Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

The clinical utility of PGD with HLA matching: a collaborative multi-centre ESHRE study.

STUDY QUESTION: Has PGD-HLA been successful relative to diagnostic and clinical efficacy? SUMMARY ANSWER: The diagnostic efficacy of PGD-HLA protocols was found lower in this study in comparison to published PGD-HLA protocols and to that reported for general PGD by ESHRE (78.5 vs 94.1% and vs 92.6%, respectively), while the clinical efficacy has proven very difficult to assess due to inadequate follow-up of both the ART/PGD and HSCT procedure outcomes. WHAT IS KNOWN ALREADY: The first clinical cases for PGD-HLA were reported in 2001. It is now a well-established procedure, with an increasing number of cycles performed every year. However, PGD-HLA is still offered by relatively few PGD centres, the currently available data is fragmented and most reports on PGD-HLA applications are limited in number and scope. Published systematic details on methodology, diagnostic results, overall ART success and haematopoietic stem cell transplantation (HSCT) outcomes are limited, precluding an evaluation of the true clinical utility of PGD-HLA cycles. STUDY DESIGN, SIZE, DURATION: This retrospective multi-centre cohort study aimed to investigate the diagnostic and clinical efficacy of the PGD-HLA procedure and the aspects of PGD-HLA cycles influencing positive outcomes: birth of genetically suitable donor-baby (or babies) and HSCT. In April 2014, 32 PGD centres (Consortium members and non-members) with published/known PGD-HLA activity were invited to participate. Between February and September 2015, 14 centres submitted their data, through a custom-designed secure database, with unique login access for each centre. Data parameters covered all aspects of PGD-HLA cycles (ART, embryology and genetic diagnosis), donor-babies born and HSCT. PARTICIPANTS/MATERIALS, SETTING, METHODS: From 716 cycles submitted by 14 centres (performed between August 2001 and September 2015), the quality evaluation excluded 12 cycles, leaving 704, from 364 couples. The online database, based on REDCap, a free, secure, web-based data-capture application, was customized by Centre for Clinical Epidemiology and Outcomes Research (CLEO), Athens. Continuous variables are presented using mean, standard deviation, median and interquartile range, and categorical variables are presented as absolute and relative frequencies. MAIN RESULTS AND THE ROLE OF CHANCE: The data included 704 HLA-PGD cycles. Mean maternal age was 33.5 years. Most couples (81.3%) requested HLA-typing with concurrent exclusion of a single monogenic disease (58.6% for beta-thalassaemia). In 92.5% couples, both partners were fertile, with an average 1.93 HLA-PGD cycles/couple. Overall, 9751 oocytes were retrieved (13.9/cycle) and 5532 embryos were analysed (7.9/cycle). Most cycles involved fresh oocytes (94.9%) and Day 3 embryo biopsy (85.3%). In 97.5% of cycles, the genotyping method involved PCR only. Of 4343 embryos diagnosed (78.5% of analysed embryos), 677 were genetically suitable (15.4% of those analysed for HLA alone, 11.6% of those analysed for HLA with exclusion of monogenic disease). Of the 364 couples, 56.6% achieved an embryo transfer (ET) and 598 embryos were transferred in 382 cycles, leading to 164 HCG-positive pregnancies (pregnancy rate/ET 41.3%, pregnancy rate/initiated cycle 23.3%) and 136 babies born (live birth rate/ET 34.3%, live birth rate/initiated cycle 19.3%) to 113 couples. Data analysis identified the following limitations to the overall success of the HLA-PGD procedure: the age of the mother undergoing the treatment cycle, the number of oocytes collected per cycle and genetic chance. HSCT was reported for 57 cases, of which 64.9% involved combined umbilical cord-blood and bone marrow transplantation from the HLA-identical sibling donor; 77.3% of transplants reported no complications. LIMITATIONS REASONS FOR CAUTION: The findings of the study may be limited as not all PGD centres with PGD-HLA experience participated. Reporting bias on completion of the online database may be another potential limitation. Furthermore, the study is based on retrospective data collection from centres with variable practices and strategies for ART, embryology and genetic diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: This is the first multi-centre study evaluating the clinical utility of PGD-HLA, indicating variations in practice and outcomes throughout 15 years and between centres. The study highlights parameters important for positive outcomes and provides important information for both scientists and couples interested in initiating a cycle. Above all, the study underlines the need for better collaboration between all specialists involved in the ART-PGD/HLA procedure, as well as the need for comprehensive and prospective long-term data collection, and encourages all specialists to aim to properly evaluate and follow-up all procedures, with the ultimate aim to promote best practice and encourage patient informed decision making. STUDY FUNDING/COMPETING INTEREST(S): The study wishes to acknowledge ESHRE for funding the customization of the REDCap database. There are no competing interests. TRIAL REGISTRATION NUMBER: N/A.

