Alzheimer's disease amyloid beta and prion protein amyloidogenic peptides promote macrophage survival,DNA synthesis and enhanced proliferative response to CSF-1 (M-CSF)

Microglial cells, macrophage-lineage cells in the brain, are increased in amyloid-containing plaques in Alzheimer’s disease (AD) and in the lesions of prion diseases. Recent studies suggest that microglia have a central role in turnover of amyloid in these diseases. We report here that synthetic amyloid beta (Aβ) 1-42 and prion protein (PrP) 106-126 peptides promote macrophage survival; they also induce macrophage DNA synthesis, particularly in the presence of sub-optimal concentrations of the growth factor, macrophage-colony stimulating factor (M-CSF or CSF-1). These responses are proposed to provide a means to increase brain microglia/macrophage numbers thereby enhancing subsequent inflammatory/immune responses. These fibrillogenic peptides join the list of aggregates having these effects on macrophages, indicating the generality of this type of response.     

Amyloidogenicity and neurotoxicity of peptides corresponding to the helical regions of PrP(C)

An alpha-helical to beta-sheet conformational change in the prion protein, PrP(C), is believed to be causative in transmissible spongiform encephalopathies. Recent nuclear magnetic resonance structures of PrP(C) have identified three helical regions in the normal full-length protein. We have synthesised peptides corresponding to these helical regions (PrP144-154, helical region one; PrP178-193, helical region two; and PrP198-218, helical region three). Circular dichroism results show that the peptide corresponding to helical region one is unstructured, while peptides corresponding to the second and third helical regions have a high propensity to form beta-sheet structure in a pH-dependent manner in aqueous solutions. Peptides corresponding to the second helical region, PrP180-193 and PrP178-193, are the only ones that form amyloid by electron microscopy and congo red birefringence. PrP178-193 and the amyloidogenic Alzheimer's disease Abeta25-25 peptide were found to promote Cu (II)-induced lipid peroxidation and cytotoxicity in primary neuronal cultures, while PrP144-154, PrP198-218 and the nonamyloidogenic Abeta1-28 had no effect on Cu (II) toxicity. There was no increase in toxicity induced by PrP178-193 in cultures treated with Fe (II) or hydrogen peroxide, indicating a preferential modulatory effect on Cu (II) toxicity by PrP178-193. The data suggest that the PrP178-193 peptide has both structural and bioactive properties in common with Abeta25-35 and that the second putative helical region of PrP could be involved in modulation of Cu (II)-mediated toxicity in neurons during prion disease.     

Wada testing in pediatric patients by use of propofol anesthesia

BACKGROUND AND PURPOSE: Wada testing may provide important information for surgical planning in pediatric patients with medically refractory epilepsy, but it is often not used because of the difficulties in performing the angiographic portion of the procedure in conscious children. We reviewed our experience using propofol, a short-acting IV administered anesthetic agent, for pediatric patients undergoing Wada testing. METHODS: In a retrospective review of Wada tests performed on patients younger than 18 years, we identified 24 cases in which propofol anesthesia was used. We reviewed the medical records of these patients, with particular reference to dose of propofol, physiological parameters during anesthesia, and adequacy of neuropsychological testing after emergence from anesthesia. RESULTS: Patients ranged in age from 6 to 16 years (mean age, 12.5 years). Propofol induced mild reductions in blood pressure (12.4% for systolic and 13.9% for diastolic blood pressure) and heart rate (mean reduction of 4.7%), which did not require specific treatment in any patient. Recovery from anesthesia was smooth and rapid, allowing initiation of Wada testing within 15 to 25 minutes of cessation of propofol. Wada testing was successfully accomplished in all patients. CONCLUSION: Propofol provided rapid induction of anesthesia, was administered without endotracheal intubation, and did not cause substantial changes in cardiorespiratory parameters. Propofol anesthesia allowed controlled angiography among patients as young as 6 years and did not interfere with neuropsychological testing.     

