HIV-exposed infants with acute respiratory failure secondary to acute lower respiratory infections managed with and without mechanical ventilation.

OBJECTIVES: The decision to provide mechanical ventilation (intermittent positive pressure ventilation (IPPV)) to HIV-exposed infants in resource-poor settings has remained difficult owing to problems in confirming HIV infection and the lack of data on outcome. We evaluated the predictive value of the HIV antibody test in confirming infection in infants requiring mechanical ventilation for acute lower respiratory infections (ALRIs), and compared the outcome for children denied access with the outcome for similar subjects who were ventilated. SETTING AND DESIGN: This investigative study was conducted over a 12-month period at the paediatric intensive care unit (PICU) at King Edward VIII Hospital (KEH) in Durban, and at Ngwelezana Hospital in northern KwaZulu-Natal. SUBJECTS: HIV-exposed patients with acute respiratory failure (ARF) secondary to ALRI entering the PICU at KEH were enrolled into the IPPV arm, while similar children who were refused such care at Ngwelezana Hospital were admitted into the non-IPPV arm. Standardised protocols for entry and management of enrolled subjects were utilised. OUTCOME MEASURES: HIV DNA polymerase chain reaction (PCR) testing was performed to establish HIV status. Clinical and laboratory parameters were correlated with HIV status to determine predictors of infection and outcome (survival to discharge). RESULTS: One hundred and sixteen HIV-exposed infants were enrolled, 49 into the IPPV arm and 67 into the non-IPPV arm. The median age of both groups was 3.0 months (0.5-11 months), and the male/female ratio and proportion of infants under 3 months of age were similar in both groups. The predictive values of the HIV antibody test in determining HIV infection in the IPPV and non-IPPV arms were 87.8% and 85.0% respectively. Splenomegaly and a serum globulin of > 35 g/l increased the likelihood of being HIV PCR-positive (p = 0.006 and p = 0.04 respectively). Survival to discharge rates for HIV-infected children in the IPPV and non-IPPV arms were 41.9% and 24.6% respectively (p = 0.08). Age less than 3 months (p = 0.04) and very severe pneumonia (p = 0.007) were the only indicators of poor outcome. CONCLUSION: Mechanical ventilation provided little benefit in HIV-infected children with ARF from ALRI. An HIV antibody test in infants with ALRI and ARF is highly suggestive of HIV infection. Splenomegaly and a serum globulin of greater than 35 g/l were the only useful markers in identifying HIV infection.     

The association of anemia and hypoalbuminemia with accelerated decline in GFR among adolescents with chronic kidney disease

We sought to describe rates of kidney function decline and to identify modifiable risk factors for CKD progression in a multicenter prospective cohort study of adolescents with CKD aged 11 to 18 years seen semiannually for up to three years. Of the 23 subjects meeting inclusion criteria, the average estimated GFR was 51 ± 27 ml/min/1.73 m² (0.85 ± 0.45 ml/s/1.73 m²) at entry. The overall annualized decline in GFR was 5.6 ml/min/1.73 m² (0.093 ml/s/1.73 m²) per year (95% confidence interval [95% CI]: 1.9 to 9.3 [0.032 to 0.16]). The adjusted annualized decline in GFR was found to be accelerated in males, as well as among those over 15 years of age. The adjusted annualized decline in GFR was greater among those with either anemia (hematocrit below 36%), or hypoalbuminemia (albumin below 4 g/dl [40 g/L]). After adjustment, anemia was associated with an accelerated decline of 7.8 ml/min/1.73 m² (0.13 ml/s/1.73 m²) (95% CI: 3.3 to 12 [0.055 to 0.20]) and hypoalbuminemia was associated with an accelerated decline of 17 ml/min/1.73 m² (0.28 ml/s/1.73 m²) (95% CI: 11 to 22 [0.18 to 0.37]). Further study is needed to evaluate whether treatment of anemia or hypoalbuminemia, as outlined in current clinical care guidelines for CKD, may slow the progression of CKD in adolescents.     

