Human energy expenditure: advances in organ-tissue prediction models.

Humans expend energy at rest (REE), and this major energy exchange component is now usually estimated using statistical equations that include weight and other predictor variables. While these formulas are useful in evaluating an individual's or group's REE, an important gap remains: available statistical models are inadequate for explaining underlying organ-specific and tissue-specific mechanisms accounting for resting heat production. The lack of such systems level REE prediction models leaves many research questions unanswered. A potential approach that can fill this gap began with investigators who first showed in animals and later in humans that REE reflects the summated heat production rates of individual organs and tissues. Today, using advanced imaging technologies, REE can be accurately estimated from the measured in vivo mass of 10 organ-tissue mass components combined with their respective mass-specific metabolic rates. This review examines the next frontier of energy expenditure models and discusses how organ-tissue models have the potential not only to better predict REE but also to provide insights into how perturbations in organ mass lead to structure-function changes across other interacting organ systems. The introductory ideas advanced in this review provide a framework for future human energy expenditure modelling research.

Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men.

BACKGROUND/OBJECTIVE: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance. SUBJECTS/METHODS: Twenty-nine healthy men (27±5 years old; body mass index 25.5±2.3 kg m-2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6±2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp. RESULTS: Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P=0.001 and P=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day-1 (P=0.003) and tended to increase fat oxidation by 6±16 g day-1 (P=0.07) but did not affect carbohydrate oxidation (P=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, P=8 × 10-5) but not fat oxidation rates (P=0.09). CONCLUSIONS: The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Lifestyle modification intervention improves glycemic control in Mongolian adults who are overweight or obese with newly diagnosed type 2 diabetes.

OBJECTIVE: To evaluate the effectiveness of a weight loss intervention in Mongolian adults with newly diagnosed type 2 diabetes mellitus and with BMIs ≥ 25.0 kg/m2. METHODS: Eighty participants (33 men/47 women) aged 32-56 years old received education sessions to improve nutritional habits and increase physical activity. Participants were counselled in-person on two occasions with regular follow-up by phone to eat less (reduce calorie intake by 30-40% and consume fewer fatty foods), shift food intake to earlier in a day and increase physical activity such as walking, jogging, running and biking. Measurements were performed before and after the 6-month intervention. RESULTS: After 6 months, the average weight loss was 4.3 ± 4.7 kg, representing a 4.9 ± 5.4% reduction in body weight (p < 0.0001). Mean HbA1c decreased from 8.5 ± 2.7% to 6.0 ± 1.8% (p < 0.0001), and the percent of individuals with HbA1c in the diabetic range dropped from 76.3% to 27.5%. These changes were accompanied by marked improvements in cardiovascular risk factors, including total cholesterol (3.92 ± 1.02 to 3.13 ± 0.80 mmol/l; p < 0.0001) and triglycerides (2.11 ± 0.82 to 1.54 ± 0.51 mmol/l; p < 0.0001), and modest reductions in systolic and diastolic blood pressure (p < 0.05). CONCLUSION: The remarkable improvement in glycemic control and lipid profile in participants suggests that a lifestyle modification intervention targeting weight loss may be highly effective for early diabetes treatment and prevention in Mongolians.

Why are there race/ethnic differences in adult body mass index-adiposity relationships? A quantitative critical review.

Body mass index (BMI) is now the most widely used measure of adiposity on a global scale. Nevertheless, intense discussion centers on the appropriateness of BMI as a phenotypic marker of adiposity across populations differing in race and ethnicity. BMI-adiposity relations appear to vary significantly across race/ethnic groups, but a collective critical analysis of these effects establishing their magnitude and underlying body shape/composition basis is lacking. Accordingly, we systematically review the magnitude of these race-ethnic differences across non-Hispanic (NH) white, NH black and Mexican American adults, their anatomic body composition basis and potential biologically linked mechanisms, using both earlier publications and new analyses from the US National Health and Nutrition Examination Survey. Our collective observations provide a new framework for critically evaluating the quantitative relations between BMI and adiposity across groups differing in race and ethnicity; reveal new insights into BMI as a measure of adiposity across the adult age-span; identify knowledge gaps that can form the basis of future research and create a quantitative foundation for developing BMI-related public health recommendations.

Pain typology and incident endometriosis.

STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Effect of feeding ractopamine hydrochloride on growth performance and responses to handling and transport in heavy-weight pigs.

