Intra-arterial urokinase infusion in diabetic patients with rapidly progressive ischemic foot lesions.

OBJECTIVE: The effectiveness of local intra-arterial thrombolysis by urokinase was evaluated in eight non-insulin-dependent diabetic patients with angiographic evidence of infrapopliteal occlusive disease and rapidly progressive foot lesions. RESEARCH DESIGN AND METHODS: With an electric peristaltic pump, urokinase was infused for 96 h by a 5-6 F catheter introduced into the femoral artery and placed immediately above the occluded infrapopliteal arteries. After baseline, angiography was repeated at 24- to 48-h intervals and at conclusion of the treatment. RESULTS: Six patients showed immediate improvement of clinical symptoms. Angiography revealed the reestablishment of blood flow in collateral vessels of the leg and foot in the dorsal pedal artery in three patients and in the plantar arch in two. Recanalization of the major arteries of the trifurcation was not achieved. After 12 mo of follow-up, all limbs were salvaged, although four patients required vascular reconstruction to further improve foot perfusion and complete healing. CONCLUSIONS: Intra-arterial urokinase, which opens collateral and smaller vessels of the leg and foot in patients with diabetes, may be effective in improving blood flow in lower extremities and in making the patient a better candidate for vascular surgery.     

Magnetic resonance imaging findings in piriformis syndrome: a case report

Piriformis syndrome (PS) is an unusual cause of sciatica that, because of the lack of strict diagnostic criteria, remains a controversial clinical entity. The diagnosis of PS is still primarily clinical because no diagnostic tests have proven to be definitive. We report the case of a 30-year-old woman, affected by a severe scoliosis, who developed a persistent buttock pain resembling that of PS. The clinical suspicion was confirmed by magnetic resonance imaging (MRI) of the pelvis, which showed an enlargement of the left piriformis muscle with an anterior isplacement of the sciatic nerve. The role of MRI in the diagnosis, clinical definition, and therapeutic approach to PS is discussed.     

A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway.     

Circulating anti-insulin receptor antibodies in a patient suffering from lupus nephritis and hypoinsulinemic hypoglycaemia

A 46-year-old female patient suffering from Lupus Nephritis came to our attention in 1981 for severe recurrent hypoglycaemia; she was obliged to eat every 5-7 hr to maintain glucose values not below 1.3-1.6 mM. All known causes of hypoglycaemia were excluded by performing selective angiography of the pancreas and skull, chest and abdominal computerized tomography, as well as stimulation and suppression tests. Oral glucose tolerance, tolbutamide and intravenous insulin (0.4 U/Kg b.w.) tests demonstrated that the patient was highly insulin resistant; furthermore, studies on the patient's red blood cells suggested that her insulin receptors were completely unable to bind insulin. Studies carried out to reveal the reason for this binding inhibition demonstrated that red blood cells from normal subjects as well as adipocytes from normal rats incubated with the patient's serum did not bind insulin (50% inhibition occurring at about 1:30 serum dilution). Insulin binding inhibitors were found in the fraction of the serum precipitated by ammonium sulphate. The serum cleared of IgG fraction was unable to affect insulin binding. These data demonstrate that the serum from the female patient investigated contained anti-insulin receptor antibodies blocking the binding of insulin to its receptors. Plasmapheresis improved the patient's metabolic status. The clinical picture would suggest that recurrent hypoglycaemia was caused by anti-insulin receptor antibodies acting as insulin on target cells.     

