The dynamic network associations of food craving, restrained eating, hunger and negative emotions.

OBJECTIVE: Food craving, restrained eating, hunger, and negative emotions may predict and reinforce one another. However, less is known about how they interact together as a complex system in daily life. Therefore, we used a dynamic network approach to examine the associations between food craving, restrained eating, hunger and negative emotions in daily life. METHODS: Food craving, restrained eating, hunger and negative emotions were measured using ecological momentary assessment three times a day over ten days in a community sample in Israel (n = 123). A two-step multilevel vector auto-regression network analysis was used to estimate temporal, contemporaneous and between-persons networks. RESULTS: In the temporal network, restrained eating was the most central predictor of eating behaviors and negative emotions, predicting food craving and hunger as well as sadness and loneliness. Food craving was also predicted by hunger and stress, and hunger predicted loneliness. In the contemporaneous network, food craving was associated with hunger and feeling bored, and higher anger was associated with lower restrained eating. Stress and sadness were central negative emotions in the models. DISCUSSION: This study suggests possible temporal and contemporaneous relationships between food craving, restrained eating, hunger and negative emotions, emphasizing their complex interactions in daily life. Restrained eating and stress should be investigated as potential targets for interventions addressing food craving and overeating.

The effects of frequent nocturnal home hemodialysis: the Frequent Hemodialysis Network Nocturnal Trial.

Prior small studies have shown multiple benefits of frequent nocturnal hemodialysis compared to conventional three times per week treatments. To study this further, we randomized 87 patients to three times per week conventional hemodialysis or to nocturnal hemodialysis six times per week, all with single-use high-flux dialyzers. The 45 patients in the frequent nocturnal arm had a 1.82-fold higher mean weekly stdKt/V(urea), a 1.74-fold higher average number of treatments per week, and a 2.45-fold higher average weekly treatment time than the 42 patients in the conventional arm. We did not find a significant effect of nocturnal hemodialysis for either of the two coprimary outcomes (death or left ventricular mass (measured by MRI) with a hazard ratio of 0.68, or of death or RAND Physical Health Composite with a hazard ratio of 0.91). Possible explanations for the left ventricular mass result include limited sample size and patient characteristics. Secondary outcomes included cognitive performance, self-reported depression, laboratory markers of nutrition, mineral metabolism and anemia, blood pressure and rates of hospitalization, and vascular access interventions. Patients in the nocturnal arm had improved control of hyperphosphatemia and hypertension, but no significant benefit among the other main secondary outcomes. There was a trend for increased vascular access events in the nocturnal arm. Thus, we were unable to demonstrate a definitive benefit of more frequent nocturnal hemodialysis for either coprimary outcome.

Bone resorption in syndromes of the Ras/MAPK pathway.

Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.

Soluble domain 1 of platelet-endothelial cell adhesion molecule (PECAM) is sufficient to block transendothelial migration in vitro and in vivo.

The inflammatory response involves sequential adhesive interactions between cell adhesion molecules of leukocytes and the endothelium. Unlike the several adhesive steps that precede it, transendothelial migration (diapedesis), the step in which leukocytes migrate between apposed endothelial cells, appears to involve primarily one adhesion molecule, platelet-endothelial cell adhesion molecule (PECAM, CD31). Therefore, we have focused on PECAM as a target for antiinflammatory therapy. We demonstrate that soluble chimeras made of the entire extracellular portion of PECAM, or of only the first immunoglobulin domain of PECAM, fused to the Fc portion of IgG, block diapedesis in vitro and in vivo. Furthermore, the truncated form of the PECAM-IgG chimera does not bind stably to its cellular ligand. This raises the possibility of selective anti-PECAM therapies that would not have the untoward opsonic or cell-activating properties of antibodies directed against PECAM.

Migration of monocytes across endothelium and passage through extracellular matrix involve separate molecular domains of PECAM-1.

