Pediatric antifungal therapy. Part II: neonatal infections.

The management of neonatal fungal infections poses several challenges, including the fact that the choices of available agents are limited, given the paucity of data relating to the use of newer antifungal agents in the group of infants. The information summarized herein represents in part the consensus of a group of clinicians involved in the care of neonates at risk of and with fungal infections. The document addresses the prophylaxis and treatment of fungal infections in neonates. It highlights the role of current and emerging antifungal agents, including the lipid amphotericin B products, echinocandins and triazoles.

Acanthosis nigricans: a dermatologic marker of metabolic disease.

Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. We undertook a study to estimate the insulin sensitivity of a group of patients referred from the dermatologist with biopsy proven acanthosis nigricans. Thirty-six patients were evaluated in the Endocrinology clinic. Plasma glucose and serum Insulin levels were estimated after a 75 gms oral glucose load (OGTT). An intravenous Insulin Tolerance Test (ITT) was performed with measurement of Glucose Disposal Rate (GDR). There were 28 females and 8 males (M:F--3.5:1; mean age 26.3+/-1.7 years) in the study. 25/36 patients were morbidly obese (BMI--36.0 +/- 1.2 Kg/m2) with an abnormal body fat distribution (WH ratio--0.9 +/ - 0.02). One patient had generalized lipoatrophy. 16/36 patients with acanthosis nigricans had IGT or overt diabetes and all had highly significant hyperinsulinemia (AUCI = 20825 +/ 1287.7 vs. 6340.0 +/- 984.2 mIU/ml/hr in controls, p < 0.0005). The GDR in patients with acanthosis nigricans was reduced (-0.66 +/- 0.07) compared to controls (-0.39 +/- 0.08; p < 0.01). There was a significant positive correlation between indices of adiposity and insulin resistance in subjects with impaired tolerance.

A study of insulin resistance in subjects with acanthosis nigricans.

AIM: To study the prevalence of insulin resistance (IR) and its sequelae in patients with acanthosis. METHODOLOGY: Thirty six patients (28 females; eight males) with biopsy proven acanthosis nigricans and eight controls were evaluated for insulin sensitivity (IS) by estimating (a) the glucose and insulin responses to a 75 gm glucose load (Oral glucose tolerance test-OGTT), (b) the glucose disposal rate (GDR) during an intravenous insulin tolerance test (ITT). Serum androgen levels (testosterone--Te, androstenedione--ASD, Dehydro-epiandrosterone sulphate--DHEAS) were estimated in the basal state and 60 min after a bolus of insulin. Thyroid function tests (tri-iodo-thyronine--T3, thyroxine--T4, thyroid stimulating hormone--TSH) were performed in all subjects. RESULTS: The acanthotic population, overall had insignificant hyperglycemia (Area under curve of glucose--AUC-G : 17,745.5 +/- 847.5 v/s 11,051.3 +/- 274.5 mg/dl/min) and hyperinsulinemia (Area under curve of insulin -AUC-I: 20,825.2 +/- 1,287.7 v/s 6,340.1 +/- 984.2 microlU/ml/min) compared to controls during OGTT. Eight patients with acanthosis nigricans had impaired glucose tolerance and eight had overt diabetes using WHO criteria. 69.4% of the acanthotic subjects were obese and 13.9% (5/36) were hypertensive. Thyroid dysfunction was present in three (one had hypothyroidism and two had thyrotoxicosis). Reproductive disorders--menstrual irregularity (46.5%), amenorrhea (21.4%), hirsuitism (21.4%) and infertility (3.6%) was encountered in a significant number of acanthotics. Acanthotics overall had statistically higher levels of androgens; Te (females)--0.74 +/- 0.09 v/s 0.27 +/- 0.09 ng/ml (p < 0.005), ASD--1.8 +/- 0.21 v/s 0.94 +/- 0.2 ng/ml (p < 0.005) and DHEAS--1,880.8 +/- 216.3 v/s 772.8 +/- 210.4 ng/ml (p < 0.005). An elevated DHEAS correlated positively to body mass index (BMI) and android obesity. Serum Te levels correlated positively with GDR. Serum insulin levels increased progressively with obesity and acanthosis. Serum insulin was associated with progressive worsening of hyperandrogenism (as seen in non-obese controls, non-obese and obese acanthotics). CONCLUSIONS: Subjects with acanthosis nigricans should be screened for insulin resistance and its clinical and metabolic sequelae. Thyroid dysfunction should be sought in these subjects as it can be easily treated.

Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs.

Inhaled nitric oxide (NO), frequently administered in combination with hyperoxic gas mixtures, was recently shown to protect against the injurious consequences of prolonged hyperoxia. We investigated the possibility that this protective effect is attributable to the ability of NO to block pulmonary apoptosis. We show that rats exposed to 100% O2 for 60 h develop severe lung injury consisting of pronounced vascular leak and alveolar apoptosis as inferred from the presence of positive terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and DNA ladders in agarose gels and a decrease in constitutive procaspase-3 levels. However, the inclusion of NO (20 parts/million) in the hyperoxic gas mixture significantly attenuated both the vascular leak and apoptosis. NO reversed the hyperoxia-associated changes in the activity of the redox-sensitive transcription factors nuclear factor-kappaB, activator protein-1, and Sp1 after 24 h, lowered intercellular adhesion molecule-1 levels, and increased glutathione content. We therefore show, for the first time, that NO can protect against both hyperoxia-induced apoptosis and inflammation. The data suggest that this protection may occur at the transcriptional and caspase-activation levels.

Microalbuminuria in insulin dependent diabetes mellitus.

This study aimed to evaluate the prevalence of microalbuminuria (MAU) and albumin excretion rate (AER) in a timed overnight (12 hours) urine sample, in 72 insulin-dependent-diabetic (IDD) patients and to correlate the same to the clinical profile, glycemic control and to diabetic complications. Nine IDD patients (prevalence--12.5%) were detected to be microalbuminuric. Males had significantly higher prevalence of MAU (17.4%) than females (3.8%; p < 0.05). The prevalence of MAU was 4% in the third decade of age, 15% each in the fourth and fifth and 28.6% and 60% in the sixth decade and above (p < 0.05%). Prevalence of MAU also increased progressively with duration of diabetes. It increased from 8.3% (< 5 yrs) to 12.5% (6-10 yrs) and 33.3% (> 15 yrs). High AER in obese patients--33.1 +/- 23.2 v/s 11.4 +/- 3.4 micrograms/min in lean patients supports an association of obesity with albuminuria. Higher prevalences of MAU (62.5%; p < 0.001) was observed in hypertensive IDD patients in comparison to normotensive patients (3.6%). AER in patients with borderline hypertension (21.0 +/- 14.5 micrograms/min; p < 0.05) and in overt hypertensives (49.1 +/- 19.2 micrograms/min; p < 0.0005) were significantly higher compared to normotensive IDD-patients (6.2 +/- 2.4 micrograms/min). Prevalence of MAU and AER increased progressively with the deterioration of glycemic control. Well controlled subjects were normoalbuminuric. The incidence of MAU increased from 11.1% in fairly controlled (NS) and 21.1% in poorly controlled (p < 0.01) subjects. Also AER increased significantly from 2.4 +/- 0.5 micrograms/min. to 9.8 +/- 6.7 and 23.1 +/- 7.3 micrograms/min with the deterioration of glycemic control. Glycemic control in terms of glycated hemoglobin (GHb) did not show much agreement with the prevalence of MAU and AER, though they worsened with deteriorating control. The prevalences of peripheral neuropathy (PN) (34.4% v/s 33.3%) and diabetic retinopathy (DR) (9.8% v/s 11.1%) were similar in normo- and microalbuminuric patients. Patients with PN had high AER (15.2 +/- 6.3 micrograms/min). Also, AER was significantly high in patients with DR (27.7 +/- 23.5 micrograms/min; p < 0.05). High prevalences of cardio-vascular disease (CVD) (33.3%; p < 0.05) were observed in microalbuminuric compared to normoalbuminuric (1.6%) patients. Also AER was significantly high in association with CVD (53.9 +/- 21.9 micrograms/min; p < 0.0005). It can be concluded that, in IDD patients, MAU is common in males, older individuals and subjects with longer duration of diabetes. Raised blood pressure and hyperglycemia were identified as risk factors for the development of MAU.

