Axial rotation and pain are associated with facet joint osteoarthritis in adolescent idiopathic scoliosis.

OBJECTIVE: Facet joints are crucial for spinal stability but develop premature osteoarthritis in patients with adolescent idiopathic scoliosis (AIS). Here, we evaluated the association between facet joint cartilage and subchondral bone homeostasis, perceived back pain and 3-dimensional spinal deformity to better understand the role of facet joint degeneration in AIS progression and pain. METHOD: The osteoarthritic state of cartilage and bone of AIS facet joint surgical samples were characterized using histological OARSI scoring, visual morphological grading and µCT analysis, respectively. Back pain was self-reported using a numerical rating scale and expressed relative to the location on the patient's back. The scoliotic curves from our patient cohort were digitally reconstructed using biplanar radiographs and the eOS system (EOS imaging). The deformity was then reduced to three intervertebral angles (coronal, sagittal and axial) for each pair of bilateral facet joints. Statistical associations between the intervertebral angles, osteoarthritis parameters and pain intensity were performed using the Spearman method and Friedman test. RESULTS: Facet joint cartilage degeneration was associated with decreased subchondral bone volume and quality. Most importantly, asymmetrical, and overall degeneration of facet joints was strongly correlated to intervertebral axial rotation. Additionally, kyphotic intervertebral segments in the sagittal plane were good predictors of increased facet joint degeneration and back pain. CONCLUSION: Facet joint degeneration is associated with axial deformity, kyphotic intervertebral angle and back pain intensity in AIS. These results suggest that facet joints are important features to consider for rotational instability in AIS spines and related disease progression and perceived back pain.

For whom the disc tolls: intervertebral disc degeneration, back pain and toll-like receptors.

Intervertebral disc (IVD) degeneration is characterised by catabolic and inflammatory processes that contribute largely to tissue degradation and chronic back pain. The disc cells are responsible for the pathological production of pro-inflammatory cytokines and catabolic enzymes leading to degeneration. However, this phenotypical change is poorly understood. Growing evidence in animal and human studies implicates Toll-like receptors (TLR) and their activation through danger-associated alarmins, found increasingly in degenerating IVDs. TLR signalling results in the release of pro-inflammatory cytokines and proteolytic enzymes that can directly cause IVD degeneration and back pain. This review aims to summarise the current literature on TLR activation in IVD degeneration and discuss potential treatment modalities to alleviate the inflammatory phenotype of disc cells in order to arrest IVD degeneration and back pain.

Thermoreversible hyaluronan-hydrogel and autologous nucleus pulposus cell delivery regenerates human intervertebral discs in an ex vivo, physiological organ culture model.

Numerous studies show promise for cell-based tissue engineering strategies aiming to repair painful intervertebral disc (IVD) degeneration. However, clinical translation to human IVD repair is slow. In the present study, the regenerative potential of an autologous nucleus pulposus (NP)-cell-seeded thermoresponsive hyaluronic acid hydrogel in human lumbar IVDs was assessed under physiological conditions. First, agarose-encased in vitro constructs were developed, showing greater than 90 % NP cell viability and high proteoglycan deposition within HA-pNIPAM hydrogels following 3 weeks of dynamic loading. Second, a bovine-induced IVD degeneration model was used to optimise and validate T1ρ magnetic resonance imaging (MRI) for detection of changes in proteoglycan content in isolated intact IVDs. Finally, isolated intact human lumbar IVDs were pre-scanned using the established MRI sequence. Then, IVDs were injected with HA-pNIPAM hydrogel alone or autologous NP-cell-seeded. Next, the treated IVDs were cultured under cyclic dynamic loading for 5 weeks. Post-treatment T1ρ values were significantly higher as compared to pre-treatment scans within the same IVD and region of interest. Histological evaluation of treated human IVDs showed that the implanted hydrogel alone accumulated proteoglycans, while those that contained NP cells also displayed neo-matrix-surrounded cells within the gel. The study indicated a clinical potential for repairing early degenerative human IVDs using autologous cells/hydrogel suspensions. This unique IVD culture set-up, combined with the long-term physiological culture of intact human IVDs, allowed for a more clinically relevant evaluation of human tissue repair and regeneration, which otherwise could not be replicated using the available in vitro and in vivo models.

