Post-traumatic knee pain leading to the diagnosis of spondyloarthropathy

The authors report a patient with persistent left knee pain after traumatic injury. The initial bone scan seemed to confirm a valgus stress knee injury. The final diagnosis, however, was focal inflammation of the knee ligaments (enthesopathy) related to ankylosing spondylitis. The diagnostic procedure and the results of other imaging modalities are presented. The bone scan findings are discussed.     

Comparing the effects of 8-week treatment with fluoxetine and imipramine on fasting blood glucose of patients with major depressive disorder

This study was designed to compare the effects of fluoxetine and imipramine on fasting blood glucose (FBG) in patients with major depressive disorder. Sixty nondiabetic patients with major depressive disorder (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) entered this randomized, double-blind study. Patients did not receive any medication affecting serum FBG levels for at least 2 weeks before the initiation of the study. Patients were assigned to receive 20 to 40 mg/d of fluoxetine or 75 to 200 mg/d of imipramine for 8 weeks. Pregnant women and patients with diabetes mellitus and a history of any major heart disease were excluded from this study. Additionally, none of the patients should have received electroconvulsive therapy within 6 months before the initiation of the antidepressants. FBG levels were measured at the initiation, as well as 4 and 8 weeks after starting antidepressants. Nineteen patients in the fluoxetine and 24 patients in the imipramine groups completed the study. In the fluoxetine group, FBG level was decreased from 88.5 mg/dL (baseline) to 85.0 mg/dL at week 4 (P = 0.73), and to 79.8 mg/dL at week 8 (P < 0.001). On the other hand, in the imipramine group, FBG level was increased from 86.96 mg/dL (baseline) to 89.71 mg/dL at week 4 (P = 0.079), and to 96.90 mg/dL at week 8 (P < 0.001). This 8-week study showed that FBG levels may decrease in depressive patients receiving fluoxetine and may increase in those patients treated with imipramine. Therefore, it is suggested to measure and monitor FBG before initiation and during treatment with fluoxetine and imipramine.     

Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy

This study investigated the addition of the direct renin inhibitor aliskiren to amlodipine in patients with mild to moderate hypertension that was inadequately controlled with amlodipine alone. Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose hypertension responded inadequately to therapy (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) (n=545) were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the study's end, mean systolic blood pressure and DBP reductions with the combination of aliskiren 150 mg and amlodipine 5 mg (11.0/8.5 mm Hg) were significantly greater (P<.0001) than with amlodipine 5 mg (5.0/4.8 mm Hg)--the comparator group--but similar to amlodipine 10 mg (9.6/8.0 mm Hg). All treatments were well tolerated. Edema occurred more frequently with amlodipine 10 mg (11.2%) than with combination therapy (2.1%) or amlodipine 5 mg (3.4%). In conclusion, aliskiren 150 mg plus amlodipine 5 mg shows similar but not better blood pressure-lowering efficacy when compared with amlodipine 10 mg in patients not completely responsive to amlodipine 5 mg; less edema was noted with combination therapy.     

Multi-syndrome analysis of time series using PCA: a new concept for outbreak investigation

To date, despite widespread availability of time series data on multiple syndromes, multivariate analysis of syndromic data remains under-explored. We present a non-parametric multivariate framework for early detection of temporal anomalies based on principal components analysis of historical data on multiple syndromes. We introduce simulated outbreaks of different shapes and magnitudes into the historical data, and compare the detection sensitivity and timeliness of the multi-syndrome detection method with those of uni-syndrome. We find that the multi-syndrome detection framework provides a powerful tool for identifying such designated abnormalities in the data and significantly improves upon the detection sensitivity and timeliness of uni-syndrome analysis. The proposed multivariate framework requires minimal preprocessing of the data and can be easily adopted in settings where temporal information on multiple syndromes are routinely collected and processed, and thus can be an integral component of real-time surveillance systems.     

Assessment of vitrification outcome by xenotransplantation of ovarian cortex pieces in γ-irradiated mice: morphological and molecular analyses of apoptosis

Purpose

The aim of this study was the investigation of caspase-3/7 activity and apoptosis related gene expression after vitrification and xenotransplantation of human ovarian fragments.

