Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose

BACKGROUND: Plasma transfusion is standard therapy for urgent warfarin reversal in the United States. "Four-factor" prothrombin complex concentrate (PCC), available in Europe, has advantages over plasma therapy for warfarin reversal; however, only "three-factor" PCCs (containing relatively low Factor [F]VII) are available in the United States.
STUDY DESIGN AND METHODS: The efficacy of a three-factor PCC for urgent warfarin reversal was evaluated in 40 patients presenting with supratherapeutic international normalized ratio (ST-INR > 5.0) with bleeding (n = 29) or at high risk for bleeding (n = 11). In 13 patients, pre- and posttherapy vitamin K-dependent factors were assayed. Historical controls (n = 42) treated with plasma alone were used for rate of ST-INR correction comparison.
RESULTS: Treatment with plasma alone (mean, 3.6 units) lowered the INR to less than 3.0 in 63 percent of historical controls. Low-dose (25 U/kg) and high-dose (50 U/kg) PCC alone lowered INR to less than 3.0 in 50 and 43 percent of patients, respectively. Additional transfusion of a small amount of plasma (mean, 2.1 units) increased the rate of achieving an INR of less than 3.0 to 89 and 88 percent for low- and high-dose PCC therapy, respectively. FII, F IX, and FX increments were similar for PCC-treated patients with or without supplemental plasma; FVII was significantly higher in the PCC plus plasma group compared to the PCC-only group (p = 0.001).
CONCLUSION: Three-factor PCC does not satisfactorily lower ST-INR due to low FVII content. Infusion of a small amount of plasma increases the likelihood of satisfactory INR lowering.     

Rapidly progressive bilateral ophthalmoplegia and enlarging sellar mass caused by amelanotic melanoma.

A 63-year-old woman with diplopia and bilateral ptosis underwent brain MRI that showed a pituitary mass with signal characteristics suggestive of adenoma. Within one week she had developed nearly complete bilateral ophthalmoplegia. A repeat MRI showed extension of the mass into both cavernous sinuses. Hypophysectomy disclosed an amelanotic melanoma. Extensive search for a primary source was unsuccessful. Despite local radiation treatment, the tumor continued to grow and the patient became blind and died within several months of diagnosis. There are seven reported cases of melanoma arising primarily in the sella turcica. Two cases of metastatic melanoma to the cavernous sinuses have been reported. Amelanotic melanoma has not been reported as a cause of cavernous sinus syndrome.     

Crotamiton-loaded tea tree oil containing phospholipid-based microemulsion hydrogel for scabies treatment: in vitro,in vivo evaluation,and dermatokinetic studies

Crotamiton (CRT) is a commonly approved drug prescribed for the scabies treatment in many countries across the globe. However, poor aqueous solubility and low bioavailability, and side effects restrict its use. To avoid such issues, an appropriate carrier system is necessary which can address the aforementioned challenges for attaining enhanced biopharmaceutical attributes. The current study intends to provide a detailed account on the development and evaluation of CRT-loaded microemulsion (ME) hydrogel formulation containing tea tree oil (TTO) for improved drug delivery for scabies treatment in a safe and effective manner. Pseudo-ternary phase diagrams were constructed with TTO as the oily phase, and Cremophor^®EL was used as the surfactant in a mass ratio 2:1 with co-surfactants (mixture of phospholipid 90G and Transcutol^®P), and aqueous solution as the external phase. The optimized drug-loaded ME formulation was evaluated for skin penetration, retention, compliance, and dermatokinetics. The nonirritant behavior of the formulation was revealed by skin histopathology, which showed no changes in normal skin histology. In comparison to the conventional product, dermatokinetic experiments revealed that CRT has greater penetration and distribution in the epidermis of the mice skin. The findings imply that the proposed lipid-based ME hydrogel can aid in the resolution of CRT issues by providing a better and safer delivery option to epidermis and deeper epidermis in substantial quantities.     

Podocyte proteins in Galloway-Mowat syndrome

Galloway-Mowat syndrome is an autosomal recessive disorder characterized by early onset nephrotic syndrome and central nervous system anomalies. Mutations in podocyte proteins, such as nephrin, α-actinin 4, and podocin, are associated with proteinuria and nephrotic syndrome. The genetic defect in Galloway-Mowat syndrome is as yet unknown. We postulated that in Galloway-Mowat syndrome the mutation would be in a protein that is expressed both in podocytes and neurons, such as synaptopodin, GLEPP1, or nephrin. We therefore analyzed kidney tissue from normal children (n=3), children with congenital nephrotic syndrome of the Finnish type (CNF, n=3), minimal change disease (MCD, n=3), focal segmental glomerulosclerosis (FSGS, n=3), and Galloway-Mowat syndrome (n=4) by immunohistochemistry for expression of synaptopodin, GLEPP1, intracellular domain of nephrin (nephrin-I), and extracellular domain of nephrin (nephrin-E). Synaptopodin, GLEPP1, and nephrin were strongly expressed in normal kidney tissue. Nephrin was absent, and synaptopodin and GLEPP1 expression were decreased in CNF. The expression of all three proteins was reduced in MCD and FSGS; the decrease in expression being more marked in FSGS. Synaptopodin, GLEPP1, and nephrin expression was present, although reduced in Galloway-Mowat syndrome. We conclude that the reduced expression of synaptopodin, GLEPP1, and nephrin in Galloway- Mowat syndrome is a secondary phenomenon related to the proteinuria, and hence synaptopodin, GLEPP1, and nephrin are probably not the proteins mutated in Galloway-Mowat syndrome. Received: 27 April 2001 / Revised: 15 June 2001 / Accepted: 18 June 2001     

Lumbar punctures: use and diagnostic efficiency in emergency medical departments

Background

Lumbar punctures (LP) are regularly and effortlessly used in the emergency medical departments (EMD). LP use and efficiency have not been fully explored in the published literature.

