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1.  Adrenocorticotropic hormone analog use for podocytopathies 
Adrenocorticotropic hormone is being increasingly studied for treatment of various glomerulopathies, most notably membranous nephropathy. Less data are available regarding its use in idiopathic nephrotic syndrome (INS) secondary to minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). We report here our experience with H.P. Acthar® Gel (repository corticotropin injection) as first-line or subsequent therapy in patients with INS.
Data were taken from three patients with MCD and ten patients with FSGS from around the US, who were treated with Acthar Gel as initial or subsequent therapy. Treatment was solely at the discretion of the primary nephrologist without a specific protocol. A complete response (CR) was defined as final urine protein-to-creatinine ratio <500 mg/g and a partial response (PR) as 50% decrease without rise of serum creatinine. Side effects and tolerability were noted.
All three patients with MCD received Acthar Gel as second-line or later immunosuppressive (IS) therapy and all responded (one CR and two PRs). Two of the ten patients with FSGS received Acthar Gel as first-line IS therapy, while the other eight had failed multiple agents. Four of the ten patients with FSGS had responses, including two CRs and two PRs. The three patients with MCD tolerated therapy well without side effects. Five patients with FSGS tolerated therapy well, while five had various steroid-like side effects, resulting in therapy discontinuation in two patients.
Acthar Gel is a viable alternative IS agent for treatment of INS in patients intolerant or resistant to conventional therapy. More data are needed to better define its appropriate place.
PMCID: PMC4935005  PMID: 27418857
nephrotic syndrome; minimal change disease; focal segmental glomerulosclerosis; adrenocorticotropic hormone; ACTH; Acthar Gel
2.  The Performance of Five Bioelectrical Impedance Analysis Prediction Equations against Dual X-ray Absorptiometry in Estimating Appendicular Skeletal Muscle Mass in an Adult Australian Population 
Nutrients  2016;8(4):189.
Appendicular skeletal muscle mass (ASM) is a diagnostic criterion for sarcopenia. Bioelectrical impedance analysis (BIA) offers a bedside approach to measure ASM but the performance of BIA prediction equations (PE) varies with ethnicities and body composition. We aim to validate the performance of five PEs in estimating ASM against estimation by dual-energy X-ray absorptiometry (DXA). We recruited 195 healthy adult Australians and ASM was measured using single-frequency BIA. Bland-Altman analysis was used to assess the predictive accuracy of ASM as determined by BIA against DXA. Precision (root mean square error (RMSE)) and bias (mean error (ME)) were calculated according to the method of Sheiner and Beal. Four PEs (except that by Kim) showed ASM values that correlated strongly with ASMDXA (r ranging from 0.96 to 0.97, p < 0.001). The Sergi equation performed the best with the lowest ME of −1.09 kg (CI: −0.84–−1.34, p < 0.001) and the RMSE was 2.09 kg (CI: 1.72–2.47). In men, the Kyle equation performed better with the lowest ME (−0.32 kg (CI: −0.66–0.02) and RMSE (1.54 kg (CI: 1.14–1.93)). The Sergi equation is applicable in adult Australians (Caucasian) whereas the Kyle equation can be considered in males. The need remains to validate PEs in other ethnicities and to develop equations suitable for multi-frequency BIA.
PMCID: PMC4848658  PMID: 27043617
sarcopenia; bioelectrical impedance; muscle; dual-energy X-ray absorptiometry
3.  Perceived psychosocial stress and glucose intolerance among pregnant Hispanic women 
Diabetes & metabolism  2014;40(6):466-475.
Prior literature suggests a positive association between psychosocial stress and the risk of diabetes in non-pregnant populations, but studies during pregnancy are sparse. We evaluated the relationship between stress and glucose intolerance among 1115 Hispanic (predominantly Puerto Rican) prenatal care patients in Proyecto Buena Salud, a prospective cohort study in Western Massachusetts (2006–2011).
Cohen’s Perceived Stress Scale (PSS-14) was administered in early (mean = 12.3 weeks gestation; range 4.1–18 weeks) and mid-(mean = 21.3 weeks gestation; range 18.1–26 weeks) pregnancy. Participants were classified as having a pregnancy complicated by gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance, based on the degree of abnormality on glucose tolerance testing between 24 and 28 weeks of gestation.
