Factors associated with virological suppression among HIV-positive individuals on highly active antiretroviral therapy in a multi-site Canadian cohort.

OBJECTIVE: The aim of the study was to evaluate time to virological suppression in a cohort of individuals who started highly active antiretroviral therapy (HAART), and to explore the factors associated with suppression. METHODS: Eligible participants were HIV-positive individuals from a multi-site Canadian cohort of antiretroviral-naïve patients initiating HAART on or after 1 January 2000. Viral load and CD4 measurements within 6 months prior to HAART initiation were assessed. Univariate and multivariate analyses were conducted using piecewise survival exponential models where time scale was divided into intervals (<10 months; ≥10 months). Virological suppression was defined as the time to the first of at least two consecutive viral load measurements <50 HIV-1 RNA copies/mL. RESULTS: A total of 3555 individuals were included in the study, of median age 40 years [interquartile range (IQR) 34-47 years]. Eighty per cent were male, 18% had a history of injecting drug use (IDU), and 13% presented with an AIDS-defining illness at baseline. The median time to suppression was 4.55 months (IQR 2.99-7.89 months). In multivariate analyses, older age, male sex, treatment in Ontario rather than British Columbia, non-IDU history, and having an AIDS diagnosis at baseline predicted increased likelihood of suppression. Patients with low baseline viral load were more likely to have suppression [4-5 log(10) copies/mL, hazard ratio (HR) 1.27, 95% confidence interval (CI) 1.18-1.38; <4 log(10) copies/mL, HR 1.49, 95% CI 1.32-1.68] than patients with baseline viral load ≥5 log(10) copies/mL; however, this effect ceased after 18 months of follow-up. Suppression was more likely with nonnucleoside reverse transcriptase inhibitors and ritonavir-boosted HAART. CONCLUSION: Identification of patients at risk for diminished likelihood of virological suppression will allow focusing of efforts and the utilization of resources to maximize the benefits of HAART.

Characters of aerated compost tea from immature compost that limit colonization of bean leaflets by Botrytis cinerea.

AIMS: The aim was to produce and characterize an aerated compost tea (ACT) that suppressed growth of the plant pathogen Botrytis cinerea. METHODS AND RESULTS: Three different open-windrow composts were sampled weekly from the early secondary mesophilic stage until maturity. Each 10kg of compost sample was extracted in 30 l of aerated water for 24, 48 or 72h. Relative to water, all batches of ACT applied to detached bean leaflets reduced lesion development following single-point inoculations of B. cinerea. There was a significant linear, inverse relationship between the internal windrow temperature of compost (≤51°C) used to prepare ACT and the extent of lesion development. Bacterial diversity in ACTs from one windrow was highest using compost sampled at 48°C. The compost weight-to-water volume ratios of 1:3, 1:10 or 1:30, using compost sampled from a fourth windrow at 50°C, also produced ACTs that reduced the growth of B. cinerea on bean leaflets. The '1 : 3' ACT, and to a lesser degree the same ACT filtered to remove micro-organisms, inhibited the germination of B. cinerea conidia. CONCLUSIONS: ACT produced using the methods reported here suppressed the growth of B. cinerea on bean leaflets, with an abundant and diverse microbial community likely to contribute to pathogen suppression. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of the use of immature compost to produce a pathogen-suppressive ACT, suggesting that compost stage is an important production variable.

Bone density comparison of selected carpal and tarsal bones: validation for their use in compression fracture fixation studies of scaphoid screws.

INTRODUCTION: To determine if trabecular, total and cortical bone densities of the capitate, navicular, cuboid, and first cuneiform were equivalent to those of the scaphoid, such that these bones could be used in place of the scaphoid in evaluating new headless scaphoid compression screws. METHODS: Fifty scaphoids, capitates, naviculars, cuboids, and first cuneiforms were harvested from fresh frozen cadavers. The trabecular, total and cortical bone densities were measured using pQCT technology and statistically compared. RESULTS: A paired t comparison between paired scaphoids and capitates showed no difference between the trabecular bone densities. However, their total bone and cortical densities were found to be different. An independent measures ANOVA comparison of the five bones, showed no significant difference in mean trabecular density between the capitates, naviculars and first cuneiforms when compared to the scaphoids. However, the mean total and cortical densities of the first cuneiforms were less than the scaphoids and the mean trabecular, total and cortical bone densities of the cuboids were all less than the scaphoids. DISCUSSION: Compression fracture fixation studies of headless compression screws could be conducted using the capitate, navicular, and first cuneiform as models of the scaphoid when the supply of scaphoids is limited.

