Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet.

OBJECTIVE: Human milk is the best form of nutrition for preterm infants and has been associated with a lower incidence of necrotizing enterocolitis (NEC). Infants that develop NEC have a higher incidence of feeding intolerance and longer hospitalizations. The combination of a donor milk bank and donor milk-derived fortifier has changed feeding practices in neonatal intensive care units (NICU). The purpose of this study is to assess the benefits and cost of an exclusive human milk (EHM) diet in very low birth weight (VLBW) infants in a community level III NICU. STUDY DESIGN: This is a retrospective study including preterm infants ⩽28 weeks and/or VLBW (⩽1500 g) who were enrolled from March 2009 until March 2014. Infants were grouped as follows: group H (entirely human milk based, born March 2012 to 2014), group B (bovine-based fortifier and maternal milk, born March 2009 to 2012), group M (mixed combination of maternal milk, bovine-based fortifier and formula, born March 2009 to 2012) and group F (formula fed infants, born March 2009 to 2012). Baseline characteristics among the four groups were similar. RESULT: The study included 293 infants between gestational ages 23 to 34 weeks and birth weights between 490 and 1700 g. Feeding intolerance occurred less often (P<0.0001), number of days to full feeds was lower (P<0.001), incidence of NEC was lower (P<0.011), and total hospitalization costs were lower by up to $106,968 per infant (P<0.004) in those fed an EHM diet compared with the other groups. Average weight gain per day was similar among the four groups (18.5 to 20.6 g per day). CONCLUSIONS: Implementing an EHM diet in our VLBW infants has led to a significant decrease in the incidence of NEC. Other benefits of this diet include: decreased feeding intolerance, shorter time to full feeds, shorter length of stay, and lower hospital and physician charges for extremely premature and VLBW infants.

Cardiovascular responses to nonrespiratory and respiratory arousals in a porcine model.

Spontaneous and provoked nonrespiratory arousals can be accompanied by a patterned hemodynamic response. To investigate whether a patterned response is also elicited by respiratory arousals, we compared nonrespiratory arousals (NRA) to respiratory arousals (RA) induced by airway occlusion during non-rapid eye movement sleep. We monitored mean arterial blood pressure (MAP), heart rate, iliac and renal blood flow, and sleep stage in 7 pigs during natural sleep. Iliac and renal vascular resistance were calculated. Airway occlusions were obtained by manually inflating a chronically implanted tracheal balloon during sleep. The balloon was quickly deflated as soon as electroencephalogram arousal occurred. As previously reported, NRA generally elicited iliac vasodilation, renal vasoconstriction, little change in MAP, and tachycardia. In contrast, RA generally elicited iliac and renal vasoconstriction, an increase in MAP and tachycardia. The frequent occurrence of iliac vasoconstriction and arterial pressure elevation following RA but not NRA suggests that sleep state change alone does not account for the hemodynamic response to airway occlusion during sleep.

Polymorphism of the beta(2)-adrenergic receptor gene and desensitization in human airway smooth muscle.

We examined the influence of two common polymorphic forms of the beta(2)-adrenergic receptor (beta(2)AR): the Gly16 and Glu27 alleles, on acute and long-term beta(2)AR desensitization in human airway smooth muscle (HASM) cells. In cells from 15 individuals, considered without respect to genotype, pretreatment with Isoproterenol (ISO) at 10(-7) M for 1 h or 24 h caused approximately 25% and 64% decreases in the ability of subsequent ISO (10(-6) M) stimulation to reduce HASM cell stiffness as measured by magnetic twisting cytometry. Similar results were obtained with ISO-induced cyclic adenosine monophosphate (cAMP) as the outcome indicator. Data were then stratified post hoc by genotype. Cells containing at least one Glu27 allele (equivalent to presence of the Gly16Glu27 haplotype) showed significantly greater acute desensitization than did cells with no Glu27 allele, whether ISO-induced cell stiffness (34% versus 19%, p < 0.03) or cAMP formation (58% versus 11%, p < 0.02) was measured. Likewise, cells with any Glu27 allele showed greater long-term desensitization of cell stiffness and cAMP formation responses than did cells without the Glu27 allele. The distribution of genotypes limited direct conclusions about the influence of the Gly16 allele. However, presence of the Gly16Gln27 haplotype was associated with less acute and long-term desensitization of ISO-induced cAMP formation than was seen in cells without the Gly16Gln27 haplotype (14% versus 47%, p < 0.09 for short-term desensitization; 32% versus 84%, p < 0.01 for long-term desensitization), suggesting that the influence of Glu27 is not through its association with Gly16. The Glu27 allele was in strong linkage disequilibrium with the Arg19 allele, a polymorphic form of the beta(2)AR upstream peptide of the 5'-leader cistron of the beta(2)AR, and this polymorphism in the beta(2)AR 5'-flanking region may explain the effects of the Glu27 allele. Cells with any Arg19 allele showed significantly greater acute and long-term desensitization of ISO-induced cAMP formation than did cells without the Arg19 allele (54% versus 2%, p < 0.01 for short-term desensitization; 73% versus 35%, p < 0.05 for long-term desensitization). Similar results were obtained for ISO-induced changes in cell stiffness. Thus, the presence of the Glu27 allele is associated with increased acute and long-term desensitization in HASM.

