Ex Vivo Urinary Bactericidal Activity and Urinary Pharmacodynamics of Fosfomycin after Two Repeated Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Subjects.

The ex vivo bactericidal activity and pharmacodynamics of fosfomycin in urine were evaluated in 18 healthy subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses or vice versa. Serial urine samples were collected before and up to 24 h after dosing on days 1 and 5. Eight bacterial strains with various genotypic and phenotypic susceptibilities to fosfomycin were used for all experiments (5 Escherichia coli, 2 Klebsiella pneumoniae, and 1 Proteus mirabilis). MICs were performed via agar dilution. Urinary bactericidal titers (UBTs) were performed via modified Schlichter test using participant's drug-free urine as the diluent. Urinary time-kill analyses were performed on pooled 24-h urine aliquots from days 1 and 5. All experiments were performed in triplicate with and without the addition of 25 mg/liter of glucose-6-phosphate (G6P). Mean 24-h urine concentrations of fosfomycin ranged from 324.7 to 434.6 mg/liter regardless of study day or dosing regimen. The urinary antibacterial activity of fosfomycin was also similar across study days and dosing regimens. UBT values did not correlate with MICs determined in the presence of G6P. Fosfomycin was reliably bactericidal in urine only against the 5 E. coli strains, regardless of genotype or MIC value. Together, these data do not support the use of oral fosfomycin tromethamine for pathogens other than E. coli or at a dosing frequency higher than QOD. Fosfomycin MICs determined in the presence of G6P may not accurately reflect the in vivo activity given the lack of G6P in human urine. (This study has been registered at ClinicalTrials.gov under identifier NCT02570074.).

Haematological parameters and screening tests of haemostasis in children with sepsis: results from a tertiary care centre in India.

Sepsis is a common cause of death in infants and children. Haemostatic abnormalities have been reported in such patients. There is scant information on the nature and frequency of these abnormalities in children especially from India. Our aim was to evaluate the nature and frequency of haematological and haemostatic abnormalities in children with sepsis. Fifty children between 1-10 years of age admitted with sepsis and 50 age-matched, healthy controls were included in the study. Complete blood counts, examination of stained peripheral blood film, prothrombin time (PT), activated partial thromboplastin time (APTT), plasma fibrinogen, C-reactive protein, liver function tests and serum creatinine were done in all patients and controls. Prolonged PT and APTT were seen in 9 (18%) and 24 (48%) patients respectively. Plasma fibrinogen was decreased in 6% and increased in 8% patients. One or more haemostatic parameter was abnormal in 35 (70%) patients and in all patients who died.

Pressure mapping and performance of the compression bandage/garment for venous leg ulcer treatment.

A study has been conducted on the commercially available compression bandages as regards their performance with time. Pressure mapping of these bandages has been done using a fabricated pressure-measuring device on a mannequin leg to see the effect on pressure due to creep, fabric friction and angle of bandaging. The results show that the creep behavior, frictional behavior and the angle of bandaging have a significant effect on the pressure profile generated by the bandages during application. The regression analysis shows that the surface friction restricts the slippage in a multilayer system. Also the diameters of the limb and the amount of stretch given to the bandage during application have definite impact on the bandage pressure. In case of compression garments, washing improves the pressure generated but not to the extent of the pressure of a virgin garment. Comparing the two compression materials i.e. bandage and garment, it is found that the presence of higher percentage of elastomeric material and a highly close construction in case of garment provides better holding power and a more homogeneous pressure distribution.

Mathematical modeling to predict the sub-bandage pressure on a conical limb for multi-layer bandaging.

The effectiveness of the compression treatment by a medical compression bandage is dependent on the pressure generated at the interface between the bandage and the skin. This pressure is called interface pressure or sub-bandage pressure. The performance of a bandage depends upon the level of interface pressure applied by the bandage and the sustenance of this pressure over time. The interface pressure exerted by the bandage depends on several other factors like limb shape or size, application technique, physical and structural properties of the bandage, physical activities taken by the patient, etc. The current understanding of how bandages apply pressure to a limb is based on the Law of Laplace, which states that tension in the walls of a container is dependent on both the pressure of the container's content and its radius. This concept was translated mathematically into equation relating pressure to tension and radius by Thomas. In addition, a modified equation was generated by multiplying the model with a constant that represents the number of bandage layers in order to use the model to estimate the pressure applied by multi-layer bandages. This simple multiplication adjustment was questioned by researchers. They had doubts about the model validity and whether it can be used to predict the sub-bandage pressure applied by pressure garments. One of the questions that were raised regarding the bandage thickness affecting the sub-bandage pressure has been recently explored by Al Khaburi where he used the thin and thick cylinder shell theory to study the effect of Multi Component Bandage's (MCB) thickness on the sub-bandage pressure. The model by Al Khaburi and the earlier models developed for pressure prediction are all based on calculations considering the cylindrical limb shapes although the human limb normally is wider at the calf and reduces in circumference towards the ankle. So in our approach, the bandage is assumed to take a conical shape during application and membrane shell theory is used for developing pressure prediction model for multi-layers of bandage. Both analytical and experimental work showed that the effect of bandage thickness and the geometry of the limb on pressure produced by multi-layers of bandage are significant. The model developed when compared to the data obtained using experimental setup confirmed the validity of the mathematical model for multi-layers of bandage based on conical geometry of the limb.

