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Changes in metabolic status gate reproductive activity by still incompletely deciphered mechanisms. Many neuropeptides have been shown to be involved in restraining hypothalamic gonadotropin releasing hormone (GnRH) release under conditions of negative energy balance. Broadly, on the basis of their effect on feeding, these can be grouped as orexigenic and anorexigenic neuropeptides. Reciprocally correlated, in response to changes in systemic concentrations of metabolic hormones, the secretion of orexigenic neuropeptides increases while that of anorexigenic neuropeptides decreases during conditions of food restriction. Recently, kisspeptin signaling in hypothalamus has appeared as a pivotal regulator of the GnRH pulse generator. Kisspeptin apparently does not affect feeding, but in light of accumulating data, it has emerged as one of the major conduits in relaying body metabolic status information to GnRH neurons. The present review examines such data obtained from rodent and primate models, which suggest kisspeptin-Kiss1r signaling as a possible pathway providing a link between metabolism and reproduction., (Copyright © 2013 Elsevier Inc. All rights reserved.)

RF amide peptide family with distinctive terminal -Arg-Phe-NH(2) signature is evolutionarily conserved from invertebrates to mammals. These neuropeptides have been shown to affect diverse functions in invertebrates and vertebrates including influencing pituitary hormone secretion. More recently, two members of this family 26-amino acid and 43-amino acid RF amide peptide (26RFa and 43RFa, respectively) originally isolated from frog have been cloned in rats and humans. Actions of these peptides on hormone secretion have not been studied in primates. In the present study, effect of iv administration of three different doses of human 26RFa and 43RFa on GH secretion was studied in a representative higher primate, the rhesus monkey. As control against these two peptides, normal saline and a scrambled sequence of 26RFa was administered. A set of four intact adult male monkeys received the administration in a random order. Peripheral blood samples were obtained from the chairrestrained but fully conscious animals for a period of 30 min before and 240 min after the administration at 15-min intervals. For quantitative measurement of GH concentration, a human GH chemiluminescent immunometric assay was used. Peripheral administration of 38 and 76 nmol doses of 26RFa significantly (P < 0.05) stimulated GH AUC during a 0-120 min period after injection of 26RFa. In contrast to 26RFa, administration of 43RFa appeared to suppress GH levels during the later stages of the sampling i.e. from 120 to 240 min period. Mean AUC during the period was significantly (P < 0.05) reduced by 76 nmol dose of 43RFa, while 38 nmol dose of 43RFa also had similar effect but lacked full statistical significance (P = 0.058). To our knowledge present study reports for the first time-specific stimulatory effect of 26RFa on the GH secretion and a novel inhibitory and delayed effect of 43RFa on the GH secretion in higher primates. In conclusion, present findings extend evidence for endocrine actions of RF amides in primates and suggest differential effect of these peptides on GH secretion in primates.

RF-amides (RFa), a superfamily of evolutionary-conserved neuropeptides, are expressed in both invertebrates and vertebrates. While some endocrine functions have been attributed to these peptides in lower vertebrates and few mammalian models, not much is known about their actions in primates. Therefore, the present study was designed to examine the effects of peripheral administration of two recently cloned human RFa peptides, 26RFa and 43RFa, on testosterone and prolactin secretion in the adult male adult male rhesus monkey (Macaca mulatta). For control purposes, a scrambled sequence of 26RFa (Sc-26RFa) and normal saline (1ml) were injected. Three different doses of 26RFa and 43RFa (19-nmol, 38-nmol and 76-nmol) and a single dose (38-nmol) of Sc-26RFa were tested. A set of four chair-restraint habituated monkeys was used. Comparison of post-treatment T levels with respective pre levels showed that none of the doses of both 26RFa and 43RFa changed T release. Similarly, Sc-26RFa and saline administration also did not affect T levels. In contrast, all doses of 26RFa and 43RFa significantly (P<0.05) stimulated prolactin secretion. 43RFa dose dependently increased prolactin secretion while dose dependency was not observed for 26RFa. Saline and Sc-26RFa injection had no effect on prolactin concentrations. Thus, present study demonstrated that peripheral administration of 26RFa and 43RFa, in the doses tested, have no effect on T secretion, suggesting possible selective lack of their neuroendocrine role in controlling hypothalamic-pituitary-gonadal axis in the adult male primates. The prominent stimulation of prolactin suggests a neuroendocrine role of RFa peptides in regulation of prolactin release in primates., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Despite the small or near-zero Seebeck coefficient of metallic nanotubes, a nanotube film can be readily scaled up in length. Thus so can its thermoelectric power. In this work, we inserted a nanomesh pattern into a carbon nanotube film by using an anodized aluminum oxide membrane as an etching mask. We found that by patterning densely packed nanoscale holes into the nanotube film, its total thermoelectric power can be further increased, by as much as 30% (from 29 to 39 μV K(-1)). We present this finding, attributed to electron localization due to nanopatterning, as indicative of the potential of a new degree of freedom.