An investigation of the general, reproductive and postnatal developmental toxicity of Betapol, a human milk fat equivalent.

Betapol consists of triglyceride fatty acids commonly found in vegetable and animal fats. A similarity to human milk fat indicated a potential use in infant formulae as well as for food use in general. To test the potential for substantial equivalence with a related food grade oil, palm oil, Betapol was fed to rats at 15% content in the diet using an augmented two-generation study, in order to obtain information on general (6 months), reproductive and postnatal developmental toxicity in a single study rather than separate studies. For comparison there were two control groups, namely a comparative control fed a diet containing 15% of food grade oil and a negative, or laboratory standard control fed a commercial rodent breeding diet (LAD), containing 2.3-4.7% fat. It was reasoned that if Betapol fed groups showed differences from the comparative control in the direction of the negative control these would reflect differences in the nutritional value of the high fat diets. Presence of a toxicant might be indicated by differences from the comparative control group opposite to the negative control group. The group fed 15% Betapol showed occasional, statistically significant differences from the comparative control group but the direction of difference was towards the negative control group and did not indicate the presence of an unexpected toxicant.

The role of arthroscopy in the evaluation and treatment of triangular fibrocartilage complex injuries in athletes.

Treating athletes with TFCC injuries can be a difficult but very rewarding undertaking. Each athlete has individual priorities and concerns, ranging from general health and fitness for the recreational athlete to earning or potentially earning a living as a professional athlete. It is crucial for the treating surgeon to understand these issues to offer the appropriate treatment options at the appropriate time. Triangular fibrocartilage complex injuries are quite common in athletes because of the high loads placed on the ulnar side of the wrist, especially with ulnar-neutral and positive variance. The goal of treatment for the competitive athlete with a TFCC lesion is to hasten maximal recovery and return the athlete to participation at the pre-injury level of performance. Early wrist arthroscopy and treatment of TFCC pathology in this population is certainly a real and valuable treatment option. As has been stated, "the TFCC is the new frontier of wrist surgery" and arthroscopy has helped blaze the trail to this frontier. Competitive and recreational athletes alike benefit from arthroscopic treatment of their TFCC injuries.

Tri-isobutylphosphate: a prenatal toxicity study in rats.

To assess the prenatal toxicity to rats of the anti-foaming agent, tri-isobutylphosphate (CAS 126-71-6), a study was conducted in which daily dosages of 0, 100, 300 and 1000 mg/kg were administered to different treatment groups by gavage from day 6 to 15 of pregnancy. Dams were killed and foetuses examined on day 20 of pregnancy. Maternal effects during the dosing period included a dosage-related increase in the frequency, persistence and severity of post dosing salivation in all test groups and significantly increased water consumption at 1000 mg/kg. Bodyweight gain at 1000 and 300 mg/kg was lower than that of controls but the differences were not statistically significant. The lowest dosage of 100 mg/kg could be considered as the maternal 'lowest observed adverse effect level' (LOAEL) or 'no observed adverse effect level' (NOAEL) according to whether increased salivation is perceived to be a true toxic effect or simply a reaction to the taste of the test material. Neither litter values nor the prevalence of foetuses with abnormalities indicated any embryotoxic effects (including teratogenicity) at any dosage. The most notable feature of the results was the occurrence of a cluster of foetuses with the congenital abnormality referred to as 'hunched posture syndrome' or 'squat foetus syndrome'. However, the incidence of this finding was similar to that noted among background data for the same strain and, in the absence of any other embryotoxic findings, was considered likely to have arisen coincidentally.