The prevalence of gestational diabetes mellitus, impaired glucose tolerance, and abnormal glucose tolerance was 4.1%, 7.2%, and 14.5%, respectively. Absolute levels of early or mid-pregnancy stress were not significantly associated with glucose intolerance. However, participants with an increase in stress from early to mid-pregnancy had a 2.6-fold increased odds of gestational diabetes mellitus (95% confidence intervals: 1.0–6.9) as compared to those with no change or a decrease in stress after adjusting for age and pre-pregnancy body mass index. In addition, every one-point increase in stress scores was associated with a 5.5 mg/dL increase in screening glucose level (β = 5.5; standard deviation = 2.8; P = 0.05), after adjusting for the same variables.
In this population of predominantly Puerto Rican women, stress patterns during pregnancy may influence the risk of glucose intolerance.
PMCID: PMC4810008  PMID: 24948416
Epidemiology; Psychosocial stress; Gestational diabetes; Prospective; Hispanic
4.  Physical activity before and during pregnancy and risk of abnormal glucose tolerance among Hispanic women 
Diabetes & metabolism  2013;40(1):67-75.
Women diagnosed with abnormal glucose tolerance and gestational diabetes mellitus are at increased risk for subsequent type 2 diabetes, with higher risks in Hispanic women. Studies suggest that physical activity may be associated with a reduced risk of these disorders; however, studies in Hispanic women are sparse.
We prospectively evaluated this association among 1241 Hispanic participants in Proyecto Buena Salud. The Pregnancy Physical Activity Questionnaire was used to assess pre, early, and mid pregnancy physical activity. Medical records were abstracted for pregnancy outcomes.
A total of 175 women (14.1%) were diagnosed with abnormal glucose tolerance and 57 women (4.6%) were diagnosed with gestational diabetes. Increasing age and body mass index were strongly and positively associated with risk of gestational diabetes. We did not observe statistically significant associations between total physical activity or meeting exercise guidelines and risk. However, after adjusting for age, BMI, gestational weight gain, and other important risk factors, women in the top quartile of moderate-intensity activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio = 0.48, 95% Confidence Interval 0.27–0.88, Ptrend = 0.03) as compared to those in the lowest quartile. Similarly, women with the highest levels of occupational activity in early pregnancy had a decreased risk of abnormal glucose tolerance (odds ratio = 0.48, 95% Confidence Interval 0.28–0.85, Ptrend = 0.02) as compared to women who were unemployed.
In this Hispanic population, total physical activity and meeting exercise guidelines were not associated with risk. However, high levels of moderate-intensity and occupational activity were associated with risk reduction.
PMCID: PMC4763308  PMID: 24161237
Epidemiology; Gestational diabetes; Hispanic; Physical activity; Prospective
5.  Clinical Screening Tools for Sarcopenia and Its Management 
Sarcopenia, an age-related decline in muscle mass and function, is affecting the older population worldwide. Sarcopenia is associated with poor health outcomes, such as falls, disability, loss of independence, and mortality; however it is potentially treatable if recognized and intervened early. Over the last two decades, there has been significant expansion of research in this area. Currently there is international recognition of a need to identify the condition early for intervention and prevention of the disastrous consequences of sarcopenia if left untreated. There are currently various screening tools proposed. As yet, there is no consensus on the best tool. Effective interventions of sarcopenia include physical exercise and nutrition supplementation. This review paper examined the screening tools and interventions for sarcopenia.
