Kidney disease in antiretroviral-naïve HIV-positive adults with high CD4 counts: prevalence and predictors of kidney disease at enrolment in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: HIV infection has been associated with an increased risk of chronic kidney disease (CKD). Little is known about the prevalence of CKD in individuals with high CD4 cell counts prior to initiation of antiretroviral therapy (ART). We sought to address this knowledge gap. METHODS: We describe the prevalence of CKD among 4637 ART-naïve adults (mean age 36.8 years) with CD4 cell counts > 500 cells/µL at enrolment in the Strategic Timing of AntiRetroviral Treatment (START) study. CKD was defined by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) and/or dipstick urine protein ≥ 1+. Logistic regression was used to identify baseline characteristics associated with CKD. RESULTS: Among 286 [6.2%; 95% confidence interval (CI) 5.5%, 6.9%] participants with CKD, the majority had isolated proteinuria. A total of 268 participants had urine protein ≥ 1+, including 41 with urine protein ≥ 2+. Only 22 participants (0.5%) had an estimated glomerular filtration rate < 60 mL/min/1.73 m(2) , including four who also had proteinuria. Baseline characteristics independently associated with CKD included diabetes [adjusted odds ratio (aOR) 1.73; 95% CI 1.05, 2.85], hypertension (aOR 1.82; 95% CI 1.38, 2.38), and race/ethnicity (aOR 0.59; 95% CI 0.37, 0.93 for Hispanic vs. white). CONCLUSIONS: We observed a low prevalence of CKD associated with traditional CKD risk factors among ART-naïve clinical trial participants with CD4 cell counts > 500 cells/µL.

Glomerular filtration rate estimated using creatinine, cystatin C or both markers and the risk of clinical events in HIV-infected individuals.

OBJECTIVES: The accuracy and precision of glomerular filtration rate (GFR) estimating equations based on plasma creatinine (GFR(cr)), cystatin C (GFR(cys)) and the combination of these markers (GFR(cr-cys)) have recently been assessed in HIV-infected individuals. We assessed the associations of GFR, estimated by these three equations, with clinical events in HIV-infected individuals. METHODS: We compared the associations of baseline GFR(cr), GFR(cys) and GFR(cr-cys) [using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations] with mortality, cardiovascular events (CVEs) and opportunistic diseases (ODs) in the Strategies for the Management of Antiretroviral Therapy (SMART) study. We used Cox proportional hazards models to estimate unadjusted and adjusted hazard ratios per standard deviation (SD) change in GFR. RESULTS: A total of 4614 subjects from the SMART trial with available baseline creatinine and cystatin C data were included in this analysis. Of these, 99 died, 111 had a CVE and 121 had an OD. GFR(cys) was weakly to moderately correlated with HIV RNA, CD4 cell count, high-sensitivity C-reactive protein, interleukin-6, and D-dimer, while GFR(cr) had little or no correlation with these factors. GFR(cys) had the strongest associations with the three clinical outcomes, followed closely by GFR(cr-cys), with GFR(cr) having the weakest associations with clinical outcomes. In a model adjusting for demographics, cardiovascular risk factors, HIV-related factors and inflammation markers, a 1-SD lower GFR(cys) was associated with a 55% [95% confidence interval (CI) 27-90%] increased risk of mortality, a 21% (95% CI 0-47%) increased risk of CVE, and a 22% (95% CI 0-48%) increased risk of OD. CONCLUSIONS: Of the three CKD-EPI GFR equations, GFR(cys) had the strongest associations with mortality, CVE and OD.

Determinants of incident chronic kidney disease and progression in a cohort of HIV-infected persons with unrestricted access to health care.