Methods

Ovarian specimens were obtained from normal female-to-male transsexual women during laparoscopic surgery and cut into small pieces and were considered as vitrified and non-vitrified groups. The morphological study, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, caspase-3/7 activity and apoptosis related gene expression analysis were done in both non-vitrified and vitrified groups in two steps (before transplantation of ovarian tissues and 30 days after transplantation).

Result(s)

In spite of high rate of normal follicles in both non-transplanted tissues these rates were significantly decreased in vitrified and non-vitrified grafted tissues, moreover grafted-vitrified tissue showed significantly less normal follicles than grafted-non-vitrified group (P < 0.05). The expression of some pro and anti-apoptotic genes in vitrified-warmed tissues were not changed compared to non-vitrified ones but the expression of Fas and caspase8 was increased and the expression of BRIC5 was decreased in this group (P < 0.05). In transplanted vitrified group the Bcl2, FasL and BRIC5 gene expression was high and caspase8 was low (P < 0.05). The expression of all genes in both grafted groups was more than non-grafted tissues except for caspase8 (P < 0.05). The TUNEL positive signals and caspase-3/7 activity were increased in both grafted groups compared to non-grafted groups and this enzyme activity in grafted-vitrified group was more than grafted-non-vitrified group (P < 0.05).

Conclusion(s)

This study provides the first evidence on the significant effect of vitrification on follicular apoptosis of grafted human ovarian tissue at mRNA level. The signs of follicular survival or degeneration detected by morphological assessment and caspase-3/7 activity were closely correlated to the changes in expression of apoptosis-related genes.     

Pharmacokinetic and Pharmacodynamic Considerations of Antibiotics of Last Resort in Treating Gram-Negative Infections in Adult Critically Ill Patients

Purpose of Review

We provide an overview of antimicrobials that are considered last resort for the treatment of resistant gram-negative infections in adult critically ill patients. The role in therapy, pharmacodynamic (PD) goals, and pharmacokinetic (PK) changes in critical illness for aminoglycosides, polymyxins, tigecycline, fosfomycin, and fluoroquinolones are summarized.

Recent Findings

Altered PK in septic patients in the intensive care unit (ICU) is observed with many of our agents of last resort. Based on the available literature, dosage adjustments may be required to optimize PK parameters and meet PD targets for most effective bacterial killing. Data is limited, studies are conducted in heterogeneous patient populations, and conclusions are frequently conflicting. Strategic dosing regimens such as high-dose extended interval dosing of aminoglycosides or loading doses with colistin and polymyxin B are examples of ways to optimize antibiotic PK in critically ill patients. Benefits of these strategies must be balanced with risks of increased toxicity.

Summary

Patients with resistant gram-negative infections may present with septic shock in the ICU. Sepsis can significantly alter the PK of antibiotics and require dosage adjustments to attain optimal drug levels. An understanding of PK and PD properties of these agents of last resort will help to maximize therapeutic efficacy while minimizing toxic effects.

     

Aliskiren exhibits similar pharmacokinetics in healthy volunteers and patients with type 2 diabetes mellitus

