Oxidation of cytosolic proteins and expression of creatine kinase BB in frontal lobe in different neurodegenerative disorders

The presence of the biomarkers of oxidative damage, protein carbonyl formation and the inactivation of oxidatively sensitive brain creatine kinase (CK BB, cytosolic isoform), were studied in frontal lobe autopsy specimens obtained from patients with different age-related neurodegenerative diseases: Alzheimer's disease (AD), Pick's disease (PkD), diffuse Lewy body disease (DLBD), Parkinson's disease (PD), and age-matched control subjects. The CK activity was significantly reduced in the frontal lobe of AD, PkD and DLBD subjects, and CK BB-specific mRNA was significantly reduced in AD and DLBD. Protein carbonyl content was significantly increased in AD, PkD and DLBD. The results of this study confirm that the presence of biomarkers of oxidative damage is related to the presence of histopathological markers of neurodegeneration. Our data suggest that oxidative damage contributes to the development of the symptoms of frontal dysfunction in AD, PkD and DLBD. The development of frontal dysfunction in idiopathic PD might be secondary to oxidative damage and neuronal loss primarily located in the nigrostriatal system. The results of CK BB expression analysis demonstrate that the loss of the isoenzyme in different neurodegenerative diseases is likely the consequence of its posttranslational modification, possibly oxidative damage. Changes in CK BB expression may be an early indicator of oxidative stress in neurons.     

An audit of the quality of operation notes in an otolaryngology unit

Hand-written operation notes are often produced as evidence in medico-legal cases. Incomplete and illegible notes, along with the use of confusing abbreviations, are a common source of weakness in a surgeon's defence. An audit of 100 sets of operation notes was carried out in a single otolaryngology department. Notes were scrutinised for the accuracy of data, ward, department and name of surgeon, as well as for the inclusion of unacceptable abbreviations. Using an aide-memoire attached to the front of the operation sheet, the audit was repeated with identical criteria. The aide-memoire improved the standard of operation note with respect to all measured criteria. Clear identification of operating surgeon improved from 74% to 93%, and the avoidance of unacceptable abbreviations rose from 53% to 84%. We conclude that a simple aide-memoire attached to operation note sheets can significantly improve the quality of note-keeping and potentially avoid medico-legal problems.     

Office system interventions supporting primary care-based health behavior change counseling

CONTENT: This article reviews the literature on the effectiveness of office system interventions to improve behavior-change counseling in primary care. These instructions consist of two principle components: tools and teamwork. Tools have been developed to assist providers with health risk assessment (questionnaires, health risk appraisals), prompting and reminding (chart stickers, checklists, flow charts, reminder letters), and education (manuals and handbooks). Teamwork entails the coordination and delegation of tasks between providers and staff. CONCLUSIONS: A number of clinical trials, particularly in the area of smoking cessation, have demonstrated the effectiveness of tools and teamwork for increasing counseling rates and counseling effectiveness. Although no one type of tool or method of teamwork is consistently more effective than another-with effectiveness varying according to practice, provider, and patient characteristics-the use of different tools and teamwork approaches leads to additive improvements in counseling and patient behavior-change rates. More high-quality research is needed, particularly in the areas of health risk assessment and electronic reminder systems, to develop effective office interventions that can be readily implemented into a wide variety of primary care practices.     