The impact of feeding ractopamine hydrochloride (RAC) on growth performance and responses to handling and transport in heavy BW pigs was evaluated in a study performed as a split-plot design with a 3 × 3 factorial arrangement of treatments: 1) RAC level (0 vs. 5 vs. 7.5 mg/kg of feed) and 2) handling intensity (HI; gentle vs. moderate vs. aggressive); RAC level was the main plot and HI was the subplot. A total of 288 pigs housed in groups of 8 were used to evaluate growth performance over a 28-d RAC feeding period (98.5 ± 4.58 to 131.5 ± 7.45 kg BW). On d 29 of the study, the HI treatment was applied to 216 pigs (6/pen; 2/pen on each HI). This was followed by transportation for 1 h on a livestock trailer at the end of which pigs were subjected to a final handling procedure. Blood samples (to measure acid-base, cortisol, and catecholamine levels) were collected and rectal temperature was measured 2 h before the HI treatment (baseline) and after the final handling procedure (final). Feeding RAC (5 and 7.5 mg/kg) improved ( < 0.01) ADG (9.9 and 9.0% for 5 and 7.5 mg/kg RAC, respectively) and G:F (8.8 and 11.8%, respectively) compared to controls, with no differences ( > 0.05) between the 2 RAC levels. Increasing the intensity of handling decreased ( < 0.001) final blood pH, bicarbonate, and base excess and increased ( < 0.001) final blood lactate and plasma cortisol and norepinephrine levels. Aggressive compared to gentle handling increased ( < 0.05) the incidence of pigs exhibiting open-mouth breathing and skin discoloration after the final handling procedure but had no effect ( > 0.05) on the incidence on nonambulatory, noninjured pigs. There was no effect ( > 0.05) of feeding RAC on final rectal temperature or blood acid-base measurements. Feeding 7.5, but not 5, compared to 0 mg/kg RAC increased ( < 0.05) final plasma epinephrine levels and the incidence of nonambulatory, noninjured pigs. This study confirms the improved growth performance of pigs fed RAC and the negative effects of aggressive handling on physical, metabolic, and physiological responses of pigs. It also suggests that pigs fed 5 compared to 0 mg/kg RAC showed similar responses to transport and handling. However, pigs fed 7.5 mg/kg of RAC had a greater incidence of nonambulatory, noninjured pigs when subjected to the handling/transport model and this warrants further investigation.

COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE.

The purpose of this study was to model data from a head to head comparison of the in vivo fate of hyper-branched PAMAM dendrimers with linear HPMA copolymers in order to understand the influence of molecular weight (MW), hydrodynamic size (Rh) and polymer architecture on biodistribution in tumor-bearing mice using compartmental pharmacokinetic analysis. Plasma concentration data was modeled by two-compartment analysis using Winnonlin® to obtain elimination clearance (E.CL) and plasma exposure (AUCplasma). Renal clearance (CLR) was calculated from urine data collected over 1 week. A plasma-tumor link model was fitted to experimental plasma and tumor data by varying the tumor extravasation (K4, K6) and elimination (K5) rate constants using multivariable constrained optimization solver in Matlab®. Tumor exposures (AUCtumor) were computed from area under the tumor concentration time profile curve by the linear trapezoidal method. Along with MW and Rh, polymer architecture was critical in affecting the blood and tumor pharmacokinetics of the PAMAM-OH dendrimers and HPMA copolymers. Elimination clearance decreased more rapidly with increase in hydrodynamic size for PAMAM-OH dendrimers as compared to HPMA copolymers. HPMA copolymers were eliminated renally to a higher extent than PAMAM-OH dendrimers. These results are suggestive of a difference in extravasation of polymers of varying architecture through the glomerular basement membrane. While the linear HPMA copolymers can potentially reptate through a pore smaller in size than their hydrodynamic radii in a random coil conformation, PAMAM dendrimers have to deform in order to permeate across the pores. With increase in molecular weight or generation, the deforming capacity of PAMAM-OH dendrimers is known to decrease, making it harder for higher generation PAMAM-OH dendrimers to sieve through the glomerulus as compared to HPMA copolymers of comparable molecular weights. PAMAM-OH dendrimer had greater tumor extravsation rate constants and higher tumor to plasma exposure ratios than HPMA copolymers of comparable molecular weights which indicated that in the size range studied, when in circulation, PAMAM-OH dendrimers had a higher affinity to accumulate in the tumor than the HPMA copolymers.

Evolving concepts on adjusting human resting energy expenditure measurements for body size.