During the inflammatory response, the adhesion molecule PECAM plays a crucial role in transendothelial migration, the passage of leukocytes across endothelium. We report here an additional role for PECAM in the subsequent migration of monocytes through the subendothelial extracellular matrix. PECAM has six immunoglobulin (Ig) superfamily domains. Monoclonal antibodies whose epitopes map to domains 1 and/or 2 selectively block monocyte migration through the endothelial junction, whereas those that map to domain 6 block only the migration through the extracellular matrix, trapping the monocyte between the endothelium and its basal lamina. Therefore, transendothelial migration (diapedesis) and passage through extracellular matrix (interstitial migration) are distinct and separable phases of monocyte emigration. Furthermore, distinct and separate Ig domains of PECAM are involved in mediating these two steps.

Serum alkaline phosphatase and mortality in hemodialysis patients.

BACKGROUND: Alkaline phosphatase is typically considered as an innocent by-stander, but emerging data suggest that alkaline phosphatase might play a pathogenic role in vascular calcification and thus contribute to increased mortality in hemodialysis patients. STUDY DESIGN: Longitudinal analyses of the existing HEMO Study database. SETTING AND PARTICIPANTS: 1,827 HEMO Study participants. PREDICTOR: Serum alkaline phosphatase level. OUTCOME AND MEASUREMENTS: All-cause and cardiovascular mortality. RESULTS: Based on the median serum alkaline phosphatase of 97 IU/l, participants were divided into low (< 97 IU/l) and high (> or = 97 IU/l) serum alkaline phosphatase groups. The lower serum alkaline phosphatase group was associated with older age, male gender, non-black race and shorter dialysis years as well as higher serum calcium, higher serum calcium-phosphorus product and lower parathyroid hormone levels. Mean serum liver enzyme values were in the normal range in both groups, but the high alkaline phosphatase group had slightly higher values. In a multivariate time-dependent Cox model using baseline and follow-up values of serum alkaline phosphatase levels, adjusted for demographics, HEMO Study groups, comorbidity, bone metabolism parameters and liver enzymes, each doubling of serum alkaline phosphatase was significantly associated with increased hazard of all-cause (hazard ratio 1.44, 95% CI 1.30 - 1.59) and cardiovascular mortality (hazard ratio 1.35, 95% CI 1.16 - 1.57). LIMITATIONS: Nonstandardized measurements of alkaline phosphatase. CONCLUSIONS: Serum alkaline phosphatase is associated with increased mortality in hemodialysis patients, independent of bone metabolism parameters and liver enzymes. Alkaline phosphatase might be a potential therapeutic target in hemodialysis patients.

Premature ovarian failure among hairdressers.

BACKGROUND: Hairdressers constitute a major occupational group of female workers who are exposed to chemicals that cause reproductive abnormalities in animal models. The purpose of this study was to examine whether hairdressers are at increased risk of premature ovarian failure (POF) compared with women of similar age in other occupations. METHODS: This study analyzed data from a population-based sample of 443 hairdressers and 508 women in other occupations, who responded to a mailed survey. POF was assessed in all eligible participants by self-report of a doctor's diagnosis. RESULTS: Among 443 hairdressers and 508 women in other occupations, 14 (3.2%) and 7 (1.4%) developed POF, respectively. A non-significant increase in the risk of POF was observed among hairdressers compared with non-hairdressers (adjusted relative risk (RR) 1.90; 95% confidence interval (CI) 0.76, 4.72). When limited to Caucasian women only (approximately 85% of respondents), the increased risk was statistically significant (RR 3.24; 95% CI 1.06, 9.91). Among Caucasian women of 40-55 years of age, hairdressers were more than five times as likely to report POF compared with non-hairdressers (RR 5.58; 95% CI 1.24, 25.22). CONCLUSIONS: Hairdressers may be at increased risk for POF compared with women employed in other occupations.

Neuropsychological, Psychiatric, and Functional Correlates of Clinical Trial Enrollment.

Screen failure rates in Alzheimer's disease (AD) clinical trial research are unsustainable, with participant recruitment being a top barrier to AD research progress. The purpose of this project was to understand the neuropsychological, psychiatric, and functional features of individuals who failed screening measures for AD trials. Previously collected clinical data from 38 patients (aged 50-83) screened for a specific industry-sponsored clinical trial of MCI/early AD (Biogen 221AD302, [EMERGE]) were analyzed to identify predictors of AD trial screen pass/fail status. Worse performance on non-memory cognitive domains like crystalized knowledge, executive functioning, and attention, and higher self-reported anxiety, was associated with failing the screening visit for the EMERGE AD clinical trial, whereas we were not able to detect a relationship between screening status and memory performance, self-reported depression, or self-reported daily functioning. By identifying predictors of AD trial screen passing/failure, this research may influence decision-making about which patients are most likely to successfully enroll in a trial, thereby potentially lowering participant burden, maximizing study resources, and reducing costs.

