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[Recurrent Miller Fisher syndrome and anti-GQ1b antibodies].

INTRODUCTION: Miller-Fisher syndrome is defined by the triad: ophthalmoplegia, ataxia and areflexia. This rare entity is generally regarded as a variant of the Guillain-Barré syndrome, although neurophysiological patterns differ. In the acute phase of the disease, sera of affected patients contain high titers of antiganglioside anti-GQ1b, which is a specific marker. Recurrences are exceptional. EXEGESE: We report the case of a man with three recurrences of Miller-Fisher syndrome within 16 years. Anti-GQ1b antibody titers were elevated during an episode, decreasing but not completely and vanishing 2 years later. Intravenous human immunoglobulin treatment probably accelerated improvement at the two last episodes. CONCLUSIONS: Some experimental and immunohistochemical data from the literature argue for a probable direct pathogenic role of antibodies against GQ1b ganglioside in this syndrome. This should be a rationale for the use of immunomodulating treatments.

Antibodies↗

[Bilobular pancreas: another variant of the divided pancreas?].

BACKGROUND: Pancreas divisum is the most common anomaly of the pancreas. This anomaly has been known as a possible cause of recurrent pancreatitis. CASE REPORT: We performed computerized tomography (CT) of the abdomen in 5 children in whom a divided pancreas was confirmed using endoscopic cholangiopancreatography. In a girl, who had three episodes of severe acute pancreatitis, a CT examination confirmed a completely divided embryonal dorsal and ventral primordium. We named this variant of the divided pancreas the "bilobular pancreas". Contrary to the remaining 4 children in whom the control of the number and severity of attacks, as well as the control of pancreatic pain were achieved by pharmacotherapeutics and an adequate diet, in the reported patient sphincteroplasty of the papilla duodeni minor resulted in a full control of the disease. CONCLUSION: The paper discussed the possibility that the variant of the divided pancreas, with anatomically completely separated ventral and dorsal pancreas and their ductal systems, is the key factor that determines the severity of pancreatic disease and an indication for sphincteroplasty of the papilla duodeni minor as the major therapeutic method.

Acute Disease↗

External beam radiotherapy in the management of differentiated thyroid cancer.

AIMS: No randomised trials have addressed the use of external beam radiotherapy (EBRT) in the treatment of differentiated thyroid cancer. The indications for EBRT, the technique and recommended dose all remain controversial. MATERIALS AND METHODS: We included patients treated with EBRT with curative intent from two cancer centres between 1988 and 2001. Data were collected from hospital notes, radiotherapy prescriptions and local cancer registry. RESULTS: The indications for treatment in the 41 identified patients were macroscopic residual disease 23 (56%), microscopic residual disease 10 (25%), Hurthle cell variants 3 (7%), multiple lymph-node involvement 3 (7%) and other 2 (5%). Delivered doses ranged from 37.5-66 Gy over 3-6.5 weeks. Rate of local recurrence and overall survival at 5 years were as follows: papillary 26% and 67%; follicular 43% and 48%; well differentiated 21% and 67%; focus of poor differentiation/Hurthle cell variants 69% and 32%; complete excision 25% and 61%; residual disease 37% and 59%; EBRT total dose < 50 Gy 63% and 42%; 50-54 Gy 15% and 72%; > 54 Gy 18%, and 68%. CONCLUSIONS: The results in this study are consistent with previous retrospective studies of EBRT. The wide range of indications and doses used with radical intent highlights the lack of clinical and radiobiological data on the response of differentiated thyroid cancer to EBRT. Despite the small study size, the 5-year local recurrence results indicate a possible dose response within the dose range used.

Carcinoma, Papillary, Follicular↗

A novel frameshift variant leads to familial osteopetrosis with variable phenotypes in a Chinese Han consanguineous family.