Microalbuminuria in non-insulin dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is the commonest form of diabetes. The aim of this study was to evaluate the nature and prevalence of microalbuminuria (MAU) in NIDDM. One hundred and twenty-eight NIDDM patients participated in this study on the prevalence of microalbuminuria and albumin excretion rate (AER). An attempt was made to correlate them to the clinical profile, glycemic control and to diabetic complications. Eighteen patients had MAU with 14.1% prevalence (males--17.5% v/s females--10.8%; NS). Prevalence of MAU was higher in the third and fourth decades of age (28.6%) with a decrease in the fifth decade (12.5%). Prevalence of MAU also increased progressively with duration of diabetes--13 to 14% (< 10 yrs) to 25% (> 10 yrs). High AER in obese patients (13.4 +/- 5.5 v/s 7.9 +/- 1.4 micrograms/min) supports an association of obesity with albuminuria. The prevalence of MAU in patients with borderline and overt hypertension was not statistically different from that in normotensive NIDDM patients. However, NIDDM with borderline hypertension showed high AER 16.2 +/- 5.6 micrograms/min compared to 7.8 +/- 1.3 micrograms/min in normotensives. Prevalence to MAU and AER increased progressively with the deterioration of glycemic control--from 3.3% in well controlled to 18.9% in fairly controlled (P < 0.5) and 31% in poor controlled patients (P < 0.01). Also AER increased significantly from 3.9 +/- 0.8 to 12.3 +/- 4.1 and 18.4 +/- 4.6 micrograms/min, in patients with well to fairly and poorly controlled glycemia respectively. The prevalence of MAU and AER did not correlate with glycated hemoglobin (GHb) levels. The prevalences of peripheral neuropathy (PN) (42.6% v/s 55.6%) were similar in normo- and microalbuminuric patients. Patients with PN had high AER 11.9 +/- 2.7 micrograms/min. Diabetic retinopathy (DR) was equally prevalent in normo- and microalbuminuric NIDDM patients of (20.4% v/s 22.2), and AER was not significantly higher (12.1 +/- 4.3 micrograms/min) in NIDDM with retinopathy. High prevalences of cardiovascular disease (CVD) in MAU-NIDDM (22.2%; NS) was observed compared to normoalbuminuric (9.3%) patients. Also AER was significantly high in NIDDM associated with CVD (21.9 +/- 10.9 micrograms/min; P < 0.025). It can be concluded that, MAU is more prevalent in third and fourth decades and with longer duration of diabetes. Poor glycemic control was identified as a risk factor as in IDDM for development of MAU. MAU was a marker of generalised vascular dysfunction.

Prevalence of islet cell antibodies and its correlation with glucose and insulin response to oral glucose tolerance test in 1st degree relatives of insulin dependent diabetes mellitus probands.

93 first degree relatives (1st DR) of insulin dependent diabetes mellitus (IDDM) patients were investigated for detection of islet cell antibodies (ICA) and beta cell functional status. ICA were detected in 26.9% Ist DR subjects (25/93), equally in parents, siblings and offspring. Normal (n = 16), impaired (n = 5) and diabetic (n = 4), glucose curves were seen in 1st DR. Low insulin levels were observed in parents and siblings with normal glucose tolerance test (N-GTT) at 90 min (p < 0.05), and (p < 0.0005) relatives with impaired glucose tolerance and diabetes. Insulin release to glucose (IRG-insulinogenic index) in control group was 352 +/- 42 mu U/mg. From the group of 25 ICA positive cases, 4 had mean IRG of 394 +/- 70 mu U/mg (group A) comparable to control, and had N-GTT; 12 had mean IRG of 107 +/- 15.9 mu U/mg (group B) significantly low (P < 0.005) compared to controls and group A and 9 showed IRG of 75 +/- 29.3 mu U/mg, lower than group B (NS) with abnormal response to glucose load. Loss of insulin secretory ability thus can precede hyperglycemia by years. The ICA positive relatives were grouped based on the immunological status with their probands. ICA status in probands does not give an idea about ICA status in their relatives. This indepth study leads to understand the correlation of genetic, metabolic and immunological parameters for early detection of IDDM in first degree relatives.

Prevalence of islet cell antibodies and B cell functional status in insulin dependent diabetes.