Aims

The goal of this study was to assess in a French EMD, the frequency of use and the diagnostic efficiency of LP, the final diagnoses, and related medical practices.

Methods

We retrospectively studied all patients who underwent an LP after admission to our adult EMD in 2004 and 2005. Patients’ medical files were reviewed to collect clinical and paraclinical features. We defined efficient LP as abnormal LP, which confirmed a suspected diagnosis in an emergency setting.

Results

A total of 247 patients, representing 0.5% of all admissions, underwent an LP. LP were efficient in fewer than 15% of cases and confirmed aseptic meningitis (8.5%), bacterial meningitis (2.4%), Guillain-Barré syndromes (1.6%), subarachnoid hemorrhages (SAH, 0.4%), and carcinomatous meningitis (0.4%). The principal differential diagnoses were infections outside the central nervous system (CNS, 30%), noninfectious neurological disorders (28.7%), and benign headaches (14.2%). The main assumed LP indications were to search for CNS infection (62%) and for SAH (25%). LP efficiency decreased dramatically according to patients’ age. Brain imaging was performed in 90% of patients prior to LP. Excessive use of polymerase chain reaction to detect herpes simplex in cerebrospinal fluid was observed. The only LP complications found were postdural puncture headaches (6.1% of cases). The rate of traumatic LP was 17%.

Conclusions

Our results are in accordance with the few published surveys on this topic. LP efficiency is modest but must be considered in light of the seriousness of suspected diagnoses. However, the search for differential diagnoses should not be neglected.     

Overweight, obesity and breast cancer prognosis: optimal body size indicator cut-points

Background Evidence from the data provided in numerous published articles indicates that obesity and overweight can have a negative prognosis role in breast cancer. However, different Body Size Indicators (BSI) and cut-points have been employed and may partly explain discrepancies between the findings of various studies. Material and methods 14,709 women were recruited, treated and followed for a first unilateral breast cancer. After randomly splitting the patients’ data into two groups, a maximum statistical outcome approach was used to select optimal BSI cut-points from a “training sample”, when prognosis events were investigated. External validation was then carried out using a “validation sample”, and agreement between the selected optimal BSI cut-points was assessed. Body Mass Index (BMI), weight (W), Ideal Weight Ratio (IWR) and Body Surface Area (BSA) were used, and were assessed at the time of diagnosis. Results The selected optimal BSI cut-points were reliable when overall survival, metastasis recurrence and disease free interval events were investigated. The chosen BMI cut-point values matched the overweight cut-point value given by the World Health Organization. Agreement between defined binary BSI was acceptable; however, it varied from “fair” to “very good”. Analysis of second primary cancer occurrence and contralateral recurrence events was not conclusive. When local and node recurrence events were taken into account, the results were inconsistent and were linked to an unconfirmed relationship between stoutness and these prognosis events. Conclusions Efficient, optimal BSI cut-points indicate a poorer prognosis, illustrated by a shortened overall survival and an increase of metastasis recurrences, from a BMI value of 25 kg/m2, a W value of 60 kg, an IWR value of 20% and a BSA value of 1.7 m2. Further BSI cut-point investigations are needed, taking into account contralateral recurrence and second primary cancer events.     

Plasma metalloproteinase-12 and tissue inhibitor of metalloproteinase-1 levels and presence, severity, and outcome of coronary artery disease

Several matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been implicated in the development and outcome of coronary artery disease (CAD). We investigated whether MMP-12 and TIMP-1 levels were associated with risk, severity, and outcome of CAD. Plasma MMP-12 and TIMP-1 levels are measured in 50 and 44 patients with CAD, respectively, by enzyme-linked immunosorbent assay. Of all patients, 16 were taking statins. Patients who were not on statins were classified into 3 groups according to number of >50% stenotic vessels. Compared with 29 volunteers without CAD, patients without statins (n = 34) had higher MMP-12 concentrations (1.71 vs 1.08 ng/ml, p = 0.021). MMP-12 levels were significantly lower in patients with than in those without statin treatment (0.99 vs 1.71 ng/ml, p = 0.008). There was no association between MMP-12 levels and number of >50% stenotic vessels. MMP-12 concentrations were not associated with outcome of CAD. However, plasma TIMP-1 levels were associated with restenosis independently of number of stenotic vessels and age (p = 0.035) but not with risk or severity of CAD. In conclusion, plasma MMP-12 concentration was associated with the presence of CAD. Statin therapy decreases plasma MMP-12 levels in patients with CAD. Increased TIMP-1 levels may prevent restenosis after angioplasty.