Comparative analysis in continuous expansion of bovine and human primary nucleus pulposus cells for tissue repair applications.

Autologous NP cell implantation is a potential therapeutic avenue for intervertebral disc (IVD) degeneration. However, monolayer expansion of cells isolated from surgical samples may negatively impact matrix production by way of dedifferentiation. Previously, we have used a continuous expansion culture system to successfully preserve a chondrocyte phenotype. In this work, we hypothesised that continuous expansion culture could also preserve nucleus pulposus (NP) phenotype. We confirmed that serial passaging drove NP dedifferentiation by significantly decreasing collagen type II, aggrecan and chondroadherin (CHAD) gene expression, compared to freshly isolated cells. Proliferation, gene expression profile and matrix production in both culture conditions were compared using primary bovine NP cells. Both standard culture and continuous culture produced clinically relevant cell populations. However, continuous culture cells maintained significantly higher collagen type II, aggrecan and CHAD transcript expression levels. Also, continuous expansion cells generated greater amounts of proteoglycan, collagen type II and aggrecan protein deposition in pellet cultures. To our surprise, continuous expansion of human intervertebral disc cells - isolated from acute herniation tissue - produced less collagen type II, aggrecan and CHAD genes and proteins, compared to standard culture. Also, continuous culture of cells isolated from young non-degenerate tissue did not preserve gene and protein expression, compared to standard culture. These data indicated that primary bovine and human NP cells responded differently to continuous culture, where the positive effects observed for bovine cells did not translate to human cells. Therefore, caution must be exercised when choosing animal models and cell sources for pre-clinical studies.

Dynamic loading, matrix maintenance and cell injection therapy of human intervertebral discs cultured in a bioreactor.

Low back pain originating from intervertebral disc (IVD) degeneration affects the quality of life for millions of people, and it is a major contributor to global healthcare costs. Long-term culture of intact IVDs is necessary to develop ex vivo models of human IVD degeneration and repair, where the relationship between mechanobiology, disc matrix composition and metabolism can be better understood. A bioreactor was developed that facilitates culture of intact human IVDs in a controlled, dynamically loaded environment. Tissue integrity and cell viability was evaluated under 3 different loading conditions: low 0.1-0.3, medium 0.1-0.3 and high 0.1-1.2 MPa. Cell viability was maintained > 80 % throughout the disc at low and medium loads, whereas it dropped to approximately 70 % (NP) and 50 % (AF) under high loads. Although cell viability was affected at high loads, there was no evidence of sGAG loss, changes in newly synthesised collagen type II or chondroadherin fragmentation. Sulphated GAG content remained at a stable level of approximately 50 µg sGAG/mg tissue in all loading protocols. To evaluate the feasibility of tissue repair strategies with cell supplementation, human NP cells were transplanted into discs within a thermoreversible hyaluronan hydrogel. The discs were loaded under medium loads, and the injected cells remained largely localised to the NP region. This study demonstrates the feasibility of culturing human IVDs for 14 days under cyclic dynamic loading conditions. The system allows the determination a safe range-of-loading and presents a platform to evaluate cell therapies and help to elucidate the effect of load following cell-based therapies.

Acute mechanical injury of the human intervertebral disc: link to degeneration and pain.