Ventilatory responses to ozone are reduced in immature rats.

During ozone (O(3)) exposure, adult rats decrease their minute ventilation (VE). To determine whether such changes are also observed in immature animals, Sprague-Dawley rats, aged 2, 4, 6, 8, or 12 wk, were exposed to O(3) (2 ppm) in nose-only-exposure plethysmographs. Baseline VE normalized for body weight decreased with age from 2.1 +/- 0.1 ml. min(-1). g(-1) in 2-wk-old rats to 0. 72 +/- 0.03 ml. min(-1). g(-1) in 12-wk-old rats, consistent with the higher metabolic rates of younger animals. In adult (8- and 12-wk-old) rats, O(3) caused 40-50% decreases in VE that occurred primarily as the result of a decrease in tidal volume. In 6-wk-old rats, O(3)-induced changes in VE were significantly less, and in 2- and 4-wk-old rats, no significant changes in VE were observed during O(3) exposure. The increased baseline VE and the smaller decrements in VE induced by O(3) in the immature rats imply that their delivered dose of O(3) is much higher than in adult rats. To determine whether these differences in O(3) dose influence the extent of injury, we measured bronchoalveolar lavage protein concentrations. The magnitude of the changes in bronchoalveolar lavage induced by O(3) was significantly greater in 2- than in 8-wk-old rats (267 +/- 47 vs. 165 +/- 22%, respectively, P < 0.05). O(3) exposure also caused a significant increase in PGE(2) in 2-wk-old but not in adult rats. The results indicate that the ventilatory response to O(3) is absent in 2-wk-old rats and that lack of this response, in conjunction with a greater specific ventilation, leads to greater lung injury.

Role of ERK MAP kinases in responses of cultured human airway smooth muscle cells to IL-1beta.

We have previously reported that interleukin (IL)-1beta causes beta-adrenergic hyporesponsiveness in cultured human airway smooth muscle cells by increasing cyclooxygenase-2 (COX-2) expression and prostanoid formation. The purpose of this study was to determine whether extracellular signal-regulated kinases (ERKs) are involved in these events. Levels of phosphorylated ERK (p42 and p44) increased 8.3- and 13-fold, respectively, 15 min after treatment with IL-1beta (20 ng/ml) alone. Pretreating cells with the mitogen-activated protein kinase kinase inhibitor PD-98059 or U-126 (2 h before IL-1beta treatment) decreased ERK phosphorylation. IL-1beta (20 ng/ml for 22 h) alone caused a marked induction of COX-2 and increased basal PGE(2) release 28-fold (P < 0.001). PD-98059 (100 microM) and U-126 (10 microM) each decreased COX-2 expression when administered before IL-1beta treatment. In control cells, PD-98059 and U-126 had no effect on basal or arachidonic acid (AA; 10 microM)-stimulated PGE(2) release, but both inhibitors caused a significant decrease in bradykinin (BK; 1 microM)-stimulated PGE(2) release, consistent with a role for ERK in the activation of phospholipase A(2) by BK. In IL-1beta-treated cells, prior administration of PD-98059 caused 81, 92 and 40% decreases in basal and BK- and AA-stimulated PGE(2) release, respectively (P < 0.01), whereas administration of PD-98059 20 h after IL-1beta resulted in only 38 and 43% decreases in basal and BK-stimulated PGE(2) release, respectively (P < 0.02) and had no effect on AA-stimulated PGE(2) release. IL-1beta attenuated isoproterenol-induced decreases in human airway smooth muscle stiffness as measured by magnetic twisting cytometry, and PD-98059 or U-126 abolished this effect in a concentration-dependent manner. These results are consistent with the hypothesis that ERKs are involved early in the signal transduction pathway through which IL-1beta induces PGE(2) synthesis and beta-adrenergic hyporesponsiveness and that ERKs act by inducing COX-2 and activating phospholipase A(2).

[Neuropsychiatric disorders in insulinoma]. / Neuropsykiatriske forstyrrelser ved insulinom.

