Nonspecific transcription factor binding can reduce noise in the expression of downstream proteins.

Transcription factors (TFs) interact with a multitude of binding sites on DNA and partner proteins inside cells. We investigate how nonspecific binding/unbinding to such decoy binding sites affects the magnitude and time-scale of random fluctuations in TF copy numbers arising from stochastic gene expression. A stochastic model of TF gene expression, together with decoy site interactions is formulated. Distributions for the total (bound and unbound) and free (unbound) TF levels are derived by analytically solving the chemical master equation under physiologically relevant assumptions. Our results show that increasing the number of decoy binding sides considerably reduces stochasticity in free TF copy numbers. The TF autocorrelation function reveals that decoy sites can either enhance or shorten the time-scale of TF fluctuations depending on model parameters. To understand how noise in TF abundances propagates downstream, a TF target gene is included in the model. Intriguingly, we find that noise in the expression of the target gene decreases with increasing decoy sites for linear TF-target protein dose-responses, even in regimes where decoy sites enhance TF autocorrelation times. Moreover, counterintuitive noise transmissions arise for nonlinear dose-responses. In summary, our study highlights the critical role of molecular sequestration by decoy binding sites in regulating the stochastic dynamics of TFs and target proteins at the single-cell level.

Outcomes of starting first-line antiretroviral therapy in hepatitis B virus/HIV-coinfected patients in Ghana.

OBJECTIVES: HIV/hepatitis B virus (HBV) coinfection is common in Ghana, where first-line antiretroviral therapy (ART) comprises lamivudine with zidovudine or stavudine and nevirapine or efavirenz. Little is known about ART outcomes in the context of coinfection. This study evaluated outcomes of ART among HIV/HBV-coinfected Ghanaians, focusing on locally available parameters. PATIENTS AND METHODS: An observational study comparing clinical and virological outcomes in HIV-infected individuals who were either hepatitis B surface antigen (HBsAg) positive or HBsAg negative was conducted over 36 months. Clinical events, hepatic transaminases, CD4 count and body mass index (BMI) were evaluated among 143 HBsAg-positive and 228 HBsAg-negative patients. In a random subset of HBsAg-positive patients, HBV-DNA levels and polymerase sequences were analysed. RESULTS: Comparing HBsAg-positive and HBsAg-negative patients, 44/143 (30.8%) and 83/228 (36.4%) defaulted follow-up, 15/143 (10.5%) and 30/228 (13.2%) experienced a new clinical event, and 8/143 (5.6%) and 11/228 (4.8%) discontinued their initial regimen, respectively. Transaminase levels were higher in HBsAg-positive patients, although elevations were low grade. HBV coinfection was associated with an adjusted 2.04 (95% CI 0.59-3.49) cells/mm(3)/month smaller CD4 cell increase; there was no significant effect on BMI changes. After a median of 9 months of ART, 64/66 (97.0%) patients showed detectable HBV-DNA (median 3.3 log(10) IU/mL; IQR 2.6-6.2); 12/53 (22.6%) of these showed lamivudine-associated resistance mutations. CONCLUSIONS: HIV/HBV-coinfected Ghanaians tolerated first-line ART well, but experienced blunted CD4 cell responses. There was evidence of ongoing HBV replication, mild but persistent transaminase elevations and emerging lamivudine resistance in a proportion of treated patients, indicating the potential for progressive liver damage.

The psychological impact of facial changes in scleroderma.

The physical disabilities associated with scleroderma are well known but the psychological impact of the condition has received less attention. Few studies have examined appearance related issues, most notably of the face. The aim of this study is to evaluate the psychological impact of facial, aesthetic and functional changes in scleroderma. One hundred seventy-one patients with a clinical diagnosis of scleroderma were recruited into the study. Digital photographs were objectively graded into groups based on severity of disfigurement as judged by an observer. Facial movement was recorded using a modified House-Brackmann Grading Scale. Psychological evaluation comprised the Derriford Appearance Scale short-form (DAS), the Noticeability and Worry score and the Hospital Anxiety and Depression Scale (HADS). Severity of disfigurement predicted decreased mouth opening, the extent to which participants judged their appearance as noticeable to others, and the level of appearance-related concern as measured by the DAS24. There was an inverse relationship with age. Facial changes were ranked as the most worrying aspect of the condition. This study shows facial disfigurement impacts on patient with scleroderma independent of functional changes related to systemic disease. The major difficulty is with the perceived noticeably of the condition to other people and the resulting self-consciousness in social encounters.