Excessive mechanical loading or acute trauma to intervertebral discs (IVDs) is thought to contribute to degeneration and pain. However, the exact mechanisms by which mechanical injury initiates and promotes degeneration remain unclear. This study investigates biochemical changes and extracellular matrix disruption in whole-organ human IVD cultures following acute mechanical injury. Isolated healthy human IVDs were rapidly compressed by 5% (non-injured) or 30% (injured) of disc height. 30% strain consistently cracked cartilage endplates, confirming disc trauma. Three days post-loading, conditioned media were assessed for proteoglycan content and released cytokines. Tissue extracts were assessed for proteoglycan content and for aggrecan integrity. Conditioned media were applied to PC12 cells to evaluate if factors inducing neurite growth were released. Compared to controls, IVD injury caused significant cell death. Injury also caused significantly reduced tissue proteoglycan content with a reciprocal increase of proteoglycan content in culture media. Increased aggrecan fragmentation was observed in injured tissue due to increased matrix metalloproteinase and aggrecanase activity. Injured-IVD conditioned media contained significantly elevated interleukin (IL)-5, IL-6, IL-7, IL-8, MCP-2, GROα, and MIG, and ELISA analysis showed significantly increased nerve growth factor levels compared to non-injured media. Injured-disc media caused significant neurite sprouting in PC12 cells compared to non-injured media. Acute mechanical injury of human IVDs ex vivo initiates release of factors and enzyme activity associated with degeneration and back pain. This work provides direct evidence linking acute trauma, inflammatory factors, neo-innervation and potential degeneration and discogenic pain in vivo.

Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain.

Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.

Functional status and quality of life in patients with first-episode major depression.

The aim of this study was to analyse the level of severity of major depression and its relation to functioning and health-related quality of life over time in patients treated for their first episode of major depression. Thirty-three adult patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depression were included in the study. Semi-structured interviews and self-assessment questionnaires were used at baseline and at 6-monthly intervals in a 2-year follow-up, in order to measure the level of severity of depression, functioning and quality of life. The results showed that the first episode of major depression was rated as severe in 43% of cases. Multiple domains of functioning as well as quality of life were strongly affected in patients at baseline, although the level of functioning increased significantly over the study period, as did quality of life, but not concurrently with the decrease in the level of severity of the depression. Psychosocial functioning is an important outcome measure related to major depression, which underlines the importance of separate evaluations initiated and conducted by mental health nurses in order to determine whether or not patients have actually achieved a state of health.

Immunohistochemical localization of cytochrome P-450 and reduced nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase in the rat ventral prostate.

Rabbit antibodies raised against the major isozymes of cytochrome P-450 isolated from hepatic microsomes of beta-naphthoflavone- (BNF) and phenobarbital-treated rats (cytochrome P-450 BNF-B2 and cytochrome P-450 PB-B2, respectively) and against rat liver NADPH-cytochrome P-450 reductase were used to localize these enzymes immunohistochemically in the rat ventral prostate. Using the unlabeled antibody peroxidase-antiperoxidase technique, NADPH-cytochrome P-450 reductase was detected exclusively in the epithelial cells of the gland to the same magnitude in untreated, phenobarbital-, and BNF-treated rats. Cytochrome P-450 BNF-B2-like immunoreactivity was exclusively present in the glandular epithelium in BNF-treated rats, whereas staining could not be visualized in untreated or in phenobarbital-treated rats. The staining for NADPH-cytochrome P-450 reductase was more uniformly distributed within the epithelium than was the cytochrome P-450 BNF-B2-like immunoreactivity. Cytochrome P-450 PB-B2-like immunoreactivity was not found, regardless of animal pretreatment. These findings support our previous results (Haaparanta, T., Halpert, J., Glaumann, H., and Gustafsson, J-A., Cancer Res. 43: 5131-5137, 1983) demonstrating the presence of constitutive NADPH-cytochrome P-450 reductase in the prostate and that an isozyme of cytochrome P-450 is highly inducible by BNF in this gland. The significance of these findings are discussed in view of the essentially unknown etiology of human prostatic cancer.

A diffuse alpha MSH-immunoreactive projection to the hippocampus and spinal cord from individual neurons in the lateral hypothalamic area and zona incerta.

