Enhanced loading regimen of teicoplanin is necessary to achieve therapeutic pharmacokinetics levels for the improvement of clinical outcomes in patients with renal dysfunction

We evaluated the clinical efficacy and safety of teicoplanin according to the pharmacokinetics (PK) therapeutic level achieved in patients with renal dysfunction. Target trough concentration (C_min) was ≥15–30 μg/ml which has been recommended in patients with normal renal function. Adult patients (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m²) who were treated by teicoplanin were included in the study. We adopted two types of regimen for the initial 3 days: the conventional regimen, and the enhanced loading regimen (10 mg/kg twice daily on the 1st day, followed by 6.7–10 mg/kg once daily for the 2nd and 3rd days]. Two hundred and eighty-eight patients were evaluated for safety, and 106 patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were evaluated for clinical efficacy. A significantly higher success rate was obtained in patients who achieved the target initial C_min compared with those that did not (75.0 % vs 50.0 %, p?=?0.008). In a multivariate analysis, initial C_min ≥15 μg/ml was an independent factor for clinical success (adjusted odds ratio: 4.20, 95 % confidence interval: 1.34–13.15). In patients with 15–30 μg/ml of maximal C_min during therapy, nephrotoxicity occurred in 13.1 %, and hepatotoxicity in 2.6 %, and these incidences were not significantly higher compared with those patients with <15 μg/ml. In conclusion, achievement of C_min of 15–30 μg/ml without delay was necessary to improve clinical outcomes for the treatment by teicoplanin in patients with renal dysfunction. Further investigation is required regarding the optimal loading regimen to achieve the therapeutic levels in those patients.     

Cord blood transplantation in a young child with pyruvate kinase deficiency

Unrelated cord blood transplantation (CBT) was performed for the treatment of pyruvate kinase (PK) deficiency in a female pediatric patient at the age of 1 year 7 months, who had been in severe and frequent transfusion‐dependent hemolytic anemia, despite red blood cell (RBC) PK activity 5.52 IU/gHb. pyruvate kinase‐liver and RBC (PK‐LR) had a compound heterozygous mutation located on exon 8: c.1044G > T/c.1076G > A (K348N/R359H). Hemoglobin and RBC PK corrected to 13.5 g/dL and 9.00 IU/gHb, respectively, with gene correction at 6 months after CBT. CBT should be considered as an option for useful treatment in children with severe PK deficiency in the absence of HLA identical sibling with normal RBC PK activity.     

Glomerular cytokine expression in murine lupus nephritis

Background

Aberrant expression of T helper cell (Th) cytokines is believed to play a central role in the pathogenesis of systemic lupus erythematosus (SLE). While the glomerulus is one of the major targets of lupus inflammation, little is known about the cytokine expression in glomeruli. The current study aimed to explore the profiles of Th cytokine gene expressions in isolated glomeruli of lupus-prone mice.

Methods

Glomeruli were purified from lupus-prone MRL/lpr mice using the magnetic microbead method. Expressions of cytokine genes representing the Th subset and FoxP3 were examined using real-time polymerase chain reaction. Serum levels of these cytokines were also measured by enzyme-linked immunosorbent assay. MRL/n mice were used as controls. Histologic glomerular damages were scored semiquantitatively. To examine the role of TNF-α in glomerular damage, we administered etanercept, a TNF-α antagonist, into the subjects.

Results

Glomerular gene expressions of TNF-α in lpr mice increased with week postpartum and reached statistically significant levels at 16 weeks compared with those of the glomeruli from control mice. Expressions of IFN-γ, IL-4 and FoxP3 also increased, but the difference was not significant. There was a significant increase in serum levels of TNF-α, IFN-γ, and IL-17 and decrease in those of IL-4. Among the genes examined, TNF-α significantly correlated with glomerular damage score. Administration of etanercept did not affect glomerular cytokine expressions or proteinuria and failed to ameliorate histologic glomerular damages.

Conclusion

Our data suggest that Th1 cytokines, especially TNF-α, are dominantly expressed in the glomeruli of lupus-prone mice, but its pathophysiological role remains unclear.

     

Role of TGF-beta in proliferative vitreoretinal diseases and ROCK as a therapeutic target

Cicatricial contraction of preretinal fibrous membrane is a cause of severe vision loss in proliferative vitreoretinal diseases such as proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). TGF-β is overexpressed in the vitreous of patients with proliferative vitreoretinal diseases and is also detectable in the contractile membranes. Therefore, TGF-β is presumed to contribute to the cicatricial contraction of the membranes, however, the underlying mechanisms and TGF-β's importance among various other factors remain to be elucidated. Vitreous samples from PDR or PVR patients caused significantly larger contraction of hyalocyte-containing collagen gels, compared with nonproliferative controls. The contractile effect was strongly correlated with the vitreal concentration of activated TGF-β2 (r = 0.82, P < 0.0001). PDR or PVR vitreous promoted expression of α-smooth muscle actin (α-SMA) and phosphorylation of myosin light chain (MLC), a downstream mediator of Rho-kinase (ROCK), both of which were dramatically but incompletely suppressed by TGF-β blockade. In contrast, fasudil, a potent and selective ROCK inhibitor, almost completely blocked the vitreous-induced MLC phosphorylation and collagen gel contraction. Fasudil disrupted α-SMA organization, but it did not affect its vitreal expression. In vivo, fasudil significantly inhibited the progression of experimental PVR in rabbit eyes without affecting the viability of retinal cells by electroretinographic and histological analyses. These results elucidate the critical role of TGF-β in mediating cicatricial contraction in proliferative vitreoretinal diseases. ROCK, a key downstream mediator of TGF-β and other factors might become a unique therapeutic target in the treatment of proliferative vitreoretinal diseases.     