The case of a young female presenting severe mental problems and episodic neurological symptoms is described. Obsessive-compulsive disorder was diagnosed upon psychiatric treatment for eight months. No neurological condition was found. Hypoglycaemia was observed during an episode of long-lasting somnolescence and the patient referred for endocrinological examination. Reactive hypoglycaemia was ruled out in an oral glucose tolerance test. A test of prolonged starvation revealed hypoglycaemia associated with neuropsychiatric symptoms. Glucose abolished this condition, suggesting an insulinoma as the basis of the spontaneous hypoglycaemia. Subsequently, two insulinomas were resected from the tail of the pancreas. The patient has recovered completely after her surgery, with no signs of mental or neurological disease and blood glucose within normal limits. As insulinoma is often associated to the MEN1-syndrome, the patient and her relatives are now being investigated for this condition.

Patterned cardiovascular responses to sleep and nonrespiratory arousals in a porcine model.

Patients with obstructive sleep apnea experience marked cardiovascular changes with apnea termination. Based on this observation, we hypothesized that sudden sleep disruption is accompanied by a specific, patterned hemodynamic response, similar to the cardiovascular defense reaction. To test this hypothesis, we recorded mean arterial blood pressure, heart rate, iliac blood flow and vascular resistance, and renal blood flow and vascular resistance in five pigs instrumented with chronic sleep electrodes. Cardiovascular parameters were recorded during quiet wakefulness, during non-rapid-eye-movement and rapid-eye-movement sleep, and during spontaneous and induced arousals. Iliac vasodilation (iliac vascular resistance decreased by -29.6 +/- 4.1% of baseline) associated with renal vasoconstriction (renal vascular resistance increased by 10.3 +/- 4.0%), tachycardia (heart rate increase: +23.8 +/- 3.1%), and minimal changes in mean arterial blood pressure were the most common pattern of arousal response, but other hemodynamic patterns were observed. Similar findings were obtained in rapid-eye-movement sleep and for acoustic and tactile arousals. In conclusion, spontaneous and induced arousals from sleep may be associated with simultaneous visceral vasoconstriction and hindlimb vasodilation, but the response is variable.

Induction of low-affinity GABAA receptors by the GABA-agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cultured rat cerebellar granule cells is prevented by inhibition of polyamine biosynthesis.

GABAA agonist-induced formation of low-affinity GABAA receptors in cultured cerebellar granule cells was studied in the presence or absence of alpha-difluoromethylornithine (DFMO), a blocker of polyamine formation. High- and low-affinity GABAA receptors were monitored by Scatchard analysis of [3H]GABA binding to membranes from cells cultured for either 4 or 10 days in the presence or absence of the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Cultures grown for 4 days were exposed to THIP and DFMO for an additional period of 6 hr (acute exposure), whereas cultures grown for 10 days were exposed to the same agents during the entire culture period (chronic exposure). Regardless of the culture period or drug exposure protocol, control cells expressed only a high-affinity (KD 7 nM) binding site for GABA, whereas the cultures treated with THIP for either 6 hr or 10 days exhibited an additional low-affinity binding site (KD approximately 500 nM). Chronic exposure to DFMO prevented the THIP induction of low-affinity GABAA receptors, whereas acute exposure to DFMO had no effect on the ability of THIP to induce low-affinity GABAA receptors. Measurements of the intracellular polyamine concentration demonstrated a slight decrease in the putrescine level in the granule cells exposed to DFMO or THIP + DFMO for 6 hr. In contrast, granule cells chronically (10 days) exposed to DFMO or THIP + DFMO were depleted of putrescine and spermidine. Hence, the ability of THIP to induce low-affinity GABAA receptors was prevented by the simultaneous depletion of the cellular content of putrescine and spermidine, whereas inhibition of ornithine decarboxylase and of putrescine formation was not sufficient to prevent THIP-induced receptor formation.

Treatment of Lyme arthritis.

OBJECTIVE: To test treatment regimens for Lyme arthritis. METHODS: Patients were randomly assigned to treatment with doxycycline or amoxicillin plus probenecid for 30 days. Patients who had persistent arthritis for at least 3 months after treatment with oral antibiotics or parenteral penicillin were given intravenous ceftriaxone for 2 weeks. RESULTS: Eighteen of the 20 patients treated with doxycycline and 16 of the 18 patients who completed the amoxicillin regimen had resolution of the arthritis within 1-3 months after study entry. However, neuroborreliosis later developed in 5 patients, 4 of whom had received the amoxicillin regimen. Of 16 patients (2 from the oral antibiotic study and 14 additional patients) who had persistent arthritis despite previous oral antibiotics or parenteral penicillin, none had resolution of the arthritis within 3 months after ceftriaxone therapy. The HLA-DR4 specificity and OspA reactivity were associated with a lack of response. CONCLUSION: Lyme arthritis can usually be treated successfully with oral antibiotics, but patients may still develop neuroborreliosis. Patients with certain genetic and immune markers may have persistent arthritis despite treatment with oral or intravenous antibiotics.