An investigation of the potential effect of sperm nuclear vacuoles in human spermatozoa on DNA fragmentation using a neutral and alkaline Comet assay.

Presence of vacuoles and degree of sperm DNA damage are considered to be the basic factors used for the assessment of sperm fertilization capacity. We aimed to investigate the link between these two parameters. According to our knowledge, this is the first study where the Comet assay was used to assess the degree of DNA fragmentation of sperm categorized by Motile Sperm Organelle Morphology Examination (MSOME) Grades. Semen samples from 10 patients were assessed. Spermatozoa were graded into four MSOME groups according to the Vanderzwalmen's criteria. A total of 3930 motile spermatozoa were selected one-by-one using an inverted microscope and transferred onto two different slides. The degree of DNA fragmentation was analyzed by alkaline and neutral Comet assay. Results of the neutral Comet assay showed that Grade I spermatozoa (absence of vacuoles) presented significantly lower dsDNA fragmentation level (mean: 3.13 ± 1.17%) than Grade II (maximum of two small vacuoles; mean: 10.34 ± 2.65%), Grade III (more than two small vacuoles or at least one large vacuole; mean: 23.88 ± 8.37%), and Grade IV (large vacuoles associated with abnormal head shapes or other abnormalities; mean: 36.94 ± 7.78%; p < 0.05). Results of the alkaline Comet assay showed that Grade I spermatozoa had significantly lower DNA (ssDNA + dsDNA) fragmentation level (mean: 8.33 ± 3.62%) than Grade III (mean: 25.64 ± 9.15%) and Grade IV (mean: 40.10 ± 9.10%, p < 0.05), but not significantly lower than Grade II (mean: 12.73 ± 5.06%; p > 0.05). Probably, the vacuoles may be responsible for double strand DNA breaks rather than single strand DNA breaks (only 2.39% spermatozoa in MSOME Grade II, 1.76% in III, and 3.16% in IV has single strand breaks). The results demonstrate that lower MSOME grading correlates with lower sperm DNA fragmentation. Therefore, the observation of sperm nuclear vacuoles using real-time optical microscopy without precise DNA fragmentation examination is not sufficient for optimal sperm selection for intracytoplasmic sperm injection.

Influence of the conclusion of a recent large cooperative study in changing standard protocol of inducing menses in anovulatory women with oligomenorrhea prior to initiating ovulation induction with anti-estrogens and outcome.

PURPOSE: To compare pregnancy rates following ovulation induction in anovulatory women with clomiphene citrate vs. letrozole and to determine the relative confounding effect of inducing menses or not. The study also evaluated whether starting these anti-estrogen drugs later in the menstrual cycle has-less adverse effect on endometrial thickness. MATERIALS AND METHODS: Prospective series with choice by physician of inducing menses or not or choosing clomiphene citrate or letrozole for ovulation induction. Peak endometrial thickness was compared between drugs and between those conceiving or not. RESULTS: There were 21 first cycles using letrozole and 42 using clomiphene. Menses were not induced in 18/21 (86%) letrozole cycles and 24/42 (57%) clomiphene cycles. Clinical pregnancies occurred in four (22.2%) letrozole cycles without induced menses with one miscarriage vs. 4/24 (16.6%) clomiphene cycles, no mis- carriage. One of three (33.3%) letrozole cycles with menses induced achieved a clinical pregnancy vs. only 1/18 (5.5%) of clomiphene cycles. There were no miscarriages. CONCLUSIONS: Though the endometrial thickness was higher with clomiphene without induced menses vs. menses induced (11 mm vs. 9.5 mm), one cannot explain the trend for lower pregnancy rates in women with induced menses because of thinner endometria since the thickness was 10.3 mm for clomiphene and 10.0 with letrozole.

