Switching from oral extended-release methylphenidate to the methylphenidate transdermal system: continued attention-deficit/hyperactivity disorder symptom control and tolerability after abrupt conversion.

OBJECTIVE: To evaluate symptom control and tolerability after abrupt conversion from oral extended-release methylphenidate (ER-MPH) to methylphenidate transdermal system (MTS) via a dose-transition schedule in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: In a 4-week, prospective, multisite, open-label study, 171 children (164 intent-to-treat) with diagnosed ADHD aged 6-12 years abruptly switched from a stable dose of oral ER-MPH to MTS in nominal dosages of 10, 15, 20, and 30 mg using a predefined dose-transition schedule. After the first week on the scheduled dose, the dose was titrated to optimal effect. The primary effectiveness outcome was the change from baseline (while taking ER-MPH) to week 4 in ADHD-Rating Scale-IV (ADHD-RS-IV) total scores. Adverse events (AEs) were assessed throughout the study. RESULTS: Most subjects (58%) remained on the initial MTS dose defined by the dose-transition schedule; 38% increased and 4% decreased their MTS dose for optimization. MTS dose optimization resulted in significantly better ADHD-RS-IV total (mean +/- SD) scores at week 4 than at baseline (9.9 +/- 7.47 vs. 14.1 +/- 7.48; p < 0.0001). The most commonly reported AEs included headache, decreased appetite, insomnia, and upper abdominal pain. Four subjects (2.3%) discontinued because of application site reactions and three discontinued because of other AEs. CONCLUSIONS: Abrupt conversion from a stable dose of oral ER-MPH to MTS was accomplished using a predefined dose-transition schedule without loss of symptom control; however, careful titration to optimal dose is recommended. Most AEs were mild to moderate and, with the exception of application site reactions, were similar to AEs typically observed with oral MPH. Limitations of this study included its open-label sequential design without placebo, which could result in spurious attribution of improvement to the study treatment and precluded superiority determinations of MTS over baseline ER-MPH treatment. The apparent superiority of MTS was likely due to more careful titration and clinical monitoring rather than the product itself. ClinicalTrials.gov: NCT00151983.

Evaluation of Z-(R,R)-IQNP for the potential imaging of m2 mAChR rich regions of the brain and heart.

Alterations in the function or density of the m2 muscarinic (mAChR) subtype have been postulated to play an important role in various dementias such as Alzheimer's disease. The ability to image and quantify the m2 mAChR subtype is of importance for a better understanding of the m2 subtype function in various dementias. Z-(R)-1-Azabicyclo[2.2.2]oct-3-y (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-(R,R)-IQNP) has demonstrated significant uptake in cerebral regions that contain a high concentration of m2 mAChR subtype in addition to heart tissue. The present study was undertaken to determine if the uptake of Z-(R,R)-IQNP in these regions is a receptor mediated process and to identify the radiospecies responsible for binding at the receptor site. A blocking study demonstrated cerebral and cardiac levels of activity were significantly reduced by pretreatment (2-3 mg/kg) of (R)-3-quinuclidinyl benzilate, dexetimide and scopolamine, established muscarinic antagonists. A direct comparison of the cerebral and cardiac uptake of [I-125]-Z-(R,R)-IQNP and [I-131]-E-(R,R)-IQNP (high uptake in ml, m4 rich mAChR cerebral regions) demonstrated Z-(R,R)-IQNP localized to a higher degree in cerebral and cardiac regions containing a high concentration of the m2 mAChR subtype as directly compared to E-(R,R)-IQNP. In addition, a study utilizing [I-123]-Z-(R,R)-IQNP, [I-131]-iododexetimide and [I-125]-R-3-quinuclidinyl S-4-iodobenzilate, Z-(R,R)-IQNP demonstrated significantly higher uptake and longer residence time in those regions which contain a high concentration of the m2 receptor subtype. Folch extraction of global brain and heart tissue at various times post injection of [I-125]-Z-(R,R)-IQNP demonstrated that approximately 80% of the activity was extracted in the lipid soluble fraction and identified as the parent ligand by TLC and HPLC analysis. These results demonstrate Z-(R,R)-IQNP has significant uptake, long residence time and high stability in cerebral and cardiac tissues containing high levels of the m2 mAChR subtype. These combined results strongly suggest that Z-(R,R)-IQNP is an attractive ligand for the in vivo imaging and evaluation of m2 rich cerebral and cardiac regions by SPECT.