Long-term outcomes in nondiabetic chronic kidney disease.

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of strict blood pressure control and dietary protein restriction on the progression of kidney disease. Here, we retrospectively evaluated outcomes of nondiabetic participants with stages 2-4 chronic kidney disease (CKD) from randomized and nonrandomized cohorts of the MDRD Study. Kidney failure and survival status through December of 2000, were obtained from the US Renal Data System and the National Death Index. Event rates were calculated for kidney failure, death, and a composite outcome of death and kidney failure. In the 1666 patients, rates for kidney failure were four times higher than that for death. Kidney failure was a more likely event than death in subgroups based on baseline glomerular filtration rate, proteinuria, kidney disease etiology, gender, and race. It was only among those older than 65 that the rate for death approximated that for kidney failure. In contrast to other populations with CKD, our study of relatively young subjects with nondiabetic disease has found that the majority of the participants advanced to kidney failure with a low competing risk of death. In such patients, the primary emphasis should be on delaying progression of kidney disease.

Susceptibilities of clinical Clostridium difficile isolates to antimicrobials: a systematic review and meta-analysis of studies since 1970.

OBJECTIVES: Although exposure to antibiotics can cause Clostridium difficile infection, certain antibiotics are used to treat C. difficile. Measurements of antimicrobial C. difficile activity could help to identify antibiotic risk and emergent resistance. Here, we describe publication patterns relating to C. difficile susceptibilities and estimate minimum inhibitory concentrations (MIC) for antibiotic classes in the published literature between January 1970 and June 2014. METHODS: We queried PUBMED and EMBASE for studies reporting antibiotic C. difficile MIC in English or French. We used mixed-effects models to obtain pooled estimates of antibiotic class median MIC (MIC50), 90th percentile of MIC (MIC90), and MIC90:MIC50 ratio. RESULTS: Our search identified 182 articles that met our inclusion criteria, of which 27 were retained for meta-analysis. Aminoglycosides (MIC50 120 mg/L, 95% CI 62-250), 3rd (MIC50 75 mg/L, 95% CI 39-130) and 2nd generation cephalosporins (MIC50 64 mg/L, 95% CI 27-140) had the least C. difficile activity. Rifamycins (MIC50 0.034 mg/L, 95% CI 0.012-0.099) and tetracyclines (MIC50 0.29 mg/L, 95% CI 0.054-1.7) had the highest level of activity. The activity of 3rd generation cephalosporins was more than three times lower than that of 1st generation agents (MIC50 19 mg/L, 95% CI 7.0-54). Time-trends in MIC50 were increasing for carbapenems (70% increase per 10 years) while decreasing for tetracyclines (51% decrease per 10 years). CONCLUSIONS: We found a 3500-fold variation in antibiotic C. difficile MIC50, with aminoglycosides as the least active agents and rifamycins as the most active. Further research is needed to determine how in vitro measures can help assess patient C. difficile risk and guide antimicrobial stewardship.

Trajectories of traumatic stress symptoms during conflict: A latent class growth analysis.

BACKGROUND: The ways in which traumatic stress symptoms unfold under situations of ongoing threat and trauma exposure are poorly understood. The current study aims to identify traumatic stress symptom trajectories during conflict, as well as potential risk factors. METHODS: Experience sampling methods were used to study traumatic stress symptoms during the 2014 Israel-Gaza conflict in 100 Israeli civilians exposed to rocket fire. Summary reports of traumatic symptoms were made twice-daily for 30 days via mobile phone. RESULTS: Latent class growth analysis revealed four distinct classes (low, reducing, moderate, and high) characterised by their trajectory of traumatic stress symptoms during the conflict. Female gender, not being in a relationship, and higher prior trauma exposure were identified as potential risk factors. LIMITATIONS: Data were not collected in the early phase of the conflict, the sample was relatively small, and only traumatic stress symptoms were investigated as outcomes. CONCLUSIONS: This study identified heterogeneous traumatic stress symptom trajectories among civilians during a conflict, with different subgroups showing distinct response patterns over time, associated with various risk factors. Investigating responses to ongoing trauma, and identifying predictors of different stress symptom trajectories has clinical implications for the targeted delivery of interventions. Further exploration of heterogeneous trajectories could potentially elucidate mechanisms that drive resilience and recovery, including in situations of ongoing exposure such as during conflict.