Efficacy of a single injection of human chorionic gonadotropin at peak follicular maturation in natural cycles on pregnancy rate and mid-luteal hormonal and sonographic parameters.

PURPOSE: To discover if infertile women with presumed luteal phase deficiency would improve pregnancy rates, mid-luteal sera estradiol (E2) and progesterone (P), and increase the percentage of women achieving a mid-luteal sonographic homogeneous hyperechogenic endometrial texture by the addition of a single injection of human chorionic gonadotropin (hCG). MATERIALS AND METHODS: Women with over one year of infertility with regular menses and with no other known infertility factor were presumed to have the need for extra P in the luteal phase based on previous studies. Women aged ≥ 30 years were selected along with women < 30 years who had pelvic pain or dysmenorrhea. Women aged 40-45 were evaluated separately. They were treated with either vaginal micronized P 8% twice daily alone or 10,000 units of hCG at the time of peak follicular maturation was also given. Women were eliminated if they did not achieve an 18-24 average diameter follicle with a serum E2 of > 200 pg/ml. Seven days after ovulation, sera E2 and P were measured along with endometrial thickness and echo patterns. RESULTS: The only significant difference between groups was an increased mid-luteal serum E2 in the group receiving additional hCG. However, this did not result in an increased pregnancy rate. CONCLUSIONS: In general, adding a single injection of hCG to P luteal support does not improve pregnancy rates in natural cycles where women were treated with supplemental P.

The effect of clomiphene citrate vs. letrozole on post-coital tests.

PURPOSE: To determine if letrozole is less likely to create a hostile cervical mucus than clomiphene citrate. MATERIALS AND METHODS: Post-coital testing compared at time of peak follicular maturation in women attaining mature follicles in first or second cycle of these two drugs. The study was randomized. Intercourse occurred at least 8-16 hours before. RESULTS: Poor post-coital tests were found in twice the frequency in letrozole cycles than clomiphene citrate cycles. CONCLUSIONS: Despite its shorter half-life, letrozole seems to be as least as likely, if not more, to adversely affect cervical mucus.

The impact of the presence of antithyroid antibodies on pregnancy outcome following intracytoplasmatic sperm injection-ICSI and embryo transfer in women with normal thyreotropine levels.

PURPOSE: The aim of our study was to investigate the impact of anti-thyroid peroxidase antibodies (Anti-TPO) on pregnancy outcome following the in vitro fertilization and embryo transfer (IVF-ET) in general groups and in subgroups divided according to AMH level and age. METHODS: A total of 114 patients positive for anti-thyroid peroxidase antibodies (Anti-TPO+ group) and 495 infertile women negative for anti-thyroid peroxidase antibodies (Anti-TPO- group) undergoing IVF with ICSI from April 2010 to April 2012 were analyzed retrospectively. RESULTS: There were no significant differences in age, BMI, basal FSH, LH, AMH levels and duration of infertility between the two main groups. No significant differences in terms of the days of ovarian stimulation, estradiol level in day 8, total gonadotropin dose, number of oocytes retrieved, available embryos and blastocysts, number of embryos transferred nor in rates of fertilization, implantation, clinical pregnancy, live birth and abortion rate between two main groups were found. The only statistically significant difference among the groups with different anti-TPO antibodies levels was found in basal FSH concentration and BMI. Among the clinical outcomes of IVF with respect to the different anti-TPO levels, the only significant difference was found for the number of oocytes retrieved. Analysis of the baseline parameters in relationship to age categories and AMH levels found significant differences between women positive and negative for thyroid antibodies with respect to basal FSH and LH levels for women >37 years and for basal FSH in AMH <0.6 subgroup. CONCLUSIONS: The present study reveals that patients with anti-TPO antibodies showed no significant differences in fertilization, implantation, pregnancy rates, live birth rates and no higher risk for miscarriage following IVF-ET when compared with those negative for anti-thyroid antibodies.

Serum caffeine concentrations and short-term outcomes in premature infants of ⩽29 weeks of gestation.

