Monitoring CD27+ memory B-cells in neuromyelitis optica spectrum disorders patients treated with rituximab: Results from a bicentric study.

BACKGROUND: Rituximab (RTX) is increasingly used in the treatment of neuromyelitis optica spectrum disorder (NMO-SD). Administration regimen is not consensual as there is no reliable biomarker of RTX efficacy. In most cases, after induction, RTX is administered systematically every 6months. OBJECTIVE: To assess efficacy and safety of a maintenance regimen based on CD19+ CD27+ memory B-cell (mBc) detection. METHODS: We conducted a study in two French centers, including patients with NMO-SD who received an induction therapy with RTX. We compared the number of administered infusions, relapses and EDSS depending on two maintenance schemes (S1: administration of 1g RTX infusion every 6months or S2: a scheme based on regular mBc detection. 1g RTX was administered if mBc was >0.05%) RESULTS: 40 patients were included (mean age: 40.2years, F/M sex ratio: 5/1). Aquaporin-4 antibodies were positive in 75% patients. Under S1 regimen, all patients received 2 infusions per year, whereas under S2, they received 1.62 infusion per year. The mean interval between infusions under S2 was 7.4months, without decrease of clinical efficacy. CONCLUSION: In our study, mBc-based administration of RTX allowed personalizing treatment administration and in several cases to lower the cumulative dose without loss of efficacy.

Rheumatologic Manifestations of Hematologic Neoplasms.

BACKGROUND: The rheumatologic manifestations of hematologic neoplasms are a collection of diverse syndromes. This review aims to describe the most common syndromes in the context of potential mechanisms of pathogenesis. METHODS: We undertook a structured search of the available peer-reviewed literature describing paraneoplastic phenomena associated with hematologic neoplasms and the most current literature on the biology of inflammation and neoplasm. RESULTS: This review describes the common rheumatologic manifestations and discusses their possible underlying pathogenesis. CONCLUSIONS: This review describes common clinical features of paraneoplastic phenomena prevalent in hematologic malignancies that may help differentiate them from primary rheumatologic disease and discusses the most current understanding of underlying pathogenesis with a specific focus on the biology of inflammation in neoplastic transformation.

Peripheral blood stem cells collection on spectra optia apheresis system using the continuous mononuclear cell collection protocol: A single center report of 39 procedures.

BACKGROUND: The aim of the study was to assess the performance of the new Continuous Mononuclear Cell Collection (CMNC) protocol on the Spectra Optia Apheresis System for collecting autologous Peripheral Blood Stem Cells (PBSC) in adult patients with respect to collection variables, CD34+ cells harvest prediction and engraftment data. In this retrospective study, 39 CMNC procedures on 23 mobilized patients with multiple myeloma and lymphoma were analyzed. CD34+ cells and blood cells yields, collection efficiencies (CE1 and CE2), cell losses were calculated. Engraftment data of 17 autologous transplantations were collected. RESULTS: Apheresis duration was 239 min for a product volume of 220 mL. Cell product haematocrit, MNC and platelets counts were acceptable (respectively 2.4%, 65%, 834 x 109/L). Median platelet loss was 27.3%. Median CD34+ CE1 and CE2 were 64.6% and 48.5% respectively. We harvested 2.92 × 106 CD34+ cells/kg, with a CD34 dose ≥ 2 × 106 /kg for 67% of the procedures. Linear correlation between preapheresis CD34 count and the CP CD34 dose/kg allowed a prediction model with a decrease trend for high WBC precount. Procedures were well tolerated. For 17 autologous transplantations, median time to neutrophils and platelets reconstitutions were 12 and 13 days respectively. CONCLUSIONS: Spectra Optia CMNC protocol successfully collected CD34+ cells with yields permitting the harvest of sufficient enriched grafts for autologous transplantation. The CD34+ cell yield prediction was excellent. PBSC collection with CMNC protocol had advantages of high processing rate, low product volume, and acceptable contamination by platelets. J. Clin. Apheresis 32:182-190, 2017. © 2016 Wiley Periodicals, Inc.

Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors.

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

Hollow viscus injury due to blunt trauma: A review.

Blunt abdominal trauma results in injury to the bowel and mesenteries in 3-5% of cases. The injuries are polymorphic including hematoma, seromuscular tear, perforation, and ischemia. They preferentially involve the small bowel and may result in bleeding and/or peritonitis. An urgent laparotomy is necessary if there is evidence of active bleeding or peritonitis at the initial examination, but these situations are uncommon. The main diagnostic challenge is to promptly and correctly identify lesions that require surgical repair. Diagnostic delay exceeding eight hours before surgical repair is associated with increased morbidity and probably with mortality. Because of this risk, the traditional therapeutic approach has been to operate on all patients with suspected bowel or mesenteric injury. However, this approach leads to a high rate of non-therapeutic laparotomy. A new approach of non-operative management (NOM) may be applicable to hemodynamically stable patients with no signs of perforation or peritonitis, and is being increasingly employed. This attitude has been described in several recent studies, and can be applied to nearly 40% of patients. However, there is no consensual agreement on which criteria or combination of clinical and radiological signs can insure the safety of NOM. When NOM is decided upon at the outset, very close monitoring is mandatory with repeated clinical examinations and interval computerized tomography (CT). Larger multicenter studies are needed to better define the selection criteria and modalities for NOM.

Circulating microRNAs in follicular fluid, powerful tools to explore in vitro fertilization process.

Circulating or "extracellular" microRNAs (miRNAs) detected in biological fluids, could be used as potential diagnostic and prognostic biomarkers of several disease, such as cancer, gynecological and pregnancy disorders. However, their contributions in female infertility and in vitro fertilization (IVF) remain unknown. This study investigated the expression profiles of five circulating miRNAs (let-7b, miR-29a, miR-30a, miR-140 and miR-320a) in human follicular fluid from 91 women with normal ovarian reserve and 30 with polycystic ovary syndrome (PCOS) and their ability to predict IVF outcomes. The combination of FF miR-30a, miR-140 and let-7b expression levels discriminated between PCOS and normal ovarian reserve with a specificity of 83.8% and a sensitivity of 70% (area under the ROC curve, AUC = 0.83 [0.73-0.92]; p < 0.0001). FF samples related to low number of mature oocytes (≤2) contained significant less miR-320a levels than those related to a number of mature oocytes >2 (p = 0.04). Moreover, FF let-7b predicted the development of expanded blastocysts with 70% sensitivity and 64.3% specificity (AUC = 0.67 [0.54-0.79]; p = 0.02) and FF miR-29a potential to predict clinical pregnancy outcome reached 0.68 [0.55-0.79] with a sensitivity of 83.3% and a specificity of 53.5% (p = 0.01). Therefore, these miRNAs could provide new helpful biomarkers to facilitate personalized medical care during IVF.

[Antenatal palliative plan following diagnosis of fetal lethal condition: Rennes Teaching Hospital experience]. / Projet palliatif anténatal après diagnostic de malformation fœtale létale : expérience du CHU de Rennes de 2006 à 2012.

OBJECTIVES: To study the pregnancies followed at Rennes University Hospital from 2006 to 2012, after prenatal diagnosis of lethal fetal condition and prenatal project of palliative care at birth consisting of comfort care emphasizing parent-child encounters and bonding. MATERIAL AND METHODS: Retrospective study of 20 pregnancies with diagnosis of lethal fetal condition where parents accepted antenatally the proposal or sought for palliative care at birth. RESULTS: Diagnosis was made at a median age of 20 weeks gestation (12-33). Birth occurred at 37.4 WG, 6 caesarean sections were performed for maternal conditions. Six cases of hypoplastic left heart syndrome (HLHS) share common characteristics: good Apgar score, prolonged survival (26hours to 159days) transfer to neonatology ward (6) or later at home (4). In four multiple pregnancies, the choice of SP mainly contributed to protect healthy twins during pregnancy. In birth room, there was no need for invasive procedure or drugs. Death: one occurred during labor, 8 in birth room before H2, others in neonatal ward before d4 (excluding HLHS). CONCLUSION: These data will enable better antenatal preparation of both teams and parents. Lifetime, however short, allowed parents to meet with their child alive this permitting collection of memory traces and bonding.