Incidence and management of catheter occlusion in implantable arm ports: results in 391 patients.

PURPOSE: To evaluate the incidence and management of catheter occlusion in implantable arm ports. MATERIALS AND METHODS: Findings were prospectively examined in 391 patients in whom 393 arm ports were placed. The indications for port placement included chemotherapy (n = 347), antibiotic administration (n = 35), combination chemotherapy/antibiotic use (n = 7), transfusion (n = 3), and phlebotomy (n = 1). Of the total catheters, 323 (82.2%) underwent tip modification prior to placement. Malfunctioning catheters were usually treated with urokinase instillation. RESULTS: Three hundred ninety-three devices were implanted with 247 mean days of catheter use (total, 97,256 days; range, 1-694 days). The overall incidence of catheter occlusion was 0.14 per 100 catheter days. A single catheter occlusion occurred in 90 (22.9%) catheters, with a mean of 90.1 days before the event. A second occlusion occurred in 36 (9.2%) of the above catheters, with a mean of 60.1 catheter days before the second event. Eighty-five (24.0%) of the 347 cancer patients had at least one occlusive event, yielding a complication rate of 0.098 per 100 catheter days at risk (95% confidence interval [CI]; 0.079-0.114). Of the 35 patients receiving antibiotics, three (8.6%) had at least one occlusive event. This represented a complication rate of 0.032 per 100 catheter days at risk (95% CI; 0.010-0.061). Seventeen (24.3%) of the nonmodified catheters developed an occlusion versus 72 (22.3%) of the modified (P > .05; Fisher exact test). Of the catheters with a first occlusive event, 75 (98.7%) were treated successfully with urokinase instillation. Four (1.0%) patients developed symptomatic subclavian vein thrombosis. No bleeding complications occurred. CONCLUSION: Catheter occlusion is a common complication of long-term arm port placement, with a significantly higher incidence in the cancer patients in our series (P <. 05, Fisher exact test). Catheter tip modification, however, does not considerably affect the incidence of occlusion. Low-dose urokinase therapy is a safe and efficacious treatment of catheter occlusion, obviating the need for catheter removal.

Infectious complications of 393 peripherally implantable venous access devices in HIV-positive and HIV-negative patients.

PURPOSE: To compare and investigate the rate of infection in patients with and without human immunodeficiency virus (HIV) who have implantable venous access devices placed by interventional radiologists. MATERIALS AND METHODS: Three hundred ninety-one patients undergoing radiologically guided placement of peripheral arm ports were grouped according to their HIV serologic status. Findings were prospectively reviewed in 393 peripherally placed arm ports that were implanted in the basilic, cephalic, or brachial vein under fluoroscopic or sonographic guidance over a 4-year span. Infectious complications were categorized according to severity (local or systemic) and time (periprocedural or late). RESULTS: Three hundred ninety-three ports have been indwelling for a total of 97,256 patient days (range, 1-694; mean duration, 247 days). Among the 30 catheter placements in 29 HIV-positive patients with a total exposure time of 7,242 days, five (one local and four systemic) infections occurred, resulting in a 16.6% overall infection rate, yielding 0.069 infections per 100 catheter days at risk (95% confidence interval [CI], 0.032-0.127). In the remaining 362 HIV-negative patients, 27 (14 local and 13 systemic) infectious complications (7.4%) occurred, translating into 0.030 infections per 100 catheter days (95% CI, 0.021-0.042). The odds ratio of getting an infection from the implantable arm ports in the HIV-positive group was 2.5 times higher than that of the HIV-negative group. The relative risk was similar and was calculated to be 2.3. The P value was .084 (P < .05 required to be considered significant). CONCLUSIONS: These results suggest a significant difference in the infectious complication rate encountered in HIV-positive patients compared with the general population. However, the HIV-positive peripheral arm port infection rate compares favorably with the surgically placed catheters and ports. Many more arm ports in HIV-positive patients must be evaluated for the data to achieve an acceptable level of statistical significance.

Use of a motorized wheelchair in conjunction with a guide dog for the legally blind and physically disabled.