Genetic Variation of DKK3 May Modify Renal Disease Severity in ADPKD

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/β-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.Autosomal dominant polycystic kidney disease ( ADPKD) is the most common monogenic kidney disease worldwide, affecting one in 500 to 1000 births.^1,2 It is characterized by focal development of renal cysts in an age-dependent manner. Typically, only a few renal cysts are clinically detectable during the first three decades of life; however, by the fifth decade, tens of thousands of renal cysts of different sizes can be found in most patients.³ Progressive cyst expansion with age leads to massive enlargement and distortion of the normal architecture of both kidneys and, ultimately, ESRD in most patients. ADPKD is also associated with an increased risk for cardiac valvular defects, colonic diverticulosis, hernias, and intracranial arterial aneurysms. Overall, ADPKD accounts for approximately 5% of ESRD in North America.²Mutations of PKD1 and PKD2 respectively account for approximately 85% and approximately 15% of linkage-characterized European families. Polycystin-1 (PC-1) and PC-2, the proteins encoded by PKD1 and PKD2, respectively, function as a macromolecular complex and regulate multiple signaling pathways to maintain the normal tubular structure and function.¹ Monoclonal expansion of individual epithelial cells that have undergone a somatic “second hit” mutation, resulting in biallelic inactivation of either PKD1 or PKD2, seems to provide a major mechanism for focal cyst initiation,⁴ possibly through the loss of polycystin-mediated mechanosensory function in the primary cilium.⁵ In addition, a large prospective, observational study indicated that renal cysts in ADPKD expand exponentially with increasing age, and patients with large polycystic kidneys are at higher risk for developing kidney failure⁶; however, the key factors that modulate renal disease progression in ADPKD remain incompletely understood.Renal disease severity in ADPKD is highly variable, with the age of onset of ESRD ranging from childhood to old age.^7–11 A strong genetic locus effect has been noted in ADPKD. Adjusted for age and gender, patients with PKD1 have larger kidneys and earlier onset at ESRD than patients with PKD2 (mean age at ESRD 53.4 versus 72.7 years, respectively).^8,9 By contrast, a weak allelic effect (based on the 5′ versus 3′ location of the germline mutations) on renal disease severity may be present for PKD1¹⁰ but not PKD2.¹¹ Marked intrafamilial variability in renal disease is well documented in ADPKD and suggests a strong modifier effect.^10–15 In an extreme example, large polycystic kidneys were present in utero in one of a pair of dizygotic twins affected with the same germline PKD1 mutation, whereas the kidneys of the co-twin remained normal at 5 years of age.¹² Several studies have quantified the role of genetic background in the phenotypic expression of ADPKD. In a comparison of monozygotic twins and siblings, greater variance in the age of onset of ESRD in the siblings supported a role for genetic modifiers.¹³ Two other studies of intrafamilial disease variability in PKD1 have estimated that genetic factors may account for 32 to 42% of the variance of creatinine clearance before ESRD and 43 to 78% of the variance in age at ESRD.^14,15 The magnitude of the modifier gene effect from these studies suggests that mapping such factors is feasible. Here, we report the results of an association study of modifier genes for PKD1 renal disease severity.     

Effect of Anesthesia Staffing Ratio on First-Case Surgical Start Time

On time start of the first case of the day is an important operating room (OR) efficiency metric, in which delays can have effects throughout the day. Although previous studies have identified various causes of first case start delays, none have attempted to evaluate the effect anesthesia staffing ratios have on first case start times. We performed a single-center retrospective analysis at an academic teaching hospital. Data was collected and analyzed over a period of 4 years and on more than 8,700 cases. We examined whether staffing ratios of attending only (solo staffing ratio), attending working with 1 resident/certified registered nurse anesthetist (CRNA) (1 to 1), or attending covering 2 residents/CRNAs (1 to 2) had a significant effect on first patient in room time (FPIR) and first case on time start (FCOTS). In addition, we examined whether staffing ratios had an effect on start times in various surgical subspecialties. We performed a univariate logistic regression analysis to determine if age, anesthesia base units, American Society of Anesthesiologists Physical Status (ASA PS) classification score, and staffing ratio was associated with FPIR and FCOTS being on time. Then, we performed a multivariate logistic regression analysis to determine if staffing ratio was associated with these outcomes, utilizing age, anesthesia base units, and ASA PS class as covariates. A decreased odds for FPIR being on time were seen in general and orthopedic surgeries when staffed 1 to 1, and cardiac surgery when staffed 1 to 2, when compared to solo staffing. FCOTS showed statistically significant differences when looking at all services with solo staffing having the highest odds for FCOTS being on time. This effect was seen also when analyzing only oncologic and orthopedic surgeries. Hospitals should consider using different staffing ratios in different surgical specialties to minimize delays and maximize OR efficiency.     

