Prophylactic zinc supplementation modulates hippocampal ionic zinc and partially remediates neurological recovery following repetitive mild head injury in mice.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to impaired executive functioning, emotional disturbances, and disordered memory, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic zinc (Zn) supplementation; however, Zn supplementation remains poorly understood. This study explored the effects of Zn supplementation in a mouse model of repetitive mild TBI. Four-week-old male (n = 50) and female (n = 50) C57BL/6J mice consumed tap water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 h after which they completed behavioral tests. Zinc-supplemented injured mice righted themselves and regained normal ambulatory function as fast as non-injured mice across four out of the five injury days. In contrast, non-supplemented injured mice exhibited impairment in normal ambulation by days 4 and 5. Injury also reduced free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus and Zn supplementation partially remediated this reduction but not to the levels of non-injured mice. There were no structural differences in cortex, hippocampus, striatum, and corpus callosum, suggesting that Zn reduction was not due to macroscopic abnormalities. Overall, these results suggest that Zn may improve short-term and physical neurological recovery, but it may not be sufficient as a single pre-treatment for consequences of repetitive mild TBI such as cognitive impairment. These results further demonstrate the need for additional research documenting the underlying mechanisms of Zn in TBI-related neuropathology.

Motor responsivity during habituation testing of normal human fetuses.

Features of fetal motor responsivity include both the magnitude of the startle response elicited by a single stimulus (i.e., basal reactivity) and the ease by which responding to successive stimuli is inhibited (i.e., habituation). We examined basal motor reactivity and habituation of the motor response in 56 normal human fetuses between 34 and 40 weeks of gestation. Testing consisted of 8 trials of a 1-sec vibroacoustic stimulus (VAS) with a 10-sec interstimulus interval. A score of 0-10 was assigned for each trial based on subjective assessment of intensity and duration of the fetal motor response. Measures of habituation included the ratio of responding after a fixed number of trials divided by the initial response, and the rate of change in the behavioral response over trials. No relationship was found between the rate of motor habituation and either basal reactivity, gestational age, or prestimulus fetal heart rate (FHR) variability. In contrast, more mature fetuses responded less intensely to the first stimulus than did their younger counterparts (r = -0.329, p = 0.005), and fetuses who were initially in a quiet state exhibited a more vigorous startle response as compared to fetuses who were initially in a more active state (r = -0.372, p = 0.001). The relationship between basal reactivity and prestimulus FHR variability was statistically significant even after controlling for gestational age (r = 0.295, p = 0.01). These findings may have important clinical implications regarding the appearance in early life of certain behavioral tendencies such as temperament.

Developmental trends in fetal habituation to vibroacoustic stimulation.

Habituation is a measure of the ability to inhibit responding and is a more mature form of behavior than is persistent responding. We examined the developmental trend in habituation of the fetal startle response to repeated vibroacoustic stimulation in 90 normal human fetuses between 28 and 40 weeks of gestation. Fetal movement was graded according to the nature of the behavioral response: general startle (3), fast limb movement (2), slow rolling movement (1), and no movement (0). A significant developmental difference (p < 0.0004) in the rate of habituation was found, with response decrement occurring faster in fetuses of more than 32 weeks of gestation. Furthermore, by dividing the patients into three gestational age groups, it was determined that the greatest change in the rate of habituation occurred between 28 and 32 weeks and 32 and 36 weeks. We conclude that the rate of fetal habituation may be determined by the degree of maturation of the neural circuitry governing this form of nonassociative learning.

The relationship between heart rate and eye movement in the human fetus at 38-40 weeks of gestation.

The purpose of this study was to compare two different methods for assessing fetal heart rate (FHR)--fetal eye movement (FEM) synchronization: (1) periods of high (HV) and low (LV) variability in the FHR and the presence (EM) and absence (NEM) of FEM were determined by visual inspection and the degree of association between FHR and FEM was assessed in terms of the fraction of study time for which no periods of LV-NEM and HV-EM could be identified; and (2) the maximum cross-correlation coefficient (rmax) and the lag at rmax (Lmax) were determined by direct computer analysis of FHR and FEM data for each fetus. Twenty normal human fetuses between 38 and 40 weeks of gestation were examined for a total of 2051 min (mean 103 min, range 72-150 min). In general, the state HV-EM was observed approximately twice as often as was the state LV-NEM; neither of these two states could be identified during 12.4% of the study time. The coefficient rmax was calculated assuming a sliding 3-min moving window, using either the average FHR (mean 0.53, range 0.31-0.85) or the variability in the FHR (mean 0.52, range 0.18-0.77). No relationship was found between rmax and Lmax calculated using the mean FHR and the fraction of time for which no state could be identified (P = 0.995). When the cross-correlation analysis was performed using FHR variability, a statistically significant relationship was found between the periods of no coincidence (of states LV-NEM and HV-EM) and rmax and Lmax (r2 = 0.32; P = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Oligohydramnios: antepartum fetal urine production and intrapartum fetal distress.