There is limited literature concerning use of wheelchairs by patients with combined visual impairment and neuromuscular diseases. This case report describes the use of a motorized wheelchair and guide dog by a legally blind patient with severe visual loss due to oculocutaneous albinism. He had concomitant decreased functional mobility from degenerative joint disease of both knees, which limited his ambulation capability. After careful consideration of risks and a successful trial of its use in the corridors of our institution, as well as successfully traveling with it outdoors, he was given a motorized wheelchair. He has continued to use it safely and successfully along with his guide dog. Combined visual and neuromuscular diseases will be encountered with increasing frequency because of the aging population, and it is therefore important for physiatrists to be able to provide assistive devices for such individuals. Vision loss is not an absolute contraindication to motorized wheelchair use.

Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice.

The chemotherapeutic effectiveness of cytosine nucleoside analogues used in cancer therapy is limited by their dose-dependent myelosuppression. A way to overcome this problem would be to insert the drug-resistance gene, cytidine deaminase (CD), into normal hematopoietic cells. CD catalyzes the deamination and pharmacological inactivation of cytosine nucleoside analogues, such as cytosine arabinoside (Ara-C). The objective of this study was to determine if we could obtain long-term persistence and expression of proviral CD in hematopoietic cells following transplantation of CD-transduced bone marrow cells in mice. Murine hematopoietic cells were transduced with an MFG retroviral vector containing CD cDNA and transplanted into lethally irradiated mice. The recipient mice were administered three courses of 10-15 h i.v. infusions of Ara-C (75-110 mg/kg). Blood, marrow and spleen samples were obtained and analyzed for CD proviral DNA by PCR, CD activity by enzyme assay, and drug resistance to Ara-C by clonogenic assay. We detected the presence of the CD proviral DNA in most of the samples examined. Approximately 1 year after transplantation several mice showed increased expression of CD activity in these tissues and some mice displayed signs of Ara-C resistance. These data demonstrate that persistent in vivo expression of proviral CD can be achieved in transduced hematopoietic cells and indicate some potential of this gene for chemoprotection to improve the efficacy of cytosine nucleoside analogues in cancer therapy.

Resistance to cytosine arabinoside by retrovirally mediated gene transfer of human cytidine deaminase into murine fibroblast and hematopoietic cells.

Dose-limiting hematopoietic toxicity produced by the cytosine nucleoside analogue cytosine arabinoside (ARA-C) is one of the major factors that limit its use in the treatment of neoplastic diseases. An interesting approach to overcome this problem would be to insert a gene for drug resistance to ARA-C in normal hematopoietic cells to protect them from drug toxicity. The deamination of ARA-C by cytidine deaminase results in a loss of its antineoplastic activity. The objective of this study was to determine if gene transfer of human cytidine deaminase into murine fibroblast and hematopoietic cells would confer drug resistance to ARA-C. Retrovirally mediated transfer of the human cytidine deaminase gene into 3T3 fibroblasts resulted in efficient expression of the proviral RNA for this gene and in increased cytidine deaminase activity in cytoplasmic extracts. These cells showed marked resistance to ARA-C as determined by the effects of this drug on colony formation, cell growth, and DNA synthesis. The transfer of the human cytidine deaminase gene into murine bone marrow cells by the retroviral vector conferred a high level of drug resistance to ARA-C in clonogenic assays. These studies indicate that the cytidine deaminase gene could be used in cancer gene therapy by protecting normal hematopoietic cells against the cytotoxic effects of ARA-C and related cytosine nucleoside analogues.

Retrovirus-mediated gene transfer of rat glutathione S-transferase Yc confers in vitro resistance to alkylating agents in human leukemia cells and in clonogenic mouse hematopoietic progenitor cells.