PMCID: PMC4757731  PMID: 26966433
6.  Microbial analysis of in situ biofilm formation in drinking water distribution systems: implications for monitoring and control of drinking water quality 
Biofilm formation in drinking water distribution systems (DWDS) is influenced by the source water, the supply infrastructure and the operation of the system. A holistic approach was used to advance knowledge on the development of mixed species biofilms in situ, by using biofilm sampling devices installed in chlorinated networks. Key physico-chemical parameters and conventional microbial indicators for drinking water quality were analysed. Biofilm coverage on pipes was evaluated by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). The microbial community structure, bacteria and fungi, of water and biofilms was assessed using pyrosequencing. Conventional wisdom leads to an expectation for less microbial diversity in groundwater supplied systems. However, the analysis of bulk water showed higher microbial diversity in groundwater site samples compared with the surface water site. Conversely, higher diversity and richness were detected in biofilms from the surface water site. The average biofilm coverage was similar among sites. Disinfection residual and other key variables were similar between the two sites, other than nitrates, alkalinity and the hydraulic conditions which were extremely low at the groundwater site. Thus, the unexpected result of an exceptionally low diversity with few dominant genera (Pseudomonas and Basidiobolus) in groundwater biofilm samples, despite the more diverse community in the bulk water, is attributed to the low-flow hydraulic conditions. This finding evidences that the local environmental conditions are shaping biofilm formation, composition and amount, and hence managing these is critical for the best operation of DWDS to safeguard water quality.
Electronic supplementary material
The online version of this article (doi:10.1007/s00253-015-7155-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4786615  PMID: 26637423
Bacteria; Biofilms; Drinking water distribution systems; Fungi
7.  Theoretical modelling of fibrinogen supplementation with therapeutic plasma, cryoprecipitate, or fibrinogen concentrate 
BJA: British Journal of Anaesthesia  2014;113(4):585-595.
We aimed to create a theoretical tool to model the effect of three haemostatic agents containing fibrinogen (therapeutic plasma, cryoprecipitate, and fibrinogen concentrate) on the patient's plasma fibrinogen level.
A mathematical model was developed step-wise. The relationship between the amount of haemostatic agent and plasma fibrinogen level was plotted for each agent. A fibrinogen concentration simulator (FCSamount) was developed, where the amount of haemostatic agent was calculated from patient characteristics, agent characteristics, and target plasma fibrinogen level. Refinements were introduced so that (i) FCSamount would account for in vivo fibrinogen recovery, (ii) circulatory volume would not increase ad infinitum with increasing amounts, and (iii) red blood cells would be included in the simulation if haematocrit decreased below a certain level. A second FCS (FCSlevel) was created to calculate fibrinogen levels resulting from specified amounts of haemostatic agents.
Fibrinogen concentration in haemostatic agents has a critical impact on their ability to increase patients' fibrinogen levels. If the target plasma fibrinogen level approaches the concentration of the fibrinogen source, the required amounts increase exponentially; it is impossible to achieve a target above the concentration of the fibrinogen source.
We successfully developed two theoretical tools answering the questions: ‘How much therapeutic plasma, cryoprecipitate, or fibrinogen concentrate would be needed to achieve a specified target fibrinogen level?’ and ‘What would be the resultant fibrinogen level for a specified amount of haemostatic agent?’ The current tools are not intended for clinical application, but they are potentially useful for educational purposes.
PMCID: PMC4166889  PMID: 25064078
computer simulation; cryoprecipitate; drug dosage calculations; fibrinogen; plasma
8.  Reply from the authors 
BJA: British Journal of Anaesthesia  2014;112(6):1121-1123.
PMCID: PMC4020385  PMID: 24829427
9.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
10.  Haemostatic monitoring during postpartum haemorrhage and implications for management 
BJA: British Journal of Anaesthesia  2012;109(6):851-863.
Postpartum haemorrhage (PPH) is a major risk factor for maternal morbidity and mortality. PPH has numerous causative factors, which makes its occurrence and severity difficult to predict. Underlying haemostatic imbalances such as consumptive and dilutional coagulopathies may develop during PPH, and can exacerbate bleeding and lead to progression to severe PPH. Monitoring coagulation status in patients with PPH may be crucial for effective haemostatic management, goal-directed therapy, and improved outcomes. However, current PPH management guidelines do not account for the altered baseline coagulation status observed in pregnant patients, and the appropriate transfusion triggers to use in PPH are unknown, due to a lack of high-quality studies specific to this area. In this review, we consider the evidence for the use of standard laboratory-based coagulation tests and point-of-care viscoelastic coagulation monitoring in PPH. Many laboratory-based tests are unsuitable for emergency use due to their long turnaround times, so have limited value for the management of PPH. Emerging evidence suggests that viscoelastic monitoring, using thrombelastography- or thromboelastometry-based tests, may be useful for rapid assessment and for guiding haemostatic therapy during PPH. However, further studies are needed to define the ranges of reference values that should be considered ‘normal’ in this setting. Improving awareness of the correct application and interpretation of viscoelastic coagulation monitoring techniques may be critical in realizing their emergency diagnostic potential.