Tumors of soft tissues and bone.

The recent literature pertaining to tumors of articular structures and bone is reviewed. In pigmented villonodular synovitis, the bone resorptive cell is a macrophage polykaryon rather than an osteoclast. Complete arthroscopic synovectomy was successful in most diffuse articular forms of the disease. The early synovial changes in synovial chondromatosis were described; the lesion may be difficult to distinguish from synovial chondrosarcoma. Free body removal may be sufficient to treat synovial chondromatosis. Magnetic resonance imaging has been found useful in association with plain radiographs in the diagnosis of hemangioma and synovial sarcoma. Intracapsular osteoid osteoma, a benign neoplasm, may cause chronic monoarthritis. Computed tomography is essential in the diagnosis of this lesion. Aneurysmal bone cysts frequently show fluid-fluid levels on magnetic resonance imaging. Osteosarcoma, predominantly a tumor of childhood or adolescence, may occur in individuals over age 40 with underlying bone conditions. Computed tomography and magnetic resonance imaging are complementary in defining the extent of this lesion.

Depletion of polyamines prevents the neurotrophic activity of the GABA-agonist THIP in cultured rat cerebellar granule cells.

Effects of polyamine depletion by alpha-difluoromethylornithine (DFMO) were studied on the GABA-agonist mediated enhancement of the morphological development of cultured rat cerebellar granule cells. An increase in the number of neurite extending cells and in the cytoplasmic density of organelles relevant for protein synthesis was observed upon culturing in the presence of 4,5,6,7-tetrahydro-isoxazole[5,4-c]pyridin-3-ol (THIP) for 4 days. The intracellular concentrations of putrescine, spermidine, and spermine in these cultures were similar to the concentrations of the polyamines observed in cultures grown in a plain culture medium for 1, 2, 3 or 4 days, respectively. Upon culturing in the simultaneous presence of THIP and DFMO, the concentrations of putrescine and spermadine were reduced to less than 20% of the levels in the controls. This depletion was associated with a severely impaired morphological development of the granule cell cultures. Thus, the number of neurite extending cells was reduced to 50% of the number in the control cultures upon culturing in the presence of DFMO alone or in combination with THIP. Moreover, the THIP mediated increase in the cytoplasmic density of rough endoplasmic reticulum, Golgi apparatus and different types of vesicles was prevented by the exposure to DFMO.

Effects of taurine on cell morphology and expression of low-affinity GABA receptors in cultured cerebellar granule cells.

Effects of taurine and THIP were studied on the development of cultured cerebellar granule cells with regard to GABA receptor expression and morphological development. Culturing in the presence of taurine or THIP led to the formation of low affinity GABA receptors as revealed from Scatchard analysis of [3H]GABA binding. This formation of receptors was susceptible to inhibition upon culturing in the simultaneous presence of taurine and bicuculline demonstrating the involvement of the high affinity GABA receptors which are present on the cells regardless of the culture condition. Superfusion experiments on cells cultured under the different conditions demonstrated that the low affinity GABA receptors expressed after culturing in the presence of THIP or taurine mediated an inhibition by GABA of evoked transmitter release from the granule cells. Cells cultured in either plain culture media or in the presence of taurine were indistinguishable with respect to the number of neurite extending cells observed after 4 days in culture. In contrast, culturing in the presence of THIP increased the number of neurite extending cells by 8% relative to the controls.

Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons.

Of 2135 elderly residents of nursing homes in Arkansas (mean age, 79.4 years) who have been treated with isoniazid for prevention of tuberculosis, data from 1935 were suitable for analysis. About 12 months of therapy was successfully completed in 1600 persons. Therapy could not be completed in 84 persons (4.4%) because of incipient hepatic toxicity and in 116 (6.0%) because of other types of drug intolerance. Although 135 persons (7.0%) died during the course of therapy, no evidence was found that isoniazid contributed to any death. The ratio of benefit (reduction of risk for tuberculosis) to risk (for nonfatal isoniazid-related hepatitis) was clearly favorable in persons who had definite conversions (1.6 for women, 3.4 for men) but less so for persons who had tuberculin reactions of unknown duration and for persons with minor increases in size of tuberculin reaction (less than 12 mm increase from an initially negative reaction).