Animal and human studies suggest that fetal oliguria is a normal physiologic response to hypoxemia. To assess the clinical significance of this observation, we studied (before their admission) 51 fetuses of women whose pregnancies were complicated by oligohydramnios at greater than or equal to 38 weeks' gestation. We found that the mean hourly fetal urine production decreased significantly in relation to the severity of subsequent intrapartum fetal compromise. The mean antepartum rate was 95 ml/hr in the 21 fetuses with a normal intrapartum heart rate pattern; this fell to 59 ml/hr in the 18 fetuses who had an abnormal intrapartum heart rate pattern but who responded to intrauterine resuscitation. The rate was 33 ml/hr in the 12 fetuses who were delivered by cesarean section as a result of fetal distress. These findings suggest that oligohydramnios associated with fetal oliguria may be used to identify those fetuses who have less intrinsic or uteroplacental reserve than do those of women with oligohydramnios who have a higher rate of fetal urine production.

Pneumocystis carinii antigenemia in adults with malignancy, infection, or pulmonary disease.

A counterimmunoelectrophoresis test for Pneumocystis carinii antigenemia was employed to assess the extent of subclinical infection or colonization with this agent in adults with infection, pulmonary disease, or malignancy and in healthy homosexual men. Antigenemia was detected in 6 of 208 (3%) of normal controls, 3 of 28 (11%) of patients with pulmonary infection, 3 of 33 (9%) of those with chronic lung disease, 1 of 36 (3%) of patients with lung cancer, 7 of 271 (3%) of afebrile subjects with malignancy, 6 of 19 (32%) of febrile patients with malignancy, 2 of 22 (9%) of those with nonpulmonary infection, and 0 of 21 (0%) of healthy young homosexual men. These data suggest that P. carinii is a common commensal or saprophyte that becomes clinically significant only when host defenses are impaired. Antigenemia may occur intermittently during various disease states in the absence of positive clinical signs and should alert the physician to subacute infection or colonization. Treatment appears advisable when clinical data and counterimmunoelectrophoresis results concur.

Combination chemotherapy with mitomycin C, methotrexate, cisplatin, and vinblastine in the treatment of non-small cell lung cancer.

The combination of mitomycin C, methotrexate, cisplatin, and vinblastine was administered to 45 patients with unresectable non-small cell lung cancer. Thirty-nine patients satisfied criteria for assessment of response to chemotherapy. All patients had a performance status of greater than 50%, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 54% with responses seen in 12 of 19 squamous cell, 8 of 16 adenocarcinoma, and 1 of 4 undifferentiated large cell lung cancer patients. Median survival was increased by 3 months in those patients with an objective response to chemotherapy. Drug-associated toxicity was rare, but apparent mitomycin C-related pulmonary fibrosis was observed in two patients. This four-drug combination was shown to be an active regimen in the treatment of non-small cell bronchogenic carcinoma.

Incidence of Pneumocystis carinii antigenemia in ambulatory cancer patients.

Although the existence of subclinical Pneumocystis carinii infection in pediatric patients with solid tumors or hematologic malignancies has been documented, similar data are lacking in adults. In addition, data are needed to define the epidemiology of this agent in adult malignancies to assess the validity of the methodology employed in antigen detection, and to elucidate the value of these methods in the diagnosis, prophylaxis, and prognosis of P carinii infection in adults with cancer. The study was designed to determine the incidence of P carinii antigenemia in ambulatory patients with solid tumors or hematologic malignancies. The authors also sought to determine if antigenemia as detected by a counterimmunoelectrophoresis test correlated with any clinical parameter. Patients included in the study were ambulatory, asymptomatic, afebrile, adult cancer patients seen in the clinic for follow-up or treatment. Coded sera were electrophoresed against high-titered rabbit antiserum to P carinii organisms. Two hundred forty-seven patients were studied, including 172 hematologic malignancies (average age, 57 years), 109 men and 63 women; 75 solid tumors (average age, 55 years), 39 women and 36 men. One hundred three healthy adults served as controls. Only five patients had positive antigen (2%). All of these patients had hematologic malignancies and were women. None of the control sera were antigen-positive. We conclude that the incidence of P carinii antigenemia in asymptomatic adults with neoplastic disease is extremely low. A positive P carinii antigen in the absence of clinical symptoms most likely represents subclinical infection. Positive antigen does not always indicate active disease, but probably reflects mobilization of antigen during generalized inflammatory response or possible pulmonary insult. In making the decision to treat consideration should be given to clinical presentation and history.

Use of tumor colony assay in clinical oncology.

We have evaluated the usefulness of the tumor colony assay in predicting chemotherapeutic drug response in our cancer patient population. We found that a wide variety of human tumors will produce clonal growth in this in vitro assay. Low growth rates in many of the common human tumors, however, severely restrict the utility of this assay in a large number of cancer patients. A retrospective analysis using the assay to predict anticancer drug response revealed a true-positive predictive rate of 63% and a true-negative predictive rate of 96%. We conclude that if growth stimulants can be developed to enhance clonal growth without altering the predictability of the assay, the tumor colony assay could prove to be extremely useful in selecting appropriate chemotherapy for individual cancer patients.