Context: KISS1 is a candidate gene for GnRH deficiency., Objective: Our objective was to identify deleterious mutations in KISS1., Patients and Methods: DNA sequencing and assessment of the effects of rare sequence variants (RSV) were conducted in 1025 probands with GnRH-deficient conditions., Results: Fifteen probands harbored 10 heterozygous RSV in KISS1 seen in less than 1% of control subjects. Of the variants that reside within the mature kisspeptin peptide, p.F117L (but not p.S77I, p.Q82K, p.H90D, or p.P110T) reduces inositol phosphate generation. Of the variants that lie within the coding region but outside the mature peptide, p.G35S and p.C53R (but not p.A129V) are predicted in silico to be deleterious. Of the variants that lie outside the coding region, one (g.1-3659C→T) impairs transcription in vitro, and another (c.1-7C→T) lies within the consensus Kozak sequence. Of five probands tested, four had abnormal baseline LH pulse patterns. In mice, testosterone decreases with heterozygous loss of Kiss1 and Kiss1r alleles (wild-type, 274 ± 99, to double heterozygotes, 69 ± 16 ng/dl; r(2) = 0.13; P = 0.03). Kiss1/Kiss1r double-heterozygote males have shorter anogenital distances (13.0 ± 0.2 vs. 15.6 ± 0.2 mm at P34, P < 0.001), females have longer estrous cycles (7.4 ± 0.2 vs. 5.6 ± 0.2 d, P < 0.01), and mating pairs have decreased litter frequency (0.59 ± 0.09 vs. 0.71 ± 0.06 litters/month, P < 0.04) and size (3.5 ± 0.2 vs. 5.4 ± 0.3 pups/litter, P < 0.001) compared with wild-type mice., Conclusions: Deleterious, heterozygous RSV in KISS1 exist at a low frequency in GnRH-deficient patients as well as in the general population in presumably normal individuals. As in Kiss1(+/-)/Kiss1r(+/-) mice, heterozygous KISS1 variants in humans may work with other genetic and/or environmental factors to cause abnormal reproductive function.

Amplification of the neurosecretory activity of the GnRH system is the defining neuroendocrine event for sexual maturation. The physiological mechanisms that drive GnRH secretion at puberty have been difficult to identify but the discovery in 2003 that the G protein coupled receptor KISS1R is a key regulator of pubertal development in mice and men has ushered in a new chapter in reproductive neuroendocrinology. KISS1R is activated by endogenous peptides derived from a precursor protein, kisspeptin. Despite kisspeptin's importance in driving the reproductive cascade, relatively few patients with GnRH deficient states and mutations in the kisspeptin pathway have been described. Yet, these cases, coupled with loss-of-function mouse models, provide unique and complementary information into the biological role of this signaling system in the control of GnRH secretion. This article will examine some of the subtleties in genotype-phenotype correlations in both mice and men carrying disabling mutations in the kisspeptin pathway., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Background: The hazards of cigarette smoking and its increasing consumption are well known despite the ongoing tussle between the tobacco industry and global governments. To curb the menace of smoking, anti-smoking laws have been enforced from time to time by various governments. In 2003, Ministry of Health (MoH) Government of Pakistan has imposed certain regulations on cigarette manufacturing industry. The aim of this study was to highlight the compliance of the industry with these regulations., Methods: A cross-sectional study of major cigarette selling shops was conducted in Abbottabad. It was aimed at determining the availability of total cigarette brands and their compliance with the regulations and also to find out attributes of cigarette customers., Results: A total of 39 varieties of 18 cigarette brands are available in Abbottabad city, out of which 71.8% are imported varieties. A total of 38.4% varieties have displayed health warnings (28.2% pictorial health warning, 10.2% have written health warning. Majority of cigarette customers are between 20-40 years of age, while 5.6% customers include youngsters between 10-20 years of age. Female customers, accounting for 8% of total cigarette customers, buy only those brands which have not displayed the health warning., Conclusions: Observed compliance with governmental regulation for displaying health warning is 39% which is far less than desired. Sale of cigarette to children is also practiced. Ministry of Health (MoH) should assure the display of these warnings on all the brands so that smokers must be fully aware about the risk involved in smoking

