Interferon alpha treatment of patients with impaired interferon gamma signaling.

Patients with deficiency in the interferon gamma receptor (IFN-γR) are unable to respond properly to IFN-γ and develop severe infections with nontuberculous mycobacteria (NTM). IFN-γ and IFN-α are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-α for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-γ signaling defect. We treated four patients with IFN-γR deficiency with adjunctive IFN-α therapy in addition to best available antimicrobial therapy, with or without IFN-γ, depending on the defect. During IFN-α treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-α driven gene expression in patients' cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-α therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-γ signaling who have refractory infections, IFN-α may have adjunctive anti-mycobacterial effects.

Healthcare personnel intestinal colonization with multidrug-resistant organisms.

OBJECTIVES: This study aims to assess the association between patient contact and intestinal carriage of multidrug-resistant organisms (MDRO) by sampling healthcare personnel (HCP) and staff without patient contact. METHODS: For this observational study, we recruited 400 HCP who worked in our 200-bed research hospital and 400 individuals without patient contact between November 2013 and February 2015. Participants submitted two self-collected perirectal swabs and a questionnaire. Swabs were processed for multidrug-resistant Gram-negative bacteria and vancomycin-resistant enterococci (VRE). Questionnaires explored occupational and personal risk factors for MDRO carriage. RESULTS: Among 800 participants, 94.4% (755/800) submitted at least one swab, and 91.4% (731/800) also submitted questionnaires. Extended spectrum ß-lactamase-producing organisms were recovered from 3.4% (26/755) of participants, and only one carbapenemase-producing organism was recovered. No VRE were detected. The potential exposure of 68.9% (250/363) of HCP who reported caring for MDRO-colonized patients did not result in a rate of MDRO carriage among HCP (4.0%; 15/379) significantly higher than that of staff without patient contact (3.2%; 12/376; p 0.55). CONCLUSIONS: This is the largest US study of HCP intestinal MDRO carriage. The low colonization rate is probably reflective of local community background rates, suggesting that HCP intestinal colonization plays a minor role in nosocomial spread of MDROs in a non-outbreak setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01952158.

Serum potassium and acid-base parameters in severe dialysis-associated hyperglycemia treated with insulin therapy.

We analyzed the changes in serum potassium concentration ([K]) and acid-base parameters in 43 episodes of dialysis-associated hyperglycemia (serum glucose level > 33.3 mmol/L), 22 of which were characterized as diabetic ketoacidosis (DKA) and the remaining 21 as nonketotic hyperglycemia (NKH). All episodes were treated with insulin therapy only. Age, gender, initial and final serum values of glucose, sodium, chloride, tonicity and osmolality did not differ between DKA and NKH. At presentation, serum values of [K] (DKA 6.2 +/- 1.3 mmol/L; NKH 5.2 +/- 1.5 mmol/L) and anion gap [AG] (DKA 27.2 +/- 6.4 mEq/L; NKH 15.4 +/- 3.5 mEq/L) were higher in DKA, whereas serum total carbon dioxide content [TCO2 ] (DKA 12.0 +/- 4.6 mmol/L; NKH 22.5 +/- 3.1 mmol/L), arterial blood pH (DKA 7.15 +/- 0.09; NKH 7.43 +/- 0.07) and arterial blood PaCO2 (DKA 26.2 +/- 12.3 mm Hg; NKH 34.5 +/- 6.7 mm Hg) were higher in NKH. At the end of insulin treatment, serum values of [K] (DKA 4.0 +/- 0.7 mmol/L, NKH 4.0 +/- 0.5 mmol/L), [AG] (DKA 16.3 +/- 5.4 mEq/L, NKH 14.9 +/- 3.0 mEq/L), [TCO2 ] (DKA 23.5 +/- 5.0 mmol/L, NKH 24.1 +/- 4.2 mmol/L), arterial blood pH (DKA 7.42 +/- 0.09, NKH 7.51 +/- 0.14) and arterial blood PaCO2 (DKA 31.8 +/- 6.7 mm Hg, NKH 34.2 +/- 8.3 mm Hg) did not differ between the two groups. Linear regression of the decrease in serum [K] value during treatment, (Delta[K]), on the presenting serum [K] concentration,([K]2 ), was: DKA, Delta[K] = 2.78 - 0.81 x [K]2 , r = -0.85, p < 0.001; NKH, Delta[K] = 2.44 - 0.71 x [K]2 , r = -0.90, p < 0.001. The slopes of the regressions were not significantly different. Stepwise logistic regression including both DKA and NKH cases identified the presenting serum [K] level and the change in serum [TCO2 ] value during treatment as the predictors of Delta[K] (R2 = 0.81). Hyperkalemia is a feature of severe hyperglycemia (DKA or NKH) occurring in patients on dialysis. Insulin administration brings about correction of DKA and return of serum [K] concentration to the normal range in the majority of the hyperglycemic episodes without the need for other measures. The initial serum [K] value and the change in serum [TCO2 ] level during treatment influence the decrease in serum [K] value during treatment of dialysis-associated hyperglycemia with insulin.