OBJECTIVE: Caffeine is effective in the treatment of apnea of prematurity but it is not well known if the therapeutic concentration of the drug has an impact on other neonatal outcomes such as chronic lung disease (CLD). The aim of this study was to determine if there is an association between caffeine concentrations and the incidence of CLD in premature infants of ⩽29 weeks of gestation. STUDY DESIGN: A retrospective chart review of all the infants born ⩽29 weeks of gestation from 2007 to 2011, who survived until discharge or 36 weeks postmenstrual age, was conducted. Caffeine concentrations were obtained weekly on infants getting the drug. Average caffeine concentrations (ACCs) were determined for the duration of caffeine therapy and correlated with CLD, length of stay (LOS), oxygen at discharge (OD), duration of ventilation (DV) and total charges for hospitalization for each patient. RESULTS: Of the 222 eligible infants, 198 met the inclusion criteria. ACC for infants without CLD was 17.0±3.8 µg ml(-1) compared with infants with CLD 14.3±6.1 µg ml(-1) (P<0.001). Infants receiving high ACC (>14.5 µg ml(-1)) had lower incidence of patent ductus arteriosus, lesser number of days on ventilator and oxygen, lesser need for diuretics, lower incidence of CLD, were more likely to go home without supplemental OD and had lower LOS and lower total hospital charges (all differences were significant P<0.05) Multiple logistic regression modeling after adjusting for confounding variables indicated that higher caffeine concentrations were significantly associated with decrease in CLD. Receiver operating curve analysis confirmed a significant predictive ability of caffeine concentration for CLD with a cutoff concentration of 14.5 µg ml(-1) (sensitivity of 42.6 and specificity of 86.8). The AUC (area under the curve) for the prediction of CLD was 0.632 (95% confidence interval 0.56-0.69, P=0.009). CONCLUSIONS: Caffeine concentrations >14.5 µg ml(-1) were strongly correlated with reduced CLD in infants born at ⩽29 weeks of gestation. Higher caffeine concentrations were associated with decreased total hospital charges, DV, OD and LOS. Additional randomized trials are needed to confirm these findings, to identify ideal serum concentrations and determine possible long-term neurologic benefits.

A comparison of three types of therapies for three different ovulation disorders in establishing pregnancies and evaluation of laboratory parameters that could influence the outcome.

PURPOSE: To evaluate the empirical use of progesterone (P) in the luteal phase for unexplained infertility. METHODS: Clinical and live-delivered pregnancy rates in three treatment cycles were compared in women with unexplained infertility vs women taking follicle maturing drugs for women completely anovulatory or those who release the oocyte before the follicle is mature. RESULTS: There was insufficient power to show a significant difference in the 19.5% live-delivered pregnancy rate found in women with a mean length of infertility duration of 2.1 years who just used P in the luteal phase vs the 30.1% rate seen in women with clear-cut ovulatory defects treated with follicle-maturing drugs in the follicular phase and P in the luteal phase. CONCLUSIONS: Though a larger study would possibly show a lower pregnancy rate in those women with unexplained infertility empirically treated with P vs the women with ovulation defects, the empirical use of P allows easy treatment without the side-effects of follicle-maturing drugs, e.g., hostile cervical mucus, vasomotor symptoms or ovarian cysts. The study was not designed to determine if empirical use of follicle-maturing drugs with P support for unexplained infertility would be more effective than P supplementation alone.

The effect of diminished oocyte reserve in younger women (age < or = 37) on pregnancy rates in natural cycles.

PURPOSE: To determine the relative confounding effect of diminished oocyte reserve on the chance of successful pregnancy in non-in vitro fertilization-embryo transfer (IVF-ET) cycles. MATERIALS AND METHODS: Matched controlled study comparing pregnancy outcome in women aged < or = 37 years with severely decreased oocyte reserve as manifested by a day 3 serum follicle stimulating hormone (FSH) > or = 15 mIU/ml compared to women with normal oocyte reserve (serum FSH < or = 8 mIU/ml). Couples were excluded if they did not have tubal patency or a semen analysis that required IVF-ET. Only couples that tried at least three natural cycles (unless pregnancy occurred first) were included. RESULTS: The live delivered pregnancy rates within a maximum of five cycles of luteal phase support with progesterone (P) or at most mild FSH stimulation, or intrauterine insemination for mild male factor or cervical factor was 33.3% (8/24) with increased day 3 FSH and 62.5% (16/24) for the normal group (p = 0.08, Fisher's exact test). CONCLUSION: Women with marked oocyte depletion are half as likely to conceive with assisted reproductive techniques compared to women with normal oocyte reserve.