Complications of endoscopic and open carpal tunnel release.

Separate questionnaires regarding surgically treated complications of endoscopic and open carpal tunnel release over a 5-year period were sent to members of the American Society for Surgery of the Hand to assess and compare major complications of the 2 procedures. Four hundred fifty-five major complications from endoscopic carpal tunnel release were treated by the 708 respondents. This included 100 median nerve lacerations, 88 ulnar nerve lacerations, 77 digital nerve lacerations, 121 vessel lacerations, and 69 tendon lacerations. There were 283 major complications from open carpal tunnel release treated by 616 respondents, including 147 median nerve lacerations, 29 ulnar nerve lacerations, 54 digital nerve lacerations, 34 vessel lacerations, and 19 tendon lacerations. Although this is a retrospective voluntary study with resultant methodologic flaws, the data support the conclusion that carpal tunnel release, be it endoscopic or open, is not a safe and simple procedure. Major, if not devastating, complications can and do occur with both procedures, of which surgeons should be ever cautious.

An anatomic study of the ligamentous structure of the triangular fibrocartilage complex.

An anatomic study of the ligamentous structures of the triangular fibrocartilage complex and their attachments on the ulnar styloid was performed using 27 embalmed cadaver wrists. The dorsal and palmar distal radioulnar ligaments of the triangular fibrocartilage complex in each specimen contained a superficial and a deep portion. The deep portion of both ligaments inserted on the fovea of the ulna. The superficial portion of both ligaments surrounded the articular disc uniting at the ulnar-most portion of the articular disc. The tissue that is between the ulnar aspect of the superficial ligament (and integrated on its periphery) and the ulnar capsule is defined as the meniscus homologue. Anatomic variations in the meniscus homologue and the prestyloid recess (the cavity adjacent to the ulnar styloid) were seen in 1 of 3 ways; the narrow opening type in 74% of specimens, the wide opening type in 11%, and the no opening type in 15%. The ulnotriquetral ligament inserted on the palmar-radial aspect of the base of the ulnar styloid and the ulnolunate ligament inserted on the palmar border of the articular disc.

Pressure distribution in the distal radioulnar joint.

Measurement of the pressure distribution within the distal radioulnar joint was performed in fresh cadaver forearms at varying positions of forearm rotation. Axial loads of 0 N, 36 N, and 89 N were applied to the wrist flexors and extensors. At neutral forearm rotation and application of 89 N axial load, an average of 12.5% of the sigmoid notch area was in contact with the ulna. Analysis of the pressure plots reveals that in pronation, the pressure was concentrated in the dorsal portion of the sigmoid notch and that in supination the pressure was distributed in the palmar portion.

Changes in carpal tunnel pressures following endoscopic carpal tunnel release: a cadaveric study.

The purpose of this experiment was to determine the amount of tissue that must be sectioned to adequately decompress the median nerve during an endoscopic carpal tunnel release procedure. In 6 fresh cadaver forearms, 2 balloons were inserted into the carpal tunnel. The first balloon was filled with saline solution to cause an initial carpal intracanal pressure of 50 mmHg. Pressure measurements were recorded, using the second balloon, at various increments of the flexor retinaculum division at 3 wrist positions (neutral, 35 degrees ; flexion, 35 degrees extension). At all increments of sectioning, carpal tunnel pressures in the neutral wrist position were consistently lowest and the values in 35 degrees extension were greatest. At each wrist flexion/extension angle, the pressure statistically decreased during incremental division of the flexor retinaculum. Incomplete release of the transverse carpal ligament resulted in incomplete decompression in the canal. Sectioning the overlying aponeurosis caused a further significant decrease in intracanal pressure.

The relative contribution of selected carpal bones to global wrist motion during simulated planar and out-of-plane wrist motion.