Dialysance of adrenocorticoids during continuous ambulatory peritoneal dialysis.

We postulated that significant quantities of both protein-bound and unbound adrenocorticoids are lost during continuous ambulatory peritoneal dialysis (CAPD). To test this hypothesis we measured the dialysate removal rates (DRR) of adrenocorticoids in six CAPD patients. The distribution of the adrenocorticoids among unbound, albumin-bound, and transcortin-bound fractions in dialysate effluent was determined. The distribution of cortisol among unbound, albumin-bound, and transcortin-bound fractions in plasma was determined in six other CAPD patients. The mean DRR of cortisol was 193.8 +/- 20.3 (+/- SE) nmol/day. Smaller quantities of 11-deoxycorticosterone, corticosterone, aldosterone, 18-hydroxy-11-deoxycorticosterone, and 18-hydroxycorticosterone were removed during CAPD. The mean DRR values for total protein, albumin, and transcortin were 11.2 +/- 2.1, 6.0 +/- 2.2, and 0.087 +/- 0.018 g/day, respectively. The distribution of cortisol among unbound, albumin-bound, and transcortin-bound fractions was normal in plasma from CAPD patients. Plasma transcortin had a normal affinity (2 x 10(7) mol/L-1) and a normal binding capacity (559 nmol/L) for cortisol. In contrast, dialysate transcortin had a low affinity (1.4 x 10(7) mol/L-1) for cortisol and a low cortisol-binding capacity (11.5 nmol/L). The fractional occupancy rates of high affinity cortisol-binding sites on transcortin were 52.0 +/- 3.3% and 3.3 +/- 0.6% in plasma and dialysate effluent, respectively (P less than 0.001). The transcortin to cortisol molar concentration ratio in dialysate (6.3 +/- 0.6) was significantly higher than that in plasma (1.6 +/- 0.2; P less than 0.001). These results demonstrate that cortisol is the major adrenocorticoid lost during CAPD. However, the amount of cortisol removed in the dialysate is less than 1% of the normal daily secretion rate. Significant quantities of other adrenocorticoids are also lost during CAPD. The adrenocorticoids present in dialysate effluent are principally unbound, in contrast to their state in plasma. However, small fractions of the respective steroids are bound to transcortin and albumin.

Distribution of 18-hydroxycorticosterone between red blood cells and plasma.