Osteopetrosis, a group of highly heterogeneous genetic bone disorders, is characterized by deafness, increased bone density, hepatosplenomegaly, pancytopenia and intellectual disability. Osteopetrosis can be divided into three subtypes: autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IARO), and autosomal dominant osteopetrosis (ADO). CLCN7 has been reported to be the most common gene responsible for the ADO-II subtype. In this study, a novel variant, c.175dupA (p.Met59Asnfs*8), of CLCN7 was identified in a Chinese Han consanguineous family with suspected ADO-II. The proband was homozygous for the p.Met59Asnfs*8 variant and exhibited multiple severe phenotypes, including deafness, short stature, brittle bones, optic atrophy, hepatosplenomegaly, intellectual disability, cleft palate and recurrent infection. However, except for the mother of the proband, who presented a series of clinical phenotypes caused by bone marrow failure, all the other family members who were heterozygous had no obvious abnormal phenotypes. Our study suggested that the novel variant p.Met59Asnfs*8 in CLCN7 was very likely pathogenic factor in our suspected ADO-II family. The phenotypes of heterozygous carriers may be affected by incomplete penetrance. Loss of function of CLCN7 caused by nonsense-mediated mRNA decay (NMD) due to the frameshift variant was likely the underlying pathogenic mechanism. This study broadened the mutation spectrum of CLCN7, provided a foundation for timely and effective clinical intervention for related diseases, and demonstrates the importance of genetic counselling.

Adult↗

Recurrent otitis media: genetic immunoglobulin markers in children and their parents.

The likelihood that hereditary factors play a significant role in the development of recurrent acute otitis media (rAOM) in children has been suggested. The genetically determined immunoglobulin variants, Gm and Km, are useful tools for mapping out the genetic loci involved in antibody responses. Certain Gm and Km types, G2m(23) and Km(1), appear to be linked to genes which regulate the concentrations of antibodies to pneumococcal polysaccharide antigens in adults. Our aim was to identify such immunoglobulin markers in rAOM children, since these children have extremely low concentrations of IgG antibodies against the pneumococcal types associated with this disease. The markers G1m(1), G1m(2), G1m(3), G2m(23) and Km(1) were identified in 20 families, each comprising 1 parent and 1 child with a history of rAOM and 1 parent free from rAOM. In addition, G2m(23) was identified in 47 children without AOM. The distribution of Gm and Km markers between rAOM and healthy subjects did not differ significantly. If anything, rAOM children exhibited a high rate of the G2m(23) marker, whereas earlier observations in adults have demonstrated low responders to polysaccharide antigens to be preferentially G2m(-23). Our findings indicate that mechanisms responsible for the low concentrations of antibodies to pneumococcal polysaccharides in rAOM children may differ from those causing certain adults to be low responders when exposed to pneumococcal polysaccharides.

Adult↗

A multi-model genome-wide association study identifies genetic variants underlying resistance to Largemouth Bass Ranavirus (LMBV) in Micropterus salmoides.

Largemouth bass (Micropterus salmoides) is an economically important freshwater aquaculture species, yet recurrent outbreaks of Largemouth Bass Ranavirus (LMBV) continue to impair production and cause substantial losses. The genetic basis of host variation in LMBV resistance remains insufficiently characterized. Here, we applied a multi-model genome-wide association study (GWAS) to identify loci associated with resistance following a controlled challenge with the LMBV-23PY strain. Whole-genome resequencing was performed for 146 phenotyped fish, including 72 susceptible and 74 resistant individuals. After stringent quality control, 877,262 high-quality variants were retained and tested using six GWAS models. Across binary survival status and survival time phenotypes, 32 shared suggestive variants were consistently detected across models, representing suggestive loci for LMBV-23PY resistance. Genes within &#xb1;50&#xa0;kb of these loci were annotated, and functional enrichment highlighted immune- and redox-related biological processes. Three prioritized candidates-GSTT3L (glutathione S-transferase theta-3-like), CGRP2 (calcitonin gene-related peptide 2), and NPPC (natriuretic peptide C)-were associated with pathways involved in oxidative stress responses and immune regulation. Collectively, these results provide insight into the genetic architecture of LMBV-23PY resistance in largemouth bass and identify suggestive variants and associated candidate genes for downstream validation, functional interrogation, and the development of marker-assisted and genome-enabled breeding strategies.

