Remission Maintenance Therapy for Meningeal Leukemia: Intrathecal Methotrexate vs. Intravenous bis-Nitrosourea

Central nervous system infiltrates havebecome a major cause of morbidityamong leukemic children and may constitute a site from which a remissionmarrow is again infiltrated. Conventionalintrathecal methotrexate (IT MTX) therapy produces excellent palliation andcomplete reversal of abnormal cerebrospinal fluid findings for periods rangingfrom 6 to 414 days (median 87 days).The CNS remission maintenance potential of (1) IT MTX, 12 mg/sq m, every6-8 wk, and (2) bis-nitrosourea (BCNU),100 mg/sq m intravenously, every 6-8wk were compared with "no therapy"maintenance. Only those children inCNS remission 6-8 wk following induction therapy were eligible for randomization to the maintenance study. Theduration of CNS remission for BCNU-maintained and "no therapy" patients wassimilar, with a median length of remission of 96 days and 112 days, respectively. The median duration of remissionfor the MTX maintenance group was 472days. The differences in length of CNSremission between the MTX group andthe other two groups were statisticallyhighly significant (p < 0.01 for bothcomparisons). Headache, fever, and/orvomiting occurred in 38% of the childrenafter one or more of the intrathecal maintenance treatments and, in general,symptoms tended to worsen as maintenance continued.

Submitted on May 4, 1971 Revised on June 24, 1971 Accepted on June 29, 1971     

Triple-Site Versus Standard Cardiac Resynchronization Therapy Study (TRUST CRT): Clinical Rationale, Design, and Implementation

Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure (HF), lowered LV ejection fraction, and wide QRS. However, many patients (≤40%) do not respond to this form of pacing. TRUST CRT is a prospective, single-center, randomized, single-blind, parallel, and controlled study that has been designed to treat patients with moderate to severe HF (NYHA III-IV), QRS ≥120 ms, sinus rhythm, LV dysfunction (EF ≤ 35%), and signs of mechanical dyssynchrony.
Objective: The primary objective will evaluate the 6-month's combined endpoint of alive status, freedom from hospitalization for HF or heart transplantation, relative ≥10% increase in LV ejection fraction, ≥10% in peak oxygen consumption, and ≥10% in 6-minute walking distance.
Methods: Patients with HF receiving optimal pharmacotherapy, with LV dysfunction, mechanical dyssynchrony, wide QRS and sinus rhythm will be randomized in a 1: 1 fashion to standard or triple-site CRT-D. Patients will be followed for 1 week, 1, 3, and 6 months during a blind phase, then every 6 months until study completion. One hundred patients will be enrolled by the study center.
Conclusions: TRUST CRT is a randomized, clinical trial in CRT candidates to evaluate the effectiveness of triple-site pacing versus standard resynchronization in patients with HF.     

DDD Pacing with Rate Drop Response Function Versus DDI with Rate Hysteresis Pacing for Cardioinhibitory Vasovagal Syncope

Background: The effectiveness of cardiac pacing in preventing vasovagal syncope remains controversial. However, DDI pacing with rate hysteresis has been reported to prevent the recurrence of Cardioinhibitory vasovagal syncope in up to 35% of affected subjects and to reduce the overall incidence of syncopal episodes in the others. Recently, DDD pacing with a new promising rate drop response function (Medtronic Thera-I model 7960) has become available in clinical practice. Aim of the study: The aim of the present open trial was to test the effectiveness of this new pacing modality in patients with Cardioinhibitory vasovagal syncope. Study population and methods: The study population included 20 patients (12 males and 8 females; mean age 61.1 ± 14 yrs) with recurrent syncope (mean number of prior episode = 6.8, range 5–11) and Cardioinhibitory responses during two head-up tilt tests: the first diagnostic and the second during drug therapy with either β-blockade or etilephrine. The study patients were randomized to receive either DDI pacing with rate hysteresis (8 patients) or DDD pacing with rate drop response function (11 patients). The head-up tilt test performed 1 month after pacemaker implantation was positive in 3 of 12 patients (25%) with DDD pacing with rate drop response function and in 5 of 8 patients (62.5%) with DDI pacing with rate hysteresis. The mean duration of follow-up was 17.7 ± 7.4 months. During follow-up no patients with a DDD pacemaker with rate drop response function had syncope, while 3 of 8 patients with a DDI pacemaker with rate hysteresis had recurrence of syncope (P < 0.05). Conclusions: These data suggest that DDD pacing with rate drop response function is effective in Cardioinhibitory vasovagal syncope and may be preferable to DDI pacing with rate hysteresis.     

A Randomized Comparison of a Bipolar Steroid-Eluting Electrode and a Bipolar Microporous Platinum Electrode: Implications for Long-Term Programming

Differences in acute and chronic pacing thresholds were compared in patients receiving either the Medtronic Model 4004 steroid-eluting lead or the Medtronic Model 4012 microporous platinum lead. Patients (n = 35) were randomized at the time of implant to receive either a steroid-eluting (n = 17) or a microporous (n = 18) lead. Pacing thresholds were determined within 24 hours and at 2, 4, 6, 12. 24, and 52 weeks postimplant. By 2 weeks postimplant. pacing thresholds measured at 0.8, 1.6, 2.5, 3.3, and 4.2 V were significantly lower in the steroid lead group compared to the microporous Jead group (P < 0.05). At 24 weeks, the voltage threshold at 0.3 msec was 0.8 V in 88% of patients with a steroid lead whereas this threshold was only observed in 33% of patients with the microporous lead (P < 0.01). At 52 weeks the pacing energy measured at 1.6 V, twice pulse duration threshold, was significantly lower in the steroid lead group (0.81 ± 0.59 μJ) compared to the microporous lead group (1.25 ± 0.60 μJ, P < 0.05). Thirteen patients in the steroid lead group and 9 patients in the microporous lead group have been programmed at a pulse amplitude of 1.6 V since the 24-week follow-up visit. These patients have been followed for a minimum of 6 months without documented failure to capture. This study shows that pacemaker/lead systems with stable chronic low thresholds can be safely programmed to low pulse amplitude settings. This practice will prolong the longevity of pulse generators.     