Kisspeptin (KP)-Kiss1r, a ligand-receptor pair, has recently been implicated as a pivotal regulator of the neuroendocrine reproductive axis. KISS1 (encoding KP) as well as KISS1R (encoding receptor for KP) are expressed in several peripheral tissues including the pancreas. But the specific role of KP in the physiology of pancreas is still incompletely deciphered. This study was designed to examine the effect of peripheral KP administration on basal and glucose-induced plasma insulin (an important pancreatic hormone) secretion under fed and fasting conditions in the adult male rhesus monkey. A set of 4 chair-restraint habituated intact adult male rhesus monkeys were assigned to receive intravenous bolus administration of human kisspeptin-10 (KP10, 50 μg), and vehicle (1 ml) in normal fed and fasting conditions without or with glucose infusions. Plasma concentrations of insulin were measured by using a specific IRMA. Glucose infusion significantly stimulated plasma insulin levels (p<0.005). Vehicle administration did not affect both basal and glucose stimulated insulin in fed as well as in fasting condition. KP10 administration had no effect on the basal insulin levels in both fed and fasting as compared to pretreatment or vehicle treatment levels, while it significantly heightened glucose stimulated insulin levels (p<0.05) in both fed and fasted monkeys. The present results show that KP administration does not affect the basal secretion of insulin under both fed and fasting condition while potentiated the glucose-induced insulin levels in the adult male rhesus monkey. Therefore, these findings suggest a potential role of KP in the physiology of pancreas., (© Georg Thieme Verlag KG Stuttgart · New York.)

Infective endocarditis remains an interesting and challenging disease in which the presenting features have been modified by medical progress. We report a case of a 63-year-old woman who presented with pyrexia, weight loss, night sweats and fatigue over a period of 7 weeks, at the end of which she developed severe right hypochondrial pain, mimicking acute abdomen. She was provisionally diagnosed with and treated for acute cholecystitis to no avail. An abdominal computed tomography scan was performed and revealed the presence of right kidney infarction, the source of which was later proven to originate from aortic valve endocarditis. The patient made a remarkable recovery following 6 weeks of treatment with intravenous antibiotics. This case demonstrates that endocarditis can present as an acute abdomen which is caused mainly by embolism in various organs (the kidney in our patient).

Objective: To determine the frequency of common risk factors for multi-drug resistant tuberculosis in patients presented at a tertiary care hospital, Peshawar., Study Design: Cross-sectional, observational study., Place and Duration of Study: Pulmonology Department, Khyber Teaching Hospital, Peshawar, from December 2006 to October 2007., Methodology: Patients with positive AFB culture and sensitivity results and found resistant to both rifampicin and isoniazid with or with resistance to other first line anti-tuberculosis drugs, were recruited from both Pulmonology Ward and Outpatient Department (OPD). Informed verbal consent was taken and a questionnaire administered to all participants of the study. Information regarding demographics, education status, occupation, monthly household income, AFB C/S, details of past history of tuberculosis and family history of TB or Multi-Drug Resistant (MDR-TB) was recorded. Data was analyzed on SPSS version 11., Results: A total of 30 patients of MDR-TB were interviewed. Male (n=17) and female (n=13) ratio was 1.3:1. Mean age was 34.2+/-15.3 years. Ninety-two percent female and 52.9% male were uneducated. In 56.7%, monthly income was less than 5,000 rupees and in 40% between 5,000-10,000 rupees. All patients had previous history of Antituberculous Treatment (ATT), in which 20% had undertaken ATT course once, 53.3% twice and 26.7% thrice in the past. In the study group, 13 (43.3%) patients had not completed their first ATT course and 11 of them were receiving ATT from a general practitioner (GP) at that time. Seven (23.3%) patients had family history of TB but no one had documented MDR-TB in the family. Resistance to RH was present in all patients; moreover, 56.7% had resistance to RHEZ+S., Conclusion: The most common factors in the study group were previous history of tuberculosis, repeated courses of ATT, prescribed by different clinicians and unsupervised treatment by a GP during the initial course of ATT.

