemia, and hypovitaminosis D had a significant association with infection. Moreover, inadequate counseling of steroid side effects and history of daily intake of prednisolone (>10mg/day) were also significant factors associated with infection.

Wound Infection in Surgical Ward of a Tertiary Care Hospital in Dhaka City: The Identification of Organisms and Their Sensitivity Pattern.

Wound infection is one of the most important causes of morbidity and mortality worldwide. The aim of this study was to identify the organisms and their sensitivity pattern from wound infection patients attending in a tertiary care hospital in Dhaka city. This cross-sectional study was carried out in a total of 240 aseptically collected wound swab samples from wound infection suspected patients visiting Bangladesh Medical College Hospital, Dhaka, Bangladesh were analyzed from July 2017 to June 2019. Bacteriological culture of the samples, colony morphology, Gram's staining, and biochemical tests were done following standard microbiological techniques. The antimicrobial susceptibility testing was performed by modified Kirby-Bauer disc diffusion technique following clinical and laboratory standards institute guidelines. Out of 240 wound swab samples from suspected patients of wound infection, 126(52.5%) showed bacterial growth whereas 114(47.5%) were culture negative. No sample yielded more than one organism. Among 126 culture positive cases 75(59.52%) were male and 51(40.48%) were female. The higher rate of bacterial infections 26.19% was noted in the age group of 21-30 years, followed by the age group of 31-40 years, 41-50 years, 51-60 years. Among 126 culture positive cases, 74.6% were Gram negative and 25.4% were Gram positive bacteria. Out of total 126 isolates, E. coli was the most prevalent pathogen 31(24.60%) followed by Staphylococcus aureus 29(23.01%); Pseudomonas 27(21.43%); Klebsiella 18(14.29%); Enterobacter 12(9.52%); Acinetobacter 4(3.17%), while Coagulase negative Staphylococcus 3(2.38%) and Proteus 2(1.59%) were least detected isolates in wound swab. Highly effective antibiotics against Staph aureus were vancomycin 100.0%; imipenem 100.0%; linezolid 100.0% and meropenem 89.65%. Amikacin; gentamicin; netilmicin; imipenem and meropenem showed higher sensitivity in E coli, Klebsiella and Enterobacter species. Colistin was 88.88% effective against Pseudominas spp. followed by imipenem 81.48%, piperacillin-tazobactam 77.78%, meropenem 70.37% and amikacin 51.85%. Acinetobacter spp. showed 75.0% and 50.0% sensitivity to netilmicin and colistin respectively. Injectable and reserve drugs were sensitive to bacterial populations among patients of wound infections in our hospital. It is a wake-up call for clinician to treat wound infections. To prevent the increase resistance to antibiotics, it is necessary to avoid the administration of uncontrolled and unnecessary antibiotics available.

Difference in presentation, outcomes, and hospital epidemiologic trend of COVID-19 among first, second, and third waves: a review of hospital records and prospective cohort study.

This study aimed to examine the differences in epidemiologic and disease aspects among patients with coronavirus disease-19 (COVID-19). Methods: The authors reviewed the hospital records between April 2020 and September 2021 and followed up on the patients for post-COVID complications. Findings: Older adult patients were predominantly affected during the third wave, and middle-aged patients were predominantly affected during the first and second waves. Men were predominantly admitted, considering the three waves, although more women were admitted in the second wave. Cough was more common in the second and third waves than in the first wave 522 (59.7%). Respiratory distress was the most common in the third wave, 251(67.1%), and least common in the first wave, 403 (46.1%). Anosmia was more common in the third wave 116 (31.2%). In the third wave, patients presenting in a critical state 23 (6.2%) and with severe disease 152 (40.8%) were more common. The hospital admission median (IQR) was longer in the first wave, 12 (8-20), than in other waves. More patients were admitted in the first wave (52%) than in the other waves, and patients received more oxygen in the third wave (75%) than in the other waves. Death occurred more commonly in the first wave (51%) than in the other waves. The positivity rate was higher in the third wave (22.8%) than in the other waves. In the third wave, the positivity rate was higher in women (24.3%) than in men. Post-COVID cough increased in the second wave, and fatigue was higher in the third wave than in the other waves. Tiredness and memory loss were greater during the second wave than in other waves. Conclusion: The authors found differences in the presentation, outcomes, and hospital epidemiologic trend of COVID-19 among the three waves.