PMCID: PMC3498756  PMID: 23075633
blood coagulation tests; point-of-care systems; postpartum haemorrhage; thrombelastography
11.  Life Course Weight Characteristics and the Risk of Gestational Diabetes 
Diabetologia  2009;53(4):668-678.
To prospectively determine the risk of gestational diabetes (GDM) in association with life-course weight characteristics and adult abdominal adiposity.
We investigated the joint and independent impact of birth weight, childhood size by somatotypes, adolescent and adult body mass index (BMI) and abdominal adiposity on GDM risk among 21,647 women in the Nurses’ Health Study II who reported a singleton pregnancy between 1989 and 2001. 1,386 incident GDM cases were reported. Relative risk (RR) was estimated by pooled logistic regression adjusting for age, prematurity, race, smoking status, parental history of diabetes, age of first birth, parity, and physical activity.
Birth weight was inversely associated with GDM risk (P-trend 0.02). Childhood somatotypes at ages 5 and 10 years were not associated with risk. U-shaped associations were found for BMI at age 18 and somatotype at age 20 years. Weight gain between adolescence and adulthood, pre-gravid BMI and abdominal adiposity were positively associated with risk (p-trends all<0.01). Multivariate adjusted RR for GDM from lowest to highest quintile of waist-to-hip ratio were 1.00, 1.50, 1.51, 2.03, 2.12 (P-trend 0.0003). Lower birth weight (<7 pounds) without adulthood overweight (BMI>25 kg/m2) was associated with 20% increased risk (95% CI: 1.02–1.41). However, adulthood overweight alone was related to 2.36 times greater GDM risk (95% CI: 2.12–3.77).
Although lower birth weight is an independent risk factor for GDM, weight gain since early adulthood, and overall and central obesity in adulthood were more strongly associated with elevated GDM risk independent of other known risk factors.
PMCID: PMC2901841  PMID: 20043144
birth weight; body mass index; gestational diabetes; life-course weight; waist
12.  Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery 
BJA: British Journal of Anaesthesia  2010;104(5):555-562.
Normalization of plasma fibrinogen levels may be associated with satisfactory haemostasis and reduced bleeding. The aim of this retrospective study was to assess fibrinogen recovery parameters after administration of fibrinogen concentrate (Haemocomplettan® P) to patients with diffuse bleeding in cardiovascular surgery. Data on transfusion and patient outcomes were also collected.
Patient characteristic and clinical data were obtained from patient records. Results of the thromboelastometry (FIBTEM®) and of the standard coagulation tests, including plasma fibrinogen level, measured before surgery, before and after haemostatic therapy, and on the following day, were retrieved from laboratory records.
Thirty-nine patients receiving fibrinogen concentrate for diffuse bleeding requiring haemostatic therapy after cardiopulmonary bypass were identified. The mean fibrinogen concentrate dose administered was 6.5 g. The mean fibrinogen level increased from 1.9 to 3.6 g litre−1 (mean increment of 0.28 g litre−1 per gram of concentrate administered); maximum clot firmness increased from 10 to 21 mm. The mean fibrinogen increase was 2.29 (sd 0.7) mg dl−1 per mg kg−1 bodyweight of concentrate administered. Thirty-five patients received no transfusion of fresh-frozen plasma (FFP) or platelet concentrate after receiving fibrinogen concentrate; the remaining four patients received platelet concentrate intraoperatively. Eleven patients received platelets, FFP, or both during the first postoperative day. No venous thromboses, arterial ischaemic events, or deaths were registered during hospitalization.
In this retrospective study, fibrinogen concentrate was effective in increasing plasma fibrinogen level, and contributed to the correction of bleeding after cardiovascular surgery.
PMCID: PMC2855672  PMID: 20348140
blood, coagulation; fibrinogen concentrate; pharmacokinetics, uptake; surgery, cardiovascular
13.  Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study 
BJA: British Journal of Anaesthesia  2009;102(6):785-792.
Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration.
A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy.
A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B].
In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.