Aims: In primates, changes in nutritional status affect the hypothalamic-pituitary-gonadal (HPG) axis by still poorly understood mechanisms. Recently, hypothalamic kisspeptin-GPR54 signaling has emerged as a significant regulator of this neuroendocrine axis. The present study was designed to examine whether suppression of the reproductive function by acute food-restriction in a non-human primate is mediated by decreased responsiveness of the HPG axis to endogenous kisspeptin drive., Main Methods: Five intact adult male rhesus monkeys habituated to chair-restraint, received intravenous boli of human kisspeptin-10 (KP10, 50 microg), hCG (50 IU), and vehicle (1 ml) in both fed and 48-h fasting conditions. Plasma concentrations of glucose, cortisol and testosterone (T) were measured by using enzymatic and specific RIAs, respectively., Key Findings: The acute 48-h fasting decreased plasma glucose (P<0.01) and T (P<0.005) levels, and increased cortisol levels (P<0.05). KP10 administration caused a robust stimulation of T secretion in both fed and fasted monkeys. However, mean T concentration and T AUC after KP10 administration were significantly (P<0.01-0.005) reduced in fasted monkeys. Likewise, the time of the first significant increase in post-KP10 T levels was also significantly (P<0.01) delayed. T response to hCG stimulation was similar in fed and fasted monkeys., Significance: The present results indicate that under fasting conditions the KP10 induced T response is delayed and suppressed. These data support the notion that fasting-induced suppression of the HPG axis in the adult male rhesus monkey may involve, at least in part, a reduction in the sensitivity of the GnRH neuronal network to endogenous kisspeptin stimulation.

Background: Due to advancement of non-surgical methods of coronary revascularization the patients referred for surgery have extensive and complex coronary anatomy. Patients with diffuse atheromatous coronary artery disease required coronary artery reconstruction or coronary endarterectomy (CE). Coronary endarterectomy on beating heart needs skill and better surgical technique. Coronary endarterectomy along with coronary artery bypass grafting (CABG) done on beating heart is compared with coronary endarterectomy done by using conventional CABG technique., Methods: Seven hundred and ninety five consecutive patients underwent CABG from January 2006 to March 2007 in a prospective randomized trial at cardiac surgery department, Punjab Institute of Cardiology, Lahore; out of these 115 patients underwent coronary endarterectomy (CE) and were included in this study., Results: Coronary artery bypass grafting was performed in 115 patients. Seventy two (62.6%) were in group A on-pump and 43 (37.39%) were in group B off-pump. Mean age in group A was 55.68 +/- 1.06 and 52.63 +/- 1.40 in group B. Sixty six male and 6 female were included in group A, 40 male and 3 female patients were in group B. In-hospital mortality among patients undergoing CABG was 5.6 % in on-pump group and 2.3 % in off-pump group (p = 0.649), the duration of post-operative mechanical ventilation in on-pump was 6.78 +/- 9.34 hours and 5 +/- 4.0 hours in off-pump group (p = 0.060), 66.7% patients in on-pump and 58.1% patients in off-pump group required blood transfusions, Intra-aortic balloon pump (IABP) was required in 5.6% of the patients in on-pump group. Other factors included, smoking 26.4% in on-pump and 41.9% in off-pump group (p = 0.01), Intensive care unit (ICU) stay was statistically significant 4 +/- 3 in on-pump group and 4 +/- 2 in off-pump group (p = 0.02), and drain in on-pump group was 455 +/- 208 ml and 540 +/- 370 ml in off-pump group (p = 0.01)., Conclusion: Coronary endarterectomy (CE) has higher post-operative morbidity and mortality but the post-operative outcome after the procedure on either technique is comparable and CE is feasible on off-pump technique as well.