Clinicopathological Patterns of Malignant Solid Tumors in Adult Patients: A Hospital-Based Study From Bangladesh.

BACKGROUND: Solid malignant tumors are abnormal masses of tissue that usually do not contain any cysts or liquid areas. The causation of these tumors is multifactorial, and the disease process differs at different sites. AIM: This study aims to determine the clinicopathological patterns of malignant solid tumors in adult patients admitted into the department of internal medicine of a tertiary care hospital in Bangladesh. METHOD: This cross-sectional study was conducted between January 2018 and June 2018 at the Department of Medicine, Dhaka Medical College Hospital, Bangladesh. We recorded the complete socio-demographic characteristics, clinical patterns, and pathological characteristics of malignant solid tumors in adult patients. RESULTS: A total of 100 patients with confirmed malignant solid tumors were included in our study. The mean age of the patients was 47.5 years (SD: ±4.20); most of them (27%) were between 58 and 67 years of age. Male patients constitute 59% of the total study sample. Most of the patients were of the middle socio-economic class (59%) and most of them (61%) were nonsmokers. Among the patient diagnoses, 19% had lung cancer, 29.27% had breast cancer, and in 14%, lymphoma (tumor arising from the lymphatic system) was the common solid tumor. Lung cancer was found to be the most common form of cancer in males. Additionally, the majority of those diagnosed with lung cancer smoked. Breast cancer was found to be the most common type of cancer in females. CONCLUSION: This study reflects that solid malignant tumors can affect any socio-economic class of people. Based on findings in our study as well as others, prevention efforts should focus on the reduction in tobacco use and the incorporation of other lifestyle changes, such as diet modification and exercise. Additionally, the incorporation of economic factors and how they affect cancer presentation in different contexts is crucial.

The RRM-mediated RNA binding activity in T. brucei RAP1 is essential for VSG monoallelic expression.

Trypanosoma brucei is a protozoan parasite that causes human African trypanosomiasis. Its major surface antigen VSG is expressed from subtelomeric loci in a strictly monoallelic manner. We previously showed that the telomere protein TbRAP1 binds dsDNA through its 737RKRRR741 patch to silence VSGs globally. How TbRAP1 permits expression of the single active VSG is unknown. Through NMR structural analysis, we unexpectedly identify an RNA Recognition Motif (RRM) in TbRAP1, which is unprecedented for RAP1 homologs. Assisted by the 737RKRRR741 patch, TbRAP1 RRM recognizes consensus sequences of VSG 3'UTRs in vitro and binds the active VSG RNA in vivo. Mutating conserved RRM residues abolishes the RNA binding activity, significantly decreases the active VSG RNA level, and derepresses silent VSGs. The competition between TbRAP1's RNA and dsDNA binding activities suggests a VSG monoallelic expression mechanism in which the active VSG's abundant RNA antagonizes TbRAP1's silencing effect, thereby sustaining its full-level expression.

Para Kala-Azar Dermal Leishmaniasis: A Case Report.

Rarely, post-kala-azar dermal leishmaniasis (PKDL) may coexist with visceral leishmaniasis (VL). The concomitant PKDL and VL are referred to as Para-kala-azar dermal Leishmaniasis. We report a case of Para kala-azar dermal leishmaniasis in a chronic Hepatitis-B virus-infected patient who presented with an abdominal lump and multiple maculopapular skin lesions and is resistant to sodium stibogluconate but successfully treated with liposomal Amphotericin-B.

Systemic lupus erythematosus with acute ischemic optic neuropathy complicated with neuromyelitis optica: a case report.

