Development of a novel transdermal patch of alendronate,a nitrogen‐containing bisphosphonate,for the treatment of osteoporosis

Bisphosphonates are widely used for the treatment and prevention of bone diseases, including Paget disease, hypercalcemia of malignancy, and postmenopausal osteoporosis. In this study, we developed a novel transdermal patch of alendronate, a nitrogen‐containing bisphosphonate, for the treatment of bone diseases. The maximum permeation fluxes of alendronate through rat and human skin after application of this patch were 1.9 and 0.3 µg/cm² per hour, respectively. The bioavailability (BA) of alendronate in rats was approximately 8.3% after the application of alendronate patch and approximately 1.7% after oral administration. These results indicated that the transdermal permeation of alendronate using this patch system was sufficient for the treatment of bone diseases. The plasma calcium level was effectively reduced after application of the alendronate patch in 1α‐hydroxyvitamin D₃–induced hypercalcemia model rats. The alendronate patch also effectively suppressed the decrease in bone mass in model rats with osteoporosis. Modest alendronate‐induced erythema of rat skin was observed after application of the alendronate patch. Incorporation of butylhydroxytoluene in the alendronate patch almost completely suppressed this alendronate‐induced skin damage while maintaining the transdermal permeation and pharmacologic effects of alendronate. These findings indicate that our novel transdermal delivery system for alendronate is a promising approach to improve compliance and quality of life of patients in the treatment of bone diseases. © 2010 American Society for Bone and Mineral Research.     

Tibial Component Alignment After Total Knee Arthroplasty with Intramedullary Instrumentation: A Prospective Analysis

The best operative technique for achieving appropriate postoperative alignment following total knee arthroplasty (TKA) remains controversial, with proponents of extramedullary, intramedullary and computer-assisted techniques. One hundred ninety-two consecutive patients undergoing TKA were prospectively evaluated with full-length lower extremity radiographs. Patients underwent cemented TKA using femoral and tibial intramedullary instrumentation. Digital radiographs were analyzed using PACS (AGFA Healthcare, Ridgefield Park, NJ) software. Tibial component alignment was measured in the coronal and sagittal planes. Tibial component slope averaged 3.89° + 1.96 for the cruciate-retaining components and averaged 1.7° + 1.92 for PS components. The average coronal tibial component alignment was 90.00°, and 99% were within 3° of neutral mechanical alignment with only 2 (1%) outliers. Intramedullary instrumentation resulted in excellent postoperative tibial component and lower extremity alignment.     

Hyperimmunoglobulinemia D and periodic fever syndrome

Hyperimmunogloblinemia D and periodic fever syndrome (HIDS) is inherited autoinflammatory syndrome caused by deficiency of the mevalonate kinase (MK), which is involved in metabolism of cholesterol. The disease is characterized as periodic fever from early infancy accompanied by elevated serum C-reactive protein. Since clinical symptoms such as abdominal symptom, skin rash, and arthritis are common to other autoinflammatory disease, the diagnosis of HIDS during clinical work is difficult for the physicians without suspicion of HIDS for infants suffering from fever of unknown origin. Moreover, serum IgD levels are not high during infancy conflicting to the name of the disease, which is often misunderstood in the clinicians. Thus, the diagnosis of HIDS in Japan is bothering, depending on the lack of correct recognition of the disease and on the lack of commercially available examination for the disease. It is important for clinicians, especially pediatricians to update current knowledge about HIDS and to learn the appropriate way to the definitive diagnosis of HIDS, because HIDS patients exist also in Japan and the specific therapies for HIDS would be developed in the near future.     

An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer

Nucleophosmin (NPM) is a multifunctional protein involved in a complex network of interactions. The role of NPM in oncogenesis is controversial. The NPM gene (NPM1) is mutated or rearranged in a number of hematological disorders, but such changes have not been detected in solid cancers. However, experiments with cultured NPM-null cells and with mice carrying a single inactivated NPM allele indicate a tumor suppressor function for NPM. To resolve the role of NPM in solid cancers, we examined its expression and localization in histologically normal breast tissue and a large array of human breast carcinoma samples (n = 1160), and also evaluated its association with clinicopathological variables and patient survival. The intensity and localization (nucleolar, nuclear, cytoplasmic) of NPM varied across clinical samples. No mutations explaining the differences were found, but the present findings indicate that expression levels of NPM affected its localization. Our study also revealed a novel granular staining pattern for NPM, which was an independent prognostic factor of poor prognosis. In addition, reduced levels of NPM protein were associated with poor prognosis. Furthermore, luminal epithelial cells of histologically normal breast displayed high levels of NPM and overexpression of NPM in the invasive MDA-MB-231 cells abrogated their growth in soft agar. These results support a tumor suppressive role for NPM in breast cancer.     