As autoimmunity is an important factor in the etiopathogenesis of IDDM, 85 ketosis prone i.e. insulin dependent diabetes (IDD) were evaluated for immunological and beta cell functional status. Islet cell antibodies (ICA) against purified islet cells used in Microwell ELISA Method, were detected in 27.1% of cases (23/85). There was a prevalence of 36.4% of ICA positivity in newly diagnosed cases and its prevalence declined with duration. The highest ICA positivity was observed in fourth decade of life. 17 of the 23 ICA positive cases (73.9%) had a mean duration of 2.1 years whereas the remaining 6/23 (26.1%) had a mean duration of 9 years. Females showed a younger age of onset of diabetes. Only one female with duration of 10 years tested positive for ICA.ICA positive males had later age of onset and longer duration of diabetes as compared to ICA positive females. Ten ICA positive cases studied were showing non-significant C-peptide (CP) release (after glucose load) in comparison to negative cases (14); p < 0.05, 8 of these cases were with < 3 months duration. Significantly low delta % C-peptide response implies a low residual beta-cell function and further loss of beta cell function earlier in ICA +ve cases. Thus this study leads to understand in depth the immune mechanism of IDDM.

Interleukin-6 expression in cord blood of patients with clinical chorioamnionitis.

The objective of this study was to define whether IL-6 is an early marker of infection in the newborn. To correlate the occurrence of clinical chorioamnionitis with the levels of IL-6 expression in neonates, IL-6 was measured in cord plasma by ELISA and in mononuclear cells by reverse transcriptase-PCR before and after mitogenic stimulation. Eight neonates were included in each of the following four groups: elective cesarean section, uncomplicated normal spontaneous vaginal delivery, delivery after prolonged rupture of amniotic membranes with no evidence of chorioamnionitis, and delivery with evidence of chorioamnionitis. All 32 neonates were clinically well after delivery, and all 16 babies with prolonged rupture of membranes or clinical chorioamnionitis had negative blood cultures. Elevated IL-6 levels were found only in neonates born to mothers with chorioamnionitis (119.7 +/- 33.5 pg/mL versus 2.71 +/- 0.59 pg/mL, p < 0.005). Mononuclear cells from five of these neonates expressed no IL-6 mRNA in vivo despite elevated levels of IL-6 in their cord plasma. Cord blood mononuclear cells from healthy term babies were capable of synthesizing IL-6 in vitro in response to stimulation with bacterial lipopolysaccharide. These results suggest that IL-6 levels in cord plasma increased with clinical chorioamnionitis, despite the lack of evidence of infection in the neonates. Therefore, we conclude that, although a high level of IL-6 may be a good marker of chorioamnionitis, it may not be a specific marker of infection in the newborn.

Waivers for disqualifying medical conditions in U.S. Naval aviation personnel.

In the United States Navy, many diagnoses are considered disqualifying for aviation duty, but aircrew may be "waived" to return to flight duties after resolution of the disease or appropriate treatment of the condition. Personnel with waivers are usually subject to more frequent physical examinations and/or special diagnostic procedures. Although the Naval Aerospace and Operational Medical Institute promulgates written aeromedical guidelines as to which diseases may be waived and which may not, waivers are granted on a case-by-case basis considering not only the diagnosis, but the age, experience, and type of aviation duty of the individual in question. This study was undertaken to determine which conditions were most and least likely to be waived. We reviewed all records of aviators entered into the Naval Aviation Medical Data Retrieval System who had been diagnosed with a condition considered disqualifying for aviation duty, totaling over 39,000 records. Cases were stratified by diagnosis and aviation duty, and the percentage waived was calculated for major diagnostic groups. Among designated aviation personnel, approximately 68% of all aviators with a disqualifying diagnosis were recommended for a waiver. Otolaryngologic, musculoskeletal, and cardiovascular disorders accounted for nearly 50% of diagnoses in personnel recommended for a waiver. Fear of flying, personality disorders, and adjustment disorders were the three diagnoses least likely to be granted a waiver. The most frequently occurring disqualifying diagnoses were allergic rhinitis, obesity, disorders of refraction and accommodation, urolithiasis, and alcohol dependence.

Primate testicular histone H1t genes are highly conserved and the human H1t gene is located on chromosome 6.

The testis-specific histone H1t gene is known to be transcribed only in pachytene primary spermatocytes during spermatogenesis. Previous studies of the rat histone H1t gene revealed a unique promoter sequence element between the H1/GC box and the H1/CCAAT box. Proteins in crude nuclear extracts of rat testis bind specifically to this sequence element and a temporal correlation exists between the appearance of these DNA binding proteins and the onset of transcription. These discoveries led to a search for histone H1t genes in other mammalian species. The human and monkey histone H1t genes were amplified from genomic DNA using the polymerase chain reaction (PCR). The amplified genes were cloned and the genomic derived inserts were sequenced using linear PCR. Both proximal promoters contained the highly conserved H1/AC box, H1/CCAAT box, and H1/TATA box found in nongerminal H1 genes. Both promoters also contained the H1/GC box and the H1t/CCTAGG sequence element between the H1/GC box and H1/CCAAT box previously seen only in the H1t promoter. Specific amplification of the human H1t gene using template DNA samples from a NIGMS human/rodent somatic cell hybrid mapping panel has shown that the human histone H1t gene is located on chromosome 6.