BACKGROUND: Neuromyelitis optica is a relapsing-remitting disease characterized by a recurrent attack of optic neuritis and transverse myelitis; sometimes associated with acute brainstem syndrome. Systemic lupus erythematosus is an autoimmune multisystem disorder in which ocular involvement such as acute ischemic optic neuropathy is a rare manifestation. However, neuromyelitis optica can be associated with systemic lupus erythematosus. CASE PRESENTATION: A 24-year-old Bangladeshi woman was admitted to the hospital with complaints of sudden, progressive, painless vision loss in both eyes, and progressive weakness in both lower limbs for 48 hours. She also gave a history of arthralgia, a photosensitive skin rash, intermittent fever, oral ulcerations, and alopecia for the last 2 months. On examination, the fundus was suggestive of bilateral acute ischemic neuropathy, and examinations of the lower limb revealed spastic paraparesis with sensory abnormality. Laboratory investigations revealed the presence of positive anti-aquaporin 4 antibody, strongly positive antinuclear antibody, and anti-ds DNA with the longitudinally extensive lesion on magnetic resonance imaging of the spinal cord. She was treated with methylprednisolone, hydroxychloroquine, and mycophenolate, and was discharged with improvement of her paraparesis. However, her vision did not improve substantially. CONCLUSION: The importance of this report is to shed some light on the occurrence of two devastating complications that is, bilateral acute ischemic optic neuropathy in systemic lupus erythematosus complicated by neuromyelitis optica, as well as evidence of rare presentations for systemic lupus erythematosus and treatment modalities of ischemic optic neuropathy with systemic lupus erythematosus.

Acute Hemorrhagic Leucoencephalitis (AHLE): A Rare CNS Presentation of Mycoplasma pneumoniae.

Acute hemorrhagic leucoencephalitis (AHLE) is a rare inflammatory disease of the brain. Literature on the presentation and management of this rare disease is limited. A Mycoplasma pneumoniae infection is considered a possible trigger for acute hemorrhagic leucoencephalitis (Weston-Hurst syndrome). We report a case of a 58-year-old man presenting with an altered level of consciousness following a history of acute respiratory tract infection. He had also clinical and laboratory features of disseminated intravascular coagulation (DIC). Brain imaging was suggestive of hemorrhagic encephalitis involving both the fronto-temporo-parieto-occipital lobes involving the cortical, subcortical, and splenium of the corpus callosum and the posterior limb of the right internal capsule. Antibodies against Mycoplasma were strongly positive in serum. The patient was treated with fresh frozen plasma, broad-spectrum antibiotics, and methylprednisolone. However, the patient died after 17 days of hospitalization probably due to multiorgan failure and brain herniation.

Health hazards related to using masks and/or personal protective equipment among physicians working in public hospitals in Dhaka: A cross-sectional study.

BACKGROUND: Wearing masks or personal protective equipment (PPE) has become an integral part of the occupational life of physicians due to the coronavirus disease 2019 (COVID-19) pandemic. Most physicians have been developing various health hazards related to the use of different protective gears. This study aimed to determine the burden and spectrum of various health hazards associated with using masks or PPE and their associated risk factors. METHODS: This cross-sectional survey was conducted in Dhaka Medical College from March 01-May 30, 2021, among physicians from different public hospitals in Dhaka, Bangladesh. We analyzed the responses of 506 physicians who completed case record forms through Google forms or hard copies. FINDINGS: The mean (SD) age of the respondents was 35.4 [7.7], and 69.4% were men. Approximately 40% were using full PPE, and 55% were using N-95 masks. A total of 489 (96.6%) patients experienced at least one health hazard. The reported severe health hazards were syncope, severe dyspnea, severe chest pain, and anaphylaxis. Headache, dizziness, mood irritation, chest pain, excessive sweating, panic attack, and permanent facial disfigurement were the minor health hazards reported. Extended periods of work in the COVID-19-unit, reuse of masks, diabetes, obesity, and mental stress were risk factors for dyspnea. The risk factors for headaches were female sex, diabetes, and previous primary headaches. Furthermore, female sex and reusing masks for an extended period (> 6 h) were risk factors for facial disfigurement. The risk factors for excessive sweating were female sex and additional evening office practice for an extended period. CONCLUSIONS: Healthcare workers experienced several occupational hazards after using masks and PPE. Therefore, an appropriate policy is required to reduce such risks.

Acute Ischemic Stroke With Central Retinal Artery Occlusion as a Rare Presentation of COVID-19 Disease.

In this report, we present a case where the patient developed a border-zone ischemic stroke with central retinal artery occlusion (RAO) following coronavirus disease 2019 (COVID-19) disease. The COVID-19 disease has been described to induce inflammatory changes that predispose to thrombotic disease in both venous and arterial circulation. Angiotensin-converting enzyme 2 (ACE2) receptor expression in the blood vessel with which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds is the cornerstone of inflammation although the pathogenesis of central RAO is multifactorial. The effects of COVID-19 inflammatory and pro-coagulant state on cerebral and retinal vascular systems are still inadequately understood. Combined presentation of central RAO with ischemic stroke has not been documented in the literature yet. As of now, no guidelines exist regarding treatment modalities to be employed in such instances. Hence, further research is warranted regarding the treatment of this condition with respect to the association with COVID-19.

Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial.

OBJECTIVE: We evaluated whether ivermectin combined with doxycycline reduced the clinical recovery time in adults with COVID-19 infection. METHODS: This was a randomized, blinded, placebo-controlled trial in patients with mild-to-moderate COVID-19 symptoms randomly assigned to treatment (n = 200) and placebo (n = 200) groups. The primary outcome was duration from treatment to clinical recovery. Secondary outcomes were disease progression and persistent COVID-19 positivity by RT-PCR. RESULTS: Among 556 screened patients, 400 were enrolled and 363 completed follow-up. The mean patient age was 40 years, and 59% were men. The median recovery time was 7 (4-10, treatment group) and 9 (5-12, placebo group) days (hazard ratio, 0.73; 95% confidence interval, 0.60-0.90). The number of patients with a ≤7-day recovery was 61% (treatment group) and 44% (placebo groups) (hazard ratio, 0.06; 95% confidence interval, 0.04-0.09). The proportion of patients who remained RT-PCR positive on day 14 and whose disease did not progress was significantly lower in the treatment group than in the placebo group. CONCLUSIONS: Patients with mild-to-moderate COVID-19 infection treated with ivermectin plus doxycycline recovered earlier, were less likely to progress to more serious disease, and were more likely to be COVID-19 negative by RT-PCR on day 14. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04523831. DATA REPOSITORY ID: Dryad. doi:10.5061/dryad.qjq2bvqf6.

Association of ABO blood groups with presentation and outcomes of confirmed SARS CoV-2 infection: A prospective study in the largest COVID-19 dedicated hospital in Bangladesh.

BACKGROUND: Globally, studies have shown conflicting results regarding the association of blood groups with SARS CoV-2 infection. OBJECTIVE: To observe the association between ABO blood groups and the presentation and outcomes of confirmed COVID-19 cases. DESIGN, SETTING, AND PARTICIPANTS: This was a prospective cohort study of patients with mild-to-moderately severe COVID-19 infections who presented in the COVID-19 unit of Dhaka Medical College Hospital and were enrolled between 01 June and 25 August, 2020. Patients were followed up for at least 30 days after disease onset. We grouped participants with A-positive and A-negative blood groups into group I and participants with other blood groups into group II. RESULTS: The cohort included 438 patients; 52 patients were lost to follow-up, five died, and 381 completed the study. The prevalence of blood group A [144 (32.9%)] was significantly higher among COVID-19 patients than in the general population (p < 0.001). The presenting age [mean (SD)] of group I [42.1 (14.5)] was higher than that of group II [38.8 (12.4), p = 0.014]. Sex (p = 0.23) and co-morbidity (hypertension, p = 0.34; diabetes, p = 0.13) did not differ between the patients in groups I and II. No differences were observed regarding important presenting symptoms, including fever (p = 0.72), cough (p = 0.69), and respiratory distress (p = 0.09). There was no significant difference in the median duration of symptoms in the two group (12 days), and conversion to the next level of severity was observed in 26 (20.6%) and 36 patients (13.8%) in group I and II, respectively. However, persistent positivity of RT-PCR at 14 days of initial positivity was more frequent among the patients in group I [24 (19%)] than among those in group II [29 (11.1%)]. CONCLUSIONS: The prevalence of blood group A was higher among COVID-19 patients. Although ABO blood groups were not associated with the presentation or recovery period of COVID-19, patients with blood group A had delayed seroconversion.

Post-COVID-19 syndrome among symptomatic COVID-19 patients: A prospective cohort study in a tertiary care center of Bangladesh.