Increased myostatin synthesis in rat gastrocnemius muscles under high-protein diet

More than 15% dietary protein has reportedly not led to significant muscle hypertrophy in normal growing rats. The aim of this study was to test whether a high protein (HP) diet affects myostatin (Mstn) synthesis in a rat gastrocnemius muscle. Twenty-four male Wistar rats (4-wk-old) were divided into three groups: 1) control diet (15% protein; 15P, n = 8), 2) the 25P group (25% protein, n = 8), and 3) the 35P group (35% protein, n = 8). After 3 wk of isoenergetic feedings, the Mstn level in skeletal muscles was determined using Northern and Western blotting analysis. After the experimental feeding, muscle masses were similar among groups. The 35P showed significant high expressions of Mstn both at mRNA and protein levels. Obtained results suggest that a high-protein diet leads to the high Mstn level to restrict muscle hypertrophy.     

Reversible hypocalcemic heart failure with T wave alternans and increased QTc dispersion in a patient with chronic renal failure after parathyroidectomy

Despite the crucial role of calcium in myocardial contractility, hypocalcemia has very rarely been reported as a reversible cause of heart failure. In this article, we describe a case of a 51-year-old woman with advanced stages of chronic renal failure after parathyroidectomy who exhibited congestive heart failure, severe hypocalcemia, hypomagnesemia and hypokalemia. Severe hypocalcemia resulted from discontinuation of taking calcium supplements after parathyroidectomy and from reduced 1.25(OH)2D3 synthesis by damaged kidneys. The patient presented with reduced left ventricular ejection fraction (EF) and ECG abnormalities (T wave alternans and increased QTc dispersion), both of which improved after correction of serum calcium levels. Her serum levels of total calcium corrected for serum albumin, but not serum levels of magnesium or potassium, positively and negatively correlated with EF and QTc dispersion, respectively. In the present case, both heart failure and the ECG abnormalities are directly associated with hypocalcemia.     

Clinical study of a modified Brooks technique for atlanto-axial subluxation using polyethylene tape

Forty-four patients, 15 males and 29 females (3-71 years old; mean age, 52.9), were treated for the control of cervical instability with a modified Brooks operation using Tekmilon tape (an ultrahigh molecular weight polyethylene tape) instead of metal wires. Forty of the patients had rheumatoid arthritis (RA) with atlanto-axial subluxation (AAS), three patients had os odontoideum, and one patient had a cervical spine injury. The mean follow-up period was 8 years and 4 months. These patients were divided into three groups: 30 years or less, 31 to 60 years, and over 60 years. Atlanto-dental interval (ADI), inclination angle of atlanto-axial vertebrae (A-A angle), and bone fusion were examined on plain radiographs. The proportion of patients with reduced neck pain (Ranawat's grade 0 or grade 1) increased from 42.5% to 97.9% at the time of postoperative evaluation. Surgical complications, such as dural tear, lamina fracture, and spinal cord injury did not occur in any cases. Thirty-nine patients (88.6%) achieved bone union. ADI in the maximum flexed position improved from 10.3 to 2.5 mm. There was no statistical difference between ADI in males and females. ADI did not change in any age group both before and after surgery. A-A angle also improved from 9.4 to 24.4 degrees. The polyethylene tapes, used for internal fixation, caused no neurologic complications during sublaminar wiring and produced no MR artifacts. This modified Brooks technique using Tekmilon tape was proved to be a simple and safe treatment of AAS.     

Initial experience with video-assisted thoracoscopic surgery for pulmonary metastasis in the prone position

We performed video-assisted thoracoscopic surgery for pulmonary metastasis with the patient in the prone position because the use of the full lateral decubitus position was not possible owing to a deformity of the upper extremity, which existed because of a previous operation for osteosarcoma. In cases where the lateral decubitus position cannot be used, the prone position is both safe and effective for treating dorsal lesions of the lung by means of video-assisted thoracoscopic surgery.     

Adenoid Cystic Carcinoma Arising from the Lower Eyelid

Background

Primary cutaneous adenoid cystic carcinoma is one of the rarest eyelid tumors.

Case

A 39-year-old man presented with a small subcutaneous induration in his left lower eyelid close to the lower lacrimal punctum.

Observations

Under a clinical diagnosis of chalazion, the eyelid induration was extracted surgically via the palpebral conjunctiva. Histopathological examination of the extracted tumor revealed proliferation of basaloid cells with a prominent cribriform pattern containing Alcian blue-positive and periodic acid Schiff-positive material, leading to a diagnosis of adenoid cystic carcinoma. The patient subsequently underwent extended radical excision including the lacrimal sac. No recurrence was observed during 20 months after surgery.

Conclusions

Adenoid cystic carcinoma should be considered as a differential diagnosis of eyelid tumors simulating chalazion. Adenoid cystic carcinoma in the eyelid may have a more favorable prognosis than that in the lacrimal gland.?Jpn J Ophthalmol 2006;50:374–376 © Japanese Ophthalmological Society 2006