HIV prevalence and testing practices among tuberculosis cases in London: a missed opportunity for HIV diagnosis?

BACKGROUND: Universal testing for HIV in patients with tuberculosis (TB) has been advocated for over a decade. The aim of this study was to describe the prevalence and testing practices of HIV in TB centres in London. METHODS: A cohort study was undertaken of all patients with TB in Greater London in 2003-4 (n = 1941). Logistic regression was used to assess factors affecting being offered and accepting testing and having a positive HIV result. RESULTS: The overall known prevalence of HIV was 9.9% (193/1941). In those with a test result (including those diagnosed previously) it was 25.6%. Overall, 50.8% of patients aged > or =20 years without previous testing were offered HIV testing and, of these, 73% accepted. In multivariable analysis, factors associated with being HIV positive were age 20-49 years, black ethnicity and being born overseas. Those with smear-negative disease and with a poor understanding of English were significantly less likely to be offered HIV testing. Factors associated with refusal of an offered test were female gender or age >49 years. HIV status was not associated with smear status, drug resistance or death, but was associated with CNS disease (OR 1.8, 95% CI 1.0 to 3.0, p = 0.003). CONCLUSIONS: Nearly half the patients with TB in London in 2003-4 were not offered HIV testing. In those offered testing, uptake was high. Patients in higher risk groups were more likely to be offered testing but, even within the highest risk groups, testing was not universally offered. This represents a missed opportunity for diagnosing HIV in patients with TB in London.

Abandoned babies in the UK - a review utilizing media reports.

BACKGROUND: In the absence of national policy or comprehensive data, the phenomenon of abandoned babies is poorly understood in the UK. This study aims to use media reports as a resource to collate existing information on abandoned babies and to draw conclusions to inform future response. METHODS: An exhaustive media search using electronic searches and media monitoring was undertaken to glean systematic information on all abandoned babies in the UK from 1998-2005. These were matched onto two databases - the UK Crime Statistics and the UK Abandoned Children Register in an attempt to align information on infant abandonment. Media reports were coded to list gender, survival, age, parental finding and circumstantial data. RESULTS: Our figures suggest an average of 16 babies abandoned yearly, while official sources give conflicting indications because of incomplete data gathering and child over-inclusion. Through systematic coding of media reports, 124 babies were identified over a 7-year period. Of these, 96 (77.4%) were newborns (<1 week old) and 28 (22.6%) were older babies (>1 week old). Adjusted logistic regression analysis found the strongest predictors of survival were age at abandonment and 'findability'. Newborn babies were less likely to survive than older babies (33.7% newborns died vs. 0% older babies, P < 0.0001). Babies left in a non-findable location (34%) had a 5.19 (2.06, 13.11) higher odds of death compared with those to be found. Most babies (74%) were abandoned outdoors and only 9.7% were left with a memento. Few mothers, almost exclusively those of older babies, were found (37.1%). Of those found, 92% were located within 3 days of abandoning their baby. Media interest is transient - 44.8% cases have a single report - and are typified by negative headlines (81.5%). CONCLUSIONS: This database currently represents the most accurate and comprehensive picture of the newborn abandonment phenomenon in the UK, a phenomenon that is rare but with high media and social interest. If the future well-being of mother and baby are to be catered for, clearer evidence-based policy and provision is vital.

Prediction of phenotypic susceptibility to antiretroviral drugs using physiochemical properties of the primary enzymatic structure combined with artificial neural networks.