OBJECTIVES: As socioeconomic factors may impact the risk of chronic kidney disease (CKD), we evaluated the incidence and risk factors of incident CKD among an HIV-infected cohort with universal access to health care and minimal injecting drug use (IDU). METHODS: Incident CKD was defined as an estimated glomerular filteration rate (eGFR) <60 ml/min/1.73 m(2) for ≥ 90 days. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Rates were calculated per 1000 person-years (PY). Associations with outcomes were assessed using two separate Cox proportional hazard models, adjusting for baseline and time-updated covariates. RESULTS: Among 3360 participants [median age 29 years; 92% male; 44% African American (AA)] contributing 23,091 PY of follow-up, 116 developed incident CKD [5.0/1000 PY; 95% confidence interval (CI) 4.2-6.0/1000 PY]. The median first eGFR value was 97.0 mL/min/1.73 m(2) [interquartile range (IQR) 85.3-110.1 mL/min/1.73 m(2)]. Baseline factors associated with CKD included older age, lower CD4 count at HIV diagnosis [compared with CD4 count ≥ 500 cells/µL, hazard ratio (HR) 2.1 (95% CI 1.2-3.8) for CD4 count 350-499 cells/µL; HR 3.6 (95% CI 2.0-6.3) for CD4 count 201-349 cells/µL; HR 4.3 (95% CI 2.0-9.4) for CD4 count ≤ 200 cells/µL], and HIV diagnosis in the pre-highly active antiretroviral therapy (HAART) era. In the time-updated model, low nadir CD4 counts, diabetes, hepatitis B, hypertension and less HAART use were also associated with CKD. AA ethnicity was not associated with incident CKD in either model. CONCLUSIONS: The low incidence of CKD and the lack of association with ethnicity observed in this study may in part be attributable to unique features of our cohort such as younger age, early HIV diagnosis, minimal IDU, and unrestricted access to care. Lower baseline CD4 counts were significantly associated with incident CKD, suggesting early HIV diagnosis and timely introduction of HAART may reduce the burden of CKD.

The use of feathers in monitoring bioaccumulation of metals and metalloids in the South African endangered African grass-owl (Tyto capensis).

Few studies have quantified metals in South African species and no published data on residues specifically in South African owl feathers exist. Tyto capensis is listed as vulnerable within South Africa, making it preferable to use a non-invasive technique to determine metal bioaccumulation for this species. Comparisons are made with the cosmopolitan T. alba to determine whether this species could be used as a surrogate. Concentrations of various metals were thus determined in feathers of the two species and compared with liver and muscle samples. Samples were taken from 119 owls collected as road kill along a national road. A comparison of concentrations in feathers revealed similarly higher concentrations of aluminium, antimony, lead, nickel, and strontium, whereas concentrations of chromium, copper, iron, manganese, selenium, titanium and zinc were similarly higher in internal tissues for both species. Metal concentrations of owls were comparable to those reported in literature and below toxic levels, suggesting that these metals were not likely to impact the owls. Further regressions between feathers and corresponding livers were examined to determine if feathers were indicative of internal metal burdens. Significant positive relationships were found for aluminium, copper, lead, nickel and vanadium in T. alba and nickel, manganese and vanadium in T. capensis. Preliminary results support the feasibility of using feathers as non-destructive indicators of environmental contamination in T. capensis although caution needs to be taken when interpreting the results.

Tracheal intubation in the critically ill: a multi-centre national study of practice and complications.

BACKGROUND: Complications associated with tracheal intubation may occur in up to 40% of critically ill patients. Since practice in emergency airway management varies between intensive care units (ICUs) and countries, complication rates may also differ. We undertook a prospective, observational study of tracheal intubation performed by critical care doctors in Scotland to identify practice, complications, and training. METHODS: For 4 months, we collected data on any intubation performed by doctors working in critical care throughout Scotland except those in patients having elective surgery and those carried out before admission to hospital. We used a standardized data form to collect information on pre-induction physical state and organ support, the doctor carrying out the intubation, the techniques and drugs used, and complications noted. RESULTS: Data from 794 intubations were analysed. Seventy per cent occurred in ICU and 18% occurred in emergency departments. The first-time intubation success rate was 91%, no patient required more than three attempts at intubation, and one patient required surgical tracheostomy. Severe hypoxaemia ( <80%) occurred in 22%, severe hypotension (systolic arterial pressure <80 mm Hg) in 20%, and oesophageal intubation in 2%. Three-quarters of intubations were performed by doctors with more than 24 months formal anaesthetic training and all but one doctor with <6 months training had senior supervision. CONCLUSIONS: Tracheal intubation by critical care doctors in Scotland has a higher first-time success rate than described in previous reports of critical care intubation, and technical complications are few. Doctors carrying out intubation had undergone longer formal training in anaesthesia than described previously, and junior trainees are routinely supervised. Despite these good results, further work is necessary to reduce physiological complications and patient morbidity.

Amyloidosis and female protein in the Syrian hamster. Concurrent regulation by sex hormones.