A fast-degrading thiol-acrylate based hydrogel for cranial regeneration.

Successful regeneration of the cranium in patients suffering from cranial bone defects is an integral step to restore craniofacial function. However, restoration of craniofacial structure has been challenging due to its complex geometry, limited donor site availability, and poor graft integration. To address these problems, we investigated the use of a thiol-acrylate hydrogel as a cell carrier to facilitate cranial regeneration. Thiol-acrylate hydrogels were formulated with 5-15 wt% poly(ethylene glycol)-diacrylate (PEGDA) and 1-9 mm dithiothreitol (DTT). The degradation rate, swelling ratio, and shear modulus of the resulting hydrogel were first characterized. Then, pre-osteoblast-like cells (MC3T3-E1) were encapsulated in the hydrogel and cultured for up to 21 d. Our results demonstrate that compared to samples formulated from 15 wt% PEGDA, 5 wt% PEGDA samples showed lower storage modulus at day 10 (0.7 kPa versus 8.3 kPa), 62.7% higher in weight change after soaking for 10 d. While the 5 wt% PEGDA group showed an 85% weight loss between day 10 and 21, the 15 wt% PEGDA group showed a 5% weight gain in the same time period. Cell viability with 15 wt% PEGDA and 5 mm DTT hydrogel decreased by 41.3% compared to 5 wt% PEGDA and 5mM DTT gel at day 7. However, histological analysis of cells after 21 d in culture revealed that they had pericellular mineral deposition indicating that the cells were differentiating into osteoblasts lineage in all experimental groups. This study shows that thiol-acrylate hydrogels can be tailored to achieve different degradation rates, in order to enhance cell viability and differentiation. Thus, the findings of this study provide a fundamental understanding for the application of thiol-acrylate hydrogels in cranial bone regeneration.

Intraperitoneal recombinant alpha-interferon for "salvage" immunotherapy in stage III epithelial ovarian cancer: a Gynecologic Oncology Group Study.

Fourteen patients with persistent epithelial ovarian cancer documented at second look laparotomy after combination chemotherapy were treated with 146 cycles of alpha-recombinant interferon (rIFN-alpha 2) administered i.p. The initial dose was 5 X 10(6) units which was escalated weekly to 50 X 10(6) units over 4 weeks and then continued weekly for a total of 16 weeks. Eleven patients underwent surgical reevaluation after therapy which confirmed four pathological complete responses (36%), one partial response (9%), and disease progression in six patients (55%). Five of seven patients (71%) with residual tumor less than 5 mm had a surgically documented response, whereas there was no response in the four patients whose tumors were greater than or equal to 5 mm. Three patients were evaluable for clinical response only: one patient who refused surgery had a complete clinical response with total resolution of ascites; one had stable disease; and one had disease progression. Fever greater than or equal to 38 degrees C was seen in 58%, fever greater than or equal to 39.0 degrees C was seen in 18%, vomiting in 37%, abdominal pain was reported in 22%, and one patient had infectious peritonitis. Peripheral white blood cell counts and i.p. washings were obtained pretreatment and on days 1, 3, and 7 after treatment. While there was no consistent alteration in peripheral white blood cell counts, the numbers of i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood natural killer lymphocyte cytotoxicity values showed considerable variability. Pharmacokinetic studies show that i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. rIFN-alpha 2 i.p. may act by increasing concentrations of drug and augmenting regional host cells in patients with minimal residual ovarian cancer.

Quantifying calculus: a suggested new approach for recording an important indicator of diet and dental health.

