KAT6A mutations in Arboleda-Tham syndrome drive epigenetic regulation of posterior HOXC cluster.

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone-acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene-body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types.

Seal bomb explosion sound source characterization.

Small explosive charges, called seal bombs, used by commercial fisheries to deter marine mammals from depredation and accidental bycatch during fishing operations, produce high level sounds that may negatively impact nearby animals. Seal bombs were exploded underwater and recorded at various ranges with a calibrated hydrophone to characterize the pulse waveforms and to provide appropriate propagation loss models for source level (SL) estimates. Waveform refraction became important at about 1500 m slant range with approximately spherical spreading losses observed at shorter ranges. The SL for seal bombs was estimated to be 233 dB re 1 µPa m; however, for impulses such as explosions, better metrics integrate over the pulse duration, accounting for the total energy in the pulse, including source pressure impulse, estimated as 193 Pa m s, and sound exposure source level, estimated as 197 dB re 1 µPa2 m2 s over a 2 ms window. Accounting for the whole 100 ms waveform, including the bubble pulses and sea surface reflections, sound exposure source level was 203 dB re 1 µPa2 m2 s. Furthermore, integrating the energy over an entire event period of multiple explosions (i.e., cumulative sound exposure level) should be considered when evaluating impact.

[Remarkable medical advances in rheumatology : may be ]. / Une révolution thérapeutique en rhumatologie : oui, mais .

The development of new drugs is a significant activity in a university hospital that favors access to therapeutic novelties to patients. Rheumatology, whose drug armamentarium was poor in the 1980s, has benefited from the huge progresses of immunology in the 1980-1990s, allowing a therapeutic revolution in whom the academic hospital of Liège (CHU Liège) has been strongly implicated. First protocols with anti-TNF-? monoclonal antibodies have been applied in 1997. Sixty-one protocols have been initiated in rheumatoid arthritis, 12 in ankylosing spondylitis, 10 in psoriatic arthritis, 9 in systemic erythematosus lupus, 3 in giant cell arteritis, 1 in polymyalgia rheumatica, 5 in osteoarthritis and 4 in osteoporosis. Potential and pitfalls will be discussed disease by disease and also by drug categories. The balance remains globally positive, but remission is far from be reached.

La recherche clinique médicamenteuse est une activité importante dans un hôpital universitaire. Elle valide des nouveautés thérapeutiques et fait bénéficier les patients de traitements novateurs bien avant leur mise sur le marché. La rhumatologie est une discipline dont l'arsenal thérapeutique était pauvre dans les années 1980, et les immenses progrès de l'immunologie, réalisés entre 1980 et 1995, lui ont permis de vivre une véritable révolution thérapeutique à laquelle notre service a amplement participé. C'est en 1997 que les premiers traitements par anticorps monoclonaux anti-TNF-? (les traitements dits biologiques) ont été utilisés au CHU de Liège. Soixante et une études seront initiées dans la polyarthrite rhumatoïde, 12 dans la spondylarthrite ankylosante, 10 dans la polyarthrite psoriasique, 9 dans le lupus érythémateux disséminé, 3 dans l'artérite temporale de Horton, une dans la pseudopolyarthrite rhizomélique, une dans la sclérodermie, 5 dans l'arthrose, 4 dans l'ostéoporose. Les espoirs et les déceptions observées dans les différentes indications, et avec les différentes molécules, sont analysées. Le bilan est globalement positif, mais les résultats encore insuffisants que pour arriver au concept de rémission.

[General medical practice and medicinal voluntary termination of pregnancy in Grand Est, France]. / Médecine générale de ville et interruption volontaire de grossesse médicamenteuse en région Grand Est, France.