[Oncofertility program at the Montpellier university hospital 2 years after]. / Programme de préservation de la fertilité féminine au CHRU de Montpellier 2ans après.

OBJECTIVE: Female fertility preservation in the context of cancer management is crucial for patient's health care. The aim of this study was to evaluate the oncofertility practice at our university hospital of Montpellier since 2011. PATIENTS AND METHODS: The evaluation of management of young patients referred to Montpellier University Hospital from September 2011 to September 2013 for oncofertility counselling before cancer treatment. RESULTS: Seventy-one patients were referred to a specialized oncofertility center. Forty-two patients (59.1%) were included in the oncofertility program. Twenty-two patients (31%) were proposed for oocyte vitrification after COS protocol, eight patients (11.3%) for ovarian tissue cryoconservation, seven patients (9.9%) for GnRH injections, three patients (4.2%) ovarian transposition and two patients (2.8%) for embryo cryopreservation. Among the 42 indications of fertility preservation, only 18 will have finally taken place. CONCLUSION: Oncofertility counselling for young patients should now be part of the cancer management. It involves multidisciplinary teams. Further information of both oncologists and patients is needed to improve this new approach in the field of cancer treatments.

Pancreatic neuroendocrine tumor: A multivariate analysis of factors influencing survival.

BACKGROUND: The outcomes of pancreatic neuroendocrine tumors are extremely diverse, and determining the best strategy, optimal timing of therapy and the therapeutic results depend on understanding prognostic factors. We determined the clinical, radiological and histological factors associated with survival and tumor recurrence for patients with pancreatic neuroendocrine tumor. METHODS: From January 1, 1991 to December 31, 2011, 127 patients with pancreatic neuroendocrine tumor underwent pancreatectomy. The variables including clinical characteristics, surgical data and pathological findings were examined by univariate and multivariate analyses. RESULTS: There were 103 patients with non-functional tumors (81%). Sixty-four patients (50%) underwent left pancreatectomy, 51 (42%) patients underwent pancreatico-duodenectomy, 12 (9%) patients underwent enucleation and 2 patients (1%) underwent central pancreatectomy. Forty-eight patients (38%) had synchronous liver metastases. Six patients (5%) required portal vein resection, and 19 (15%) patients required enlarged "en-bloc" resection of adjacent organs. The overall morbidity and mortality rates were 48% and 2.3%, respectively. The 1-, 3- and 5-year overall survival rates were 94%, 84%, and 74%, respectively. In multivariate analyses, synchronous liver metastases (p = 0.02) and portal vein resection (p < 0.01) were independent prognostic factors of survival. CONCLUSIONS: Synchronous liver metastases and portal vein resection were found to be independent factors influencing survival.

Blunt bowel and mesenteric injuries detected on CT scan: who is really eligible for surgery?

BACKGROUND: There is no consensually accepted approach to the management of blunt bowel and mesenteric injuries. Surgery is required urgently in the case of bowel perforation or haemodynamic instability, but several patients can be treated non-operatively. This study aimed to identify the risk factors for surgery in an initial assessment. METHODS: We retrospectively reviewed the medical charts and computed tomography (CT) scans of adult patients presenting with a blunt abdominal trauma to our centre between the years 2004 and 2011. We included only patients with a CT scan showing suspected injury to the mesentery or bowel. RESULTS: There were 43 patients (33 males and 10 females), with a mean Injury Severity Score (ISS) of 22. The most frequently suspected injuries based on a CT scan were mesenteric infiltrations in 40 (93 %) patients and bowel wall thickening in 22 (51 %) patients. Surgical therapy was required for 23 (54 %) patients. Four factors were independently associated with surgical treatment: a free-fluid peritoneal effusion without solid organ injury [adjusted odds ratio (OR) = 14.4, 95 % confidence interval (CI) [1.9-111]; p = 0.015], a beaded appearance of the mesenteric vessels (OR = 9 [1.3-63]; p = 0.027), female gender (OR = 14.2 [1.3-159]; p = 0.031) and ISS >15 (OR = 6.9 [1.1-44]; p = 0.041). Surgery was prescribed immediately for 11 (26 %) patients and with delay, after the failure of initially conservative treatment, for 12 (28 %) patients. The presence of a free-fluid peritoneal effusion without solid organ injury was also an independent risk factor for delayed surgery (OR = 9.8 [1-95]; p = 0.048). CONCLUSIONS: In blunt abdominal trauma, the association of a bowel and/or mesenteric injury with a peritoneal effusion without solid organ injury on an initial CT scan should raise the suspicion of an injury requiring surgical treatment. Additionally, this finding should lead to a clinical discussion of the benefit of explorative laparotomy to prevent delayed surgery. However, these findings need validation by larger studies.