Laryngeal biomechanics of the singing voice

By transnasal fiberoptic laryngoscopy, patients with functional voice disorders often demonstrate abnormal laryngeal biomechanics, commonly supraglottic contraction. Appropriately, such conditions are sometimes termed muscle tension dysphonias. Singers working at the limits of their voice may also transiently demonstrate comparable tension patterns. However, the biomechanics of normal singing, particularly for different singing styles, have not been previously well characterized. We used transnasal fiberoptic laryngoscopy to study 100 healthy singers to assess patterns of laryngeal tension during normal singing and to determine whether factors such as sex, occupation, and style of singing influence laryngeal muscle tension. Thirty-nine male and 61 female singers were studied; 48 were professional singers, and 52 were amateurs. Examinations of study subjects performing standardized and nonstandardized singing tasks were recorded on a laser disk and subsequently analyzed in a frame-by-frame fashion by a blinded otolaryngologist. Each vocal task was graded for muscle tension by previously established criteria, and objective muscle tension scores were computed. The muscle tension score was expressed as a percentage of frames for each task with one of the laryngeal muscle tension patterns shown. The lowest muscle tension scores were seen in female professional singers, and the highest muscle tension scores were seen in amateur female singers. Male singers (professional and amateur) had intermediate muscle tension scores. Classical singers had lower muscle tension scores than nonclassical singers, with the lowest muscle tension scores being seen in those singing choral music (41%), art song (47%), and opera (57%), and the highest being seen in those singing jazz/pop (65%), musical theater (74%), bluegrass/country and western (86%), and rock/gospel (94%). Analyzed also were the influences of vocal nodules, prior vocal training, number of performance and practice hours per week, warm-up before singing, race, smoking, and alcohol consumption. (Otolaryngol Head Neck Surg 1996;115:527-37.)     

Intrahisian Functional Bundle Branch Block

A patient with functional complete left bundle branch block is presented. The site of block was localized to the area of the His bundle. This case demonstrates that functional complete left bundle branch block may be due to longitudinal dissociation in the His bundle.     

DATA ANALYSIS ISSUES FOR PROTOCOLS WITH OVERLAPPING ENROLLMENT

Many persons with HIV require and take several medications. The efficacy and safety of many of these medications are uncertain. Usually limited data on drug interactions are available. Thus simultaneous and sequential enrolment of patients into multiple studies is desired for reasons of science and efficiency. This paper discusses the analysis of data arising from coenrolment in multiple studies sponsored by the Community Programs for Clinical Research on AIDS (CPCRA). Factorial designs and those in which patients are sequentially instead of simultaneously randomized are compared. Approaches to data analysis, based on intention-to-treat, for individual and pairs of trials are described. An antiretroviral trial and a trial for prophylaxis of Pneumocystis carinii pneumonia (PCP) are used for illustration. We conclude that such analyses may yield useful information on drug interactions and that a more vigorous coenrolment policy should be pursued in AIDS research.     

Effect of secondary structure on the rate of deamidation of several growth hormone releasing factor analogs

The objective of this study was to determine whether the rates of deamidation of Asn⁸ in selected growth hormone releasing factor (GRF) analogs were related to the peptide's secondary structures in solution. Bovine or human [Leu²⁷]GRF(1–32)NH₂ (both having Gly at position 15), [Ala¹⁵ Leu²⁷]bGRF(1–32)NH₂ and [Pro¹⁵ Leu²⁷]bGRF(1–32)NH₂ were used as model peptides. The peptide helical content (assessed by CD) increased with the increasing methanol concentration and was as follows: 7, 12 and 18% in 0% MeOH; 24, 48 and 52% in 40% MeOH; and 41, 77 and 81% in 80% MeOH for Pro¹⁵ Leu²⁷ bGRF(1–32)NH₂, [Leu²⁷]hGRF(1–32)NH₂, and Ala¹⁵ Leu²⁷ bGRF(1–32)NH₂, respectively. 2D NMR studies done in the presence of 40% CD₃OH indicated more helical structure for the Ala¹⁵ analog as compared to [Len²⁷]hGRF(1–32)NH₂. In both these peptides Asn⁸ was included in the helical region. In contrast, the lack of conformational information for the Pro¹⁵ analog indicated little helical structure around Asn⁸. The peptides’ deamidation rates decreased and their half-lives increased with increasing MeOH concentrations. At 40% MeOH, the least helical Pro¹⁵ bGRF analog (t_1/2= 10.78 h) deamidated 1.5 and 2 times faster than its Gly¹⁵ (t_1/2= 15.74 h) and Ala¹⁵ (t_1/2= 21.53 h) counterparts, respectively. This study indicates that helical environment around Asn⁸ in GRF makes this residue less prone to deamidation.