Reversible findings of restricted diffusion in 5‐flourouracil neurotoxicity

A 35‐year‐old woman presented with neurotoxicity correlated to an i.v. regimen of 5‐fluorouracil as episodes of acute confusional state and abnormalities of symmetrically restricted diffusion in the periventricular white matter and corpus callosum. On discontinuing the medication, the areas of severely restricted diffusion had entirely resolved, with minimal residual T2 signal abnormality. In this case, immediate discontinuation of the chemotherapeutic agent apparently reversed the patient's symptoms and findings on MRI. The scant information available in the published literature regarding this phenomenon is reviewed with regard to 5‐fluorouracil.     

Outcomes at 1 year for the first 200 patients fitted with GyneFix at Margaret Pyke Centre.

The first 200 women to be fitted with GyneFix at the Margaret Pyke Centre, a National Health Service contraception clinic situated in central London, have been followed up at 1 year after insertion. Removals, expulsions and accidental pregnancies in that first year are recorded. Of the cohort, 80% had a known outcome at 12 months. There was one perforation with the inserter tube, leaving 199 women fitted with GyneFix who contributed 2033 woman-months of follow-up time. We recorded 22 early removals, of which 16 were for heavy or irregular bleeding and/or pain, three were because the women wished to conceive and three for other reasons. In addition there were 16 expulsions at intervals ranging from 1 day to 12 months after insertion. Four of the expulsions were unnoticed by the subjects (they were revealed by amenorrhea of pregnancy in two subjects and lost threads in the other two). There were no pregnancies with the GyneFix in situ. The expulsion rate of 8.4% (confidence interval (CI) 5.2-13.4%) and removal rate for bleeding and/or pain of 9.0% (CI 5.6-14.3%) at 12 months recorded in this cohort fall within acceptable ranges for framed intrauterine devices in a population with a large percentage of nulliparous women. However, they are perhaps not as good as had been anticipated for this revolutionary new intrauterine implant. Possible reasons for this are explored.     

Intraoperative sentinel lymph node mapping in non-small-cell lung cancer improves detection of micrometastases.

PURPOSE: Lymph node metastases are the most significant prognostic factor in localized non-small-cell lung cancer (NSCLC). Nodal micrometastases may not be detected with current standard histologic methods. We performed intraoperative technetium-99m ((99m)Tc) sentinel lymph node (SN) mapping in patients with resectable NSCLC. This study aimed to identify the first station of nodal drainage of operable lung cancers. Serial section histology and immunohistochemistry were used to validate the SN and to identify the presence of micrometastatic disease. PATIENTS AND METHODS: One hundred patients with potentially resectable suspected NSCLC were enrolled. At thoracotomy, the primary tumor was injected with 0.25 to 2 mCi (99m)Tc. Intraoperative scintigraphic readings of both the primary tumor and lymph nodes were obtained with a hand-held gamma counter. Anatomic resection with a mediastinal node dissection was then performed. RESULTS: Nine of the 100 patients did not have NSCLC (seven benign lesions and two metastatic tumors) and were excluded. Seventy-eight (86%) of 91 patients had a SN identified and a complete resection. Sixty-nine (88.5%) out of the 78 SNs were classified as true-positive with no metastases found in other intrathoracic lymph nodes without concurrent SN involvement. In nine patients, the SN was the only positive node. In seven of these nine patients, the SN was found to harbor only micrometastatic disease. CONCLUSION: Intraoperative SN mapping with (99m)Tc is an accurate way to identify the first site of lymphatic tumor drainage in NSCLC. This method may also improve the precision of pathologic staging.     

Transsulfuration, protein synthesis rate and follicle mRNA in the skin of young Merino lambs in response to infusions of methionine and serine

