Almost 2% of Spanish breast cancer families are associated to germline pathogenic mutations in the ATM gene.

PURPOSE: There is still a considerable percentage of hereditary breast and ovarian cancer (HBOC) cases not explained by BRCA1 and BRCA2 genes. In this report, next-generation sequencing (NGS) techniques were applied to identify novel variants and/or genes involved in HBOC susceptibility. METHODS: Using whole exome sequencing, we identified a novel germline mutation in the moderate-risk gene ATM (c.5441delT; p.Leu1814Trpfs*14) in a family negative for mutations in BRCA1/2 (BRCAX). A case-control association study was performed to establish its prevalence in Spanish population, in a series of 1477 BRCAX families and 589 controls further screened, and NGS panels were used for ATM mutational screening in a cohort of 392 HBOC Spanish BRCAX families and 350 patients affected with diseases not related to breast cancer. RESULTS: Although the interrogated mutation was not prevalent in case-control association study, a comprehensive mutational analysis of the ATM gene revealed 1.78% prevalence of mutations in the ATM gene in HBOC and 1.94% in breast cancer-only BRCAX families in Spanish population, where data about ATM mutations were very limited. CONCLUSION: ATM mutation prevalence in Spanish population highlights the importance of considering ATM pathogenic variants linked to breast cancer susceptibility.

Phenotype in patients with intellectual disability and pathological results in array CGH. / Fenotipo en pacientes con discapacidad intelectual y array-CGH patológico.

INTRODUCTION: Global developmental delay (GDD) and intellectual disability (ID) are frequent reasons for consultation in paediatric neurology departments. Nowadays, array comparative genomic hybridisation (array-CGH) is one of the most widely used techniques for diagnosing these disorders. Our purpose was to determine the phenotypic features associated with pathological results in this genetic test. METHODS: We conducted a blind study of the epidemiological, clinical, anthropometric, and morphological features of 80 patients with unexplained ID to determine which features were associated with pathological results in array-CGH. RESULTS: Pathological results were found in 27.5% of the patients. Factors associated with pathological results in array-CGH were a family history of GDD/ID (OR = 12.1), congenital malformations (OR = 5.33), having more than 3 facial dysmorphic features (OR = 20.9), and hypotonia (OR = 3.25). CONCLUSIONS: Our findings are consistent with those reported by other published series. We therefore conclude that the probability of having pathological results in array-CGH increases with the presence of any of the features mentioned above in patients with ID/GDD.

Neurological manifestations of neurofibromatosis type 1: our experience.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a progressive multisystem disorder following an autosomal dominant inheritance pattern that presents with multiple neurological manifestations. METHODS: We reviewed medical histories of patients with NF1 followed up at our hospital's paediatric neurology department from May 1990 to 31 December 2018. We collected data on neurological symptoms. RESULTS: A total of 128 patients with NF1 were identified. Mean age (SD) at NF1 diagnosis was 4.43 (3.38) years (range, 0.5-14.5 years). There was a slight female predominance (53.1%). Macrocephaly (head circumference over 2 SDs above average for age) was present in 37.5% of cases. Attention-deficit/hyperactivity disorder was recorded in 28.9% of patients (37): combined type in 20 patients, predominantly inattentive in 15, and predominantly impulsive/hyperactive in 2. Other manifestations included headache (18.6%), cognitive impairment (7.8%), motor deficit (6.2%), and epilepsy (4.68%). Brain MRI was performed in 85 patients, revealing T2-weighted hyperintensities in the basal ganglia and/or cerebellum in 60 patients (70.5%), Chiari malformation type 1 in 4 cases, and arachnoid cysts in 3. Optic nerve gliomas were identified by MRI in 22 patients (25.8%). Other MRI findings included plexiform neurofibromas (9.3%) and central nervous system gliomas (3.1%). CONCLUSIONS: The neurological manifestations identified in our sample are consistent with those reported in the literature. Effective transfer strategies from paediatric neurology departments and subsequent clinical follow-up by adult neurology departments are needed to prevent loss to follow-up in adulthood.

A novel mutation in the ZNF462 gene c.3306dup; p.(Gln1103Thrfs*10) is associated to Weiss-Kruszka syndrome. A case report.

BACKGROUND: Weiss-Kruszka syndrome (WSKA) is a rare disorder caused by mutations in the ZNF462 gene or deletion of 9p31.2 chromosome region, involving ZNF462. The prevalence of WSKA is unknown as only 24 affected individuals have been described. This syndrome should be suspected in individuals presenting mild global developmental delay and common craniofacial abnormalities. CASE PRESENTATION: We presented a case of an infant, 3 years and 4-month life who presented pondostatural and psychomotor retardation, generalized hypotonia with hypermobility, bilateral palpebral ptosis, epicanthal folds, and poorly expressive facies as the main clinical features. These characteristics lead to the realization of genetics studies that resulted in the identification of a novel mutation c.3306dup; p.(Gln1103Thrfs*10) in ZNF462. CONCLUSIONS: WSKA should be suspected in individuals presenting mild global developmental delay, ptosis, downslanting palpebral fissures, exaggerated Cupid's Bow, arched eyebrows, epicanthal folds and short upturned nose with a bulbous tip. Hypertrophy of the ventricular septum and severe OSA were described in our patient and should be considered in future reviews of the disease. This case is added to the reduced number of publications previously reported regarding WSKA and contributes to understanding the genetic characteristics, clinical features, and diagnosis of this syndrome.Abbreviations: WSKA: Weiss-Kruszka syndrome; CP: craniofacial perimeter; WES: whole-exome sequencing; RSV: respiratory syncytial virus; OSA: obstructive sleep apnoea; ACMG: American College of Medical Genetics and Genomics.