Total, dialyzable, and nondialyzable postabsorptive hydroxyproline. Values in patients with cancer.

The postabsorptive urinary total (T), dialyzable (D), and nondialyzable (ND) hydroxyproline (HYPRO) tests were evaluated to determine whether the patterns of excretion varied according to the predominance of osteoblastic v osteolytic bone involvement in 58 patients with neoplastic disease. In patients with osteolytic lesions from multiple myeloma, elevated T and D levels with normal ND HYPRO values were observed, along with elevated D/ND ratios. In prostate cancer, the T, D, and ND values were all elevated and the D/ND ratio was normal. Patients with Hodgkin's disease had elevated T, D, and ND HYPRO levels, and the D/ND ratio was in the range of patients with prostate cancer. The data suggest that these collagen markers may be useful in the long-term evaluation of these neoplasms in patients.

The postabsorptive hydroxyproline in the long-term evaluation of patients with breast cancer.

The postabsorptive urinary hydroxyproline excretion test (Spot-HYPRO) was evaluated for its usefulness in reflecting the presence or absence of bone metastasis in 75 women with breast cancer. A comparison was made between the Spot-HYPRO values and bone disease, as documented by bone scanning supported by skeletal x-rays. Breast cancer patients with skeletal metastasis had 3-4-fold elevations in Spot-HYPRO above the control values (P less than 0.001). Mild elevations were noted in breast cancer patients without skeletal metastasis (P less than 0.025). Thirty patients received serial Spot-HYPRO and bone scans for 6 to 48 months (average, 24 months). There was a 90% correlation between changes in Spot-HYPRO and simultaneous changes on bone scan. Elevations in Spot-HYPRO preceded changes found on bone scan by an average of 3 months. The authors conclude that the Spot-HYPRO is a simple, convenient, and accurate method of documenting and following bone metastasis in patients with breast cancer.

Postabsorptive urinary hydroxyproline test in patients with metastatic bone disease from breast cancer.

Postabsorptive urine hydroxyproline (HYPRO) excretion ("spot" HYPRO test) was compared with the 24-hour urine excretion of HYPRO in 45 patients with breast cancer and nine normal subjects on a low-gelatin diet. A good correlation was observed between the results of these two tests in both groups. Patients with skeletal metastasis showed a higher spot HYPRO value than those without bone involvement and the number of lesions by bone scanning correlated with the values of spot HYPRO. In 20 of 22 patients with bone metastasis followed up for three to 19 months, spot HYPRO values correlated well with the evolution of bone disease. We conclude that the spot HYPRO test is a simple, inexpensive, and accurate method for the diagnosis and follow-up of patients with skeletal metastasis from breast cancer.

The postabsorptive urinary hydroxyproline (spot-HYPRO) in patients with multiple myeloma.

The simple postabsorptive urine hydroxyproline (Spot-HYPRO) with dialyzable and non-dialyzable (ND) fractions was measured in 28 patients with multiple myeloma. Myeloma patients with bone disease had higher total Spot-HYPRO and dialyzable fractions (P less than 0.001) than myeloma patients without bone disease or controls. The ND fraction of the Spot-HYPRO was elevated in myeloma patients with renal disease as compared with myeloma patients without renal disease and controls (P less than 0.01). Follow-up studies of ten myeloma patients demonstrated a close correlation between Spot-HYPRO and the dialyzable fraction and the evolution of bone disease. The Spot-HYPRO and its dialyzable fraction constitute a simple, inexpensive, and accurate test for the diagnosis and follow-up of the skeletal disease in patients with multiple myeloma.

Smear platelet counts.

The average number of platelets per oil immersion field, in a count of ten oil fields, multiplied by 20,000 has proved to be a reliable estimation of platelets in normal and thrombocytopenic states. In the presence of thrombocytosis, ie, 25 or more platelets per oil immersion field, the smear count is less reliable. The multiplication factor of 20,000 was determined after statistical analysis of 288 consecutive unselected patients. Certain precautions should be observed, such as use of a fresh EDTA sample or freely flowing finger blood, a well made and well stained smear without platelet aggregates or precipitated stain particles, and an acceptable counting area on the film.

Tungiasis in Tennessee.

Tungiasis, an infestation by a burrowing flea, may cause multiple, painful lesions which, if they become secondarily infected, may eventuate in death. With increasing air travel to tropical areas, American physicians should recognize the lesion of this intracutaneous parasite. The fully developed lesion resembles an abscess with a black center. An infestation diagnosed in Memphis, Tennessee, is reported in a businessman who had returned from Brazil. Treatment consists of excision of the gravid female flea and careful cleaning of the cystic cavity. Healing is usually complete without sequelae. In an early infestation, the smaller gravid female, like a splinter, can be removed with a sterile needle. Tetanus prophylaxis may be indicated, depending on the wound and its location.