[Stab wounds in emergency department]. / Les plaies par arme blanche et leur prise en charge aux urgences.

Stab wounds represent the most common cause of penetrating wounds, occurring mainly in case of aggression or suicide attempt. Clinical severity depends on the superficial or penetrating aspect of the wound, its location and damaged organs. Medical management must be known because the vital risk is involved in penetrating wounds. Hemodynamically unstable patients should be operated without delay after performing a chest X-ray and ultrasound Focus assisted sonography for trauma (FAST) to guide the surgery. In the stable patients, the general clinical examination, exploration of the wound and medical imaging detect injuries requiring surgical management. Stab penetrating wounds require close and rapid collaboration between medical teams, tailored to the institution's resources.

Medical liability in surgery for morbid obesity by adjustable gastric band: nine case reviews.

Adjustable gastric banding is recognized for its effectiveness in obtaining long-term weight loss with low morbidity-mortality for patients with morbid obesity. However, life-threatening complications can sometimes occur, and surgeons may end up in court. We analyzed complications, some of them lethal, arising from gastric banding surgery in nine patients and the main issues identified by the experts, contributing to the judge's decision. Gastric banding is considered a benign operation, but, of the nine cases examined herein, five resulted in death while the other four had serious consequences with several damages, especially aesthetic and psychological suffering. Perforations of the oesophagus or stomach remain the leading causes of complications; the experts identified several issues from the records that helped the judge to render a decision and condemn seven of the nine surgeons. Three types of faults were considered the responsibility of the doctors: the lack of patient information or incomplete medical records, a clumsy mistake or delay of appropriate treatment due to underestimation of clinical symptoms, and finally, failure to observe the proper indications. Expert opinion focused most often on criticism of postoperative behaviour and failure to make decisions according to the state of the art.

[Effects of cigarette smoking on female reproduction: from oocyte to embryo (Part I)]. / Effets du tabagisme sur la reproduction : de l'ovocyte à l'embryon (Partie I).

Cigarette smoking is associated with lower fecundity rate, adverse reproductive outcomes and higher risk of IVF failure. Over the last decades, prevalence of smoking among women of reproductive age has increased. The aim of this work was to focus on the knowledge of the effects of cigarette smoking on all reproductive stages, from oocyte to embryo. For each reproductive functions human clinical and experimental studies were analysed in order to find hypothesis and explanations for effects observed. All reproductive functions are targets of smoke compounds and cigarette smoking impairs ovarian reserve, sexual steroids synthesis, Fallopian tubes functions and embryo development, leading to reduced fecundity. Some of smoke compounds were identified in ovarian tissue, in uterine fluid and in the embryo, suggesting direct toxicity.

[Effects of cigarette smoking on embryo implantation and placentation and analysis of factors interfering with cigarette smoke effects (Part II)]. / Effet du tabagisme sur l'implantation embryonnaire et la placentation précoce et facteurs influençant la toxicité tabagique sur la reproduction (Partie II).