Background: The resting of platelet (PLT) pellets during the preparation of whole blood-derived PLT concentrates (PCs) is considered an essential step. A reevaluation of the rest period was conducted because preparation and storage conditions have been modified during the past 20 years., Study Design and Methods: A two-site in vitro study (Study 1) was conducted with rest times of 0 to 5 minutes, 1 hour, and 4 hours (n = 31-33 per rest period). Leukoreduced PCs were stored for 5 days. A second study (Study 2) measuring in vivo viability was conducted at a third site (14 paired studies). PCs were prepared from 2 units of whole blood on the same day to simultaneously compare viability following storage and radioisotopic labeling., Results: In Study 1, comparable in vitro parameters and swirling were observed with the three rest periods. The mean (+/-1 SD) values after storage for the extent of shape change and hypotonic stress parameters were 0 to 5 minutes, 16.7 +/- 7.2 and 66.0 +/- 15.7%; 1 hour, 19.1 +/- 6.9 and 69.3 +/- 17.9%; and 4 hours, 17.6 +/- 5.5 and 64.1 +/- 11.3%. In Study 2, the in vivo recovery was 49.9 +/- 15.3 and 50.9 +/- 20.2% with 0- to 5-minute and 1-hour rest periods, respectively. The corresponding survival time was 111.2 +/- 50.7 and 114.9 +/- 43.8 hours., Conclusion: These studies indicate comparable in vitro and in vivo viability properties with 0- to 5-minute and 1-hour rest periods and at 4 hours (in vitro only).

Background: The American Red Cross has been maintaining a research database of all blood donations, including all testing results for infectious disease markers, since 1995. This study analyzes the temporal trends of major blood-borne infections among blood donors., Study Design and Methods: Temporal trends for age- and sex-specific prevalence of human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis infections in US blood donors were analyzed based on linear trend or time series model or other models as appropriate., Results: From 1995 to 2002, significant declines have been observed for infections that used to be at relatively higher levels. Declines in prevalence were slower among first-time donations than repeat donations. There was an increase in prevalence of anti-HCV among first-time male donors of 50 to 59 years of age. Anti-HIV prevalence appeared to have increased among first-time male donors of 30 to 39 years of age since 2000., Conclusion: Different sex and age groups showed various patterns of decline and even signs of increase. The increasing prevalence among some age and sex groups may merit further investigation.

Over the past decade, newly introduced methods for apheresis platelet collection have led to increased collection yields. This has resulted in "splitting," which allows transfusion of 2 patients from 1 high-yield collection. Although many small studies exist, no large studies have described the impact of methodological changes on routine blood center collections. We constructed a database containing selected parameters from 45,224 apheresis collections spanning July 1997 to April 2002, using Gambro BCT Spectra (Lakewood, CO), Fenwal CS-3000+ (Baxter Healthcare Corp, Fenwal Division, Deerfield, IL), and Baxter Amicus instruments. A Baker 9110+ hematology analyzer (Bio Chem Immunosystems, Inc., Allentown, PA) was used for platelet counting. Monthly average collection yields, distribution yields (product platelet contents after splitting), and split rates (the fraction of donations which may be split) were determined. The monthly mean collection yield and split rate correlated very closely. Both rose throughout the study period. The split rate climbed from 25% to 70% by study end. However, mean monthly distribution yields decreased by 7% because split and unsplit platelet yields both rose as split rates rose. Overcollections with the Amicus correlated with underestimation of donors' true preprocedure platelet counts during machine programming. Undercollections occurred in donors with low counts and, with-single needle Amicus, microcytic platelet collection. These results may assist in the optimization of an apheresis program. Increased collection yields correlated with cell separator type, dual-needle access, donor platelet count >250 x 10(9)/L, programming with true preprocedure platelet counts and capacity for triple product preparation from collection yields exceeding 2-bag storage capacity.