Animals↗

Angiomyofibroblastoma of the female genital tract: analysis of 17 cases including a lipomatous variant.

The clinicopathological and immunohistochemical profile of 17 cases of angiomyofibroblastoma (AMF) arising in the genital tract of females is reported. The lesions usually presented as painless masses and were located in the superficial vulvar region (15 cases), canal of Nuck (one case), and perineum (one case) in women ranging in age from 38 to 60 years (median, 46 years). The tumors were well delineated and ranged in size from 2 to 8 cm in greatest dimension. Microscopically, they were composed of spindled and epithelioid mesenchymal cells arranged in cords and nests preferentially arrayed around numerous small to medium-sized vessels. Mitotic activity ranged from 0 to 7 mitoses per 50 high-power fields (HPF) with no abnormal mitotic figures. Minimal nuclear atypia was appreciated. Intralesional fat was present in 12 cases and in two of these cases constituted most of the tumor (lipomatous variant of AMF). Tumor cells expressed vimentin (five of five cases), estrogen receptor protein (six of six cases), progesterone receptor protein (five of six cases), desmin (six of eight cases), CD34 (one of six cases), and smooth muscle actin (one of seven cases). None of the eight women with follow-up of up to 25 years (mean, 7.8 years) after simple excision developed a recurrence. This study confirms the benign nature of AMF, broadens its morphological spectrum to include a lipomatous variant, and proposes an origin from a perivascular stem cell that is capable of myofibroblastic and fatty differentiation.

Abdominal Neoplasms↗

[Value of the methylergometrin maleate test in recurrent cardio-circulatory arrests].

A 56-year-old man, with no particular past history, sustained two cardio-circulatory arrests preceded by constrictive chest pain. Coronary arteriography was normal during etiological investigations. The methylergometrine maleate (Méthergin (tm)) test enabled the diagnosis of severe spastic angina and guided appropriate management of this patient.

Angina Pectoris, Variant↗

Recurrent and persistent squamous cell cervical carcinoma in women under age 35.

Forty-five patients with invasive cervical squamous cell carcinoma were registered in the Tom Baker Cancer Centre from 1980 to 1985. The natural history of 22 patients (48.9%) who developed persistent or recurrent disease including 11 Stage IB, 8 Stage IIB, and 3 Stage IIIB is reported. Only one patient who had the uncommon papillary variant is alive without evidence of residual disease. The remainder are either dead (16) or alive with residual disease (5). Four patients never achieved a disease-free status and in the remainder recurrences developed on average in 8.7 months. Central or regional disease was not controlled in 20 of 22 patients. Neither radical surgery nor radiotherapy was evidently more effective in preventing persistent or recurrent disease. A reliable predictive marker for persistent or recurrent disease is required: lymph-vascular invasion in the radical hysterectomy specimens was present in 5 of 6 cases but it is subject to interpretive error. Since the disease is frequently systemic at the time of diagnosis, early adjuvant therapy and improved staging techniques are required to improve the survival.

Adult↗

Hepatitis B virus sequence changes evolving in liver transplant recipients with fulminant hepatitis.

BACKGROUND/AIMS: Patients undergoing liver transplantation for hepatitis B virus (HBV) related liver cirrhosis are at major risk of developing HBV recurrence, and occasionally fulminant hepatitis. Here we tested in a longitudinal study whether specific viral variants are associated with fulminant HBV infection in the graft. METHODS: The complete HBV genomes isolated from the sera of three patients with HBV and HBV and hepatitis delta virus (HDV) coinfection during chronic infection before and during fulminant reinfection after transplantation were amplified and directly sequenced. RESULTS: Twenty, 25 and 19 mutations, distributed over the entire genome, were identified which differed between the HBV genomes isolated from each patient during chronic and fulminant infection, respectively. This reflects a much higher rate of nucleotide sequence changes than expected from the natural variation of HBV. No common HBV mutation emerged in any of the three cases during fulminant infection. However, precore defective viruses were found to be present in all three patients at the time of fulminant infection and in two of the patients before fulminant infection. Two of the patients had preS2-defective HBVs both before and after transplantation. A point mutation in the 'a'-determinant of the surface protein emerged in one case after transplantation under treatment with polyclonal HBV specific immunoglobulins. CONCLUSIONS: Many new, but no specific common mutations emerged during fulminant HBV reinfection. Although HBeAg defective variants were found in all cases studied, the presence of these variants also during chronic infection in two cases demonstrates that they are not sufficient to cause fulminant hepatitis. Thus, other factors than the emergence of a specific viral strain seem to contribute to the development of fulminant reinfection in a liver graft.