Previous results have shown that when compared to male Syrian hamsters, female Syrian hamsters have a distinct predisposition to acquire amyloidosis either normally with aging or experimentally with sodium caseinate or diethylstilbestrol (DES) treatments. In the present study, we tested the influence of testosterone on expression of amyloid to determine if this hormone was solely responsible for the sex-limited amyloidosis of the Syrian hamster. Males deprived of testosterone by castration acquired amyloid at an unusually young age, an age of onset similar to that in female hamsters. Also, the amyloidogenic effect of DES in male Syrian hamsters was inhibited by concomitant injections of testosterone, indicating that estrogens induce amyloid in male hamsters by inhibiting testosterone synthesis. When administered to female hamsters, testosterone inhibited expression of amyloid in aging female Syrian hamsters and extended the life span of this gender. Of the two components of amyloid, the major component Amyloid A-derived fibril or the minor constituent, Amyloid P component, only the P component is under sex hormone control in the Syrian hamster; testosterone inhibits the hepatic synthesis of the P component homologue (called female protein), which is normally expressed 100-200-fold greater in female vs. male Syrian hamster. In general, the serum level of female protein under various experimental conditions correlated with the presence of amyloid and indicated that in the Syrian hamster the P component homologue is of primary importance in the deposition of amyloid.

Hamster female protein. A divergent acute phase protein in male and female Syrian hamsters.

Normal adult male hamsters have low levels (10-20 micrograms) of female protein (FP) in serum which increase approximately fivefold during an acute phase response. In contrast, normal females have 50- to 100-fold higher serum levels and the acute phase reaction consists of a transient decrease in FP (approximately 50%), followed by a return to normal levels even under adverse conditions such as cortisone treatment (which by itself has a depressing effect on FP levels in normal females). The acute phase response was not inherently associated with gender, as the pattern of response could be changed to that of the opposite sex by appropriate hormonal manipulation. That is, castrated or diethylstilbestrol-treated males with high FP levels showed a female-type response whereas testosterone-treated females with low FP levels showed a male-type response. Studies on catabolism of 125I-FP showed a similar rapid half-life (T1/2, 9-16 h) in normal males and females and indicated that the sex difference in serum concentration was due to greater synthesis of FP in females. The divergent acute phase reaction of serum FP was related directly to changes in the FP synthetic rate (increased in males, decreased in females). As an indicator of serious pathology, a decrease of FP to very low levels in females was associated frequently with impending death.

Use of phage immunity in molecular cloning experiments.

Immunity to phage superinfection is a useful selective marker in molecular cloning experiments. Plasmids which have unique sites for several different restriction endonucleases and which specify immunity to bacteriophage are described.

Hamster female protein, a sex-limited pentraxin, is a constituent of Syrian hamster amyloid.

Female protein (FP) is a pentraxin of Syrian hamster which is a homologue of two human pentraxins, C-reaction protein (CRP) and amyloid P component (AP). Functionally, FP has been shown to be similar to CRP, although FP has more homology at the amino terminus with AP. The present work investigated amyloid in the Syrian hamster to determine whether FP was involved in a manner analogous to AP. FP was found to be a constituent of Syrian hamster amyloid. This conclusion was based on the following results: (a) FP was consistently detected in amyloid deposits by fluorescent microscopy with specific antisera; (b) The amount of FP extractable from hamster livers directly correlated with the presence of amyloid; and (c) 125I-FP injected intravenously into amyloidotic hamsters rapidly left the intravascular compartment and was found subsequently in amyloid deposits. This unusual alteration of plasma metabolism and amyloid localization of 125I-FP was a characteristic finding in amyloidotic hamsters and was specific for 125I-FP. Therefore, as an amyloid component, FP appears to be functionally similar to human AP. However, FP synthesis is under sex steroid control and the unique sex-limited expression of this pentraxin was associated with an equally novel propensity for deposition of amyloid in female hamsters under normal or experimental conditions. Thus, a high serum level of FP, as found in normal females or diethylstilbestrol-treated males, was associated with enhanced amyloidosis. Although speculative at present, a primary role for serum FP in hamster amyloid deposition may be experimentally approachable by hormonal manipulation of FP synthesis.

Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs.

Localized thrombosis was produced in the left anterior descending (LAD) coronary artery of open chest dogs by constricting a segment so as to produce greater than 90% stenosis (reducing blood flow to 40 +/- 10% of baseline), and placing a thrombus in the segment immediately proximal to the stenosis by inducing endothelial cell injury and instilling a mixture of blood and thrombin. Intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) at a rate of 15-30 micrograms/kg per min for 30 or 60 min in eight dogs induced coronary artery reperfusion within 23 +/- 7 min (mean +/- SD), but reocclusion occurred despite heparin anticoagulation in all but one of these dogs within 7 +/- 5 min. Intravenous injection of 0.8 mg/kg of the F(ab')2 fragment of a monoclonal antibody (7E3) directed against the platelet GPIIb/IIIa receptor, prevented reocclusion in 10/10 dogs during an observation period of 2 h (P less than 0.001 vs. rt-PA alone). The antibody abolished ADP-induced platelet aggregation and markedly prolonged the bleeding time. Intravenous aspirin or dipyridamole prevented reocclusion for 1 h or more in only 2/7 and 1/6 dogs, respectively. We conclude that the monoclonal antibody is very effective in preventing reocclusion after successful thrombolysis of occluded coronary arteries with rt-PA.