BACKGROUND: Post-coronavirus disease (COVID-19) syndrome includes persistence of symptoms beyond viral clearance and fresh development of symptoms or exaggeration of chronic diseases within a month after initial clinical and virological cure of the disease with a viral etiology. We aimed to determine the incidence, association, and risk factors associated with development of the post-COVID-19 syndrome. METHODS: We conducted a prospective cohort study at Dhaka Medical College Hospital between June 01, 2020 and August 10, 2020. All the enrolled patients were followed up for a month after clinical improvement, which was defined according the World Health Organization and Bangladesh guidelines as normal body temperature for successive 3 days, significant improvement in respiratory symptoms (respiratory rate <25/breath/minute with no dyspnea), and oxygen saturation >93% without assisted oxygen inhalation. FINDINGS: Among the 400 recruited patients, 355 patients were analyzed. In total, 46% patients developed post-COVID-19 symptoms, with post-viral fatigue being the most prevalent symptom in 70% cases. The post-COVID-19 syndrome was associated with female gender (relative risk [RR]: 1.2, 95% confidence interval [CI]: 1.02-1.48, p = 0.03), those who required a prolonged time for clinical improvement (p<0.001), and those showing COVID-19 positivity after 14 days (RR: 1.09, 95% CI: 1.00-1.19, p<0.001) of initial positivity. Patients with severe COVID-19 at presentation developed post-COVID-19 syndrome (p = 0.02). Patients with fever (RR: 1.5, 95% CI: 1.05-2.27, p = 0.03), cough (RR: 1.36, 95% CI: 1.02-1.81, p = 0.04), respiratory distress (RR: 1.3, 95% CI: 1.4-1.56, p = 0.001), and lethargy (RR: 1.2, 95% CI: 1.06-1.35, p = 0.003) as the presenting features were associated with the development of the more susceptible to develop post COVID-19 syndrome than the others. Logistic regression analysis revealed female sex, respiratory distress, lethargy, and long duration of the disease as risk factors. CONCLUSION: Female sex, respiratory distress, lethargy, and long disease duration are critical risk factors for the development of post-COVID-19 syndrome.

Ethics and professionalism education during neonatal-perinatal fellowship training in the United States.

OBJECTIVE: The objectives of this study were to determine the perceived adequacy of ethics and professionalism education for neonatal-perinatal fellows in the United States, and to measure confidence of fellows and recent graduates when navigating ethical issues. STUDY DESIGN: Neonatal-Perinatal Fellowship Directors, fellows and recent graduates were surveyed regarding the quality and type of such education during training, and perceived confidence of fellows/graduates in confronting ethical dilemmas. RESULT: Forty-six of 97 Directors (47%) and 82 of 444 fellows/graduates (18%) completed the surveys. Over 97% of respondents agreed that ethics training is 'important/very important'. Only 63% of Directors and 37% of fellows/graduates rated ethics education as 'excellent/very good' (P=0.004). While 96% of Directors reported teaching of ethics, only 70% of fellows/graduates reported such teaching (P<0.001). Teaching methods and their perceived effectiveness varied widely. CONCLUSION: Training in ethics and professionalism for fellows is important, yet currently insufficient; a more standardized curriculum may be beneficial to ensure that trainees achieve competency.

Thrombospondin-1 restrains neutrophil granule serine protease function and regulates the innate immune response during Klebsiella pneumoniae infection.

Neutrophil elastase (NE) and cathepsin G (CG) contribute to intracellular microbial killing but, if left unchecked and released extracellularly, promote tissue damage. Conversely, mechanisms that constrain neutrophil serine protease activity protect against tissue damage but may have the untoward effect of disabling the microbial killing arsenal. The host elaborates thrombospondin-1 (TSP-1), a matricellular protein released during inflammation, but its role during neutrophil activation following microbial pathogen challenge remains uncertain. Mice deficient in TSP-1 (thbs1(-/-)) showed enhanced lung bacterial clearance, reduced splenic dissemination, and increased survival compared with wild-type (WT) controls during intrapulmonary Klebsiella pneumoniae infection. More effective pathogen containment was associated with reduced burden of inflammation in thbs1(-/-) mouse lungs compared with WT controls. Lung NE activity was increased in thbs1(-/-) mice following K. pneumoniae challenge, and thbs1(-/-) neutrophils showed enhanced intracellular microbial killing that was abrogated with recombinant TSP-1 administration or WT serum. Thbs1(-/-) neutrophils exhibited enhanced NE and CG enzymatic activity, and a peptide corresponding to amino-acid residues 793-801 within the type-III repeat domain of TSP-1 bridled neutrophil proteolytic function and microbial killing in vitro. Thus, TSP-1 restrains proteolytic action during neutrophilic inflammation elicited by K. pneumoniae, providing a mechanism that may regulate the microbial killing arsenal.

Incidence of thyroid cancer in England by ethnic group, 2001-2007.