Significance of mucin stain in uterine cervical cancers.

Histopathological examination of 140 cases of cervical cancer was supplemented with staining for the presence of mucin. Secretion of mucin was detected in 27 cases. Fourteen cases of large cell non-keratinizing (LCNK) squamous cell carcinoma were reclassified, 12 as squamous cell carcinoma with mucin secretion and two as adeno-squamous carcinoma. One case of undifferentiated carcinoma was labelled as adenocarcinoma on the basis of mucin stain. None of the keratinizing squamous cell carcinomas were positive for mucin. The results indicate that mucin expression should be looked for even in those carcinomas where no obvious gland formation is seen.

Interobserver agreement of the Nottingham histologic grading scheme for infiltrating duct carcinoma breast.

Interobserver agreement of the histologic grading scheme for infiltrating duct carcinoma (IDC) of breast was assessed. Three pathologists independently evaluated histologic grade using the modified Bloom and Richardson histological grading system on 40 cases of IDC breast. Pairwise K value for agreement ranged from 0.68-0.83 (median 0.68) for histological grade suggesting substantial agreement. Generalized K values were 0.54, 0.34 and 0.36 for tubule formation, nuclear pleomorphism and mitotic count respectively indicating moderate and fair agreement. Similar levels of agreement were obtained specially in the final histologic grade between pathologists routinely reporting histopathology material and one pathologist who was not. This was achieved by use of precise guidelines. The ease with which this grading system could be applied by pathologists on histopathology material will greatly help its acceptability in routine histopathology.

Congenital deficiency of factor VII.

A case of congenital factor VII deficiency in a five-year-old child is reported. The patient, born of a non-consanguineous marriage, presented with repeated bouts of epistaxis since childhood. The prothrombin time (PT) was markedly prolonged with a normal bleeding time (BT), partial thromboplastin time with Kaolin (PTTK) and platelet count. The patient has been on follow up for the last four years and is doing apparently well.

Effect of various antihypertensive drugs on plasma fibrinogen levels in patients with essential hypertension.

In recent years, substantial evidence has accumulated to unambiguously implicate high plasma fibrinogen levels as a major cardiovascular risk factor. An open prospective and randomised pilot study was therefore undertaken in mild to moderate hypertensives to evaluate the effect of various antihypertensive drugs viz enalapril, felodipine and prazosin on the blood pressure and plasma fibrinogen levels. The systolic and diastolic blood pressures were determined at 0, 4 and 8 weeks whereas plasma fibrinogen assays were done at baseline and at the end of the 8th week of treatment in all the drug-treated groups. It was observed that although all the three drugs effectively controlled blood pressure, only enalapril significantly reduced plasma fibrinogen levels. Due to this additional effect, enalapril has potential to control two major cardiovascular risk factors--hypertension and high plasma fibrinogen levels--simultaneously.

Bilateral testicular biopsy--is it necessary?

Bilateral testicular biopsies from 202 infertile males were examined to ascertain the differences in the degree of damage to the germinal epithelium on both sides. Depending on the histologic changes, the biopsies were divided into six groups. A significant difference in the morphology on both sides was seen only in 3% cases. The left and the right testes were equally damaged in cases with similar morphology.

Diagnostic distinction between unusual malignant tumors of gall bladder by histochemistry and antigenic phenotype.

In a review of 79 cases of gall bladder malignancy, nineteen cases were labelled as unusual tumors while sixty were diagnosed as adenocarcinoma. Alcian blue, PAS, Grimelius' and Masson trichrome stains were done. Expression of EMA, CEA and desmin was assessed (PAP). Histological subtype was revised, in eleven cases out of 19. Five tumors initially diagnosed as squamous cell carcinoma were found to be positive for mucin and CEA and hence were reclassified as adenosquamous carcinoma. Three undifferentiated carcinomas and two malignant carcinoids were labelled as adenocarcinoma and composite tumor respectively. Positive reactivity with CEA and alcian blue PAS and absence of AFP helped in differentiating one giant cell carcinoma from hepatocellular carcinoma. No definite marker could be identified in one case of malignant mesenchymal tumor. Histochemistry and immunohistochemistry also helped in confirming the diagnosis of three cases of carcinoma in situ, one of malignant carcinoid and three of clear cell carcinoma.