C-peptide profiles in young diabetics.

Fifty-six patients who had been diagnosed diabetic prior to the age of 30 were evaluated to determine the C-peptide (CP) secretory response to a glucose load. These individuals were classified clinically as having insulin dependent (IDDM = 18); non-insulin dependent (NIDDM = 19) and insulin requiring diabetes (IRDM = 19). Insulin dependent diabetics had lower basal CP levels (0.44 +/- (SE) 0.1 ng/ml) which were not stimulated by hyperglycaemia (0.55 +/- 0.13 ng/ml) as compared to controls (basal CP = 1.6 +/- 0.2 and peak 6.2 +/- 0.8 ng/ml). Non-insulin dependent diabetics and insulin requiring diabetics could be divided broadly into two groups - one, a set of patients with low basal CP levels (NIDDM = 0.63 +/- 0.09 ng/ml) (IRDM = 0.38 +/- 0.08 ng/ml) and a blunted response to a glucose load (peak response NIDDM = 0.83 +/- 0.05 ng/ml, IRDM = 0.59 +/- 0.12 ng/ml) and a second group who had CP reserve evident in both fasting (NIDDM = 1.6 +/- 0.2 ng/ml; IRDM = 2.1 +/- 0.6) and post-glucose levels (Peak Response NIDDM = 4.6 +/- 0.4 ng/ml; IRDM = 3.0 +/- 0.6 ng/ml). Growth Hormone (GH) and cortisol levels were found to be high in patients with IDDM and IRDM with no insulin reserve and these did not suppress during the oral Glucose Tolerance Test. NIDDM patients with no insulin reserve had normal GH and high cortisol levels. It is emphasized from this study that insulin sensitivity is as important as the insulin secretory status in determining the presenting features of diabetes mellitus in the young.

Characterization of a new cell line (ESKOL) resembling hairy-cell leukemia: a model for oncogene regulation and late B-cell differentiation.

A B-lymphoblastoid cell line ESKOL, composed of differentiated cells resembling hairy-cell leukemia (HCL) has been established from the peripheral blood (PB) of a HCL patient. Morphologically, ESKOL cells share several features with HCL B cells. Flow cytometric analysis revealed that ESKOL cells express HC2, CD21, PCA-1, CD24, FMC7, and CD25. Analysis by Northern-blot hybridization indicated that cultured cells expressed the oncogenes c-myc, H-ras and c-fos. RNA from 3T3 cells transfected with ESKOL DNA hybridized with H-ras and c-fos DNA probes. The ESKOL cells cultured in the presence of increasing concentrations, of alpha interferon demonstrated a decrease in the rate of cellular growth and an increase in the expression of CD21, CD25, FMC7 and PCA-1. Scanning electron microscopy revealed that cells incubated in the presence of alpha interferon underwent membranous changes with a loss of villosity. These observations suggest that IFN tends to drive HC out of their developmental arrest towards maturation.

Evaluation of endocrine parameters in clinical trials with beta-hCG vaccine.

This report presents data on various endocrine parameters with respect to pituitary-ovarian axis in-depth in control vs 18 subjects immunized with three beta-hCG based vaccine formulations. Hormonal parameters such as TSH, PRL, ACTH, progesterone, cortisol, T3 and T4 were measured by RIA in sera in control pre-vaccine cycles as well as at 3, 6, and 12 months after primary vaccine immunization. In 6 women urinary E1G, PdG, LH and FSH were measured by ELISA/RIA tests on early morning urine (EMU) samples collected throughout the menstrual cycle in control vs post-booster vaccine cycles. The results indicated that none of the beta-hCG vaccine formulations altered the pituitary peptide or steroid hormone levels in blood at any time during the period of study. Serum P concentration was adequate and indicative of ovulatory cycle in almost all the cycles during the study. The in-depth study on urinary excretion pattern and levels of gonadotropins and E1G and PdG throughout the control vs post-vaccine booster cycles conclusively showed that pituitary-ovarian axis was not adversely affected by the vaccine.