PMCID: PMC2683341  PMID: 19411671
blood, coagulation; measurement techniques, thrombelastograph; surgery, cardiovascular; transfusion
14.  Analysis of Michigan Medicaid costs to treat HIV infection. 
Public Health Reports  1989;104(5):416-424.
To obtain better understanding of the nature and cost of health care related to human immunodeficiency virus (HIV) infection, medical payment records were analyzed for 204 men, women, and children older than 60 months who had indications of HIV infection. The records were those of Michigan Medicaid, the General Assistance Medical Program, and the Resident County Hospitalization Program, with service dates on or after January 1, 1984, and which were processed by November 30, 1987. Patient payment records were coded according to whether the patient's condition was considered to be pre-HIV, HIV unrelated, possibly HIV related, or HIV related. Average monthly payments were found to be $150 for pre-HIV patient payment records, $114 for those HIV unrelated, $57 for those possibly related, and $1,213 for those related to HIV infection. HIV-related monthly payments rose from about $1,500 per month in the period 3 months prior to the patient's death to more than $8,000 in the last month of life. Men were found to have twice as many claims as women, and men's claims cost about three times as much. A higher percentage of women than men (91 percent versus 37 percent) received pre-HIV paid services, indicating a higher percentage of women were at least initially receiving Medicaid for reasons other than an HIV-related disability. Diagnostic categories that accounted for the bulk of the HIV-related health care utilization included infectious and parasitic diseases, acquired immunodeficiency syndrome, diseases of the respiratory system, and non-HIV-specific immunity disorders. Inpatient hospitalization accounted for more than 75 percent of the payments, followed by physician costs (11 percent), pharmacy costs (5 percent), and outpatient costs (3 percent). A total of 45, or about 22 percent of the recipients, received zidovudine (AZT) prescriptions at an average monthly cost of $404.
PMCID: PMC1579960  PMID: 2508170
15.  Effects of low temperature on in vivo and in vitro protein synthesis in Escherichia coli and Pseudomonas fluorescens. 
Journal of Bacteriology  1978;134(3):861-874.
The effects of temperature on protein synthesis by Escherichia coli, a mesophile, and Pseudomonas fluorescens, a psychotroph, were investigated by using whole-cell and cell extract preparations. After shifts to 5 degrees C, protein was synthesized at a slowly decreasing rate for 1 h by both organisms, after which P. fluorescens synthesized protein at a new rate corresponding to its 5 degrees growth rate, in contrast to E. coli which did not synthesize protein at a measurable rate. In vitro protein-synthesizing systems using MS-2 RNA, endogenous mRNA, and purified polysomes were utilized to investigate initiation of translation at 5 degrees C. In these systems, P. fluorescens cell extracts synthesized protein at linear rates for up to 2 h at 5 degrees C, whereas E. coli cell extracts synthesized protein for only 25 min at 5 degrees C. The rates of polypeptide elongation, as tested by the incorporation of phenylalanine into polyphenylalanine by cell extract protein-synthesizing systems from both organisms, were identical over the range of 25 to 0 degrees C. The polysome profiles of E. coli whole cells shifted from 37 to 5 degrees C showed accumulation of 70S ribosomal particles and ribosomal subunits at the expense of polysomes. Similar experiements done with P. fluorescens resulted in polysome reformation at 5 degrees C. In vitro experiments demonstrated that the 70S ribosomal particles, which accumulated in E. coli at 5 degrees C, were capable of synthesizing protein in vitro in the absence of added mRNA. These in vivo and in vitro results suggest that incubation of E. coli at subminimal temperatures results in a block in initiation of translation causing polysomal runoff and the accumulation of 70S particles, some of which are 70S monosomes.
PMCID: PMC222333  PMID: 96102
17.  On Antiseptic Inhalations 
British Medical Journal  1884;1(1208):353-354.
PMCID: PMC2306964  PMID: 20750832
18.  Nitrite of Amyl in Uræmic Asthma 
British Medical Journal  1883;1(1171):1115-1116.
PMCID: PMC2372585  PMID: 20750633
19.  Gout as a Tropho-Neurosis 
British Medical Journal  1881;1(1066):880.
PMCID: PMC2263806  PMID: 20749886

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