OBJECTIVES: Genotypic interpretation systems extrapolate observed associations in datasets to predict viral susceptibility to antiretroviral drugs (ARVs) for given isolates. We aimed to develop and validate an approach using artificial neural networks (ANNs) that employ descriptors of physiochemical properties for mutations in HIV-1 protease (PR) and reverse transcriptase (RT) to predict phenotypic susceptibility to all currently approved ARVs. METHOD: We extracted pairs of PR and RT gene sequences (n=1507; 98.5% sub-type B) and their corresponding exact phenotype values (PhenoSense only, n=10 132) from the Stanford HIV database. All amino acid positions and mixture codes were accounted for. For each ARV, an ANN was trained with 10-fold internal cross-validation. The predictive abilities of these trained ANNs were validated on separate datasets. RESULTS: Correlation coefficients between observed and predicted phenotype values in the 10-fold cross-validation ranged from: 0.75 (tenofovir) to 0.94 [lamivudine (3TC)] for nucleoside RT inhibitors (NRTIs); 0.82 [efavirenz (EFV)] to 0.83 [nevirapine (NVP)] for non-nucleoside RT inhibitors (NNRTIs); and 0.83 (atazanavir) to 0.92 (ritonavir) for PR inhibitors (PIs). For the validation set the correlation coefficients ranged from 0.76 (didanosine) to 0.96 (3TC) for NRTIs; 0.68 (EFV) to 0.81 (NVP) for NNRTIs; and 0.88 (amprenavir) to 0.95 (saquinavir) for PIs. For C sub-type predictions, with ANNs trained on sub-type B data, the correlation coefficient was 0.89. CONCLUSIONS: ANNs, based on the physiochemical properties of the PR and RT amino-acid sequences, predict phenotypic susceptibility to ARVs inhibiting these enzymes to an extent that is comparable to routine phenotypic susceptibility testing. These ANNs can also be used to predict resistance to C sub-types.

Surgery for metastatic spine tumors in the elderly. Advanced age is not a contraindication to surgery!

BACKGROUND: With recent advances in oncologic treatments, there has been an increase in patient survival rates and concurrently an increase in the number of incidence of symptomatic spinal metastases. Because elderly patients are a substantial part of the oncology population, their types of treatment as well as the possible impact their treatment will have on healthcare resources need to be further examined. PURPOSE: We studied whether age has a significant influence on quality of life and survival in surgical interventions for spinal metastases. STUDY DESIGN: We used data from a multicenter prospective study by the Global Spine Tumor Study Group (GSTSG). This GSTSG study involved 1,266 patients who were admitted for surgical treatments of symptomatic spinal metastases at 22 spinal centers from different countries and followed up for 2 years after surgery. PATIENT SAMPLE: There were 1,266 patients recruited between March 2001 and October 2014. OUTCOME MEASURES: Patient demographics were collected along with outcome measures, including European Quality of Life-5 Dimensions (EQ-5D), neurologic functions, complications, and survival rates. METHODS: We realized a multicenter prospective study of 1,266 patients admitted for surgical treatment of symptomatic spinal metastases. They were divided and studied into three different age groups: <70, 70-80, and >80 years. RESULTS: Despite a lack of statistical difference in American Society of Anesthesiologists (ASA) score, Frankel neurologic score, or Karnofsky functional score at presentation, patients >80 years were more likely to undergo emergency surgery and palliative procedures compared with younger patients. Postoperative complications were more common in the oldest age group (33.3% in the >80, 23.9% in the 70-80, and 17.9% for patients <70 years, p=.004). EQ-5D improved in all groups, but survival expectancy was significantly longer in patients <70 years old (p=.02). Furthermore, neurologic recovery after surgery was lower in patients >80 years old. CONCLUSIONS: Surgeons should not be biased against operating elderly patients. Although survival rates and neurologic improvements in the elderly patients are lower than for younger patients, operating the elderly is compounded by the fact that they undergo more emergency and palliative procedures, despite good ASA scores and functional status. Age in itself should not be a determinant of whether to operate or not, and operations should not be avoided in the elderly when indicated.

Changes in the cause of death among HIV positive subjects across Europe: results from the EuroSIDA study.