BACKGROUND: Access to VTOP (Voluntary Termination of Pregnancy) is a national priority in France. Once legalized in 1975, several laws contributed to improve access to VTOP, such as the 2004 family planning law which enabled urban practitioners to carry out orthogenic work. This law was supplemented by the 2016 health care modernization act. On the whole, the organization for VTOP access in the Grand Est region, complies with legislation and recommendations. However, private practitioners contribute little to this activity. Since there are very few gynecologists in certain areas (whether private or hospital practitioners), general practitioners seem to be the first line actors. This study aims at describing the orthogenic work of urban, government-regulated general practitioners, in the Grand Est region of France. MATERIAL AND METHOD: Data were collected from semi-directive interviews with the set of the government-regulated general practitioners doing family planning work in the Grand Est region. RESULTS: Out of the fifteen doctors who were interviewed, twelve actually suggested family planning work to their patients, and out of those twelve, seven practiced it in reality. What comes out is that the main motivation of professionals was to improve access to VTOP. Besides, they also mentioned the importance of being able to answer a real demand from their patients as well as an interest in gynecology. Hence the professionals' practice both benefits from services provided to their patients and from a diversification of their work, even though they regret that the value of this time-consuming procedure is not recognized. This study also brings out that although these medical acts were individualized and allowed better confidentiality for the patient, the risk for complications and home birth remained an obstacle. Finally, it emerges that the whole set of recommendations was not always implemented. DISCUSSION: Urban family planning, performed by general practitioners, seems to be a major line to focus on for better timeliness and quality of care. However, some obstacles have been identified such as its specificity, its time-consuming aspect, its lack of status, as well as the difficulty to comply with recommendations. CONCLUSION: The development of this practice is necessary to maintain an appropriate response to VTOP but actions to remove certain obstacles have to be carried out.

Safety and collection efficiency with a lower transfusion threshold for extracorporeal photopheresis in adult patients with graft-versus-host disease.

BACKGROUND: Extracorporeal photopheresis (ECP) is an established treatment for graft-versus-host disease (GVHD). Various haematocrit thresholds have been used to trigger red blood cells transfusion prior to ECP. Moderate-to-severe GVHD is frequently complicated by anaemia; the safety and collection efficiency with a lower haematocrit for ECP is unknown. METHODS: We prospectively enrolled 26 consecutive adult GVHD patients with haematocrits between 25% and 28·9% who received ECP on the CELLEX system. Preprocedural transfusion was withheld. We monitored the adverse events and transfusions avoided. A complete blood cell count with differential was performed on preprocedural peripheral blood and buffy coat collected. Lymphocyte fold enrichment (LFE) was compared between this cohort and two historical control groups with haematocrits of 29% or higher. RESULTS: Red Blood Cells transfusion was avoided in the lower-haematocrit cohort without adverse events. The median LFE was 4·5 (95%CI, 3·1-5·7) in the lower-haematocrit cohort and 5·2 (95%CI, 4·1-6·5) in the higher-haematocrit CELLEX-treated control group. The median difference was 0·7 (95%CI, -0·3 to 2·0, P = 0·14). It could not be established that the lower-haematocrit cohort was non-inferior to the higher-haematocrit control group with a prespecified non-inferiority margin of 1·3. However, LFE was significantly higher in the lower-haematocrit cohort than the higher-haematocrit UVAR XTS-treated control group (P < 0·01). CONCLUSION: Buffy coat can be collected for ECP using CELLEX in GVHD patients with a haematocrit of 25% or higher, with a collection efficiency superior to that in patients with higher haematocrits but treated using UVAR XTS. No increase in adverse events was observed at these lower haematocrits.

Pregnancy after intracytoplasmic sperm injection following extended sperm preparation and hormone therapy in an azoospermic man with maturation arrest and microlithiasis: a case report and literature review.

In the management of azoospermia, a combination of testicular sperm extraction and intracytoplasmic sperm injection (ICSI) is usually the most successful option for fatherhood. However, an outstanding question remains: How can at least a few spermatozoa be obtained from the ejaculate, thus avoiding the need for a surgical procedure? A 36-year-old man presented to Assisted Reproduction Unit with his 26-year-old wife. The ultrasound assessment revealed bilateral microlithiasis. Two spermograms revealed absolute azoospermia. Levels of follicle-stimulating hormone (FSH) and luteinising hormone were normal-low. The patient underwent 10 months of treatment with clomiphene citrate. A bilateral testicular sperm extraction failed to retrieve spermatozoa and revealed a maturation arrest at spermatocyte/spermatid stages depending on the tubules. Clomiphene citrate was replaced with recombinant FSH (rFSH). After 9-month treatment with rFSH, motile spermatozoa from droplets of ejaculate pellet were cryopreserved as a single straw. Ovarian stimulation was provided using classic antagonist protocol, and five mature oocytes were collected. Two consecutive fresh semen samples on the day of ICSI yielded seven motile spermatozoa, and fertilisation was achieved in all five oocytes. On day 3, two embryos were transferred, yielding positive beta-human chorionic gonadotropin and a healthy delivery of a boy and a girl.