Methionine (Met) is usually the first limiting amino acid for sheep and supplements of Met may increase production of wool and meat. The wool response may be due to an increased supply of cysteine (Cys) from transsulfuration (TS) of Met. Met is catabolized through homocysteine to form Cys when the S from Met is transferred to serine (Ser). We hypothesized that providing additional Met would create a deficiency of Ser and that by simultaneously providing Met and Ser, TS and wool growth could be increased more than by providing Met alone. The effects of i.v. infusions of Met and Ser to young Merino lambs on TS, fractional synthesis rate (FSR) of protein in skin, follicle mRNA and wool growth were examined. Following 4 d of constant i.v. infusion of 3 g Met/d, or 10 g Ser/d or both, the isotope tracers: L-[3-(13)C]Cys, L-[ring-d5]phenylalanine (Phe) and L-[2,3,3-d3]Ser were infused over 8 h to allow for measurements of irreversible loss rate (ILR), and TS in whole body and skin. Skin biopsies were taken for measurement of FSR. Wool growth rate was measured using autoradiography. An infusion of Met significantly (P < 0.05) improved wool growth rate and increased skin FSR, Cys supply from TS and enhanced levels of follicle mRNA (from the K2.10 intermediate filament gene and three gene families encoding keratin associated proteins KAP1, KAP4 and KAP12). The extra Met lowered Ser ILR. The infusion of Ser doubled Ser ILR in the body and increased skin FSR calculated using the Cys tracer in plasma (P < 0.05). However, there were no significant (P > 0.05) changes in TS, skin FSR calculated using the Phe and Ser tracers, follicle mRNA or wool growth rate as a result of Ser infusion. While there were trends towards increased TS and FSR with Ser infusion, the overall lack of significant changes indicates a high capacity for the de novo synthesis of Ser.     

Mitomycin-C induced hemolytic uremic syndrome: a case report and literature review

Hemolytic uremic syndrome spontaneously arises in a few patients with advanced cancer, but it is more commonly related to the use of certain chemotherapeutic agents. Mitomycin-C is, etiologically, the most common causative agent inducing hemolytic uremic syndrome, in a dose dependent manner. We report this syndrome, attributable to mitomycin-C at a cumulative dose of 40 mg/m2, in a gastric cancer patient. A 42-year-old female with stage III gastric cancer underwent radical gastrectomy and was given mitomycin-C at 10 mg/m2 intravenously every four weeks as adjuvant therapy. Hemolytic uremic syndrome was diagnosed three months after the last dose of mitomycin-C administration. The most prominent symptoms included pallor, hypertension and anasarca, with laboratory evidence of microangiopathic hemolytic anemia, azotemia and hyperkalemia. Her disease was progressive, but fortunately stabilized after staphylococcus column A dialysis. Her disease remained in remission for 24 months from the time of diagnosis, and then relapsed in the form of peritoneal carcinomatosis with partial intestinal obstruction.      

Hypersensitivity of human testis-tumour cell lines to chemotherapeutic drugs

Metastatic testis tumours, in contrast to most other types of cancer, can be cured by drugs. To investigate which classes of chemotherapeutic drug are differentially toxic to testis-tumour cells, we compared the in vitro dose-response curves of 5 human testis and 5 bladder-cancer cell lines to 12 compounds. The testis cells were hypersensitive to drugs that interact directly with DNA (m-amsa, bleomycin, cisplatin, doxorubicin, methylni- trosourea, mitozolomide, etoposide, mitomycin-C), but little or no difference between the 2 cell types was seen following exposure to drugs whose mechanisms of action do not involve direct interaction with DNA (methotrexate, 5-fluorouracil, colchicine, vinblastine). We conclude that testis tumour cells are either less tolerant of, or have a reduced capacity to repair, DNA damage.     

A Novel Digital Tourniquet Using a Sterile Glove and Hemostat

Background. Surgery of the digit is facilitated with adequate hemostasis for visualization of the operative field. Several types of tourniquets have been used for this purpose, including glove fingers, Penrose drains, Marmed digital tourniquets, and standard pneumatic tourniquets.
Objective. To present a novel method to achieve hemostasis during surgery of the digit.
Materials. A slightly oversized sterile glove, a hemostat, and a pair of scissors.
Conclusion. We present a novel method to achieve hemostasis using a sterile glove and a hemostat, that allows the surgeon to methodically titrate the amount of compression necessary to attain a bloodless field while minimizing the risks of excessive pressures.
Surgery of the digit is facilitated with adequate hemostasis for visualization of the operative field. Several types of tourniquets have been used for this purpose, including glove fingers, Penrose drains, Marmed digital tourniquets, and standard pneumatic tourniquets. We present a novel method to achieve hemostasis using a sterile glove and a hemostat that allows the surgeon to methodically titrate the amount of compression necessary to attain a bloodless field while minimizing the risks of excessive pressures.