OBJECTIVES: The causes of death among HIV-positive patients may have changed since the introduction of highly active antiretroviral therapy (HAART). We investigated these changes, patients who died without an AIDS diagnosis and factors relating to pre-AIDS deaths. METHODS: Analyses of 1826 deaths among EuroSIDA patients, an observational study of 8556 patients. Incidence rates of pre-AIDS deaths were compared to overall rates. Factors relating to pre-AIDS deaths were identified using Cox regression. RESULTS: Death rates declined from 15.6 to 2.7 per 100 person-years of follow-up (PYFU) between 1994 and 2001. Pre-AIDS incidence declined from 2.4 to 1.1 per 100 PYFU. The ratio of overall to pre-AIDS deaths peaked in 1996 at 8.4 and dropped to < 3 after 1998. The adjusted odds of dying following one AIDS defining event (ADE) increased yearly (odds ratio, 1.53; P < 0.001), conversely the odds of dying following three or more ADE decreased yearly (odds ratio, 0.79; P < 0.001). The proportion of deaths that followed an HIV-related disease decreased by 23% annually; in contrast there was a 32% yearly increase in the proportion of deaths due to known causes other than HIV-related or suicides. Injecting drug users (IDU) were significantly more likely to die before an ADE than homosexuals (relative hazard, 2.97; P < 0.0001) and patients from northern/eastern Europe (relative hazard, 2.01; P < 0.0001) were more likely to die pre-AIDS than southern patients. CONCLUSIONS: The proportion of pre-AIDS deaths increased from 1994 to 2001; however, the incidence of pre-AIDS deaths and deaths overall declined. IDU and subjects from northern/eastern Europe had an increased risk of pre-AIDS death. HIV-positive patients live longer therefore it is essential to continue to monitor all causes of mortality to identify changes.

Increased 5-HT2C receptor responsiveness occurs on rearing rats in social isolation.

To investigate whether isolation rearing alters 5-hydroxytryptamine2C (5-HT2C) receptors, the effect of the serotonin agonist m-chlorophenylpiperazine (mCPP) was examined on elevated plus-maze behaviour, plasma corticosterone and brain 5-HT2C receptor protein levels in rats. There was no distinction between behaviour or corticosterone levels in drug-free isolates or socially housed rats exposed to the elevated plus-maze. The anxiogenic response to mCPP (decrease in open arm entry and time and an increase in stretch attend postures) on the elevated plus-maze was greater in isolation than in socially reared controls without any concomitant difference in the hypolocomotor effect of mCPP in the two groups. mCPP produced a greater elevation in plasma corticosterone in isolates than in group-housed controls. Hippocampal 5-HT2C receptor protein-like immunoreactive levels were significantly lower following mCPP than saline only in rats reared in isolation. These results indicate that increased 5-HT2C receptor responsiveness accompanies isolation-rearing and may contribute to the enhanced response to stress and the increased neophobia seen in this animal model of trait anxiety/depression. In isolation reared rats, rapid down-regulation of supersensitive 5-HT2C receptors may occur in the hippocampus following 5-HT agonist challenge.

Resource allocation and prioritization in auditory working memory.

A prevalent view of working memory (WM) considers it to be capacity-limited, fixed to a set number of items. However, recent shared resource models of WM have challenged this "quantized" account using measures of recall precision. Although this conceptual framework can account for several features of visual WM, it remains to be established whether it also applies to auditory WM. We used a novel pitch-matching paradigm to probe participants' memory of pure tones in sequences of varying length, and measured their precision of recall. Crucially, this provides an index of the variability of memory representation around its true value, rather than a binary "yes/no" recall measure typically used in change detection paradigms. We show that precision of auditory WM varies with both memory load and serial order. Moreover, auditory WM resources can be prioritized to cued items, improving precision of recall, but with a concomitant cost to other items, consistent with a resource model account.

Hand weakness in Charcot-Marie-Tooth disease 1X.