Adult↗

Variant of hyper-IgE syndrome: the differentiation from atopic dermatitis is important because of treatment and prognosis.

The hyper-IgE syndrome is characterized clinically by recurrent staphylococcal abscesses of the skin, lungs and other sites from infancy. Affected patients also have a pruritic dermatitis that differs in character and distribution from lesions of atopic dermatitis. Most lack other signs of atopic disease, develop persistent pneumatoceles and have osteopenia. Laboratory abnormalities include the consistent presence of marked hyperimmunoglobulinemia E and eosinophilia of blood, sputum and tissues. They may have other inconsistent abnormalities of humoral and cellular immune responses and sometimes of phagocytic cell chemotactic responsiveness. Other clinical problems reported in such patients have included lymphomas, cryptococcal meningitis and cutaneous fungal disease. An 18-year-old male patient with a variant of the hyper-IgE syndrome, which he had acquired after a measles attack at the age of 5 years, suffered from recurrent ulcerative dermatitis and lymph node abscesses. Immunological investigation revealed an excessively elevated total serum IgE level (46,850 IU/ml), the presence of specific IgE to staphylococci, and quantitative and functional deficiency of IgG2. Skin and serological (radioallergosorbent) tests to inhalant and nutritive allergens were negative. Differentiation from atopic dermatitis should be made, because a long-term antistaphylococcal regime not only improves skin lesions but hinders the occurrence of lung abscesses and pneumatoceles.

Abscess↗

Functional impact of cancer-associated cohesin variants on gene expression and cellular identity.

Cohesin is a ring-shaped protein complex that controls dynamic chromosome structure. Cohesin activity is important for a variety of biological processes, including formation of DNA loops that regulate gene expression. The precise mechanisms by which cohesin shapes local chromosome structure and gene expression are not fully understood. Recurrent mutations in cohesin complex members have been reported in various cancers, though it is not clear whether many cohesin sequence variants have phenotypes and contribute to disease. Here, we utilized CRISPR/Cas9 genome editing to introduce a variety of cohesin sequence variants into murine embryonic stem cells and investigate their molecular and cellular consequences. Some of the cohesin variants tested caused changes to transcription, including altered expression of gene encoding lineage-specifying developmental regulators. Altered gene expression was also observed at insulated neighborhoods, where cohesin-mediated DNA loops constrain potential interactions between genes and enhancers. Furthermore, some cohesin variants altered the proliferation rate and differentiation potential of murine embryonic stem cells. This study provides a functional comparison of cohesin variants found in cancer within an isogenic system, revealing the relative roles of various cohesin perturbations on gene expression and maintenance of cellular identity.

Animals↗

Characteristics of Castleman's disease in Peru.