The course, distribution, and possible neurotransmitter specificity of a projection from the lateral hypothalamic area (LHA) and zona incerta to the hippocampal formation (dentate gyrus, Ammon's horn, subicular region, and entorhinal area) and spinal cord were examined anatomically in the adult rat. First, small injections of the fluorescent tracer fast blue were made into either the septal part of the dentate gyrus and Ammon's horn or the entorhinal area, and the distribution of retrogradely labeled cells was plotted. In each experiment many cells were labeled in the LHA and zona incerta, and little evidence for a topographically organized projection to different parts of the hippocampal formation was found. Second, a combined retrograde transport-immunofluorescence method was used to show that some 95% of the fast blue-labeled neurons in the LHA and zona incerta were also stained with an antiserum to the opiate peptide alpha-melanocyte-stimulating hormone (alpha MSH), but not an antiserum to adrenocorticotropin (ACTH)1-24. It was also found that small numbers of retrogradely labeled neurons were stained with antisera to somatostatin 14 and 28, dynorphin (1-17), and angiotensin II. Third, the distribution of alpha MSH-immunoreactive fibers was plotted, and they were found to form a diffusely organized plexus throughout all of the subfields of the hippocampal formation. These fibers were virtually eliminated after transections of the fimbria and the region between the entorhinal area and the caudal amygdala. Forth, the course of fibers from the LHA and zona incerta was examined with the anterogradely transported lectin Phaseolus Vulgaris Leucoagglutinin (PHAL). Such fibers reach the hippocampal formation by a dorsal route through the septal region and fimbria, and by a ventral route through the amygdala. And fifth, double retrograde transport and immunohistochemical methods were used to show that at least some alpha MSH-stained neurons in the LHA and zona incerta give rise to collaterals that innervate both the hippocampal formation and the spinal cord. Alpha MSH-stained fibers in the spinal cord also form a widely scattered plexus with no obvious circumscribed terminal fields. It is suggested that the diffusely organized projection from the LHA to the cerebral cortex and spinal cord may play a role in the general arousal associated with a variety of motivated behaviors.

The projection of the supramammillary nucleus to the hippocampal formation: an immunohistochemical and anterograde transport study with the lectin PHA-L in the rat.

The organization and possible neurotransmitter specificity of a projection from the lateral supramammillary nucleus to the hippocampal formation has been examined with immunohistochemical and axonal transport methods in the adult male rat. Experiments with the retrograde tracer true blue indicate that neurons throughout the rostrocaudal extent of the nucleus are labeled after injections in either dorsal parts of the dentate gyrus and Ammon's horn, or the entorhinal area, although cells labeled by the entorhinal injections tended to occupy more ventral parts of the nucleus. Combined immunohistochemical-retrograde transport studies showed that a small number (less than 5%) of cholecystokinin-immunoreactive neurons in the caudal tip of the supramammillary nucleus project to the hippocampal formation, as do some (5-10%) vasoactive intestinal polypeptide (VIP)-immunoreactive neurons throughout the nucleus. Anterograde transport studies with the lectin phaseolus vulgaris leucoagglutinin (PHA-L) indicate that fibers from the supramammillary nucleus innervate all parts of the hippocampal formation. Many varicose fibers with terminal boutons were observed in the granular and molecular layers of the dentate gyrus, throughout the molecular layer of field CA3 of Ammon's horn, and in the pyramidal layer and stratum oriens of subfield CA3a. Only scattered fibers were found in fields CA1 and CA2. Apparent terminal fields were also observed in superficial parts of the molecular layer, and deep parts of the pyramidal layer, of the subiculum, in the deepest layer of the presubiculum and parasubiculum, and in all layers of the entorhinal area.

The cytoarchitecture, histochemistry and projections of the tuberomammillary nucleus in the rat.