Cigarette smoking is associated with lower fecundity rate, adverse reproductive outcomes and higher risk of IVF failure. Over the last decades, prevalence of smoking among women of reproductive age has increased. The aim of this work was first to focus on the knowledge of the effects of cigarette smoking on reproductive stages and particularly on implantation process and early placentation. Human clinical and experimental studies were analysed in order to find hypothesis and explanations for the effects observed. Then, our second aim was to analyse which factors could influence smoke effects. We observed that smoke compounds induce impairment of endometrial maturation, disturb angiogenesis and trophoblastic invasion. Cigarette compounds also impair uterine and endometrial vascularisation and myometrial relaxation. These effects lead to implantation failure in IVF and higher risk of miscarriage. Many factors influence the effects of cigarette smoke, as smoke behaviour, dose and duration of exposition. Sidestream is also damaging on reproductive function. Prenatal exposure leads to irreversible and deleterious effects on ovarian reserve. These observations need to be confirmed in order to improve health care in women of reproductive age.

[Risks related to tobacco use in general and intestinal surgery]. / Risques liés au tabagisme en chirurgie générale et digestive.

Peri-operative smoking history is an important risk factor, which is often under-appreciated by surgeons. In the first place, tobacco use predisposes patients to specific pathologies, which may require surgical intervention. Secondarily, smoking has been shown to increase surgical risks of mortality, morbidity and length of hospital stay. Of particular importance in general surgery is the increased risk of anastomotic leak with fistula formation, of deep infections, and of abdominal wall complications (infection and ventral hernia). If the patient can stop smoking prior to surgery, there is a concomitant decrease in post-operative complications. Surgeons should be familiar with the pharmacologic and behavioral interventions, which may help the patient with smoking cessation and should not hesitate to defer elective surgery for four to eight weeks so that the patient may have the full benefit of smoking cessation.

Nefopam hydrochloride compatibility and stability with selected proton pump inhibitors in bionolyte G5 injection for intravenous infusion.

BACKGROUND: The use of extemporaneously prepared admixtures of drugs must be supported by documentation of their chemical stability. OBJECTIVE: To assess the physical compatibility and the chemical stability of nefopam hydrochloride, a centrally acting non-opioid analgesic, when admixed with selected proton pump inhibitors (omeprazole, esomeprazole or pantoprazole), in bionolyte G5 injection for intravenous infusion. METHOD: Admixtures were assessed for periods of up to 72 h after storage at ambient temperature without protection from light and at +4 degrees C protected from light. A preparation was considered stable if the compounds of the mixture retained at least 90% of their original potency during the storage. Triplicate samples of nefopam and the selected proton pump inhibitors as well as the following mixtures (nefopam/omeprazole, nefopam/esomeprazole and nefopam/pantoprazole) were prepared in the concentrations required, in polypropylene bottles of bionolyte G5 injection. The physical compatibility was assessed by visual observation at each sampling interval. The chemical stability of the drugs was evaluated by high-performance liquid chromatography and by measurement of pH values. RESULTS: During refrigerated storage, nefopam as well as the selected proton pump inhibitors, when prepared separately in bionolyte G5 injection maintained chemical stability for up to 7 days. At ambient storage conditions, the protons pump inhibitors maintained chemical stability for 24 h, but thereafter their concentrations decreased significantly at day 1. Nefopam maintained chemical stability for up to 72 h at +25 degrees C. Nefopam/omeprazole and nefopam/esomeprazole mixtures in bionolyte were physically incompatible with the mixtures exhibiting a black colour. They underwent rapid and extensive loss, making the combination unacceptable within minutes of mixing. However, the nefopam/pantoprazole mixture was compatible over the study period, but with a reduced duration of the stability. CONCLUSION: Within the limits defined above, nefopam and the selected proton pump inhibitors may be prepared separately in advance in bionolyte G5 injection. The nefopam/pantoprazole mixture was stable for a short period, while the nefopam/omeprazole and the nefopam/esomeprazole mixtures were incompatible and unusable, immediately upon admixture.

Experience of two trauma-centers with pancreatic injuries requiring immediate surgery.