This paper describes a quantitative approach to the assessment of dental calculus in human archaeological skeletal samples. The approach combines the ranked calculus scoring method described by Buikstra and Ubelaker [1994. Arkansas Archeological Survey Research Series, Arkansas Archeological Survey, Fayetteville, Arkansas] and a modified Simplified Calculus Index, utilized by dental clinicians. We recorded amounts of calculus on the buccal, lingual, and interproximal surface of all extant teeth, and generated an index for the maxillary posterior dentition, maxillary anterior dentition, mandibular posterior dentition, and mandibular anterior dentition for three skeletal samples. They include 145 Egyptian Predynastic individuals from the site of Hierakonpolis, 104 Predynastic individuals from Naqada, Egypt, and 101 Meroitic Nubians from Semna South, present-day Sudan. Mann-Whitney U tests were used to analyze differences between the sexes and among age groups at each site. The results demonstrate that the calculus indices more effectively reveal trends and differences in calculus severity than frequency data can alone. For example, at Hierakonpolis, males (18-35 years) had significantly more calculus in the maxillary posterior dentition than females, while females (50+ years) had significantly more calculus in the maxillary posterior teeth. Frequency data merely showed that 94% of both males and females had calculus. The use of calculus indices can reveal how quickly calculus accumulates with age within the dental arcade and within a sample. Moreover, better understanding of the severity and location of calculus can improve a researcher's knowledge regarding the effect of calculus on dental pathologies, such as carious lesions and periodontal disease.

A foot risk classification system to predict diabetic amputation in Pima Indians.

OBJECTIVE: To quantify the contribution of various risk factors to the risk of amputation in diabetic patients and to develop a foot risk scoring system based on clinical data. RESEARCH DESIGN AND METHODS: A population case-control study was undertaken. Eligible subjects were 1) 25-85 years of age, 2) diabetic, 3) 50% or more Pima or Tohono O'odham Indian, 4) lived in the Gila River Indian Community, and 5) had had at least one National Institutes of Health research examination. Case patients had had an incident lower extremity amputation between 1983 and 1992; control subjects had no amputation by 1992. Medical records were reviewed to determine risk conditions and health status before the pivotal event that led to the amputation. RESULTS: Sixty-one people with amputations were identified and compared with 183 control subjects. Men were more likely to suffer amputation than women (odds ratio [OR] 6.5, 95% CI 2.6-15), and people with diabetic eye, renal, or cardiovascular disease were more likely to undergo amputation than those without (OR 4.6, 95% CI 1.7-12). The risk of amputation was almost equally associated with these foot risk factors: peripheral neuropathy, peripheral vascular disease, bony deformities, and a history of foot ulcers. After controlling for demographic differences and diabetes severity, the ORs for amputation with one foot risk factor was 2.1 (95% CI 1.4-3.3), with two risk factors, 4.5 (95% CI 2.9-6.9), and with three or four risk factors, 9.7 (95% CI 6.3-14.8). CONCLUSIONS: Male Sex, end-organ complications of eye, heart, and kidney, and poor glucose control were associated with a higher amputation rate. Peripheral neuropathy, peripheral vascular disease, deformity, and a prior ulcer were similarly equally associated with an increased risk of lower extremity amputation.

Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group.

The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure (BP) goal on the progression of renal disease in patients with proteinuria. The purpose of the present analyses was to examine the achieved BP, baseline characteristics that helped or hindered achievement of the BP goals, and safety of the BP interventions. Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m2 (0.22 to 0.92 mL/s per 1.73 m2) were randomly assigned to either a usual or low BP goal (mean arterial pressure < or = 107 or < or = 92 mm Hg, respectively). Few patients had a history of cardiovascular disease. All antihypertensive agents were permitted, but angiotensin-converting enzyme inhibitors (with or without diuretics) followed by calcium channel blockers were preferred. The mean (+/- SD) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0 +/- 7.3 and 97.7 +/- 7.7 mm Hg, respectively. Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension, baseline mean arterial pressure > 92 mm Hg, a diagnosis of polycystic kidney disease or glomerular diseases, baseline urinary protein excretion > 1 g/d, age > or = 61 years, and black race. The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group, but there were no significant differences between BP groups in stop points, hospitalizations, or death. When data from both groups were combined, each 1-mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease. Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease. For patients with urinary protein excretion > 1 g/d, target BP should be a mean arterial pressure of < or = 92 mm Hg, equivalent to 125/75 mm Hg.

Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group.