Improving verb anomia in the semantic variant of primary progressive aphasia: the effectiveness of a semantic-phonological cueing treatment.

The semantic variant of primary progressive aphasia (svPPA) is known to affect the comprehension and production of all content words, including verbs. However, studies of the treatment of anomia in this disorder focused on relearning object names only. This study reports treatment of verb anomia in an individual with svPPA. The semantic-phonological cueing therapy resulted in significant improvement in naming abilities, for treated verbs only. This case study demonstrates that improvement in verb-naming abilities may be possible in svPPA. The almost complete maintenance of the treatment's effects in the patient 4 weeks after the end of the therapy also suggests improvements may be durable, at least in the short term, for some individuals with svPPA.

Molecular definition of breast tumor heterogeneity.

Cells with distinct phenotypes including stem-cell-like properties have been proposed to exist in normal human mammary epithelium and breast carcinomas, but their detailed molecular characteristics and clinical significance are unclear. We determined gene expression and genetic profiles of cells purified from cancerous and normal breast tissue using markers previously associated with stem-cell-like properties. CD24+ and CD44+ cells from individual tumors were clonally related but not always identical. CD44+ cell-specific genes included many known stem-cell markers and correlated with decreased patient survival. The TGF-beta pathway was specifically active in CD44+ cancer cells, where its inhibition induced a more epithelial phenotype. Our data suggest prognostic relevance of CD44+ cells and therapeutic targeting of distinct tumor cell populations.

A randomized, placebo-controlled trial of melatonin on breast cancer survivors: impact on sleep, mood, and hot flashes.

The purpose is to examine the effects of melatonin supplementation on sleep, mood, and hot flashes in postmenopausal breast cancer survivors. In a randomized, double-blind, placebo-controlled study, 95 postmenopausal women with a prior history of stage 0-III breast cancer, who had completed active cancer treatment (including hormonal therapy) were randomly assigned 1:1 to either 3 mg oral melatonin (n = 48) or placebo daily (n = 47) for 4 months. Sleep, mood, and hot flashes were assessed at baseline and 4 months via self-administered questionnaire using the Pittsburgh Sleep Quality Index (PSQI), Center for Epidemiologic Studies-Depression (CES-D), and the North Central Cancer Treatment Group (NCCTG) hot flash diary, respectively. Eighty-six women (91 %) completed the study and provided pre- and post-questionnaires. At baseline, 52 % of participants reported poor sleep in the month prior to enrollment. Compared to subjects on placebo, subjects randomized to melatonin experienced significantly greater improvements in subjective sleep quality as measured by the PSQI, including domains on sleep quality, daytime dysfunction and total score. For example, the mean change in PSQI score was -0.1 in the placebo group compared to -1.9 in the melatonin group (p < 0.001). There were no significant differences in measures of depression or hot flashes. Sleep disturbances are common among breast cancer survivors, even after completion of active cancer treatment. This is the first randomized placebo-controlled study among breast cancer survivors to demonstrate that melatonin was associated with an improvement in subjective sleep quality, without any significant adverse effects.

Impact of the 2nd, 3rd and 4th waves of the COVID-19 pandemic on wait times in head and neck cancer: A retrospective study in a French expert center.

BACKGROUND: Treatment delay in head and neck cancer is a major problem, with impact on survival. The COVID-19 (coronavirus disease 2019) pandemic, evolving in waves around the world, caused diagnostic and therapeutic delays in certain cancers. The main objective of the present study was to analyze whether there was a change in wait times during three successive waves in our center. METHOD: This was a single-center retrospective study of patients with a first diagnosis of head and neck cancer. Three groups, corresponding to waves 2, 3 and 4, were compared to a control group corresponding to a pre-pandemic period. Study data comprised median times between first consultation and tumor board meeting (C1-TB) and between tumor board meeting and treatment (TB-T). The significance threshold was set at P<0.005. RESULTS: Ninety-six patients were included in the control group, and 154 in the "waves 2-3-4" group. There was no increase in C1-TB interval (respectively 35 and 26days, P=0.046) or TB-T interval (respectively 27 and 28days, P=0.723). CONCLUSION: Intervals between first consultation and tumor board meeting and between tumor board meeting and treatment did not increase during the 2nd, 3rd and 4th waves of COVID-19 in our center.

Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes.

PURPOSE: We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: We recruited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of 1 hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. RESULTS: There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). CONCLUSIONS: We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study.

Cognitive rehabilitation in multiple sclerosis.

Cognitive impairments are frequent in multiple sclerosis (MS). However, most studies about efficacy of cognitive rehabilitation interventions have been criticized in terms of methods and/or design. The aim of this study is to evaluate the efficacy of cognitive rehabilitation in MS patients with a cognitive intervention (ProCogSEP* program), compared to a control intervention (discussion program). Twenty MS patients have completed this simple blind study: 10 patients followed 13 sessions (2 hours) of the ProCog-SEP(1) program. Ten other patients followed 13 sessions (2 hours) of a discussion program (Control Group). All patients underwent neuropsychological assessment, before and after their program, in order to evaluate cognitive functions. Two neuropsychologists respectively assessed the patients and conducted the group sessions. Compared to its own baseline, ProCog-SEP Group show improvements in verbal memory [free recall (p = .02), learning (p = .002)], in visual memory [free (p = .05) and delayed recall (p = .007)], in working-memory (p = .03), in verbal fluency (p = .05) and in language (p = .01). Inter group analysis show a benefit of cognitive program mainly in verbal and visual memory, and in verbal fluencies. These results support the interest of a cognitive therapeutic management of MS patients.

Internalized weight bias: ratings of the self, normal weight, and obese individuals and psychological maladjustment.

Current measures of internalized weight bias assess factors such as responsibility for weight status, mistreatment because of weight, etc. A potential complementary approach for assessing internalized weight bias is to examine the correspondence between individuals' ratings of obese people, normal weight people, and themselves on personality traits. This investigation examined the relationships among different measures of internalized weight bias, as well as the association between those measures and psychosocial maladjustment. Prior to the beginning of a weight loss intervention, 62 overweight/obese adults completed measures of explicit and internalized weight bias as well as body image, binge eating, and depression. Discrepancies between participants' ratings of obese people in general and ratings of themselves on both positive and negative traits predicted unique variance in measures of maladjustment above a traditional assessment of internalized weight bias. This novel approach to measuring internalized weight bias provides information above and beyond traditional measures of internalized weight bias and begins to provide insights into social comparison processes involved in weight bias.

Pyrocarbon interposition implant after lunate resection in Kienböck's disease: A case series.

In advanced stages of Kienböck's disease, the lunate is no longer conservable. One of the surgical options is to resect the lunate and replace it with a prosthesis. The procedure consisted in lunate resection and interposition of a free APSI® or Pi2® pyrocarbon implant through a dorsal approach. Follow-up was clinical and radiological on QuickDASH and PRWE scores. At a median follow-up of 3 years, 12 patients were reviewed, with a median age of 56 years. Flexion significantly decreased from 42° to 28° (p < 0.01). Extension and pronation-supination were conserved. Strength was 94% compared to the opposite side, with no significant difference from the preoperative measurement. Median QuickDASH and PRWE scores were 15.9 and 23.5 respectively and had significantly improved. One patient underwent scaphocapitate fusion because she was still in pain; the other patients were pain-free. No patients had to change jobs because of their wrist. Radiographically, there was no carpal collapse and carpal height was conserved. Radioscaphoid angle and ulnar translation were stable. There was 1 case of asymptomatic implant dislocation. Interposition of a pyrocarbon implant after lunate resection in advanced Kienböck's disease is a motion-conserving procedure that provides pain relief and functional recovery in the short and medium term. LEVEL OF EVIDENCE: IV.

Design of disintegrable nanoassemblies to release multiple small-sized nanoparticles.