Health questionnaires and parasitologic examinations of urine and stool were evaluated from a stratified random sample of 89,180 individuals from 17,172 households in 251 rural communities in 9 governorates of Egypt to investigate the prevalence of, risk factors for, and changing pattern of infection with Schistosoma sp. in Egypt. A subset, every fifth household, or 18,600 subjects, had physical and ultrasound examinations to investigate the prevalence of and risk factors for morbidity. Prevalence of S. haematobium in 4 governorates in Upper Egypt in which it is endemic ranged from 4.8% to 13.7% and averaged 7.8%. The geometric mean egg count (GMEC) ranged from 7.0 to 10.0 ova/10 ml of urine and averaged 8.1. Age stratified prevalence of infection peaked at 15.7% in the 10-14-year-old age group and decreased to 3.5-5.5% in all groups more than 25 years of age. Age-stratified intensity of infection peaked at approximately 10.0 ova/10 ml of urine in the 5-14-year-old age groups and was about half that in all groups more than 25 years of age. Males had higher infection rates and ova counts than females in all age groups. Schistosoma mansoni was rare in Upper Egypt, being consequential in only Fayoum, which had a prevalence of 4.3% and an average intensity of infection of 44.0 ova/g of stool. Risk factors for S. haematobium infection were male gender, an age <21 years old, living in smaller communities, exposures to canal water; a history of, or treatment for, schistosomiasis, a history of burning micturition or blood in the urine, and reagent strip-detected hematuria or proteinuria. The more severe grades (II and III) of ultrasonography-detected periportal fibrosis (PPF) were rare (15 of 906) in these schistosomiasis haematobia-endemic governorates. Risk factors for morbidity (ultrasonography-detected urinary bladder wall lesions and/or obstructive uropathy) were similar to those for infection, with the exception that risk progressively increased with age. Subjects with active S. haematobium infections were 3 times as likely as those without active S. haematobium infections to have urinary tract morbidity. The prevalence of S. mansoni in 5 governorates in Lower Egypt, where it is endemic, ranged from 17.5% to 42.9% and averaged 36.4%. The GMEC ranged from 62.6 to 93.3 eggs/g of stool and averaged 81.3. Age-stratified prevalence of infection peaked at 48.3% in the 15-19-year-old age group, but averaged 35-45% in all groups more than 10 years of age. The intensity of infection was highest in the 10-14-year-old age group, and showed a range of 70-85 eggs/g of stool in those > or =5 years of age. Males had higher infection rates and ova counts than females in all age groups. Schistosoma haematobium was rare in these governorates; Ismailia (1.8%) had the highest infection rate. Risk factors for S. mansoni were male gender, an age >10 years old, living in smaller communities, exposures to canal water, a history of, or treatment for, schistosomiasis or blood in the stool, detection of splenomegaly by either physical examination or ultrasonography, and ultrasonography-detected PPF. The more severe grades (II and III) accounted for 463 (13.3%) of the 3,494 having ultrasonography-detected PPF. Risk factors for morbidity (ultrasonography-detected PPF) were similar to those for infection except that inhabitants of smaller communities were not at increased risk. Active S. mansoni infection increased the odds ratio (OR) of having PPF by 1.37. In comparison with others with normal-size livers, subjects having hepatic enlargement in either the midclavicular line or the midsternal line detected by physical examination or ultrasonography had a reduced risk (ORs = 0.64-0.72) of PPF. The prevalences of lesions detected by ultrasonography were 23.7% for enlargement of right lobe of the liver, 11.3% for enlargement of left hepatic lobe, 20.6% for splenomegaly, and 50.3% for PPF. Schistosoma mansoni has almost totally replaced S. haematobium in Lower E

The authors examined the effect of tamoxifen (TAM), a multiple-drug resistance modulator, on the pharmacokinetics of doxorubicin (DOX) in patients with non-Hodgkin's lymphoma treated according to the CHOP-protocol which included DOX, cyclophosphamide, vincristine, and prednisone. The dose of DOX was 50 mg/m2, but was reduced 25% if the patient was older than 60 years. Of these, 10 randomly-selected patients received a daily dose of 480 mg of TAM (Group-1) and 10 others did not (Group-2). Blood samples were collected at different time intervals, and DOX was measured in plasma by liquid chromatography. The concentration-time data of DOX exhibited the characteristics of the two-compartment open model well. The mean (SEM) values of alpha, beta, k12, k21, k10, Vc, Vss, AUC, total clearance, and mean residence time observed in Group-1 were 4.06 (0.96) hr(-1), 0.0395 (0.0068) hr(-1), 3.13 (0.79) hr(-1), 0.264 (0.052) hr(-1), 0.708 (0.19) hr(-1), 525 (156) l/m2, 1060 (163) l/m2, 1145 (234) microg x hr/l, 49.3 (8.5) l/hr x m2, and 26.8 (6.6) hours, respectively. Those in Group-2 were 4.99 (1.13) hr(-1), 0.0432 (0.0073) hr(-1), 2.46 (0.63) hr(-1), 0.111 (0.026) hr(-1), 2.46 (0.86) hr(-1), 231 (53) l/m2, 812 (149) l/m2, 1690 (276) microg x hr/l, 30.3 (4.1) l/hr x m2, and 29.7 (5.1) hours, respectively. Of these parameters, the difference between the two groups was significant (p < or = 0.0169) only in k21. Thus, the coadministration of TAM at the earlier-mentioned dose appears generally to have no significant influence on the pharmacokinetics of doxorubicin when used in the CHOP-protocol.