BACKGROUND: Castleman's disease (CD) is a very rare disorder of unknown etiology that is characterized by masses of lymphoid tissue. METHODS: The records of all patients with a histological diagnosis of CD who were seen at the Hospital Nacional Cayetano Heredia and the Instituto Nacional de Enfermedades Neoplásicas between 1985 and 2003 and 1985 and 2001, respectively, were reviewed. RESULTS: The study included 10 patients. The age of onset ranged from 5 to 65 years. Nine patients met the criteria for localized CD; six of them were asymptomatic. The most common sites of presentation were the cervical lymph nodes (n=5), submaxilar lymph nodes (n=2), parotid gland (n=1), and lung (n=1). Eight patients had histological evidence of the hyaline-vascular variant and one had the plasma-cell variant. The primary treatment was complete surgical resection. One patient met the criteria for multicentric CD; he was asymptomatic, had histological evidence of the plasma-cell variant, and was treated with combination chemotherapy. All ten patients are currently alive with no evidence of recurrence. CONCLUSION: The localized form of CD presents as progressive, painless, slow-growing lymph node enlargement that is generally asymptomatic. The locations most commonly involved in the localized form are the cervical lymph nodes, followed by the submaxillary lymph nodes, where it poses a diagnostic challenge to the clinician because it tends to mimic other head and neck diseases. Localized CD is almost always of the hyaline-vascular variant and complete surgical excision of the tumor allows full recovery in all cases.

Journal Article↗

[Percutaneous therapy of primary varicocele. 6 years' experience].

Idiopathic varicocele is nowadays accepted as a "social disease" for both its high incidence among young men and its affecting male fertility. Screening is thus required for young people and, above all, early and definitive treatment. We have evaluated the effectiveness of percutaneous sclerotherapy, which has become a standard procedure, in spite of its recent introduction in interventional radiology. One hundred and thirty-nine percutaneous occlusions were performed on 147 patients with varicocele using a sclerosing agent--polidocanol--and stainless steel coils. The failure rate of percutaneous treatment was about 12%. Complications never required hospitalization or surgery; recurrence rate is 3.66%. The patients were followed 3, 6, 12 and 24 months by US and Doppler to survey recurrences, and sperm analysis to estimate the clinical results of percutaneous therapy in infertile patients. Statistical analysis with linear regression of data from spermiograms showed constant improvement in sperm count, sperm motility percentage, and sperm morphology percentage. Fertility index improvement was similar to that of surgical ligation. The radiation dose received by the patient is negligible. Percutaneous therapy represent thus the treatment of choice in case of varicocele: compared with surgery, it offers similar clinical results and a lower recurrence rate, and it can be performed on an outpatient basis. Surgery should be performed only when anatomic variants make percutaneous treatment not feasible.

Adolescent↗

[Celioscopic treatment of inguinal hernias by intraperitoneal patch of ePTFE according to Spaw. Preliminary results of a prospective study of 162 hernioplasties in 135 patients. Groupe CHIC (Cure des hernies inquinocrurales sous coelioscopie)].

Spaw's (original and modified) was technique evaluated in a prospective, multicentre study: from november 1992 to september 1993, 162 intraperitoneal laparoscopic herniorraphies were carried out in 135 patients for recurrent hernias or for hernias associated with a high risk of recurrence. Three needed an open procedure. Three early complications (2 periprosthetic hematomas, 1 microscopic bladder injury) were treated by another laparoscopy; a bowel loop retained in a trocar orifice was reintegrated under local anesthesia; dysesthesias of the lateral cutaneous nerve of the thigh in 1 patient and nonspecific parietal pain in 2 patients resolved within three weeks. Three seromas resolved after only one percutaneous aspiration. The mean post operative pain, evaluated by a visual analogic scale graduated from 1 to 10 was 1.8 (0 to 6) at D1, 05 (0 to 2) at D2 and the mean duration of analgesic requirments was 1.7 (0 to 15) days. The mean hospital stay was 2 (1 to 17) days for unilateral herniorraphies and the mean time to return to work or normal activity was 10 (2 to 44) days, even in heavy workers (35 patients). All patients were reviewed. The mean follow-up was 4 (1 to 10) months. Two complications needed further laparoscopic treatment: 1 recurrence at the internal edge of the patch, easily restapled with a stronger stapler, 1 bowel adhesion between patch and bladder revealed by pain without obstruction. The recurrence rate was 0.6% (1/162). The conversion rate was 2% (3/162) and the overall morbidity was 7.5% (12/162), decreasing respectively to 0 and 4% after the learning curve. This study confirms that Spaw's technique and its variant are feasible, and allows us to continue this study, and suggest these techniques would be useful in the treatment of some recurrent inguinal hernias.