The therapeutic and diagnostic effects of nanoparticles highly depend on the efficiency of their delivery to targeted tissues, such as tumors. The size of nanoparticles, among other characteristics, plays a crucial role in determining their tissue penetration and retention. Small nanoparticles may penetrate deeper into tumor parenchyma but are poorly retained, whereas large ones are distributed around tumor blood vessels. Thus, compared to smaller individual nanoparticles, assemblies of such nanoparticles due to their larger size are favorable for prolonged blood circulation and enhanced tumor accumulation. Upon reaching the targeted tissues, nanoassemblies may dissociate at the target region and release the smaller nanoparticles, which is beneficial for their distribution at the target site and ultimate clearance. The recent emerging strategy that combines small nanoparticles into larger, biodegradable nanoassemblies has been demonstrated by several groups. This review summarizes a variety of chemical and structural designs for constructing stimuli-responsive disintegrable nanoassemblies as well as their different disassembly routes. These nanoassemblies have been applied as demonstrators in the fields of cancer therapy, antibacterial infection, ischemic stroke recovery, bioimaging, and diagnostics. Finally, we summarize stimuli-responsive mechanisms and their corresponding nanomedicine designing strategies, and discuss potential challenges and barriers towards clinical translation.

Radiological and functional correlation following "SLIC" scapholunate-intercarpal ligamentoplasty at minimum 12 months' follow-up.

We report outcomes for scapholunate-intercarpal ligamentoplasty ("SLIC procedure"), performed in 22 patients (mean age at surgery, 39.7 years), for reducible static scapholunate (SL) instability without repairable stump. Patients were evaluated for pain and active wrist range of motion, grip strength, functional scores (QuickDASH and PRWE) and radiological appearance (SL gap, SL angle, radiolunate angle, capitolunate angle), preoperatively and at a mean 28.3 months' follow-up (range 12-65). A CT scan without injection was performed at follow-up to measure the posterior radioscaphoid angle (PRSA). The objective was to assess radiological-functional correlations after SLIC ligamentoplasty and to analyze postoperative PRSA correction. The hypothesis was that correcting the PRSA improves clinical and functional outcomes. Pain on a visual analog scale improved significantly, from 2.7 to 0.7 at rest and from 7 to 3.2 during hand use. Mean wrist flexion was 46.4° and extension 59.1°. Grip strength reached 82.8% of the contralateral value. Functional scores improved significantly. Mean SL angle decreased significantly from 81.1° to 73.5°, and static scapholunate gap from 4.7 mm to 3.6 mm. Scaphoid subluxation was fully corrected in 15 cases (68%). PRSA angle was significantly corrected, from a mean 112.7° to 104.2°. Patients in whom PRSA was corrected showed a tendency for better clinical and subjective outcomes. There was 1 case of scaphoid necrosis, 7 of recurrent static instability, including 3 early at 4 months, 3 of scaphocapitate osteoarthritis, and 5 of carpal collapse with SLAC wrist. There were no significant correlations between clinical and radiological results in the medium term after SL ligamentoplasty by the SLIC procedure. The results were quite good in the medium term and pointed to the importance of correcting rotatory subluxation of the scaphoid, revealed by the PRSA, more than correcting the scapholunate gap.

Arthroplasty for destroyed proximal interphalangeal joint in hand trauma surgery: Silicone hinged NeuFlex® or gliding Tactys®?

The treatment of proximal interphalangeal joints (PIP) after a traumatic injury has produced disappointing outcomes. The objective of this study was to evaluate the functional results of emergency hinged or gliding arthroplasty for destroyed PIP joints. A two-center retrospective study was carried out in 24 patients with open and closed trauma of the PIP joint of the fingers from 2007 to 2019. Fifteen hinged silicone implants (NeuFlex®) and nine gliding implants (Tactys®) were used. Pain on a visual analog scale (VAS), stability and total active motion (TAM), grip and pinch strength (Jamar®), QuickDASH and PRWE and satisfaction were assessed, and X-rays were performed. With a mean follow-up of 48 months, 24 patients aged 58 years on average were reviewed. Pain on VAS was 0.2/10, the TAM was 72% of the contralateral side, the QuickDASH was 15.6/100 and the PRWE was 24.5/100. PIP flexion was ≥50% of the contralateral side in 75% of patients. PIP and DIP extensor lag of 9° was significantly larger with the Tactys® than with the NeuFlex®, with no significant difference in the TAM. Three clinodactylies in fingers with the NeuFlex® and three reducible swanneck deformities in fingers with the Tactys® were noted. Three-quarters of patients were very satisfied or satisfied with the outcome. Emergency PIP arthroplasty with Tactys® seems to provide functional results that are as good as with NeuFlex®. Clinodactyly was found with NeuFlex® use. A significant PIP and IPD extensor lag of 9° and swan-neck deformities were found with Tactys® without significant functional impairment.

Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome.

BACKGROUND: In men with chronic prostatitis-chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis-chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score. RESULTS: A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, -11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar. CONCLUSIONS: Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis-chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.)

Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned.

PURPOSE: We evaluated the efficacy and tolerability of mycophenolate mofetil in patients with treatment refractory interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A total of 210 patients with interstitial cystitis/painful bladder syndrome were to be randomized into a multicenter, placebo controlled trial using a 2:1 randomization. Participants in whom at least 3 interstitial cystitis/painful bladder syndrome specific treatments had failed and who had at least moderately severe symptoms were enrolled in a 12-week treatment study. The primary study end point was the global response assessment. Secondary end points were general and disease specific symptom questionnaires, and voiding diaries. RESULTS: Only 58 subjects were randomized before a black box warning regarding mycophenolate mofetil safety was issued by the manufacturer in October 2007. The trial was halted, and interim analysis was performed and presented to an independent data and safety monitoring board. Six of the 39 subjects (15%) randomized at study cessation were considered responders for mycophenolate mofetil compared to 3 of 19 controls (16%, p=0.67). Secondary outcome measures reflected more improvement in controls. CONCLUSIONS: In a randomized, placebo controlled trial that was prematurely halted mycophenolate mofetil showed efficacy similar to that of placebo to treat symptoms of refractory interstitial cystitis/painful bladder syndrome. The results of this limited study cannot be used to confirm or refute the hypothesis that immunosuppressive therapy may be beneficial to at least a subgroup of patients with interstitial cystitis/painful bladder syndrome. Despite study termination lessons can be gleaned to inform future investigations.

Diagnosis of polycystic ovary syndrome (PCOS): revisiting the threshold values of follicle count on ultrasound and of the serum AMH level for the definition of polycystic ovaries.

BACKGROUND: Polycystic ovarian morphology (PCOM) at ultrasound is currently used in the diagnosis of polycystic ovary syndrome (PCOS). We hypothesized that the previously proposed threshold value of 12 as an excessive number of follicles per ovary (FN) is no longer appropriate because of current technological developments. In this study, we have revisited the thresholds for FN and for the serum Anti-Müllerian hormone (AMH) level (a possible surrogate for FN) for the definition of PCOM. METHODS: Clinical, hormonal and ultrasound data were consecutively recorded in 240 patients referred to our department between 2008 and 2010 for exploration of hyperandrogenism (HA), menstrual disorders and/or infertility. RESULTS: According to only their symptoms, patients were grouped as: non-PCOS without HA and with ovulatory cycles (group 1, n = 105), presumption of PCOS with only HA or only oligo-anovulation (group 2, n = 73) and PCOS with HA and oligo-anovulation (group 3, n = 62). By cluster analysis using androgens, LH, FSH, AMH, FN and ovarian volume, group 1 appeared to be constituted of two homogeneous clusters, most likely a non-PCOM non-PCOS subgroup (n = 66) and a PCOM, non-PCOS (i.e. asymptomatic) subgroup (n = 39). Receiver operating characteristic curve analysis was applied to distinguish the non-PCOM non-PCO members of group 1 and to group 3. For FN and serum AMH respectively, the areas under the curve were 0.949 and 0.973 and the best compromise between sensitivity (81 and 92%) and specificity (92 and 97%) was obtained with a threshold values of 19 follicles and 35 pmol/l (5 ng/ml). CONCLUSIONS: For the definition of PCOM, the former threshold of >12 for FN is no longer valid. A serum AMH >35 pmol/l (or >5 ng/ml) appears to be more sensitive and specific than a FN >19 and should be therefore included in the current diagnostic classifications for PCOS.