The residues of 5 samples of powdered human enamel, each subjected to 5 sequential equilibrations at 37 degrees C with either 17 or 4 mmol/l phosphoric acid, were examined microscopically. With 17 mmol/l acid, both brushite and monetite were found after 1 equilibration but, after further equilibrations, brushite was no longer present and the abundance of monetite crystals increased. Formation of monetite probably contributed to the lower metastability of this system compared to similar low-pH systems at 25 degrees C, where monetite does not form. Neither brushite nor monetite were present after equilibration with 4 mmol/l acid. Whitlockite was identified by transmission electron microscopy and electron diffraction in all residues. In the 4 mmol/l systems, the ionic activity product (IMWH) for magnesium whitlockite, Ca9Mg(HPO4)(PO4)6, became constant after 1-3 equilibrations, at a mean value of 3.6 (+/-0.51 SE).10(-105), which may reflect saturation with respect to this solid. For the 17 mmol/l systems, higher values of IMWH, and supersaturation with respect to monetite, were interpreted as evidence for persistent metastability due to slow crystal growth of whitlockite and monetite. It is concluded that neither brushite nor monetite are likely to form within carious lesions, but the results are consistent with the known association of whitlockite with caries.

The authors examined the activity of N-acetyltransferase and that of microsomal P-450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N-demethylantipyrine (MCLnora), 3-hydroxymethylantipyrine (MCLhma), and 4-hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnora in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N-acetyltransferase and that of P-450 IIIA3 responsible for the N-demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near-significantly larger metabolic clearances including MCLnora, which suggests that P-450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.

The pharmacokinetics of azathioprine (AZN) were examined in 28 renal transplant patients treated orally with 25 to 150 mg AZN once daily in combination with cyclosporin A and prednisone, and after single intravenous (IV) injection of 5 mg/kg AZN using the rabbit as an in vivo model. The steady-state concentrations of AZN observed in these patients ranged from 6 to 583 micrograms/L, and the interday coefficients of variation of the concentration in three randomly selected patients were 38%, 12%, and 4.6%. The frequency distribution pattern of the apparent oral clearance (TCLor) of AZN separates the patients almost equally into poor (TCLor = 0.126 to 4 L/hour.kg) and extensive metabolizers (TCLor = 5 to 12 L/hour.kg). The data obtained from the IV administration displayed the two-compartment model characteristics with mean (standard error of the mean) of alpha, beta, Vc, and total body clearance of 15.3 (2)/hour, 2.38 (.64)/hour, 1.05 (.3) L/kg, and 8.12 (1.26) L/hour.kg, respectively. The large variability in the pharmacokinetic parameters of AZN in patients and even in rabbits under carefully controlled conditions that may be ascribed to the complexity of its metabolism necessitates a careful approach to its dose selection.

Five samples of powered enamel were each sequentially equilibrated 5 times at 37 degrees C with either 4 or 17 mmol/l H3PO4, in contact with air, and the ionic activity product for hydroxyapatite (IHA) estimated. There was evidence for preferential release of Mg and Na, especially in the first equilibrations. In two experiments, raised values of IHA were observed in the first equilibration but otherwise IHA was reasonable constant within experimental error and was much closer to the solubility product of hydroxyapatite than many previous estimates, mainly at 25 degrees C, suggest. The mean value of IHA for the majority fraction, averaged over all samples, was 1.7 (+/- 0.7) x 10(-58). Non-apatitic solids formed in all systems but solubility appeared nevertheless to be controlled by an apatitic phase: either the enamel mineral itself or apatite reprecipitated during the course of equilibration. High values of IHA reported previously may be due to use of conditions favouring dissolution only of more soluble factions or to metastability artifacts associated with control of solubility by non-apatitic phases.

We report an expedient analysis of azathioprine (AZN) in plasma by use of a radial compression liquid chromatography and silica solid phase extraction. The separation of the drug and internal standard (antipyrine) was achieved on a C18 cartridge using a mixture of 0.01 M aqueous solution of sodium phosphate (pH = 4.5) and methanol (87:13; vol/vol) as the mobile phase. The assay is highly specific with no interference from any endogenous substance or concomitantly used drug. The peak height ratio of drug to internal standard was linearly (r greater than 0.09976) related to concentration in the range 0.005-2 micrograms/ml, and the within-run and between-day coefficient of variation did not exceed 6.9% at any concentration. This study measured the steady-state concentration of azathioprine in plasma of renal transplants patients. Also, the applicability of this method to study the pharmacokinetics of AZN following a single intravenous administration was examined, using the rabbit as an in vivo model.