Adolescent↗

Prognostic value of the tall cell variety of papillary cancer of the thyroid.

We analyse a new variety of papillary carcinoma of the thyroid, known as the tall cell variant. The lesion is characterized by a papillary cancer (PCT) in which more than 30% of the tumour is made up of a population of tall columnar cells over twice as tall as their width. Of a population of 158 differentiated thyroid carcinomas we found five cases of this rare variant. We studied their clinico-pathological features, the importance of an early diagnosis and their prognostic implications. The data were compared with those of Well-Differentiated or Classical PCT (WDPC), the most important features of which were: (a) later age of appearance; (b) greater predilection for males; (c) greater frequency of extrathyroid tumor extensions; (d) greater frequency of recurrences; and (e) a shorter survival or disease-free interval. The prognostic importance involved in recognizing this variant is based on the need to give patients a more aggressive treatment and more exhaustive follow-up.

Aged↗

Antithrombin III Nagasaki (Ser116-Pro): a heterozygous variant with defective heparin binding associated with thrombosis.

A novel variant of antithrombin III (AT III) that lacks affinity for heparin was found in a 33-year-old man who suffered from recurrent cerebral infarction. The propositus had a history of recurrent ischemic attacks from the age of 28. He was obese and had a smoking habit (30 to 40 cigarettes/day), low high-density lipoprotein cholesterol, and a mild glucose intolerance as the possible risk factors for thrombosis. No family history of thromboembolic episodes was observed. Coagulation studies found low heparin cofactor activity (55%) of AT III, with a normal immunoreactive level (109.7%) and progressive antithrombin activity (117%). Other factors capable of predisposing him to hereditary thrombophilia were within normal ranges. Analysis by crossed immunoelectrophoresis in the presence of heparin and affinity chromatography on heparin-Sepharose demonstrated that the propositus' AT III was composed of two populations, one having no affinity for heparin and the other binding heparin normally. Nucleotide sequencing of 7 exons of the propositus' AT III gene using polymerase chain reaction and subcloning disclosed a transition of thymine to cytosine in exon 3a (codon 116) of the AT III gene leading to a Ser116-Pro conversion. Allele-specific oligonucleotide hybridization procedures confirmed the presence of the mutation in the propositus' genomic DNA. Using the same technique, the mutation was also found in his father's genomic DNA, but not in that of his mother. These findings indicate that Ser116 is an important amino acid residue in heparin binding and that the propositus is heterozygous for the abnormality. Furthermore, the fact that the propositus suffered from recurrent cerebral infarction suggested that being heterozygous for a heparin-binding defect would lead to a predisposition to thrombosis when associated with various risk factors. The name AT III Nagasaki is proposed for this variant AT III containing a novel Ser116-Pro mutation.

Adult↗

De-novo expression of CD44 and survival in gastric cancer.

We have examined the cell surface molecule CD44, which is attracting interest because of reports that isoforms are associated with metastasis. The prognostic value of CD44 expression has yet to be assessed for a solid tumour. Benign (59) and malignant (primary 61, metastatic 59) gastric tissues were examined with antibodies directed at epitopes common to known CD44 isoforms. Normal mucosa was CD44 negative. In atrophic gastritis and intestinal metaplasia expression was restricted to the epithelial cells of the basal glands and was positively correlated with an increased leucocyte infiltrate and with the expression of HLA DR by mucosal cells. These observations suggest a role for chronic inflammation in the induction of CD44 expression on benign mucosa. No such association was observed between inflammatory infiltrate and CD44 expression on gastric tumours. CD44 expression, observed in only 49% of primary tumours, was associated with distant metastases at time of diagnosis and, among 31 curatively resected patients, with tumour recurrence (p = 0.0014) and increased mortality (p = 0.001) during follow-up averaging 17 months. When we used an antibody directed against the CD44 variant exon 9v, we found a good correlation between the expression of total CD44 and of exon 9v containing isoforms, and 9v expression in primary tumours was significantly and positively associated with tumour recurrence and mortality.

Adenocarcinoma↗