The relative contribution of the scaphoid, lunate, triquetrum, and capitate to wrist motion was examined in 6 fresh cadaver forearms. A wrist-joint motion simulator was used to dynamically move each wrist through planar and nonplanar motions. During wrist flexion-extension, the motion of the capitate closely followed the motion of the third metacarpal, while the lunate motion was approximately 50% of the total motion; the triquetrum, 65%, and the scaphoid, 90%. Similar differences in motion for these carpal bones occurred during radioulnar deviation and circumduction and dart-throw motions. This suggests that the scaphoid, lunate, and triquetrum do not normally function as a single unit, but that each bone has an unique arc of motion during global wrist motion.

The cult of culling.

It is difficult to understand why culling (reduction of litter size) has become such a widely used procedure in reproductive toxicity studies since there appear to have been no prior investigations to ascertain that it would improve the efficiency of studies with respect to detecting adverse effects. Perhaps the only provable advantage of culling is with respect to economics and convenience. Post hoc rationalizations for culling lack conviction because many of the claims made for culling are erroneous, inconsistent, vague, and contradictory. Mostly, they are based on part truths derived from minimal studies, conducted for totally different purposes. That experimental animals have to be killed sooner or later is unquestioned, but for ethical and scientific reasons, it is imperative that the maximum amount of information is obtained from them. Currently, the most common practice is to cull litters to four per sex (total eight) on Day 4 postpartum. This is totally divorced from natural values for most rat strains and involves elimination, usually without adequate examination, of between 30 and 45% of offspring. Without culling most of these would survive, unless there was a treatment effect. Intuitively, it would seem that removal of such a proportion of offspring would severely limit the possibility of detecting the postnatal equivalent of fetal malformations. Culling totally nullifies litter size as an indicator of toxicity. Indirectly, it also nullifies the value of mean pup weight as an indicator of toxicity because it greatly increases the variation in mean pup weight. This is quite contrary to the claim that culling reduces variance. Further, the increased growth of offspring in culled litters can have long-term consequences of a shorter overall and reproductive life span.

Terminology of developmental abnormalities in common laboratory mammals (version 1).

This paper presents the first version of an internationally-developed glossary of terms for structural developmental abnormalities in common laboratory animals. The glossary is put forward by the International Federation of Teratology Societies (IFTS) Committee on International Harmonization of Nomenclature in Developmental Toxicology, and represents considerable progress toward harmonization of terminology in this area. The purpose of this effort is to provide a common vocabulary that will reduce confusion and ambiguity in the description of developmental effects, particularly in submissions to regulatory agencies worldwide. The glossary contains a primary term or phrase, a definition of the abnormality, and notes, where appropriate. Selected synonyms or related terms, which reflect a similar or closely related concept, are noted. Nonpreferred terms are indicated where their usage may be incorrect. Modifying terms used repeatedly in the glossary (e.g., absent, branched) are listed and defined separately, instead of repeating their definitions for each observation. Syndrome names are generally excluded from the glossary, but are listed separately in an appendix. The glossary is organized into broad sections for external, visceral, and skeletal observations, then subdivided into regions, structures, or organs in a general overall head to tail sequence. Numbering is sequential, and not in any regional or hierarchical order. Uses and misuses of the glossary are discussed. Comments, questions, suggestions, and additions from practitioners in the field of developmental toxicology are welcomed on the organization of the glossary as well as on the specific terms and definitions. Updates of the glossary are planned based on the comments received.

The interosseous membrane of the forearm: anatomy and function.

The anatomic detail of the interosseous membrane was studied by dissection of 20 preserved cadaveric specimens. The interosseous membrane was found to be a complex structure consisting of a central band, accessory bands, a proximal interosseous band, and membranous portions. The central band, a stout ligamentous structure, was found in all specimens. Fibers of the central band originate on the radius and are oriented distal and ulnar an average of 21 degrees to the longitudinal axis of the ulna. Accessory bands were of less substance than the central band but were present in all specimens. The number of accessory bands ranged from 1 to 5. The proximal interosseous band is located on the dorsal surface only, and its fibers run counter to the central band. It shares a point of origin with the central band on the radius. This structure was present in 17 of 20 specimens. Since the central band was the most dominant and consistent structure, we chose to analyze the strain in the central band in 6 preserved specimens. Maximum strain in the central band of the intact specimen occurs in neutral forearm rotation. Once the radial head is removed, the percent strain universally increases throughout the arc of forearm rotation and peak strain shifts to pronation.