Intrauterine insemination (IUI) does not improve pregnancy rates in infertile couples where semen parameters are normal and postcoital tests are adequate.

PURPOSE: To determine if intrauterine insemination (IUI) improves pregnancy rates in couples with a correctable ovulatory defect but a male partner with an apparent normal semen analysis and a normal postcoital test. MATERIALS AND METHODS: A prospective evaluation of clinical live delivered pregnancy rates following the first cycle where follicular maturation was demonstrated naturally or with a follicle maturing drug. The couples were given the option of IUI. RESULTS: The live delivered pregnancy rates per IUI cycle were similar with intercourse only vs addition of IUI (18.7% vs 21.4%). CONCLUSIONS: There is no evidence to support the notion that IUI improves pregnancy rates in circumstances where the semen analysis and postcoital tests are normal.

Atlantic salmon type I IFN subtypes show differences in antiviral activity and cell-dependent expression: evidence for high IFNb/IFNc-producing cells in fish lymphoid tissues.

This work reveals distinct roles of the two-cysteine-containing type I IFNs, IFNa and IFNd, and the four-cysteine-containing IFNb and IFNc in antiviral immunity of Atlantic salmon. IFNa and IFNc showed similar antiviral activities and ability to induce antiviral genes, IFNb was less active, and IFNd showed no activity. Expression of IFNs was compared by treatment of cells or fish with the dsRNA polyinosinic-polycytidylic acid [poly(I:C)], which induces IFNs via the viral RNA receptors MDA5 and TLR3/TLR22 and with the imidazoquinoline R848, which induces IFNs via TLR7. Poly(I:C) strongly induced IFNa in cell lines, whereas the other IFNs showed little response, indicating that IFNa is the main IFN subtype induced through the RIG-I/MDA5 pathway. In contrast, IFNb and IFNc are the main IFNs induced through the TLR7 pathway because R848 induced high transcript levels of IFNb and IFNc and low transcript levels of IFNa in the head kidney and spleen. IFNd was constitutively expressed in cells and organs but showed no response to poly(I:C) or R848. Fluorescence in situ hybridization studies showed that poly(I:C) induced IFNa and IFNc in a variety of cells in the head kidney, spleen, gills, liver, and heart, whereas R848 induced coexpression of IFNb and IFNc in distinct cells in head kidney and spleen. These cells are likely to be specialized high IFN producers because they were few in numbers despite high IFNb/IFNc transcript levels in the same organs. High IFN expression in response to TLR7 ligation is a feature shared by mammalian plasmacytoid dendritic cells.

The effect of endometriosis on pregnancy outcome following in vitro fertilization-embryo transfer (IVF-ET) in women with decreased egg reserve.

PURPOSE: To determine the effect of the presence of endometriosis on the delivered pregnancy rate following in vitro fertilization-embryo transfer. METHODS: A retrospective cohort analysis of fresh or frozen embryo transfer in women with diminished egg reserve having IVF-ET and who also had had a laparoscopy. The data was analyzed as to whether endometriosis was present or not. RESULTS: The data demonstrated that women with diminished egg reserve can achieve pregnancies following IVF-ET. The presence of endometriosis did not have any negative effects on pregnancy rates. CONCLUSIONS: At least in women with diminished egg reserve the presence of endometriosis did not impair outcome following IVF-ET.

Audiovisual Presentations on a Handheld PC are Preferred As an Educational Tool by NICU Parents.

BACKGROUND: Health literacy is critical for understanding complex medical problems and necessary for the well being of the patient. Printed educational materials (PM) have limitations in explaining the dynamics of a disease process. Multimedia formats may be useful for enhancing the educational process. OBJECTIVE: To evaluate whether a printed format or animation with commentary on a handheld personal computer (PC) is preferred as an educational tool by parents of a baby in the NICU. METHODS: PARENTS EVALUATED TWO FORMATS: A 1-page illustrated document from the American Heart Association explaining patent ductus arteriosus (PDA) and animation with commentary on a handheld PC that explained the physiology of PDA in 1 minute. The reading grade level of the PM was 8.6 versus 18.6 for the audio portion of the animated presentation. Parents viewed each format and completed a four-item questionnaire. Parents rated both formats and indicated their preference as printed, animation, or both. RESULTS: Forty-six parents participated in the survey. Parents preferred animation over PM (50% vs. 17.4%. p = 0.02); 39.1% expressed that the animation was excellent; whereas 4.3% expressed that the PM was excellent (p<0.001). The order of presentation of formats, sex, age, and educational level of parents did not influence the method preferred (p>0.05). CONCLUSION: Parents preferred animation on a small screen handheld PC despite a much higher language level. Because handheld PCs are portable and inexpensive, they can be used effectively at the bedside with low-cost animation to enhance understanding of complex disease conditions.