Calbindins decreased after space flight

Exposure of the body to microgravity during space flight causes a series of well-documented changes in Ca²⁺ metabolism, yet the cellular and molecular mechanisms leading to these changes are poorly understood. Calbindins, vitamin D-dependent Ca²⁺ binding proteins, are believed to have a significant role in maintaining cellular Ca²⁺ homeostasis. In this study, we used biochemical and immunocytochemical approaches to analyze the expression of calbinding-D_28k and calbindin-D_9k in kidneys, small intestine, and pancreas of rats flown for 9 d aboard the space shuttle. The effects of microgravity on calbindins in rats from space were compared with synchronous Animal Enclosure Module controls, modeled weightlessness animals (tail suspension), and their controls. Exposure to microgravity resulted in a significant and sustained decrease in calbindin-D_28k content in the kidney and calbinding-D_9k in the small intestine of flight animals, as measured by enzyme-linked immunosorbent assay (ELISA). Modeled weightlessness animals exhibited a similar decrease in calbindins by ELISA. Immunocytochemistry (ICC) in combination with quantitative computer image analysis was used to measurein situ the expression of calbindins in the kidney and the small intestine, and the expression of insulin in pancreas. There was a large decrease of immunoreactivity in renal distal tubular cell-associated calbindin-D_28k and in intestinal absorptive cell-associated calbindin-D_9k of space flight and modeled weightlessness animals compared with matched controls. No consistent difference in pancreatic insulin immunoreactivity between space flight, modeled weightlessness, and controls was observed. Regression analysis of results obtained by quantitative ICC and ELISA for space flight, modeled weightlessness animals, and their controls demonstrated a significant correlation. These findings after a short-term exposure to microgravity or modeled weightlessness suggest that a decreased expression of calbindins may contribute to the disorders of Ca²⁺ metabolism induced by space flight.     

In Vivo Antitumor Activity of Bropirimine Against PAIII and Dunning Mat-Lylu Rodent Prostate Cancers

Purpose

To evaluate bropirimine for in vivo activity in rodent prostate cancer.

Materials and Methods

Subcutaneously injected PAIII and Dunning MAT-LyLu rodent prostate cancer cells caused solid tumors and death in controls. Bropirimine was given on varying schedules at 250 mg./kg. by gavage, and tumor volume and survival were recorded.

Results

Bropirimine prevented growth when given on the day of tumor injection and caused 95 percent of advanced tumors to regress completely in the PAIII model. Bropirimine caused significant growth inhibition and prolongation of survival in the MAT-LyLu model.

Conclusions

Bropirimine has statistically significant in vivo activity against both of these rodent prostate cancer cell lines.     

Simultaneous adrenal and cervical pheochromocytomas in childhood.

Pheochromocytoma is an uncommon tumor in childhood. The simultaneous occurrence of adrenal and cervical pheochromocytomas is a rare phenomenon; to our knowledge, this combination has been reported in the literature only once. Cervical pheochromocytomas are more accurately termed "aorticosympathetic paragangliomas." In children, 50% of pheochromocytomas are bilateral, multiple, or extra-adrenal. An increased familial incidence in the form of simple mendelian dominance is also noted in the pediatric age group. Bolus nephrotomography is extremely effective in identifying adrenal pheochromocytomas in children. To prepare the patient for surgery, and alpha-adrenergic blocking agent is administered from 7 to 10 days before operation and a beta-blocking agent is administered 3 days before. A transabdominal approach is essential because of the frequent extra-adrenal sites and multicentricity of the tumor in children.     

C-cell disease of the thyroid gland in multiple endocrine neoplasia, type 2b.

Multiple endocrine neoplasia, type 2b (MEN 2b) is a disorder characterized by C-cell disease of the thyroid gland (medullary carcinoma or C-cell hyperplasia, or both), pheochromocytoma, ganglioneuromatosis, and skeletal and connective tissue abnormalities. The medullary thyroid carcinoma (MTC) is bilateral and multicentric; it metastasizes locally and distally, often before the disease is recognized. Histologically proven C-cell disease was present in 89 of the 107 patients (83%) reported with the condition, including 17 Mayo Clinic patients (average age at diagnosis, 19.2 years). Nineteen of the 107 patients (18%) died of MTC (average age at death, 25.3 years); 9 (8%) succumbed to pheochromocytoma, 7 of these also having metastatic MTC; 13 12%) died of other or unknown causes, but 2 of these had disseminated MTC as well; 29 (27%) survive with metastatic MTC; an additional 21 (20%) are alive, but concentrations of plasma immunoreactive calcitonin (iCT) have not been measured; 6 more (6%), 5 of whom had thyroidectomy before the age of 12 years, are alive with normal plasma concentrations of iCT; and the remaining 10 (9%) have been lost to follow-up. Survival of patients with MEN 2b after operation was reduced when compared with that of a control population -- 80% versus 99% at 5 years and 50% versus 98% at 10 years. The only effective treatment for MTC is total thyroidectomy before metastasis occurs. "Cure" of MTC in patients with MEN 2b has generally been obtained in those having total thyroidectomy before age 12. Therefore, in young patients suspected of having MEN 2b, we recommend prompt evaluation of C-cell function by measurement of stimulated concentrations of iCT and treatment by total thyroidectomy if results are abnormal.     