Haematological parameters and HbA2 levels in beta-thalassaemia trait with coincident iron deficiency.

Iron status was estimated in 463 heterozygous beta-thalassaemics to delineate the effect of iron deficiency (ID) on the haematological parameters and expression of HbA2 in these patients. One hundred and twenty six (27.2%) traits had coincident ID. These iron deficient traits had a significantly (p < 0.0002), higher prevalence of anaemia (90.5%) as compared to iron replete traits (71.5%). Mean haemoglobin concentration was significantly lower (p < 0.0001) in beta-thalassaemics with ID (10.7 +/- 1.5) g/al as compared to those without ID (11.6 +/- 1.6 g/dl). Mean MCV and MCH were significantly lowered (p < 0.0001) in patients of beta-thalassaemia trait (BTT) with ID than in these without ID. Mean HbA2 was not significantly different in the two groups of traits and was elevated (> or = 3.5%) in all except one patient. However, mean HbA2/cell was significantly (p < 0.05) lower in traits with ID. The effect of ID in BTT was apparent with significant lowering of haemoglobin concentration and increased prevalence of anaemia. Iron therapy is warranted in iron deficient traits and would help in significantly raising their haemoglobin concentration. Elevation in HbA2 values was striking and could be used with reliability for diagnosis of BTT even in the presence of ID.

Effect of maternal iron deficiency anaemia on foetal outcome.

One hundred and two pregnant women and their neonates were examined to evaluate the effect of maternal haemoglobin concentration (Hb. conc) and iron deficiency anaemia on the placental weight and the foetal outcome. Haematological and serum ferritin values were determined. It was observed that 34.3% of the pregnant women were anaemic. Maternal Hb conc. and serum ferritin showed a highly significant correlation (r = 0.40, p < 0.001) indicating that iron deficiency was the most important cause of anaemia amongst them. The maternal Hb conc. showed a significant correlation with placental weight (p < 0.05), birth weight (p < 0.01), Apgar score (p < 0.001) and birth asphyxia. Maternal serum ferritin also correlated positively with cord ferritin (p < 0.001). The study did not reveal any association between high Hb and adverse foetal outcome.

Red cell indices and discriminant functions in the detection of beta-thalassaemia trait in a population with high prevalence of iron deficiency anaemia.

Red cell indices and discriminant functions were studied in 463 heterozygous beta-thalassaemics (337 without iron deficiency, 126 with iron deficiency) and 195 patients of iron deficiency anaemia (IDA) to ascertain their utility in the detection of betathalassaemia trait (BTT). Majority of traits in both groups had an elevated RBC count (> or = 5.0 x 10(12)/L). The counts were significantly higher than of patients with IDA, only 4.6% of whom had this degree of erythrocytosis. Mean Hb concentration was significantly higher in traits as compared to iron deficient subjects (p < 0.0001). Mean MCV and MCH were significantly (p < 0.0001) lower in traits more so in those with ID as compared to patients of IDA. MCV < 80 fl and MCH < 27 pg were found to be sensitive markers in the detection of traits even in the presence of ID. Of the four discriminant functions studied MCSQ was found to be most sensitive in detection of BTT and it identified 97.9% traits. DF of England and Fraser was most specific for BTT being < 8.4 in only 6.2% patients with IDA. Detection of erythrocytosis especially in the presence of mild anaemia and calculation of discriminant functions derived from red cell indices were found to play an important role in screening for BTT even in the presence of ID and helped identify those patients who required further laboratory evaluation.

Haemostatic function in coronary artery disease (CAD).

Tests to evaluate haemostatic function bleeding time (BT), prothrombin time (PT) partial thromboplastin time with kaolin (PTTK), thrombin time (TT), platelet count, platelet function tests (platelet adhesiveness and microthrombus index) and plasma fibrinogen levels were performed in 30 patients of coronary artery disease (14 myocardial infarction, 16 angina pectoris) and 20 age and sex matched controls. There was no statistically significant difference in platelet adhesiveness and mean microthrombus index in patients and controls. The BT, PT, PTTK and TT were normal in all patients and controls. Stepwise logistic regression analysis showed that plasma fibrinogen was an independent risk factor in the production of CAD.