Microsatellite instability and HPV genotype in Polish women with cervical cancer.

INTRODUCTION: Human papillomaviruses (HPVs) are associated with anogenital cancer. Little is known about the prevalence of microsatellite instability (MSI) in cervical cancer. The aim of this study was to investigate the incidence of microsatellite instability in cervical cancer and to see whether there is a relation between MSI, HPV and clinicopathological characteristics in the study population. RESULTS: Using three assays (pU1M/2R, GP5+/6+ and E6-nested multiplex PCR) HPV was detected in 110 out of 113 patients with histologically confirmed cervical cancer. The presence of MSI was investigated in 95 of the 113 cases using seven microsatellite loci. In total, 12 out of the 95 patients (12.6%) showed MSI. None of clinicopathological parameters showed a significant difference between microsatellite stable and MSI cases. CONCLUSION: In this population of Polish cervical cancer patients, 12.6% showed microsatellite instability. There was no correlation between MSI positivity and clinicopathological parameters and/or survival.

Improved pregnancy outcome for women with decreased ovarian oocyte reserve and advanced reproductive age by performing in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the pregnancy rates with IVF-ET vs non-assisted reproductive technology in women of more advanced reproductive age with decreased egg reserve as manifested by elevated day 3 serum FSH. METHODS: A retrospective evaluation was made in women aged > or = 38 with a day 3 serum FSH of degrees 15 mIU/ml with > or = 1 year of infertility. Another inclusion criterion was three cycles (unless a pregnancy occurred before that time) of either IVF-ET or non-assisted reproductive therapy which as a minimum included luteal phase support with progesterone. RESULTS: The clinical pregnancy rates in three cycles for non-IVF were 11.7% vs 27.2% for IVF. Delivery rates were 2.9% vs 15.1%. For ages 40-42 the clinical pregnancy rates were 37.5% vs 0.0% (p = .02). CONCLUSIONS: Live deliveries are possible in women > or = age 38 with marked decreased egg reserve. In vitro fertilization is more effective than non-IVF when follicle stimulation with gonadotropins is mild.

A disorder of sympathomimetic amines leading to increased vascular permeability may be the etiologic factor in various treatment refractory health problems in women.

There is an evidence that increased capillary permeability in the standing position is related to a deficit in the sympathetic nervous system. The leakage of this fluid leads to various clinical conditions which frequently puzzle the consulting physician because despite the frequency of this condition intelligent physicians and patients are unaware of the cause of their condition. One of the most common manifestations is the inability to lose weight despite proper dieting. A randomized study comparing the efficacy of a diuretic, a converting enzyme inhibitor, spironolactone and a sympathomimetic amine on weight loss in diet refractory women found that only the latter in the form of dextroamphetamine sulfate demonstrated significant weight reduction over a six month time span. In fact, the dextroamphetamine sulfate proved effective when given in the next 6 months to the three groups failing to respond for the first 6 months. The diagnosis of a deficit in sympathomimetic amines is established by demonstrating an abnormal clearance of a water load in the erect position and exclusion of other conditions that are associated with an abnormal free water clearance, e.g., hypothyroidism, renal or liver disease or congestive heart failure. The original definition of an abnormal water load test was excretion of <55% of a 1500 ml water load in 6h but we found that <75% defines a greater population who suffer from this problem. There are several conditions that have proven refractory to conventional theory that respond quickly and effectively to sympathomimetic amines. There have been many anecdotal reports of relieving interactable pain syndromes quickly and efficiently with sympathomimetic amine theory, despite failure with a multitude of other therapies. These include interstitial cystitis and pelvic pain that was attributed to endometriosis, gastrointestinal pain including esophagitis and gastroparesis, headaches, joint pain, fibromyalgia, and carpal tunnel syndrome. It is not clear if the improvement in pain is related to a decrease in fluid retention or a direct effect of the sympathomimetic amines on the sympathetic nervous system. Sympathomimetic amine theory has helped other conditions besides pain, e.g., chronic fatigue, vasomotor symptoms in young women not associated with decreased ovarian egg reserve, and chronic urticaria resistant to all other therapies. Thus, these studies strongly suggest that physicians be aware of this condition involving a deficit in the sympathetic nervous system when faced with various enigmatic complaints especially if standard therapy has not proven effective.