Subclinical sensory neuropathy in late-onset restless legs syndrome

OBJECTIVE: To determine the prevalence of different forms of peripheral neuropathy in patients with restless legs syndrome (RLS) and correlate the findings with other clinical characteristics. BACKGROUND: RLS is characterized by a desire to move the extremities, often associated with paresthesias or dysesthesias, motor restlessness, worsening of symptoms with rest with relief by activity, and worsening of symptoms in the evening or night. The association between RLS and peripheral neuropathy remains controversial. The observation that many patients with small-fiber neuropathy also complain of RLS prompted this prospective case series. METHODS: Twenty-two consecutive patients with RLS were evaluated for evidence of large-fiber neuropathy (LFN) and small sensory fiber loss (SSFL). Results: In eight of the 22 (36%) patients, neuropathy was identified. Three patients had pure LFN; two had mixed LFN and SSFL; and three had isolated SSFL. The SSFL group had a later onset of RLS (p < 0.009), reported pain in their feet with RLS more frequently (p < 0.001), and tended to have no family history of RLS (p < 0.078). Patients with LFN did not have similar associations with age at onset, family history status, or presence of pain. CONCLUSION: The results suggest that two forms of RLS exist: one is triggered by painful dysesthesias associated with SSFL, has later onset, and no family history; and one without involvement of SSF, with an earlier onset age, positive family history for RLS, and no pain. The authors hypothesize that patients with the SSFL subtype of RLS will preferentially respond to neuropathic pain medications.     

Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy.

PURPOSE: To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. PATIENTS AND METHODS: Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. RESULTS: OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. CONCLUSION: Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook.     

Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor.

PURPOSE: To evaluate changes in epidermal growth factor receptor (EGFR) phosphorylation and its downstream signaling in tumor and surrogate tissue biopsies in patients with metastatic breast cancer treated with erlotinib, an EGFR tyrosine kinase inhibitor, and to assess relationships between biomarkers in tumor and normal tissues and between biomarkers and pharmacokinetics. PATIENTS AND METHODS: Eighteen patients were treated orally with 150 mg/d of erlotinib. Ki67, EGFR, phosphorylated EGFR (pEGFR), phosphorylated mitogen-activated protein kinase (pMAPK), and phosphorylated AKT (pAKT) in 15 paired tumor, skin, and buccal mucosa biopsies (at baseline and after 1 month of therapy) were examined by immunohistochemistry and analyzed quantitatively. Pharmacokinetic sampling was also obtained. RESULTS: The stratum corneum layer and Ki67 in keratinocytes of the epidermis in 15 paired skin biopsies significantly decreased after treatment (P = .0005 and P = .0003, respectively). No significant change in Ki67 was detected in 15 tumors, and no responses were observed. One was EGFR-positive and displayed heterogeneous expression of the receptor, and 14 were EGFR-negative. In the EGFR-positive tumor, pEGFR, pMAPK, and pAKT were reduced after treatment. Paradoxically, pEGFR was increased in EGFR-negative tumors post-treatment (P = .001). Although markers were reduced in surrogate and tumor tissues in the patient with EGFR-positive tumor, no apparent associations were observed in patients with EGFR-negative tumor. CONCLUSION: Erlotinib has inhibitory biologic effects on normal surrogate tissues and on an EGFR-positive tumor. The lack of reduced tumor proliferation may be attributed to the heterogeneous expression of receptor in the EGFR-positive patient and absence of target in this cohort of heavily pretreated patients.