African Americans (blacks) have a disproportionately high incidence of end-stage renal disease due to hypertension. The Modification of Diet in Renal Disease (MDRD) Study found that strict blood pressure control slowed the decline in glomerular filtration rate (GFR) only in the subgroup of patients with proteinuria. The present report compares the effects of blood pressure control in black and white MDRD Study participants. Fifty-three black and 495 white participants with baseline GFRs of 25 to 55 mL/min/1.73 m2 were randomly assigned to a usual or low mean arterial pressure (MAP) goal of < or = 107 or < or = 92 mm Hg, respectively. GFR decline was compared between randomized groups and correlated with the level of achieved blood pressure. The mean (+/-SE) GFR decline over 3 years in the low blood pressure group was 11.8+/-7.3 mL/min slower than in the usual blood pressure group among blacks (P=.11) compared with 0.3+/-1.3 mL/min slower among whites (P=.81) (P=.12 between blacks and whites). In both blacks and whites, higher baseline urine protein excretion was associated with a greater beneficial effect of the low MAP goal on GFR decline (P=.02 for both races). Combining both blood pressure groups and controlling for baseline characteristics, higher follow-up achieved MAP was associated with faster GFR decline in both blacks (P<.001) and whites (P=.002), with a sevenfold stronger relationship in blacks (P<.001). These secondary analyses support the prior recommendation for a lower than usual blood pressure goal (MAP < or = 92 mm Hg) in black and white patients with proteinuria (> 1 g/d). In addition, a lower level of blood pressure control may be even more important in blacks than in whites in slowing the progression of renal disease.

Intraperitoneal recombinant alpha 2-interferon for 'salvage' immunotherapy in persistent epithelial ovarian cancer.

Fourteen patients with epithelial ovarian cancer were treated with intraperitoneal (i.p.) administration of alpha-recombinant interferon (rIFN-alpha 2) after documentation of persistent disease at second-look laparotomy and combination chemotherapy. After therapy, 11 patients had a surgical re-evaluation which confirmed 4 complete responses (36%), 1 partial response (9%), and disease progression in 6 (55%). Five of 7 patients (71%) with minimal residual disease (MRD, i.e. less than 5 mm) had a surgically-documented response, whereas there was none in the 4 patients whose tumors were greater than or equal to 5 mm. Fever greater than or equal to 38 degrees C was seen in 58%, greater than or equal to 39.0 degrees C in 18%; nausea and vomiting in 37%, and abdominal pain in 22%. There was no consistent alteration in peripheral WBC's during treatment, while i.p. monocytes and lymphocytes showed a significant boost on day 1 after each dose of rIFN-alpha 2. Natural killer (NK) lymphocyte cytotoxicity was elevated in the i.p. cavity fluid obtained from most patients on day 1 after treatment, while blood NK values showed considerable variability. Pharmacokinetic studies showed i.p. levels of rIFN-alpha 2 were 30-1000 times blood levels. I.p. rIFN-alpha 2 may act by increasing concentrations of drug and augmenting regional host cells in patients with MRD ovarian cancer.

Isolation and characterization of a higher plant ADP-glucose pyrophosphorylase small subunit homotetramer.

ADP-glucose pyrophosphorylase (AGPase) is the allosterically regulated gateway for carbon entry into transient and storage starch in plants as well as glycogen in bacteria. This enzyme plays a key role in the modulation of photosynthetic efficiency in source tissues and directly determines the level of storage starch in sink tissues, thus influencing overall crop yield potential. AGPase is a tetrameric enzyme; in higher plants it consists of two regulatory large subunits (LS) and two catalytic small subunits (SS), while in cyanobacteria and prokaryotes the enzyme is homotetrameric. The potato SS gene in pML10 was mutated by hydroxylamine and mutants were screened for elevated homotetrameric activity by iodine vapor staining. This search strategy led to the isolation of SS mutants (SUP-1, TG-15) that had pyrophosphorylase activity in the absence of the LS. TG-15 has a leucine to phenylalanine change at position 48 (L(48)F) that corresponds to a phenylalanine residue at the analogous position in the Escherichia coli homotetrameric AGPase as well as a valine to isoleucine change at position 59 (V(59)I). TG-15 was partially purified and kinetic analysis revealed substrate and effector affinities equal to wild type heterotetrameric enzyme with the exception of ATP binding.