Tamoxifen inhibits estrogen-induced hepatic injury in hamsters.

Estrogens have an unusual toxic effect on the liver of two hamster species, the Armenian and the Chinese hamster. The hepatotoxicity was detectable clinically by hyperbilirubinemia and confirmed histologically by the presence of hepatic degenerative-regenerative changes. Administration of tamoxifen with estrogen [either ethynyl estradiol or diethylstilbestrol (DES)] completely abrogated the hepatotoxic effects, suggesting that estrogen receptor (ER) was necessary for estrogen to damage liver. In Armenian hamsters, estrogens decreased hepatic synthesis of female protein (FP); tamoxifen also abolished this DES effect and resulted in a net increase in serum FP levels. DES administration produced higher serum bilirubin levels and lower serum FP levels in females than in males. Paradoxically, tamoxifen blocked these DES effects more effectively and efficiently in females than in males. Estrogens did not injure uteri of Armenian and Chinese hamsters and were nontoxic to livers of other hamsters species, such as Syrian and Turkish. This model provides another perspective of the acute cellular derangement that can be effected by estrogen-ER complex and may indicate a yet unknown mode of ER action.

Medroxyprogesterone acetate induces diabetes insipidus in Chinese hamsters.

Injection of a synthetic progesterone, medroxyprogesterone acetate (MPA or Depo-ProveraR), a widely used contraceptive, into Chinese hamsters (Cricetulus griseus) induced a profound polyuria with daily output of dilute urine equal to about 50% body weight of the hamster. However, relatively normal ability for renal urine concentration was demonstrated by administration of exogenous vasopressin. Body weight did not increase during onset of MPA-induced polyuria or during interval of vasopressin-induced oliguria, suggesting that primary polydipsia was not etiologic. Administration of this steroid to Chinese hamsters was nontoxic, although these polyuric animals were unusually sensitive to water deprivation. This polyuria was not observed when progesterone alone was injected into Chinese hamsters or when MPA was given to other related hamster species (Armenian, Syrian, Turkish or Djzungarian). The MPA-injected Chinese hamster represents a unique model of vasopressin sensitive diabetes insipidus induced by a steroid in a species-specific fashion.

Sarcoidosis of the breast.

Breast involvement by sarcoidosis is rare, with only a few adequately documented cases reported in the literature. Differentiation from other granulomatous processes is important, so that the proper treatment method can be selected. One such case is described, and the current literature is reviewed.

Reappraisal of empyema thoracis. Surgical intervention when the duration of illness is unknown.

The timing of surgical treatment of empyema remains controversial. Traditionally, thoracotomy is performed either within three weeks of diagnosis or delayed until presumed pleurodesis occurs. Often, these patients are moribund and the duration of illness impossible to determine. We report our surgical results in seven patients with a deteriorating clinical course and multiple loculations which persisted after tube thoracostomy and would not have responded to multiple thoracostomies. Five patients required decortication. One required lobectomy for an abscess which developed on the contralateral side six weeks after discharge. There were no deaths or recurrences of empyema. Average times from surgery to tube removal and to discharge were six to 12 days, respectively. We conclude that one can safely and cost-effectively treat these patients surgically even when the duration of illness and presence of pleurodesis are unknown, and that the postoperative course will be uncomplicated.

An ELISA system for evaluating antiretroviral activity against Rauscher murine leukemia virus.

A system for evaluating the activity of antiviral agents against Rauscher murine leukemia virus (R-MuLV) has been developed using an enzyme linked immunosorbent assay technique. The activity of various antiviral compounds demonstrated in this assay system has been compared to their activity in the UV-XC plaque reduction assay, which has been used historically for evaluating anti-R-MuLV compounds. The assay is based upon detection of R-MuLV encoded p30 protein production in virus infected murine cells. The assay reagents are readily available and the assay system is amenable to automated data collection systems. Cytotoxicity evaluations are conducted in parallel to the Rauscher MuLV ELISA assay in order to assess drug-induced reductions in cell viability. Cytotoxicity evaluations are important to interpretation of the ELISA results since reductions in cell viability reduce viral protein production which would indicate an antiviral drug effect. This system is less sensitive than the classical UV-XC plaque reduction assay; however, it does offer an alternative to the time-consuming and labor-intensive plaque assay.