Management of pain in elderly patients receiving infusion of zoledronic acid for bone metastasis: a single-institution report

Goals of work Bone metastases are a common cause of morbidity in elderly patients with solid tumors and myeloma. We studied the safety and the effect of a new bisphosphonate, zoledronic acid (ZA), on pain and on quality of life (QoL) in elderly patients with bone metastases. Materials and methods From January 2004 to December 2005, we have enrolled elderly patients with bone metastasis for receiving ZA administration. Visual analog scale (VAS) and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire were used to assess potential benefits of ZA therapy. Results Eighty-six patients were included; the median age was 75.5 years. Before starting treatment, the mean VAS was 6.8 (±0.24), after three infusions 5.4 (±0.3), and after six courses 4.5 (±0.3) with a significant improvement of bone pain. Moreover, we found a statistically significant improvement of QoL measured by FACT-G questionnaire after six courses (p = 0.010). Median baseline and final value of serum creatinine were 0.73 and 0.72 mg/dl, respectively (p = 0.11); creatinine clearance was also normal for most patients. Osteonecrosis of the jaw was diagnosed in one patient who received a prolonged ZA treatment. Conclusions These data confirm the benefits of ZA on pain and QoL also in elderly patients with bone metastasis from solid tumors.     

丹参酮ⅡA对神经祖细胞系C17．2的保护作用

目的:了解丹参酮ⅡA对神经祖细胞系C17.2的保护作用,探讨其可能的作用机制。方法:本实验于2005年起在广州血液中心器官移植配型中心实验室进行。C17.2祖细胞系由澳大利亚新南威尔士大学解剖教研室David Walsh博士惠赠。将C17.2细胞以1×109L-1的密度接种,用含10%胎牛血清IMDM,37℃、体积分数为0.05CO2、饱和湿度的CO2培养箱培养,接近融合的C17.2细胞用含0.1mmol/LEDTA的胰酶室温消化,按1∶3的比例传代。C17.2细胞以5×107L-1的密度接种于96孔板或25cm2的培养瓶中,用含10%胎牛血清IMDM培养过夜后,加入含4g/L AAPH(水溶性偶氮引发剂2,2'-偶氮二(2-脒基丙烷)二盐酸盐)无血清的IMDM培养基培养建立神经细胞凋亡模型。C17.2细胞以5×103/孔的密度接种于96孔板中,用含10%胎牛血清IMDM培养过夜后,加入含4g/LAAPH无血清的IMDM培养基培养。对照组不加入丹参酮ⅡA,实验组分别加入0.02,0.05,0.1,0.2mg/L丹参酮ⅡA培养8h,噻唑蓝法检测细胞活性:细胞活性的相对值=(实验组吸光度值/对照组吸光度值)×100%,流式细胞仪检测细胞凋亡。结果:①AAPH处理8h后,C17.2细胞被过氧化损害,大多数细胞失去正常的形态,细胞呈圆形,脱落。加入丹参酮ⅡA后,细胞形态基本保持正常,少数细胞呈圆形。②C17.2细胞在IMDM的培养液中,细胞数量是含4g/L AAPH无血清的IMDM培养基条件下的2.5～3倍。浓度为0.02,0.05,0.1mg/L的丹参酮ⅡA对C17.2细胞有保护作用,质量浓度大于0.2mg/L丹参酮ⅡA对C17.2细胞保护作用降低。③AAPH作用前大部分C17.2细胞的线粒体完整,有少量的早期凋亡细胞和凋亡细胞,AAPH作用后凋亡细胞总数、凋亡细胞明显增加。丹参酮ⅡA处理组可以明显减少早期凋亡细胞。结论:在体外丹参酮ⅡA对神经细胞具有抗凋亡的作用,可以保护神经细胞。     

Serum procalcitonin concentrations in term delivering mothers and their healthy offspring: a longitudinal study