There have been suggestions from previous studies that patients with Charcot-Marie-Tooth disease (CMT) have weaker dominant hand muscles. Since all studies to date have included a heterogeneous group of CMT patients we decided to analyse hand strength in 43 patients with CMT1X. We recorded handedness and the MRC scores for the first dorsal interosseous and abductor pollicis brevis muscles, median and ulnar nerve compound motor action potentials and conduction velocities in dominant and non-dominant hands. Twenty-two CMT1X patients (51%) had a weaker dominant hand; none had a stronger dominant hand. Mean MRC scores were significantly higher for first dorsal interosseous and abductor pollicis brevis in non-dominant hands compared to dominant hands. Median nerve compound motor action potentials were significantly reduced in dominant compared to non-dominant hands. We conclude that the dominant hand is weaker than the non-dominant hand in patients with CMT1X.

The use and abuse of hypothesis tests: how to present P values.

This overview highlights some of the key issues involved in performing and interpreting hypothesis tests. We describe the general approach taken in performing a hypothesis test with a focus on how to state the null and alternative hypothesis, and why two-sided tests are usually more appropriate than one-sided tests. We describe best practice techniques in performing and presenting the results of hypothesis tests. We recommend that, alongside any p-values, authors should also present estimates of the size of any treatment effects and their confidence intervals. Furthermore, they should specify the exact p-value rather than using terms such as 'NS' or the commonly used asterix notation. We discuss other pitfalls that are encountered at the analysis stage such as the use of repeated observations on individuals, the use of multiple tests on the data and the erroneous use of parametric tests when data are not normally distributed and vice versa. We highlight these points using two different examples: one looking at the use of compression stockings for preventing the occurrence of DVT on long-haul flights and a second hypothetical study comparing laser versus surgery techniques for the removal of varicose veins.

Women who decline antenatal screening for HIV infection in the era of universal testing: results of an audit of uptake in three London hospitals.

Universal screening for HIV in early pregnancy is strongly promoted policy in the United Kingdom with a target of 90 per cent uptake. We identified characteristics of women declining screening by conducting an audit at three hospitals in inner north London. In early 2002 midwives were asked to complete an audit form following first antenatal appointment. Of 2,710 women attending 401 (15 per cent) declined an HIV test. Of women who declined 38 per cent reported they had been tested for HIV in the past; 65 per cent accepted every other antenatal test. In multivariable analysis parity (OR: 1.19; 95 per cent CI 1.10-1.29 per additional child), declining other tests (OR: 3.10; 95 per cent CI 2.44-3.93 per test declined) and previous HIV testing (OR: 1.70; 95 per cent CI 1.30-2.23) were predictors of declining an HIV test. Women declining screening were not obviously from high-risk demographic groups: women from sub-Saharan Africa were not at greater risk of declining an HIV test than women from other regions.

Epstein-Barr virus antibodies in patients with ataxia-telangiectasia and other immunodeficiency diseases.

An unusual antibody response to the Epstein-Barr virus (EBV) has been noted in patients with ataxia-telangiectasia. Of a group of 16 such patients 8 were found to have antibodies in their serum to the EBV viral capsid antigen (VCA), and 4 of them also had antibodies to the EBV early antigen (EA); antibodies to the nuclear antigen (EBNA), however, were absent in 3 of the 8. The antibody pattern persisted for more than 2 years in the patients available for follow-up study. In comparison, of 24 patients with various other immunodeficiency syndromes 9 were found to have EBV-VCA antibodies in their serum, but none of the 9 had EA antibodies and 3 lacked EBNA antibodies. Two other groups of subjects, all of whom had EBV-VCA and EBNA antibodies in their serum late after an EBV infection, were also studied; 82 had infectious mononucleosis and 55 were healthy and had no such history. EA antibodies were detected in 45 of the first group during the acute phase of the illness but persisted in only 6 of the 68 who were followed up for more than 2 years, and they were detected in only 7 of the second group.All eight lymphoblastoid cell lines established from the peripheral blood of the four patients with ataxia-telangiectasia who are still available for follow-up study express EBV-VCA, whereas most similar cell lines established from normal individuals express only EBNA. In two of these patients cell-mediated immunity, as assessed from lymphocyte transformation induced by mitogens, was markedly decreased but autologous cell-mediated immune regression of EBV-induced transformation of B (bone-marrow-derived)-lymphocytes was normal. The percentage of T (thymus-derived)-helper cells was greatly decreased in two of the three patients in whom it was measured, and the percentage of T-suppressor cells was greatly increased in one of them, but the percentage of total T-lymphocytes was within normal limits in all three.The possible significance of these findings - in particular, the persistence of EA antibodies and the diminished restriction of expression of EA - in the late development of tumours after an EBV infection in patients with ataxia-telangiectasia deserves careful attention. Finally, the apparent correlation between immunoglobulin deficiency and poor or absent EBNA antibody response warrants further study.