The normal morphology, efferent projections and possible neurotransmitter content of neurons in the tuberomammillary nucleus (caudal magnocellular nuclei of Bleier et al.) [Bleier, Cohn and Siggelkow (1979) In Anatomy of the Hypothalamus, Vol. 1, pp. 137-220] have been examined in the adult male rat. In Nissl-stained sections, the nucleus can be divided into a dorsomedial, ventral and diffuse part, each of which consists of large, darkly stained neurons cradling the mammillary body. The ventral part is by far the largest and consists of some 2500 neurons on each side of the brain. Immunohistochemical studies indicate that a majority of the large neurons in all three parts of the nucleus stain with antisera against glutamate decarboxylase and [Met]enkephalyl-Arg6-Phe7 heptapeptide and that a smaller subset of these neurons (about 10%) also stain with an antiserum against substance P. Single injections of retrogradely transported fluorescent tracers were made into 18 different sites in 86 animals and the results indicate that all three parts of the tuberomammillary nucleus on one side of the brain send fibers to or through various parts of the neocortex, hippocampal formation, amygdala, basal ganglia, thalamus, superior colliculus and cerebellum on both sides of the brain and that the projection neurons are not organized in a highly topographic way. Injections of two different fluorescent tracers in the same animal indicate that individual neurons in the nucleus may give rise to both ascending and descending projections, as well as projections to widely divergent parts of the forebrain. Together with previous results, this evidence suggests that the tuberomammillary nucleus has widespread projections to the numerous brain structure located in the forebrain and in the caudal medulla (it may not project to the spinal cord), and that its axons may release a mixture of neuroactive substances including gamma-amino butyrate and several peptides. Although its functional significance remains to be investigated, morphological evidence suggests that the tuberomammillary nucleus may constitute one of a series of neurotransmitter-specific cell groups in the brainstem and basal forebrain with diffuse efferent projections that may be involved in the modulation of attention or behavioral state, rather than the processing of specific sensory or motor information.

Forebrain projections of the ventral tegmentum as studied by axonal transport of [3H]dopamine in the rat.

Twenty-four hours after [3H]dopamine ([3H]DA) injections into different parts of the ventral tegmentum the radioactivity recovered in the forebrain showed a highly regional distribution which corresponded to well-known DA projections. Selective degeneration of DA-neurons with 6-hydroxydopamine (6-OHDA) markedly reduced the axoplasmic transport after [3H]DA injections. The ventral tegmental area (VTA) was found to project primarily to the nucleus accumbens, olfactory tubercle and amygdala. The DA-innervation of the entorhinal cortex and the amygdala derive from cells widely distributed in the VTA and SN.

Regional displacement by sulpiride of [3H]spiperone binding in vivo. Biochemical and behavioural evidence for a preferential action of limbic and nigral dopamine receptors.

The regional displacement by sulpiride of [3H]spiperone binding in vivo was studied in the rat. A low dose of sulpiride (20 mg/kg) displaced [3H]spiperone binding in certain limbic regions (olfactory tubercle, septum) and the substantia nigra but not in the nucleus accumbens or striatum. At this does sulpiride preferentially blocked apomorphine induced apomorphine Higher doses of sulpiride (150 and 250 mg/kg), which blocked apomorphine induced stereotypes and induced catalepsy were found to displace [3H]spiperone binding in all regions studied including the striatum and the nucleus accumbens. Haloperidol (0.1 and 1.0 mg/kg) displaced [3H]spiperone to approximately the same extent in all regions studied.

Immunohistochemical localization of serotonin nerve terminals in the lateral entorhinal cortex of the rat: demonstration of two separate patterns of innervation from the midbrain raphe.

The distribution of serotonin (5-hydroxytryptamine, 5HT) containing nerve terminals in the lateral entorhinal cortex (LEC) has been studied using antibodies against 5-HT in combination with fluorescence histochemistry. Thin, varicose, branching fibers were found to be distributed in a relatively even, diffuse pattern throughout all layers of the LEC. The largest amount of this type of 5HT innervation was in Layer I. This diffuse pattern of 5-HT terminals was supplemented by a dense network of 5HT terminals restricted to Layer III of a small (approximately 1 mm) strip of the LEC. The fibers in this layer were thicker and more convoluted and contained larger varicosities than fibers in any other layer. The existence of a distinct innervation by 5-HT terminals of only a small portion of the LEC demonstrates a hitherto unrecognized and important principle of heterogeneity in 5-HT innervation of cortex. It suggests that 5-5HT neurons in the raphe can selectively influence specific, narrow regions of the lateral perforant path system, which, in turn, affect the intrinsic hippocampal circuits.

The perinatal assessment of psychosocial risk.