Plasma 18-hydroxycorticosterone (18-OH-B) to aldosterone (aldo) concentration ratios reflect adrenal corticosterone methyloxidase type II activity. This ratio is determined not only by the relative secretion rates of the two steroids but also by differences in binding, distribution, and metabolism. Plasma cortisol alters the distribution of aldo between red blood cells (RBC) and plasma. We postulated that the distribution of 18-OH-B, like that of aldo, is determined by the availability of high affinity binding sites on plasma transcortin. Double equilibrium dialyses demonstrated that 18-OH-B, aldo, and cortisol compete for binding sites on transcortin. Increasing amounts of each of the three unlabeled steroids produced progressive decrements in the binding of all three labeled steroids to transcortin. The affinity of 18-OH-B (2 X 10(6) M-1) for transcortin was intermediate between those of cortisol (3 X 10(7) M-1) and aldo (0.9 X 10(6) M-1). Heat treatment of plasma decreased the binding of 18-OH-B and cortisol to transcortin by 82% and 75%, respectively. Gel filtration of plasma revealed that protein-bound [3H]18-OH-B and [14C]cortisol eluted in the same fractions. The addition of increasing quantities of unlabeled cortisol to whole blood in vitro produced similar increments in RBC to plasma concentration ratios of [3H]18-OH-B and [14C]aldo. The ratio of the percentage of circulating 18-OH-B in plasma to the percentage of circulating aldo in plasma was constant in blood containing low and high cortisol concentrations. Therefore, changes in plasma cortisol have similar effects on the distribution of 18-OH-B and aldo between RBC and plasma.

Low dose adrenocorticotropin infusion in continuous ambulatory peritoneal dialysis patients.

The adrenocorticoid responses to low doses of ACTH (0.03-10 ng/min) in sodium-deplete normal subjects and end-stage renal disease patients maintained on continuous ambulator peritoneal dialysis (CAPD) were compared. All subjects were pretreated with dexamethasone. ACTH was administered by graded iv infusions in doses of 0.03, 0.3, 1.0, 3.0, and 10 ng ACTH/min. Each rate of infusion was maintained for 30 min. Plasma aldosterone, 18-hydroxycorticosterone, corticosterone, 18-hydroxy-11-deoxycorticosterone, and cortisol were measured in plasma sampled at the end of each rate of infusion in both groups. Plasma 11-deoxycorticosterone was measured in CAPD patients. The plasma steroid levels in the CAPD patients after each infusion rate were equal to or greater than the levels in normal subjects. The slopes of the cumulative increases above baseline in plasma steroid levels in the CAPD patients were equal to or greater than those in the normal subjects. In both groups, plasma corticosterone increased the most and aldosterone the least. Kinetic analyses indicated that the adrenal responses to low dose ACTH were not linear. A distinct threshold for ACTH-stimulated increase in plasma adrenocorticoid levels, if present, is very low. The responses of plasma adrenocorticoids to low dose ACTH are normal in CAPD patients.

Serum tonicity, extracellular volume and clinical manifestations in symptomatic dialysis-associated hyperglycemia treated only with insulin.

The absence of osmotic diuresis modifies the effects of hyperglycemia on body fluids in patients with advanced renal failure. To determine the relationship between clinical manifestations and abnormalities in tonicity and extracellular volume in such patients, we analyzed 43 episodes of severe dialysis-associated hyperglycemia (serum glucose exceeding 600 mg/dL) treated only with insulin. The main manifestations were dyspnea in 22 cases (pulmonary edema in 19), nausea and vomiting in 15, coma in 13 and seizures in 3, while 5 patients had no symptoms. Treatment with insulin resulted in a decrease in serum glucose value from 913 +/- 197 mg/dL to 170 +/- 78 mg/dL, an increase in serum sodium level from 125 +/- 5 to 136 +/- 5 mmol/L, and a fall in calculated serum tonicity value from 300 +/- 13 to 282 +/- 11 mmol/kg (all at p < 0.001). The ratio of the change in serum sodium level over change in serum glucose concentration was -1.50 +/- 0.22 mmol/L per 100 mg/dL. The percent increase in extracellular volume secondary to hyperglycemia developing from the prior euglycemic state and calculated from changes in serum sodium and chloride concentrations, was 10.9% +/- 4.6% (1.5% +/- 0.6% per 100 mg/dL increase in serum glucose level). All clinical manifestations dissipated after correction of hyperglycemia in 42 patients. One woman developed during treatment a fatal myocardial infarction. Dialysis patients with severe hyperglycemia may develop symptoms as a result of hypertonicity and extracellular expansion. Insulin alone may be sufficient treatment for these symptoms. The changes in serum tonicity and electrolytes during treatment are consistent with theoretical predictions.