BACKGROUND: The renin system is an attractive target for antihypertensive therapy in patients with diabetes mellitus. However, diabetes is associated with changes in gastrointestinal, renal and hepatic function that may affect the absorption and disposition of oral drugs. This study compared the pharmacokinetics and pharmacodynamics of the orally active direct renin inhibitor, aliskiren, in healthy volunteers and patients with type 2 diabetes. METHODS: This was an open-label study conducted in 30 patients with type 2 diabetes and 30 healthy volunteers matched for age, bodyweight and race. Following a 10-hour fast, all participants received a single oral dose of aliskiren 300mg. Blood samples were taken at frequent intervals for 96 hours post-dose for determination of plasma concentrations of aliskiren (using a high-performance liquid chromatography-tandem mass spectroscopy method). Plasma renin activity (PRA) and renin concentration (RC) were also measured for 24 hours after dosing. RESULTS: Aliskiren exhibited similar pharmacokinetics in patients with type 2 diabetes and healthy volunteers. Exposure to aliskiren was slightly higher in patients with type 2 diabetes compared with healthy volunteers (mean area under the plasma concentration-time curve from 0 to 24 hours 1859 vs 1642 ng . h/mL; maximum observed plasma drug concentration 394 vs 348 ng/mL), while apparent clearance corrected for bioavailability was slightly lower (205 vs 234 L/h) and elimination half-life slightly longer (44 vs 39.9 hours), but there were no statistically significant differences for any pharmacokinetic parameters. There was no significant correlation between glycaemic control (% glycosylated haemoglobin) and any of the measured pharmacokinetic parameters in patients with type 2 diabetes. Aliskiren caused sustained suppression of PRA for at least 24 hours after dosing despite increasing RC; there were no major differences in the pharmacodynamic effects of aliskiren between patients with type 2 diabetes and healthy volunteers. Aliskiren was well tolerated in both patient groups, with no clinically significant changes in laboratory values and a low risk of adverse events. CONCLUSION: Aliskiren showed a similar pharmacokinetic profile in healthy volunteers and patients with type 2 diabetes, and administration of a single oral 300 mg dose of aliskiren was well tolerated by both patients and healthy volunteers. The pharmacodynamic effects of aliskiren were also similar in healthy volunteers and diabetic patients, with sustained inhibition of renin system activity observed for at least 24 hours after dosing.     

Developmental potential and ultrastructural injuries of metaphase II (MII) mouse oocytes after slow freezing or vitrification

Purpose: The purpose of this study was to determine the developmental ability and ultrastructure of MII mouse oocytes after cryopreservation by slow freezing or vitrification.Methods: Ovulated MII mouse oocytes were allocated to slow frozen, vitrified and control groups. Oocytes in the slow frozen and vitrified groups were cryopreserved using 1,2 propandiol (PROH) and ethylene glycol (EG) respectively as cryoprotectants. After thawing, the surviving MII oocytes in both cryopreserved groups and the control group were inseminated and their developmental ability was compared. The ultrastructure of MII oocytes in both cryopreserved groups was assessed immediately after thawing and 10 h post insemination at the pronuclear stage, and compared with that of the control group.Results: The survival rates were nearly identical in both cryopreserved groups. The fertilization rates were also identical and comparable to that of the control group. The further development of vitrified oocytes was similar to that of the control oocytes, whereas it was severely limited in the slow-frozen oocytes. In the slow-frozen MII oocytes, the intermediate filaments were destroyed and the oolemma and microvilli were also modified. At the pronuclear stage deterioration of mitochondria and the presence of numerous vacuoles were also observed within the ooplasm. In the vitrified MII oocytes, the intermediate filaments were the only structures affected and these cytoskeletal elements were reorganized at the pronuclear stage.Conclusions: Vitrification results in less ultrastructural damage and better post fertilization development of MII mouse oocytes than slow freezing.     

Systemic Hyperthermia Masks the Neuroprotective Effects of MK‐801, but not Rosiglitazone in Brain Ischaemia

Abstract: The use of neuroprotective agents has been under investigation for the treatment of ischaemic brain stroke. In this study, we examined the effects of rosiglitazone and MK‐801, two potential neuroprotectants, on thromboembloic focal stroke in hyperthermic rats. The animals were assigned into groups of rosiglitazone, MK‐801 and control, all under both normothermic and hyperthermic conditions. A focal ischaemia was induced by injection of preformed clot into the origin of the middle cerebral artery. The animals were assessed by measuring infarct size and brain oedema and also evaluating neurological deficit and seizure activity. Rosiglitazone improved infarct volume and neurological deficit in both normo‐ (36%) and hyperthermic (63%) animals; but MK‐801 only improved normothermic animals. Our results do not support the use of MK‐801 in hyperthermic conditions of brain stroke but suggest that rosiglitazone may preserve its efficiency even in hyperthermia.