Although evaluation of psychosocial risk factors prior to perinatal hospital discharge has been advocated, the means for accomplishing such an evaluation are not well established. This article reviews several major psychosocial risk factors together with instruments that have been utilized to assess them during the perinatal period. Formal constructs reviewed include anxiety, depression, self-concept, general attitudes, life events, stress, adaptation, social support, marital and family functioning, and the home environment. Ongoing assessment of psychosocial status using formal instruments during routine perinatal care may provide a more complete picture of the psychosocial needs of the individual mother and her family, allowing for more appropriate, timely intervention and utilization of social and health care resources.

A critical analysis of the Model of Human Occupation.

The aim of this paper is to begin a dialogue regarding the use of the Model of Human Occupation (MOHO) (Kielhofner, 1995). Three questions formed the basis for discussion: 1. Is the MOHO consistent with the values and beliefs of occupational therapy?; 2. Does the MOHO support the intervention process in occupational therapy? and; 3. Is the MOHO consistent and applicable to the current regulations and societal values in Sweden? The authors propose that the MOHO must be further developed in order to support assessment and intervention in occupational therapy. Specifically, they find the MOHO lacking with regard the influence of the environment on human behaviour, appreciation of the dialectic process between the human and the environment, and of the importance of the subsystem volition in the intervention process.

Enterococcus: an old pathogen with new tricks.

Recent clinical enterococcal isolates from the Oklahoma City Department of Veterans Affairs Medical Center were screened for high-level aminoglycoside resistance, vancomycin resistance, beta-lactamase production, and hemolysin production. Twenty-nine of 53 (55%) enterococcal isolates had high-level resistance to gentamicin, kanamycin, or streptomycin; 27 of these isolates were from the blood and 16 (59%) showed high-level gentamicin resistance. Twenty-one percent of 259 enterococcal isolates from blood, urine, stool, and other sources were hemolytic. Of thirteen blood isolates tested for both high-level gentamicin resistance and hemolysin production, 6 (46%) showed both characteristics. Vancomycin-resistant or beta-lactamase-producing isolates were not found. Nineteen of 21 charts from patients with premortem enterococcal blood isolates were reviewed, and no correlation was found between appropriate antibiotic treatment for high-level gentamicin-resistant or susceptible enterococcal bacteremia and outcome. Enterococci with multiple high-level aminoglycoside resistance, but not vancomycin resistance or beta-lactamase production, are common at this referral medical center. Clinical microbiology laboratories in Oklahoma should routinely screen enterococcal isolates causing potentially serious infections (eg, from blood or cerebral spinal fluid) for high-level aminoglycoside resistance.

Clinical experience with HIV-infected patients at the University of Oklahoma Health Sciences Center.

Two hundred seventy-two patients infected with human immunodeficiency virus (HIV) have received care from the members of the adult infectious disease section at the University of Oklahoma Health Sciences Center. The majority of these patients met the diagnostic criteria for acquired immunodeficiency syndrome. This group of patients was characterized by relatively few parenteral drug abusers, a high incidence of disseminated histoplasmosis, and an unexpectedly low frequency of toxoplasmosis. The prevalence of risk behaviors and endemic disease may be responsible for these particular case distributions.

Clinical experience with HIV-infected patients at the University of Oklahoma Health Sciences Center: an update.

We reviewed the course of 545 human immunodeficiency virus (HIV)-infected patients seen between 1983 and March 30, 1991. A majority were Caucasian homosexual or bisexual men, while parenteral drug abusers represented a smaller proportion than seen nationwide. In the 274 patients with the acquired immunodeficiency syndrome (AIDS), the distribution of AIDS-defining conditions was generally consistent with those reported in studies from elsewhere in the United States. However, toxoplasmosis remained relatively uncommon. There was a slightly higher incidence of disseminated histoplasmosis compared to other studies. HIV encephalopathy (AIDS dementia) was likely underdiagnosed. Although data suggested prolongation of the asymptomatic phase of HIV infection, median survival after AIDS diagnosis remained approximately 12 months.