Recently, we have reported that N2Yc, a Moloney-based retrovirus vector expressing the Yc isoform of rat glutathione S-transferase (GST-Yc), conferred resistance to alkylating agents in mouse NIH-3T3 fibroblasts. In this report, we address the feasibility of using rat GST-Yc somatic gene transfer to confer chemoprotection to the hematopoietic system. Human chronic myelogenous leukemia K-562 cells were efficiently transduced with the N2Yc retrovirus vector and showed a significant increase in the 50% inhibitory concentration of chlorambucil (3.2- to 3.3-fold), mechlorethamine (4.7- to 5.3-fold), and melphalan (2.1- to 2.2-fold). In addition, primary murine clonogenic hematopoietic progenitor cells transduced with the N2Yc vector were significantly more resistant to alkylating agents in vitro than cells transduced with the antisense N2revYc vector. The survival of Yc-transduced hematopoietic colonies at 400 nM mechlorethamine and 4 mu M chlorambucil was 39.4% and 42.6%, respectively, compared to 27.2% and 30.4% for N2revYc-transduced cells. Future experiments will determine the level of chemoprotection achievable in vivo, following transplantation of N2Yc-transduced hematopoietic cells in mice.

Retrovirus-mediated gene transfer of rat glutathione S-transferase Yc confers alkylating drug resistance in NIH 3T3 mouse fibroblasts.

A major limitation to successful cancer treatment is the existence of drug resistance. While several mechanisms of drug resistance have now been well characterized, mechanisms of resistance to alkylating drugs have remained less well defined. Several experimental models of alkylator resistance have implicated isoforms of glutathione S-transferase (GST) but transfection experiments using cloned isoforms of GST have yielded conflicting results. While there are several plausible explanations for these apparently contradictory findings, the issue that clonal variability might potentially confound the results of conventional transfection experiments has been raised. To address this issue properly, we have studied rat GST-Yc expression and drug sensitivity to alkylating drugs in populations of mouse NIH 3T3 fibroblasts following either transfection or transduction with an N2-based retrovirus vector. In comparison with cells treated with an antisense vector, Yc-transfected and Yc-transduced populations of NIH 3T3 cells expressed increased levels of GST-Yc mRNA (Northern blot), increased levels of immunodetectable GST-Yc (Western blot), and, respectively, 1.4- and 1.9-fold increases in total GST activity and 6.1- and 8.3-fold increases in glutathione peroxidase activity (associated with the Yc subunit). Yc-transfected and Yc-transduced cell populations were, respectively, 5.8- (P < 0.001) and 2.4-fold (P < 0.05) resistant to chlorambucil and 10.8- (P < 0.01) and 5.4-fold (P < 0.001) resistant to mechlorethamine. The range of resistance of clonal isolates from either population was 1.8-6.0-fold for chlorambucil and 4.6-6.1-fold for mechlorethamine (P < 0.05). In contrast, these cells showed unaltered sensitivity to the antimetabolite methotrexate, a nonalkylating drug. These results clearly demonstrate that the rat GTS-Yc is able to confer alkylating drug resistance in mouse fibroblasts. The ability to confer alkylating drug resistance following retrovirus-mediated gene transfer also raises the possibility of using GST-Yc somatic gene transfer to confer protection to the hematopoietic system in a gene therapy strategy applicable to cancer.

An upper limit for the effect of 60 Hz magnetic fields on bioluminescence from the photobacterium Vibrio fischeri.

Bioluminescence from Vibrio fischeri was measured in the presence and absence of 60 Hz magnetic fields. The peak value of the field was approximately 1.3 mT, a value approximately 13 times the Earth's background static field and comparable to the AC field near heavy-duty electrical equipment such as generators. The objective of this work was a search for causality between the applied magnetic field and a basic biological function at the biochemical, membrane or cellular level based on the direct linkage of bioluminescence to many of the cells mandatory functions such as enzyme (luciferase) activity, electron transport, proton translocation, iron uptake, oxidative metabolism, and cellular communication via the autoinducer N-[3-oxohexanoyl] homoserine lactone. A variation in the activity of any one of these functions will cause a change in bioluminescence. The key result of this work is that, for a signal to noise ratio of 1:1, an effect, if present at all, must be less than 1% of the baseline level of continuously monitored bioluminescence.

Alternative patient care delivery systems: a combined ophthalmic nursing unit and a cost effective ophthalmic surgery program.