Episcleral and orbital pseudorheumatoid nodules.

Pseudorheumatoid nodules are subcutaneous necrobiotic granulomas that are histopathologically similar or identical to those seen with rheumatoid arthritis, granuloma annulare, necrobiosis lipoidica diabeticorum, and systemic lupus erythematosus. Although these nodules are most common in children, they are also seen in adults and are usually located on the extremities and scalp. Eyelid and eyebrow involvement is seen infrequently. We histopathologically verified episcleral and orbital pseudorheumatoid nodules in an adult with eyelid and eyebrow nodules. Pseudorheumatoid nodules must be included in the differential diagnosis of subconjunctival mass lesions that may concomitantly involve the orbit, episclera, and periocular region.

The effects of dimethyl sulfoxide on aortic prostacyclin production and serum thromboxane and plasma fibrinogen levels in rabbits fed a normal versus a cholesterol-enriched diet.

Through an unknown mechanism, dimethyl sulfoxide (DMSO) retards atherogenesis in cholesterol-fed rabbits (CFR). We studied the effects on the development of lesions and prostacyclin (PGI2) production in the thoracic aorta and total serum lipid and cholesterol content of the abdominal aortic serum thromboxane (TXB2) and plasma fibrinogen levels in rabbits fed control versus atherogenic diets, with and without DMSO. Without DMSO, PGI2 production was significantly higher in CFR versus control animals (8.65 +/- 1.0 vs 6.38 +/- 0.3 ng/15 min [p less than 0.02]). DMSO did not influence PGI2 production in any of the groups but significantly reduced the number of atheromatous lesions in CFR (78% +/- 9% vs 8% +/- 4% [p less than 0.001]). With DMSO, CFR had a significant reduction in total lipid levels (422 +/- 5 vs 300 +/- 21 mg/gm dry wt [p less than 0.01]) and cholesterol levels (74 +/- 12.8 vs 31.8 +/- 6.4 mg/gm dry wt [p less than 0.01]) compared with control animals. Fibrinogen levels were significantly lower in CFR versus control animals (0.83 +/- 0.07 vs 2.42 +/- 0.13 mg/ml [p less than 0.01]). TXB2 was lower in DMSO plus control versus control animals alone. In conclusion, DMSO does not appear to act through changes in PGI2 or fibrinogen activity. Its effect in lowering TXB2 in CFR suggests an action on platelet function.

Histologic prognosticators in stage I squamous cell carcinoma of the vulva.

Sixty-four cases of stage I vulvar squamous cell carcinoma were analyzed histologically to define a patient subset at minimum risk for recurrence or nodal metastases. Three patterns of invasion were predefined: carcinoma in situ with early stromal invasion (33%), pushing (8%), and infiltrative (59%). Infiltrative pattern and invasion deeper than 1.5 mm equally predicted nodal metastases (P = .045), although depth measurement in biopsy specimens was subject to sampling error. Confluence and absence of carcinoma in situ each predicted extranodal recurrence (P = .011). Local recurrence appeared more related to inadequate surgical margins than failure to perform radical vulvectomy. Carcinoma in situ with early stromal invasion represents a group at zero risk for nodal metastases. We recommend wide local excision for all stage I lesions. In general, omission of lymphadenectomy should be reserved for cases of carcinoma in situ with early stromal invasion.

The changing workforce: the role of health psychology.

Because the federal government is the largest payer of all health costs, unbridled increases in the health workforce have profound fiscal implications. Recent efforts to control health spending through modifications of health delivery systems are related to the consequences of the unlimited production of health professionals. However, the federal government has established processes to review physician workforce changes, and these mechanisms have become important in accessing federal training monies. Psychologists have no concerted workforce policy and receive little federal training money. Moreover, other health professionals have attained statutory authority to perform and provide the same services as psychologists. This diffusion of professional functions impedes the ability to assess the status of the workforce and the development of psychology as a health profession.

Effects of stress inoculation training on athletes' postsurgical pain and rehabilitation after orthopedic injury.

The efficacy of a cognitive-behavioral intervention (stress inoculation training; SIT) for postsurgical anxiety, pain, and physical rehabilitation in injured athletes was tested. Sixty male athletes who underwent arthroscopic surgery for miniscus injury in 1 knee were randomly assigned to either treatment (SIT and physical therapy) or control (physical therapy only) conditions. Results showed that participants in the treatment group demonstrated significantly less postsurgical pain and anxiety during the rehabilitation process, compared with controls. Additionally, treated participants required fewer days to return to criterion physical functioning, compared with nontreated participants.