BACKGROUND: The reported sensitivities and specificities of procalcitonin (PCT) concentrations for the diagnosis of neonatal infection vary widely. A postnatal increase of PCT has been observed in healthy term newborns with a peak at approximately 24 h of age, and many questions remain regarding maternal and perinatal factors that may influence the normal PCT kinetics during the immediate postnatal period. METHODS: We prospectively investigated the association between the serum PCT values obtained from 121 mothers at delivery and serum PCT in their healthy, term offspring at birth as well as at 24 and 48 h of age. We also analyzed whether obstetric and perinatal factors would alter maternal and neonatal PCT response. RESULTS: PCT concentrations in the babies at birth were significantly higher than in the mothers (P <0.0001), with even larger differences at 24 and 48 h of age. None of the variables identified from maternal and perinatal histories had a significant effect on maternal PCT response. In the healthy neonate, the variables that significantly affected the concentration of PCT at birth were the mothers' PCT (P <0.01), maternal group B streptococcus colonization (P <0.05), and rupture of membranes >/=18 h (P <0.01). The coefficient of linear correlation between the mother's PCT concentration and that of the baby at birth was 0. 32 (P <0.01). The only variable that significantly altered the PCT concentration at both 24 (P <0.01) and 48 (P <0.01) h of age was rupture of membranes >/=18 h. Nonetheless, the PCT response observed during the 48-h period after birth among healthy babies born to mothers with risk factors for infection was well below that reported previously among age-matched neonates with sepsis. CONCLUSIONS: The postnatal increase of PCT observed in the healthy neonate with peak values at 24 h of age most likely represents endogenous synthesis. In estimating the sensitivities and specificities of PCT for diagnosis of sepsis throughout the initial 48 h of life, it is important to consider the normal PCT kinetics and the pattern(s) of PCT response in the healthy neonate.     

d-penicillamine reduces serum oxidative stress in Alzheimer's disease patients

BACKGROUND: Several lines of evidence address the emerging role for copper in Alzheimer's disease (AD) for sustaining oxidative mechanisms. Studies indicate that peripheral markers of oxidative stress in AD patients could be informative about the pathophysiology of this brain condition. Here, we present a pilot study examining the efficacy of the copper-chelating agent d-penicillamine in reducing oxidative stress in AD patients. DESIGN: Serum levels of copper sampled in AD patients and healthy controls indicate a copper homeostasis imbalance in AD. On this basis, 34 AD patients were enrolled in a 6-month, double-blind, placebo-controlled trial with the copper d-penicillamine-chelating agent. Nine patients for each group completed the trial. Oxidative stress, trace metals and clinical parameters were evaluated. RESULTS: At the start of the study (t0) total peroxides and copper serum content of AD patients were higher (P < 0.0001, P < 0.0001, respectively) and antioxidants were lower (P < 0.05) than in healthy controls. Copper and peroxides were correlated in the AD population (Pearson's r = 0.61, P < 0.001). After treatment with d-penicillamine, the extent of oxidative stress (P < 0.05) was decreased, but no difference was observed in the rate of cognitive decline. CONCLUSION: Data from this pilot study suggest that copper could play a role in the production of peroxides in AD, and that d-penicillamine has an effect in reducing oxidative damage, however, results are still inconclusive in terms of drug efficacy on the clinical progression of AD. Studies with larger cohorts are needed to elucidate the real effectiveness of d-penicillamine treatment in AD.     

Erythrocyte-mediated delivery of drugs,peptides and modified oligonucleotides

An important determinant for the success of every new therapy is the ability to deliver the molecules of interest to the target cells or organ. This selective delivery is even more complex when the therapeutic agents are peptides, modified oligonucleotides or genes. In this paper we summarize the possibility of using autologous erythrocytes for the delivery and targeting of new and conventional therapeutics. In fact, a number of macromolecules can be encapsulated by different procedures into human erythrocytes. These modified cells can then be re-infused into the same or a compatible recipient where they can circulate for several weeks. However, drug-loaded erythrocytes can also be modified to be selectively recognized by tissue macrophages. These phagocyte cells recognize the modified drug-loaded erythrocytes which are able to release their content into the macrophage. The feasibility and safety of the use of erythrocytes as drug delivery systems was evaluated in 10 cystic fibrosis patients, where a sustained release of corticosteroids from dexamethasone 21-phosphate-loaded erythrocytes was obtained. In vitro human erythrocytes were found to be able to deliver ubiquitin analogues and modified oligonucleotides to macrophages. Thus, drug-loaded erythrocytes are safe and useful carriers of new and conventional therapeutics and can be advantageous delivery systems for new clinical applications where proteins and oligonucleotides are therapeutic agents.