To be competitive as a tertiary facility in today's healthcare environment, our institute implemented two nursing programs using the Continuous Quality Improvement (CQI) framework: a) creation of the Nursing and Trauma Center, a nursing unit with the flexibility to adjust to continuing changes in patient mix comprising three nursing units (eye emergency room, same day surgery unit, and inpatient unit) designed to consolidate and standardize care to ophthalmic patients and develop a multi-skilled nursing staff to provide nursing care to all ophthalmic patient populations; and b) creation of the Controlled Medical Intensity (CMI) program, in which certain ophthalmic surgeries are performed in the most cost effective and efficient manner (while maintaining quality care). Conceived to compete with surgi-centers, CMI surgery is performed under local retrobulbar anesthesia with minimal, one-time intravenous (IV) conscious sedation (administered by operating room/recovery room nurses according to a standard protocol). Surgical supplies are standardized. These expanded roles have given nurses the opportunity to practice professional autonomy using nursing judgment.

Current concepts in bone healing. Review of the literature.

Bone healing is a process of reconstitution of tissue. With the development of rigid internal fixation, primary bone healing has exhibited certain histologic characteristics not previously seen. The authors discuss the histologic, biochemical, and physiologic processes seen in primary and secondary bone healing following fracture or osteotomy.

Attenuation of facial muscle spasticity with intramuscular phenol neurolysis.

Intramuscular phenol neurolysis is a well-known procedure used to decrease spasticity and improve function in patients who have failed to respond to more conservative forms of intervention. Traditionally, this approach has been limited to spasticity reduction in limb muscles, and its use in managing spasticity of the facial muscles has not been described in the literature. This case report describes a new and previously unreported application of intramuscular neurolysis for managing severe unrelenting facial muscle spasticity in a postanoxic encephalopathic patient. Prior to the procedure, hypertonicity in the orbicularis oris muscle was so profound that it limited speech and affected cosmetic, hygienic, and nutritional status. After intramuscular phenol neurolysis of the orbicularis oris muscle, the patient's level of functioning improved.

Ankle dislocation without fracture: an unusual case report.

Complete dislocation of the ankle joint without associated fracture is considered a rare injury. Few cases are reported in the literature. A case report is presented, and a review of the etiological factors and treatment principles are discussed.

The accuracy of diagnosing pulmonary tuberculosis at a teaching hospital.

Accuracy of the clinical diagnosis of tuberculosis and of the mycobacteriology laboratory test results was assessed in a teaching hospital by reviewing clinical and microbiologic data on patients from whom Mycobacterium tuberculosis had been recovered. Mycobacteria were isolated in 230 of 6,550 specimens (3.5%). Clinical data were available for 42 patients with tuberculosis, 20 of whom had significant underlying nonmycobacterial disease. Positive tuberculin skin tests wee recorded for 90% of the patients with no underlying disease and for 29% of the patients with underlying disease. Tuberculosis was not suspected initially in 16 of 32 patients with pulmonary disease, and had not been diagnosed by the time of discharge in 10 patients. Of all respiratory specimens from patients with cavitary disease, 57% of the acid-fast stains and 96% of the cultures were positive. In contrast, 32% of stains and 70% of cultures were positive from patients with noncavitary pulmonary tuberculosis. One false-positive acid-fast stain was observed during this study.

Ultrastructure and biochemical studies of rat CNS and viscera after subcutaneous injection of chlorphentermine.

Ultrastructural and biochemical studies were carried out on three groups of experimental models which were induced by a single subcutaneous daily dose of 10 to 40 mg./kg. body weight of chlorphentermine hydrochloride. The first group consisted of 20 young adult rats which were sacrificed at intervals of from one to four weeks. The liver and lungs showed concentrically arranged memberanous bodies in the hepatocytes and alveolar cells during the first week after the first injection, while the CNS and pancreas showed no ultrastructural alterations. During the fourth week, the pancreas displayed abnormal cytoplasmic inclusion bodies in the A and B cells of the islets of Langerhans as well as in the exocrine portion. The brain showed various neuronal alterations at four weeks which consisted of irregular dense bodies to well-developed membranous structures which were similar to those of Tay-Sachs disease. Biochemically, thin layer chromatograms showed that the major ganglioside fraction in the brain at four weeks had an RF value similar to that of GM1-ganglioside. In an analysis of the total N-acetyl neuraminic acid the brains in the experimental group contained 90.9% GM1-gandlioside as compared with 44% in the controls. The total and fractions of phospholipids in the brains and livers of the experimental animals were within normal limits.