BACKGROUND/AIMS: Pancreatic injury from blunt trauma is infrequent. The aim of the present study was to evaluate a simplified approach of management of pancreatic trauma injuries requiring immediate surgery consisting of either drainage in complex situation or pancreatectomy in the other cases. METHODOLOGY: From January 1986 to December 2006, 40 pancreatic traumas requiring immediate surgery were performed. Mechanism of trauma, clinical and laboratories findings were noted upon admission, classification of pancreatic injury according to Lucas' classification were considered. Fifteen (100%) drainages were performed for stage I (n=15), 60% splenopancreatectomies and 40% drainage was achieved for stage II (n=18), 3 Pancreaticoduonectomies and 2 exclusion of duodenum with drainage and 2 packing were performed for stage IV (n=7). RESULTS: There were 30 men and 10 women with mean age of 29+/-13 years (15-65). Thirty-eight patients had multiple trauma. Overall, mortality and global morbidity rate were 17% and 65% respectively, and the rates increased with Lucas' pancreatic trauma stage. CONCLUSIONS: Distal pancreatectomy is indicated for distal injuries with duct involvement, and complex procedures such as pancreaticoduodenectomy should be performed in hemodynamically stable patients.

[Endoscopic management of postoperative pancreatic collections]. / Prise en charge endoscopique des collections pancréatiques postopératoires.

INTRODUCTION: Treatment of pancreatic postoperative collections are usually managed with a multidisciplinary team. Different managements are possible: abstention, external drainage, endoscopic treatment or surgery. METHODS: We report on a case series of five patients with a postoperative pancreatic collection, endoscopically managed. Patients underwent all a CT scan associated or not with endoscopic ultrasonography. RESULTS: An endoscopic cystenterosotomy was performed in all the cases, with two double pig tail stents sometimes associated with nasocystic drainage for clearing the cyst lumen and with transpapillary drainage in one case. All the procedures were successful and patients healed in all the cases with the disappearance of the radiological image within a 33 days to three months range with one complication due to superinfection of the drained cyst, endoscopically managed with a nasocystic catheter. CONCLUSION: Therapeutic endoscopy, with a multidisciplinary approach, is a promising way to manage postoperative pancreatic collections.

Subcutaneous insulin resistance successfully circumvented on long term by peritoneal insulin delivery from an implantable pump in four diabetic patients.

UNLABELLED: Extreme subcutaneous insulin resistance is a rare syndrome characterized by a severe resistance to subcutaneous (S/C) insulin together with persistence of normal or near normal intravenous (IV) insulin sensitivity. Its pathophysiology is unknown, although increased insulin degrading activity has been reported in the S/C adipose tissue fraction in some cases. Until now, proposed treatments have been disappointing. We report 4 cases who were successfully treated by intraperitoneal (IP) route. METHODS: The diagnosis of subcutaneous insulin resistance was based upon following combined conditions: resistance to hypoglycaemic action of subcutaneous insulin but normal or near normal sensitivity to IV or IP insulin. RESULTS: 4 patients among those followed by EVADIAC group met these criteria: 3 with type 1 diabetes (C peptide=0), the last one with unexplained non insulin-deficient diabetes (no anti-GAD antibodies, C peptide=5 ng/ml). All of them had been treated with subcutaneous insulin therapy without success despite huge doses (up to 4000 IU/day in two patients). The 3 type 1 diabetic patients presented with a history of repeated ketoacidosis episodes. A treatment of insulin mixed with aprotinin had been proposed to 2 patients without success. The IV insulin sensitivity was proved to be normal in two patients by euglycaemic clamp data. A skin biopsy was performed in 1 patient. An accumulation of insulin in the derma was revealed with no increase of degradation products of insulin. In these 4 patients, a dramatic improvement of diabetes control was obtained by IP insulin delivery from an implantable pump (HbA1c decrease by at least 3%). CONCLUSION: Although pathophysiology of the subcutaneous insulin resistance syndrome remains unexplained, our data show that intra-peritoneal insulin therapy from an implantable pump allows diabetes control in patients affected by this uncommon but severely disabling condition.