Establishing if an adult's resting energy expenditure (REE) is high or low for their body size is a pervasive question in nutrition research. Early workers applied body mass and height as size measures and formulated the Surface Law and Kleiber's Law, although each has limitations when adjusting REE. Body composition methods introduced during the mid-20th century provided a new opportunity to identify metabolically homogeneous 'active' compartments. These compartments all show improved correlations with REE estimates over body mass-height approaches, but collectively share a common limitation: REE-body composition ratios are not 'constant' but vary across men and women and with race, age and body size. The now-accepted alternative to ratio-based norms is to adjust for predictors by applying regression models to calculate 'residuals' that establish if an REE is relatively high or low. The distinguishing feature of statistical REE-body composition models is a 'non-zero' intercept of unknown origin. The recent introduction of imaging methods has allowed development of physiological tissue-organ-based REE prediction models. Herein, we apply these imaging methods to provide a mechanistic explanation, supported by experimental data, for the non-zero intercept phenomenon and, in that context, propose future research directions for establishing between-subject differences in relative energy metabolism.

Effects of floor space during transport and journey time on indicators of stress and transport losses of market-weight pigs.

The effects of floor space on the trailer and journey time during transport from the farm to the packing plant on indicators of stress (open-mouth breathing, muscle tremors, and skin discoloration) and on the incidence of transport losses (dead on arrival, nonambulatory, noninjured, and nonambulatory, injured) were evaluated in a study involving 160 loads of market-weight pigs (BW 124.7 ± 4.38 kg) using a split-plot design with a 2 × 6 factorial arrangement of treatments: 1) journey time [main plot; short (<1 h) and long (3 h)] and 2) floor space (subplot; 0.396, 0.415, 0.437, 0.462, 0.489, and 0.520 m(2)/pig, which is equivalent to 0.317, 0.332, 0.350, 0.370, 0.391, and 0.416 m(2)/100 kg of BW, respectively). Two consecutively loaded trailers were randomly allotted to journey time treatment. Floor space treatments were compared in the front 3 compartments on the top and bottom decks of the trailer and were created by varying the number of pigs per compartment, which confounds the effect of floor space with group size. Of the 17,652 pigs transported in 954 test compartments, 0.24% died or became nonambulatory. Neither journey time nor floor space had an effect (P > 0.05) on the incidence of dead and nonambulatory, injured pigs, or on total transport losses. There were interactions (P < 0.05) between journey time and floor space treatments for the incidences of nonambulatory, noninjured pigs and open-mouth breathing. For 2 of the smallest floor spaces (0.415 and 0.437 m(2)/pig), the incidence of nonambulatory, noninjured pigs was greater on short than on long journeys; for the other 4 floor spaces there was no effect (P > 0.05) of journey time. The incidence of open-mouth breathing for the 3 smallest floor spaces was greater (P < 0.05) for short than long journeys, whereas there was no effect (P > 0.05) of journey time for the 3 greatest floor spaces. The frequency of skin discoloration was greater (P < 0.001) for pigs transported at the 2 smallest floor spaces compared with the other 4 floor spaces. In summary, short journey time increased the frequency of indicators of stress after unloading at the plant for pigs transported at smaller floor spaces and also increased the incidence of nonambulatory, noninjured pigs at 2 of the 3 smallest floor spaces. However, neither transport floor space nor journey time had an effect on total losses.

Comparative biodistribution of PAMAM dendrimers and HPMA copolymers in ovarian-tumor-bearing mice.

The biodistribution profile of a series of linear N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymers was compared with that of branched poly(amido amine) dendrimers containing surface hydroxyl groups (PAMAM-OH) in orthotopic ovarian-tumor-bearing mice. Below an average molecular weight (MW) of 29 kDa, the HPMA copolymers were smaller than the PAMAM-OH dendrimers of comparable molecular weight. In addition to molecular weight, hydrodynamic size and polymer architecture affected the biodistribution of these constructs. Biodistribution studies were performed by dosing mice with (125)iodine-labeled polymers and collecting all major organ systems, carcass, and excreta at defined time points. Radiolabeled polymers were detected in organ systems by measuring gamma emission of the (125)iodine radiolabel. The hyperbranched PAMAM dendrimer, hydroxyl-terminated, generation 5 (G5.0-OH), was retained in the kidney over 1 week, whereas the linear HPMA copolymer of comparable molecular weight was excreted into the urine and did not show persistent renal accumulation. PAMAM dendrimer, hydroxyl-terminated, generation 6.0 (G6.0-OH), was taken up by the liver to a higher extent, whereas the HPMA copolymer of comparable molecular weight was observed to have a plasma exposure three times that of this dendrimer. Tumor accumulation and plasma exposure were correlated with the hydrodynamic sizes of the polymers. PAMAM dendrimer, hydroxyl-terminated, generation 7.0 (G7.0-OH), showed extended plasma circulation, enhanced tumor accumulation, and prolonged retention with the highest tumor/blood ratio for the polymers under study. Head-to-head comparative study of HPMA copolymers and PAMAM dendrimers can guide the rational design and development of carriers based on these systems for the delivery of bioactive and imaging agents.

Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages.

Spherical and rod-shaped gold nanoparticles with surface poly(ethylene glycol) (PEG) chains were characterized for size, shape, charge, poly dispersity and surface plasmon resonance. The nanoparticles were injected intravenously to 6-8-week-old female nu/nu mice bearing orthotopic ovarian tumors, and their biodistribution in vital organs was compared. Gold nanorods were taken up to a lesser extent by the liver, had longer circulation time in the blood, and higher accumulation in the tumors, compared with their spherical counterparts. The cellular uptake of PEGylated gold nanoparticles by a murine macrophage-like cell line as a function of geometry was examined. Compared to nanospheres, PEGylated gold nanorods were taken up to a lesser extent by macrophages. These studies point to the importance of gold nanoparticle geometry and surface properties on transport across biological barriers.

Monozygotic twinning associated with assisted reproductive technologies: a review.

Twin birth rates have increased markedly in developed countries since the 1970s for two primary reasons: increasing maternal age and the advent and increasing use of fertility treatments. In addition, monozygotic (MZ) twin pregnancies have been reported to occur at a significantly higher rate following assisted reproductive technologies (ART) procedures compared with the natural incidence. Twin pregnancies are of concern due to a dramatically increased risk of associated complications. Monozygotic twin pregnancies carry a 10-20% risk of twin-twin transfusion syndrome, and monoamniotic monochorionic twins are additionally at risk for cord entanglement. While the mechanisms and contributory factors for dizygotic twinning are well established, very little is known about the mechanisms involved in MZ twinning or the factors that contribute to its occurrence. In this review, we will discuss a number of potential mechanisms involved in MZ twinning and explore factors that may be contributing to the increased incidence of ART-associated MZ twins. An improved understanding of the factors that contribute to increased MZ twinning associated with ART will help to elucidate the poorly understood mechanisms involved in the process and will further aid in reducing the overall incidence of multiple pregnancies with their associated risks following ART procedures.

NHLBI plans for the promise of cell-based therapies.

This article presents the National Heart, Lung and Blood Institute (NHLBI) perspective on the status of cell-based therapies. A summary of current and future NHLBI/National Institutes of Health (NIH) programs is given along with a history of the development of NHLBI/NIH resources to aid the advancement of cell-based therapies. A brief discussion of clinical research programs to utilize cell-based therapies is also included.

Sperm chromosome aneuploidy as related to male factor infertility and some ultrastructure defects.

Some men have elevated levels of sperm chromosome aneuploidy. In this study, we have evaluated and summarized sperm aneuploidy rates in male infertility patients and control groups. The mean aneuploidy rate for five chromosomes (X, Y, 13, 18, 21) was 1.2 +/- 0.1 for fertile controls, 1.4 +/- 0.1 for a general population control group, and 5.8 +/- 1.14 for the patients. When the patients were classified by the type of male factor infertility, the total aneuploidy rate was 2.6 +/- 0.3 in men with moderately diminished semen quality (n = 7), 4.0 +/- 0.3 patients with severe teratoasthenooligozoospermia, and 15.9 +/- 3.8 for men with rare ultrastructure defects such as round head only syndrome or severe tail agenesis. Some infertility patients have a severely elevated level of sperm chromosome aneuploidy, which may contribute to infertility or diminish the likelihood of a successful outcome from IVF/ICSI. The severity of sperm chromosome aneuploidy appears to be proportional to the severity of abnormal semen quality: in particular, abnormal morphology. The high rates of aneuploidy in patients with severe ultrastructure defects suggest that caution should be employed in counseling those patients prior to IVF/ICSI.

Sperm DNA fragmentation is increased in couples with unexplained recurrent pregnancy loss.