The glutathione S-transferase activity in the kidney of rainbow trout (Salmo gairdneri).

Trout kidney contains 2.3 mmol GSH/kg. The cytosolic glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene as substrate is 0.35 mumol/min/mg protein. There is no detectable activity with 1,2-epoxy-3-(p-nitrophenoxy)propane, ethacrynic acid, p-nitrobenzyl chloride or p-nitrophenyl acetate. A variable proportion of the activity does not bind to a glutathione-affinity matrix. Its Km values for GSH and 1-chloro-2,4-dinitrobenzene are 3.0 and 5.1 mM, respectively. The rest of the activity is eluted from the affinity matrix as one main and two minor peaks. The main peak has Km values for GSH and 1-chloro-2,4-dinitrobenzene of 0.4 and 4.5 mM, respectively. Its subunit Mr is 22,900. The activity in the main peak is inhibited progressively by 1-chloro-2,4-dinitrobenzene with a rate constant of 0.11/min.

Corticosterone methyloxidase II activity during hemodialysis.

Plasma levels of aldosterone decrease during hypokalemic hemodialysis. Our study was performed to determine whether the changes in plasma aldosterone level observed during hemodialysis are modulated by changes in corticosterone methyloxidase II activity. We measured plasma levels of adrenal zona glomerulosa steroids, for example, aldosterone and 18-hydroxycorticosterone (18-OH-B), immediately before and after 4 hours of hemodialysis (n = 8). Plasma levels of steroids originating from the adrenal zona fasciculata, for example, cortisol, corticosterone, 18-hydroxy-11-deoxycorticosterone, and 11-deoxycorticosterone, were also measured. Dialysance rates of 18-OH-B, aldosterone, and cortisol were calculated (n = 8). Plasma levels of both aldosterone (P less than 0.05) and 18-OH-B (p less than 0.01) decreased during hemodialysis. The 18-OH-B/aldosterone plasma concentration ratios did not change significantly during hemodialysis. No significant changes in plasma levels of fasciculata steroids were observed during hemodialysis. Dialysance rates for aldosterone and 18-OH-B were similar (P not significant). The dialysance of cortisol was 10-fold lower than that of aldosterone (P less than 0.01) and 18-OH-B (P less than 0.01). The relative constancy of the 18-OH-B/aldosterone plasma concentration ratios indicates that corticosterone methyloxidase II activity is normal in patients with end-stage renal disease who are maintained by hemodialysis.

Delayed presentation to clinics for sexually transmitted diseases by symptomatic patients. A potential contributor to continuing STD morbidity.

OBJECTIVE: To determine the proportion of symptomatic patients attending public sexually transmitted disease (STD) clinics who fail to seek care within 7 days of the onset of STD symptoms and their self-reported reasons for delays in obtaining care. DESIGN: Interviewers administered 23-item questionnaire to a cross section of STD clinic clients between April and September 1995. SETTING: Five urban STD clinics in the United States (Birmingham, AL; St Paul, MN; San Francisco CA; Seattle, WA; and Raleigh, NC). RESULTS: Of 1,621 patients with genitourinary symptoms, over one third (35% of men, 37% of women) presented to STD clinics only after 1 week or more of symptoms. Men with genital warts (73%) or with nongonococcal urethritis (23.1%) or symptomatic men who were recent contacts to sex partners with STDs were significantly more likely to delay clinic attendance more than a week than men with gonorrhea (6.5%, p < 0.001 for each). Overall 43.8% of women receiving specific clinical diagnoses other than genital warts delayed clinic attendance for more than 1 week. When asked why they delayed clinic attendance, respondents were most likely to respond that they had hoped their symptoms would "go away" (48.5% of men and 49.4% of women who waited a week or more before seeking care). CONCLUSION: A substantial proportion of patients with genitourinary symptoms attending public STD clinics delay seeking care for a week or more, increasing their likelihood of complications and of transmission of infection to others. Interventions to promote more timely clinic attendance may help reduce STD morbidity in the United States.