BACKGROUND: Thyroid cancer incidence is increasing worldwide, but with large variations in incidence that may reflect either diagnostic bias or true ethnic differences. We sought to determine the effect of ethnicity on the incidence of thyroid cancer in England, a multiethnic population with a single health-care system. METHODS: We analysed 11,263 thyroid cancer registrations with ethnicity obtained by linkage to the Hospital Episodes Statistics database. Incidence rate ratios (RRs) adjusted for age, sex and income were calculated for the six main non-White ethnic groups in England compared with Whites and to each other. RESULTS: Thyroid cancer incidence was higher in all ethnic groups, except Indians, compared with Whites: in Pakistanis (RR 1.79, 99% floating confidence interval (FCI) 1.47-2.19); Bangladeshis (RR 1.99, 99% FCI 1.46-2.71); Black Africans (RR 1.69, 99% FCI 1.34-2.13); Black Caribbeans (RR 1.56, 99% FCI 1.25-1.93); and Chinese (RR 2.14, 99% FCI 1.63-2.80). CONCLUSION: The risk of thyroid cancer in England varies significantly by ethnicity. The elevated incidence in most ethnic minorities is unlikely to be due to diagnostic bias and warrants further investigation.

The effect of Clostridium perfringens type C strain CN3685 and its isogenic beta toxin null mutant in goats.

Clostridium perfringens type C is an important cause of enteritis and/or enterocolitis in several animal species, including pigs, sheep, goats, horses and humans. The disease is a classic enterotoxemia and the enteric lesions and associated systemic effects are thought to be caused primarily by beta toxin (CPB), one of two typing toxins produced by C. perfringens type C. This has been demonstrated recently by fulfilling molecular Koch's postulates in rabbits and mice. We present here an experimental study to fulfill these postulates in goats, a natural host of C. perfringens type C disease. Nine healthy male or female Anglo Nubian goat kids were inoculated with the virulent C. perfringens type C wild-type strain CN3685, an isogenic CPB null mutant or a strain where the cpb null mutation had been reversed. Three goats inoculated with the wild-type strain presented abdominal pain, hemorrhagic diarrhea, necrotizing enterocolitis, pulmonary edema, hydropericardium and death within 24h of inoculation. Two goats inoculated with the CPB null mutant and two goats inoculated with sterile culture media (negative controls) remained clinically healthy during 24h after inoculation and no gross or histological abnormalities were observed in the tissues of any of them. Reversal of the null mutation to partially restore CPB production also increased virulence; 2 goats inoculated with this reversed mutant presented clinical and pathological changes similar to those observed in goats inoculated with the wild-type strain, except that spontaneous death was not observed. These results indicate that CPB is required for C. perfringens type C to induce disease in goats, supporting a key role for this toxin in natural C. perfringens type C disease pathogenesis.

Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women.

Breast cancer is an estrogen-driven disease. Consequently, hormone replacement therapy correlates with disease incidence. However, increasing male breast cancer rates over the past three decades implicate additional sources of estrogenic exposure including wide spread estrogen-mimicking chemicals or xenoestrogens (XEs), such as bisphenol-A (BPA). By exposing renewable, human, high-risk donor breast epithelial cells (HRBECs) to BPA at concentrations that are detectable in human blood, placenta and milk, we previously identified gene expression profile changes associated with activation of mammalian target of rapamycin (mTOR) pathway genesets likely to trigger prosurvival changes in human breast cells. We now provide functional validation of mTOR activation using pairwise comparisons of 16 independent HRBEC samples with and without BPA exposure. We demonstrate induction of key genes and proteins in the PI3K-mTOR pathway--AKT1, RPS6 and 4EBP1 and a concurrent reduction in the tumor suppressor, phosphatase and tensin homolog gene protein. Altered regulation of mTOR pathway proteins in BPA-treated HRBECs led to marked resistance to rapamycin, the defining mTOR inhibitor. Moreover, HRBECs pretreated with BPA, or the XE, methylparaben (MP), surmounted antiestrogenic effects of tamoxifen showing dose-dependent apoptosis evasion and induction of cell cycling. Overall, XEs, when tested in benign breast cells from multiple human subjects, consistently initiated specific functional changes of the kind that are attributed to malignant onset in breast tissue. Our observations demonstrate the feasibility of studying renewable human samples as surrogates and reinforce the concern that BPA and MP, at low concentrations detected in humans, can have adverse health consequences.