Importance of physician identification of airflow limitation in stable asthmatics.

The physician's ability to recognize airflow limitation was assessed in 92 stable asthmatics between seven and 12 years of age. A parental symptom score was obtained. The physician assigned a physical sign score and a clinical impression score based on the severity and lability of symptoms. Airflow limitation was considered significant if the forced expiratory flow between 25 and 75% of the vital capacity (FEF25-75) was less than 50% predicted. The FEF25-75 did not correlate with any of the scores and was less than 50% predicted in 27 of 92. There was no clinical suspicion of abnormality in 12 of 27. The FEF25-75 increased significantly after salbutamol inhalation in 22 of 23 but was persistently abnormal on follow-up in 9 of 21. We conclude that without pulmonary function tests the physician may fail to identify significant reversible airflow limitation in 13% of stable asthmatic children.

Response to disodium cromoglycate in children with chronic asthma.

Twenty-three children with chronic severe perennial asthma received randomly-allocated disodium cromoglycate or placebo four times a day for 12 weeks, and the alternative regimen for the subsequent 12 weeks. More than half the patients improved while on DSCG according to clinical assessment. There was a significant increase in the mean FEV(0.75 second) during the drug period, largely owing to dramatic improvement in nine patients. No reduction in the mean decrease of FEV after exercise was demonstrated. Response, when it occurred, was evident within four weeks. The effect of the medication was consistent in individual patients throughout the 12-week period. No evidence of toxicity was discovered during the period of study.

Pharmacokinetic analysis of the disposition of intravenous theophylline in young children.

The disposition of a single intravenous dose of theophylline, 3.2 mg/kg, was studied using a high-pressure liquid chromatographic assay in ten asthmatic children one to four years of age. The man plasma theophylline clearance was 0.100 +/- 0.036 l/kg/hr, kel 0.49 +/- 0.30 hr-1, betat1/2 3.38 +/- 1.11 hr, alphat1/2 0.13 +/- 0.09 hr, and V1 0.25 +/- 0.13 1/kg. Plasma theophylline clearance was approximately 40% greater in these children than that reported in adults, mainly due to an increased rate of drug elimination. Large interindividual differences were observed. Analysis of data using either a two- or one-compartment model yielded almost identical dosage regimens designed to rapidly achieve and maintain a chosen plasma theophylline concentration. Calculations based upon mean values of pharmacokinetic constants predict that a maintenance dose rate for aminophylline of 30 mg/kg/day, after a loading dose of 5.6 mg/kg, would rapidly achieve and maintain a mean steady-state plasma concentration of theophylline of 10 mg/1. Potential toxicity of such a regimen has not been excluded, since therapeutic trials (with achievement of steady state) have not yet been conducted.

Evaluation of a sustained-release theophylline product in children with asthma.