Digital imaging of the chest

During the past several years, image acquisition in nuclear medicine, computed tomography, ultrasonography, subtraction angiography, and magnetic resonance has been by digitization. Despite these advances, research in the development of digital imaging in conventional radiography has lagged behind. Although studies with a variety of digital techniques have been carried out on several fronts, we still do not possess a method that has captured the imagination of the majority of radiologists and other physicians to a point where it could replace conventional screen-film imaging. This article reviews the current status and general principles of the technology, focusing on the four digital radiographic techniques that have shown the greatest promise - film digitization, an image intensifier - based system, photostimulable phosphor plates, and a scanned projection system. The physical aspects of each of the four systems and the clinical results that have been reported to date, as well as the advantages and disadvantages of each system, are presented.     

Structure-activity relationships in the murine local lymph node assay for skin sensitization: α,β-diketones

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after metabolic activation, with appropriate skin proteins. For direct acting electrophilic compounds, this ability can be modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity parameters. Several structure-activity relationships based on this approach have been reported, but most of them cover guinea pig sensitization test data on what chemists would classify as relatively soft electrophilic chemicals. In the present work, an electrophilicity parameter based on Taft substituent constants is derived for hard electrophiles having a reactive carbonyl group, and is used to calculate RAI values for the analysis of sensitization test data obtained in the murine local lymph node assay (LLNA) for a series of alpha, beta-diketones. The sensitization potential of these reactive hard electrophilic carbonyl compounds in the LLNA shows a good correlation with the RAI. Overall, the findings reaffirm our view that physical organic chemistry is the key to understanding why some chemicals sensitize more strongly than others, while some do not sensitize at all, and provide further evidence of the value of the LLNA for SAR studies.     

Neonatal brain: color Doppler imaging. Part I. Technique and vascular anatomy

Color Doppler imaging (CDI) can demonstrate the relative direction and velocity of blood flow in color, superimposed on a conventional gray-scale ultrasound image that depicts stationary tissue. Twenty-five infants were studied with portable CDI in the coronal, sagittal, and axial planes. Bilateral antegrade flow was noted in the anterior, middle, and posterior cerebral arteries in all patients. Multiplanar CDI can image flow in the circle of Willis and its tributaries and branches.     

Cyclosporine and chronic sarcoidosis

Two patients with progressive sarcoidosis who had poor responses and side effects from corticosteroid therapy were treated with cyclosporine. Cyclosporine suppressed conventional markers of inflammation and there was clinical improvement in one patient, but the disease recurred when therapy was discontinued. The second patient who had diabetes mellitus developed unstable glucose metabolism when given cyclosporine. This unstable diabetes mellitus together with side effects of nausea and vomiting resulted in weight loss and inadequate serum therapeutic levels that was associated with a poor therapeutic response to the cyclosporine. The major side effects in both patients were headache and gastrointestinal symptoms, but there was no renal dysfunction. We conclude that while corticosteroids remain the mainstay of sarcoid therapy, when these drugs have not been successful for the skin manifestations of the disease, a trial of cyclosporine may be justified.     

Hypertension produced by constriction of the renal artery in sympathectomized dogs

1.

1. Complete sympathectomy, in seven dogs, did not prevent the development of hypertension from compression of the renal arteries.