Previous studies have indicated that sperm quality may be related to unexplained recurrent pregnancy loss. This study evaluated the degree of sperm DNA fragmentation using the TUNEL assay on sperm from 24 couples with unexplained recurrent pregnancy loss (RPL) compared to sperm from 2 control groups: donors of known fertility and unscreened men from the general population. The percentage of sperm staining positive for DNA fragmentation was increased (p < .001) in the RPL group (38 +/- 4.2) compared to the donor (11.9 +/- 1.0) or general population (22 +/- 2.0) control groups. In the RPL group, no correlation was observed between semen quality parameters and the TUNEL data. These data indicate that some RPL patients have a significant increase of sperm DNA fragmentation, which may be causative of pregnancy loss in some patients.

Water soluble polymers in tumor targeted delivery.

The rationales for the use of water soluble polymers for anticancer drug delivery include: the potential to overcome some forms of multidrug resistance, preferential accumulation in solid tumors due to enhanced permeability and retention (EPR) effect, biorecognizability, and targetability. The utility of a novel paradigm for the treatment of ovarian carcinoma in an experimental animal model, which combines chemotherapy and photodynamic therapy with polymer-bound anticancer drugs is explained. Research and clinical applications as well as directions for the future development of macromolecular therapeutics are discussed.

Combination chemotherapy and photodynamic therapy of targetable N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin/mesochlorin e(6)-OV-TL 16 antibody immunoconjugates.

The aim of this study was to evaluate the combination chemotherapy and photodynamic therapy of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin (DOX) and mesochlorin e(6) (Mce(6)) targeted with an OV-TL 16 monoclonal antibody (P-DOX-Ab and P-Mce(6)-Ab, respectively) in nude mice bearing human ovarian OVCAR-3 carcinoma xenografts. P-DOX-Ab and P-Mce(6)-Ab were synthesized by first conjugating DOX or Mce(6) to an HPMA copolymer precursor (Mw=21000), then reacting with OV-TL 16 antibody. The immunoconjugates were purified by size exclusion chromatography on Superose 6 column and analyzed. The Mce(6) concentration in tissues was determined by a fluorescence assay. Eighteen hours after administration, the tumors received a light dose of 220 J/cm(2) from a KTP 650-nm dye-laser. P-DOX-Ab and P-Mce(6)-Ab had polymer:drug:protein weight ratios of 32:3:62 and 26:2:72, corresponding to polymer:drug:protein molecular ratios of approximately 4:14:1 and 3:8:1, respectively. The biodistribution results indicated that the percentage of total administered dose of Mce(6) in tumors reached approximately 1% for the nontargeted conjugate at 18 h after administration, while that of P-Mce(6)-Ab was approximately 13 times higher. Nude mice bearing OVCAR-3 xenografts that received one i.v. dose of P-DOX-Ab (2.2 mg/kg DOX equivalent) and P-Mce(6)-Ab (1.5 mg/kg Mce(6) equivalent) with light irradiation achieved a xenograft cure rate of more than 60%. The incorporation of OV-TL 16 antibody dramatically enhanced the accumulation in tumors with a concomitant increase in the therapeutic efficacy of P-DOX-Ab and P-Mce(6)-Ab in combination therapy, which may probably be attributed to both antibody targeting and enhanced permeability and retention (EPR) effects.

A unique variant of Darier's disease.

A 45-year-old black woman presented with a chief complaint of an increasing number of "light spots" on her face, upper trunk, and legs. She had a 4-year history of a pruritic eruption on the dorsum of her hands. The eruption was particularly pruritic in the summer months. Other family members, including her sister and her daughters, reportedly had a similar dermatologic problem. The patient had been previously evaluated and biopsied by another dermatologist. The earlier biopsy was nondiagnostic, however, and she presented for further evaluation of this problem. On physical examination, the patient had hypopigmented macules along her jawline (Fig. 1), lateral neck, and upper chest. She had similar hypopigmented macules on her thighs. She had hyperkeratosis of the palmoplantar surface of her hands and feet. The dorsum of her hands had numerous coalescing, shiny, flat-topped, hypopigmented papules (Fig. 2), and several of her fingernails had distal, V-shaped notching. A punch biopsy from a papule on the dorsum of her hand was obtained. The epidermis had corps ronds present with focal areas of acantholysis above the basal layer (Fig. 3). The dermis had sparse, superficial, perivascular infiltrates composed of lymphocytes and histiocytes. These changes were consistent with our clinical diagnosis of Darier's disease (keratosis follicularis).

Microcystic adnexal carcinoma: First reported case in an African American man.

Microcystic adnexal carcinoma (MAC) is a relatively uncommon adnexal neoplasm that can display aggressive local invasion. MAC occurs most commonly on the central part of the face and can be clinically asymptomatic with a benign appearance. We describe the first reported case of MAC in an African American man who was treated by Mohs micrographic surgery.