Custom-made angled inserts for tibial coronal malalignment in total knee arthroplasty

Component malalignment continues to be common after knee arthroplasty, with treatment often requiring prosthesis revision. From 1993 to 2005, 9 angled inserts were placed to correct coronal plane deformities due to tibial component malposition. Insert exchange occurred at an average of 67 months (range, 5-149 months) from the index procedure. Two patients died before 2-year follow-up, for an overall average of 60 months (range, 12-157 months) follow-up. Limb alignment improved and Knee Society knee and function scores increased from 68 and 71, respectively, to 92 and 91, postoperatively. All patients reported excellent satisfaction with no revisions at average 5-year follow-up. It is important to be aware that specifically designed angled inserts are available and may provide a conservative method to correct mild to moderate tibial malalignment in rare cases.     

Norepinephrine and cardiovascular responses to maximal exercise in Parkinson's disease on and off medication

The aim of this experiment is to understand how Parkinson's disease (PD) medication affects the autonomic responses of individuals during an acute exercise stress test. Fourteen people with PD and fifteen healthy individuals age‐matched between 50 and 80 years performed a modified Bruce protocol. Subjects with PD performed the test once off medication (PD‐off) and then 1 week later on medication (PD‐on). Heart rate (HR), blood pressure (BP), VO₂, and norepinephrine (NE) levels were taken at rest and at peak exercise. At peak exercise HR, BP, and NE values for the PD‐on and PD‐off group were all significantly lower than healthy controls, regardless of whether subjects were on their medication. Autonomic abnormalities during exercise in this population appear to be disease manifested and not impactedby medications used to treat PD. We can assume, both on and off medication, this population will show markedly lower BP, HR, and NE responses. © 2009 Movement Disorder Society     

Changes in T1 and T2 observed in brain magnetic resonance imaging with delivery of high concentrations of oxygen

OBJECTIVE: The aim of this study was to clarify the relative contributions of the amount of oxygen in the blood, and vasoconstriction/dilation responsible for changes in T1 and T2 observed in brain during hyperoxia. METHODS: T1 and T2 values of the cerebral cortex and pituitary gland in mice were determined in room air. After room air was changed to either 100% oxygen (n = 8) or carbogen (n = 8), T1 and T2 values were again determined. Changes in each value with both gases were compared. RESULTS: In both challenges, T1 values of the cerebral cortex decreased, whereas significant T2 prolongation of the cerebral cortex and pituitary gland was demonstrated. However, both cortex and pituitary gland displayed similar responses in T1 and T2 values when exposed to 100% oxygen or carbogen. CONCLUSIONS: Reduction of T1 was introduced by the increased amount of dissolved oxygen in blood, and the increased fraction of oxyhemoglobin caused T2 prolongation. The contribution of vasoconstriction/dilation by carbogen to changes in T1 and T2 may be negligible.     

Utility of multi-detector CT for pre-operative diagnosis of internal hernia through a defect in the broad ligament (2007: 1b)

Internal hernia through a defect in the broad ligament is a rare cause of intestinal obstruction, and pre-operative diagnosis is generally difficult. Here, we report our experience in which multi-detector computed tomography (MDCT), which allows direct recognition of incarcerated small bowel, was useful in the pre-operative diagnosis of this hernia.     

Imaging by multiple modalities of patients with a carotidynia syndrome

The purpose of this article is to familiarize readers with the clinical syndrome of carotidynia. In the past, the International Headache Society (IHS) described idiopathic carotidynia as a diagnostic entity consisting of a self-limiting neck pain syndrome and tenderness over the carotid bifurcation without structural abnormality and then recently removed it from its classification. Although the clinical criteria of carotidynia in the former classification of the IHS included the absence of structural abnormality, several publications have demonstrated associated radiological findings and have described the usefulness of radiological investigations in diagnosing this syndrome. In this paper, we report four additional cases with a carotidynia clinical syndrome (according to the former classification) and the presence of abnormal soft tissue infiltration surrounding the symptomatic carotid artery as demonstrated by multiple imaging modalities, without any other underlying cause for the carotid pain syndrome. Our findings support the hypothesis that carotidynia could be a distinct disease entity, possibly caused by inflammation.