The purpose of this study was to determine the dose requirements and dose interval of a sustained-release theophylline sprinkle preparation (Somophyllin-12) necessary to maintain therapeutic serum theophylline concentrations in children with asthma. Eighteen patients aged 3-7 years (subgroup 1) and 21 patients aged 8-12 years (subgroup 2), who had been on continuous theophylline therapy with Somophyllin-12, completed the study. Prior to entry into the study, each patient's dosage of Somophyllin-12 was titrated to achieve predose and peak (4-hour postdose) theophylline levels in the therapeutic range (8-20 mg/L). The patients subsequently had predose and peak serum theophylline levels determined at baseline (week 0) and at weeks 2 and 4 of the study. The majority of children maintained theophylline levels in the therapeutic range throughout the 4-week trial, and t-tests showed no significant change from baseline in mean values of peak, trough, or peak-trough theophylline differences in either patient subgroup at weeks 2 and 4. Nevertheless, some individual patients had considerable variation from baseline in peak and trough theophylline levels at follow-up visits. Dosage requirements standardized for weight were significantly higher in patients in subgroup 1 than in subgroup 2 (21.3 +/- 4.5 mg/kg per day versus 17.5 +/- 4.7 mg/kg per day; p less than 0.05). The majority of the patients required 12-hourly administration of Somophyllin-12, but seven of 39 patients required 8-hour dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinal and extraocular cytomegalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994-2001.

This multicentre prospective cohort study by the EuroSIDA study group was designed to determine the factors affecting the incidence of cytomegalovirus (CMV) end-organ disease (CMVD) and the rate of survival after diagnosis in patients with AIDS during the years 1994-2001. This period includes two eras, the pre-HAART era and the HAART era, because HAART affects the natural history of HIV infection, especially with respect to opportunistic infections, including CMV infection. Clinical and laboratory data were collected from the charts of 8,556 patients in 63 AIDS clinics in Europe. A total of 707 patients had CMVD at recruitment and at follow-up: 449 with retinitis (CMVR), 190 with extraocular CMV disease (EOCMVD), and 58 with both. Of the cases of EOCMVD, 66% involved the gastrointestinal tract and 17% the central nervous system. Of patients with a CD4+ count of < or =200 mm(-3) initially, 1.8% on HAART developed CMVD within a 24-month period, as compared to 11.1% on dual therapy and 14.3% without treatment (P<0.0001). There were highly significant differences in survival according to the calendar year (P<0.0001), with mortality declining from 79% during the years 1994-1995 to 42% in 2000-2001. The incidence of death after any CMVD was 28.4 per 100 patient-years of follow-up. Median survival of CMVR patients and EOCMVD patients was 11 and 7 months, respectively, the prognosis being better among patients with gastrointestinal rather than neurological CMVD. The initiation of HAART was associated with a 37% decrease in mortality (P<0.05). Eighteen percent of all deaths were caused by EOCMVD itself. This study describes a decline in the incidence and mortality of CMVR and EOCMVD during the HAART era of the HIV epidemic. It furthermore serves as a reminder of the importance of EOCMVD as a cause of morbidity and mortality in AIDS in the pre-HAART era.

Regional and temporal changes in AIDS in Europe before HAART.

In a prospective observational study 4,485 patients from 46 clinical centres in 17 European countries were followed between April 1994 and November 1996. Information on AIDS-defining events (ADEs) were collected together with basic demographic data, treatment history and laboratory results. The centres were divided into four geographical regions (north, central, south-west and south-east) so that it was possible to identify any existing regional differences in ADEs. The regional differences that we observed included a higher risk of all forms of Mycobacterium tuberculosis infections (Tb) and wasting disease in the south-west and an increased risk of infections with the Mycobacterium avium complex (MAC) in the north. In Cox multivariable analyses, where north was used as the reference group, we observed hazard ratios of 6.87, 7.77, 2.29 and 0.16 (P < 0.05 in all cases) for pulmonary Tb, extrapulmonary Tb, wasting disease and MAC respectively in the south-west. Pneumocystis carinii pneumonia (PCP) was less commonly diagnosed in the central region (RH = 0.51, 95% CI 0 32-0.79, P = 0.003) and most common in the south-east (RH = 1.04, 95% CI 0.71-1.51, P = 0.85). Comparisons with a similar 'AIDS in Europe' study that concentrated on the early phase of the epidemic reveal that most of the regional differences that were observed in the 1980s still persist in the mid-1990s.