Reconstruction of the interosseous membrane of the forearm in cadavers.

The biomechanical function of the interosseous membrane of the forearm was examined in 12 fresh cadaver forearms. The strain in the central band of the interosseous membrane was found to be greatest in full pronation and was significantly increased with excision of the radial head. The proximal/distal location of the lunate fossa of the radius with respect to the ulna was measured and was found to be most distal in supination and most proximal in pronation, in both the intact specimen and after excision of the radial head. Serial sectioning of the interosseous membrane and the triangular fibrocartilage complex (TFCC) demonstrated that both the central band and the TFCC are important to the axial stability of the forearm. Reconstruction of the central band, using a graft based upon the flexor carpi radialis, was performed in all 12 specimens after the interosseous membrane and the TFCC were sectioned. It was successful in preventing complete migration of the radius to the capitellum, but it was not capable of completely restoring the longitudinal stability of the forearm. Central band reconstruction as described here has not been performed in the clinical setting and is not advocated for clinical application at this time.

Wrist arthrodesis using a dynamic compression plate.

In order to determine the effectiveness of wrist arthrodesis using dynamic compression plating and bone grafting, we reviewed 18 consecutive procedures in 17 patients performed using a standardized technique over a 6-year period. Fourteen patients had previously undergone an average of 2.1 operations prior to arthrodesis. Mean follow-up was 48 months. All but one patient reported considerable pain relief and were satisfied with their results. Grip strength remained limited compared to the contralateral wrist. Complications were limited to one case of reflex sympathetic dystrophy and metacarpophalangeal joint contracture, and minor problems related to the bone graft donor site.

Wrist joint motion simulator.

A computer controlled wrist joint motion simulator has been developed that actively moves forearms from cadavers through cyclic planar flexion-extension motions, planar radial-ulnar deviation motions, and combined motions such as circumduction. Hybrid position-force feedback control algorithms are used to determine the wrist flexor and extensor tendon forces necessary to achieve the desired motions. The simulator was used in a series of 12 fresh cadaver forearms to produce both flexion-extension and radial-ulnar deviation motions and was found to cause repeatable, physiological movements. In these experiments, the extensor tendon forces were greater than those of the flexors, typically by a factor of two.

Classification and treatment of ulnar styloid nonunion.

Symptomatic nonunion of the ulnar styloid is an uncommon problem that is usually best treated by simple excision of the ulnar styloid fragment. Two types of nonunion of the ulnar styloid are described here on an anatomic basis, and their treatment differs. Type 1 is defined as a nonunion associated with a stable distal radioulnar joint. Type 2 is defined as a nonunion associated with subluxation of the distal radioulnar joint. The postoperative follow-up period for the two types ranged from 4 months to 13 years, with a mean of 5 years 2 months. Eleven type 1 wrists were treated with excision of the fragment, and all patients had satisfactory relief of pain. Nine type 2 wrists required restoration of the anatomy of the traingular fibrocartilage complex. Three of these had large fragments that were treated by open reduction and internal fixation. All three patients were completely relieved of their discomfort. Six other patients underwent excision of the fragment and repair of the triangular fibrocartilage complex to the distal ulna. This group had four excellent, one good, and one fair result. If the distal radioulnar joint is stable on presentation or if its stability is restored, then long-term relief of pain from ulnar styloid nonunion is achieved by treatment of the nonunion.

Neurobehavioral aspects of developmental toxicity testing.

Tests for detection of neurobehavioral changes in the offspring have been a regulatory requirement in developmental toxicity testing of drugs for almost 20 years. Keeping their purpose of hazard identification and risk assessment for humans in mind, investigators and agency reviewers have become deeply ingrained with some stereotyped behaviors with respect to such relevant issues as choice of animal species and data evaluation. Other problematic areas of study design and conduct, selection of litter representatives for testing, what methods to combine in a testing battery, and statistical treatment of results and their interpretation, will need more research and discussion in the future.