A matched controlled study to evaluate the efficacy of acupuncture for improving pregnancy rates following in vitro fertilization-embryo transfer.

PURPOSE: To determine if acupuncture performed during the follicular phase and luteal phase but not on the day of embryo transfer could improve the outcome following IVF-ET compared to controls. METHODS: Acupuncture was started biweekly from day 5 of the follicular phase through the luteal phase but not on the day of the transfer. Controls were matched according to age, same number of previous failed IVF cycles and same type of embryo transfer (fresh or frozen). RESULTS: The clinical and ongoing (delivered pregnancy rates per transfer) for 32 women undergoing IVF-ET and acupuncture was 40.6% and 37.5%, respectively vs 53.1% and 43.7% for controls. The median number of previous failed IVF cycles was three. CONCLUSIONS: Acupuncture performed twice weekly during the follicular and luteal phase does not seem to improve pregnancy rates following IVF-ET.

Survival of 231 cervical cancer patients, treated by radical hysterectomy, according to clinical and histopathological features.

PURPOSE OF INVESTIGATION: The purpose of the study was to estimate the five-year survival of cervical cancer patients after radical hysterectomy, taking into account clinical data and histopathological parameters. METHODS: 231 patients with invasive cervical carcinoma were diagnosed, surgically treated--Piver III--and followed-up. Histological examination of specimens was performed according to the British NHS-CSP guidelines. RESULTS: We discovered no statistical significance as regards age at diagnosis, age at menarche and menopause, and number of pregnancies, deliveries and abortions, in relation to survival. We concluded that the clinical stage according to FIGO classification influenced survival. Statistical significances were: Ia2 vs Ib, Ib vs IIa and IIa vs more advanced than IIa. The following histopathological parameters correlated with survival: depth of cervical invasion, primary lesion volume, and parametrial, uterine, vaginal and lymph node involvement. Using Cox's proportional hazards model we found that only lymph node status and FIGO staging were independent parameters correlating with survival and mortality risk in our study. CONCLUSION: Prognostic indexes classifying patients at specific disease stages into different categories of risk should be based on histopathological features listed above. Such indexes are yet to be validated in larger, prospective studies conducted in different patient populations.

Leukocyte immunotherapy improves live delivery rates following embryo transfer in women with at least two previous failures: a retrospective review.

PURPOSE: To determine whether leukocyte immunotherapy (LIT) could improve live delivery rate following embryo transfer (ET) in women who were not successful in prior attempts. METHODS: Paternal leukocytes were intradermally injected in some women who had failed to have a successful pregnancy following at least two prior ETs approximately two weeks prior to fresh or frozen ET and repeated at the time of the 3rd rising serum beta human chorionic gonadotropin level and at eight weeks if a pregnancy occurred. Clinical pregnancy and live pregnancy rates (PRs) were compared to those women having ETs during the same time period not receiving LIT. RESULTS: Thirty-six of 94 (38.3%) patients receiving LIT (group 1) conceived following fresh or frozen ET vs 98 of 341 (28.7%) for women not receiving LIT (group 2) (p = NS). The live delivery rate per ET cycle was 30.8% (39/94) vs 19.7% for group 2 (p = .02). For the subset of women failing despite five previous ETs 17 of 37 (45.9%) group 1 women had a clinical pregnancy vs 18 of 64 (28.1%) group 2 women (p = .07%) and live delivery rates were 35.1% (13/37) vs 15.6% (10/64) (p = .024). CONCLUSIONS: These retrospective data encourage a prospective study of LIT combined with progesterone vs controls receiving progesterone only for recalcitrant patients having ETs.