Neurological manifestations of neurofibromatosis type 1: our experience. / Manifestaciones neurológicas en neurofibromatosis tipo 1. Nuestra experiencia.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is a progressive multisystem disorder following an autosomal dominant inheritance pattern that presents with multiple neurological manifestations. METHODS: We reviewed medical histories of patients with NF1 followed up at our hospital's paediatric neurology department from May 1990 to 31 December 2018. We collected data on neurological symptoms. RESULTS: A total of 128 patients with NF1 were identified. Mean age (SD) at NF1 diagnosis was 4.43 (3.38) years (range, 0.5-14.5 years). There was a slight female predominance (53.1%). Macrocephaly (head circumference over 2 SDs above average for age) was present in 37.5% of cases. Attention-deficit/hyperactivity disorder was recorded in 28.9% of patients (37): combined type in 20 patients, predominantly inattentive in 15, and predominantly impulsive/hyperactive in 2. Other manifestations included headache (18.6%), cognitive impairment (7.8%), motor deficit (6.2%), and epilepsy (4.68%). Brain MRI was performed in 85 patients, revealing T2-weighted hyperintensities in the basal ganglia and/or cerebellum in 60 patients (70.5%), Chiari malformation type 1 in 4 cases, and arachnoid cysts in 3. Optic nerve gliomas were identified by MRI in 22 patients (25.8%). Other MRI findings included plexiform neurofibromas (9.3%) and central nervous system gliomas (3.1%). CONCLUSIONS: The neurological manifestations identified in our sample are consistent with those reported in the literature. Effective transfer strategies from paediatric neurology departments and subsequent clinical follow-up by adult neurology departments are needed to prevent loss to follow-up in adulthood.

Prognostic value of minimal residual disease (MRD) in acute myeloid leukemia (AML) with favorable cytogenetics [t(8;21) and inv(16)].

Most patients with acute myeloid leukemia (AML) and t(8;21) or inv(16) have a good prognosis with current anthracycline- and cytarabine-based protocols. Tandem analysis with flow cytometry (FC) and real-time RT-PCR (RQ-PCR) was applied to 55 patients, 28 harboring a t(8;21) and 27 an inv(16), including one case with a novel CBFbeta/MYH11 transcript. A total of 31% (n=17) of CR patients relapsed: seven with t(8;21) and 10 with inv(16). The mean amount of minimal residual disease (MRD) detected by FC in relapsed and nonrelapsed patients was markedly different: 0.3 vs 0.08% (P=0.002) at the end of treatment. The mean number of fusion transcript copies/ ABL x 10(4) also differed between relapsed and non-relapsed patients: 2385 vs 122 (P=0.001) after induction, 56 vs 7.6 after intensification (P=0.0001) and 75 vs 3.3 (P=0.0001) at the end of chemotherapy. Relapses were more common in patients with FC MRD level >0.1% at the end of treatment than in patients with < or = 0.1%: cumulative incidence of relapse (CIR) was 67 and 21% (P=0.03), respectively. Likewise, using RQ-PCR, a cutoff level of >10 copies at the end of treatment correlated with a high risk of relapse: CIR was 75% for patients with RQ-PCR >10 compared to 21% for patients with RQ-PCR levels < or = 10 (P=0.04). Combined use of FC and RQ-PCR may improve MRD detection, and provide useful clinical information on relapse kinetics in AML patients.

Adverse prognostic impact of CD36 and CD2 expression in adult de novo acute myeloid leukemia patients.

BACKGROUND AND OBJECTIVES: A consecutive series of acute myeloid leukemias (AML) patients was analyzed in conditions which reduce the inter-assay variations (the same flow cytometer, the same observers and the same panel of monoclonal antibodies) in order to investigate the prognostic information provided by flow cytometry. DESIGN AND METHODS: Two hundred and sixty-six bone marrow (BM) samples from 326 patients enrolled in the LMA-99 protocol from the CETLAM group were studied by multiparametric flow cytometry. Immunophenotyping studies were performed on erythrocyte-lysed BM samples. Antigen expression of leukemic cells was analyzed using triple stainings with fluorochrome-conjugated combinations of monoclonal antibodies. RESULTS: CD2 was positive in 21 cases (8%); an associated inv(16) was detected in eight CD2+ cases (38%). Two-year overall survival (OS) rate for CD2+/inv(16)+ patients was 75%, whereas it was 0% for CD2+/inv(16)- patients and 47% for CD2- patients (p=0.0001). CD36 was expressed in 37% of patients (n=98). Two-year leukemia-free survival (LFS) rate was 34% for CD36+ patients and 55% for CD36- patients (p=0.001). In the multivariate analysis, CD2+ (RR=8.4; p=0.0001) and adverse karyotype (RR=10.2; p=0.0001) were associated with a lower CR rate, CD36+ (RR=1.5; p=0.03), CD2+ (RR=2; p=0.04) and adverse karyotype (RR=4; p=0.0001) were associated with a lower OS and CD36+ (RR=2; p=0.002) and adverse karyotype (RR=3.5; p=0.005) predicted a lower LFS. CONCLUSIONS: CD2+ patients had a very poor OS when CD2/inv(16)+ cases were excluded. CD36 and CD2 expression at diagnosis can provide prognostically important information in adult de novo AML.

The evolution of alpha heavy chain disease.

Two patients with alpha heavy chain disease are described. In the first patient, treatment with cyclophosphamide, prednisone and doxycycline was associated with a 28 month-long remission and the disappearance of the paraprotein and lymphoplasmocytic infiltration of the intestine. Shortly afterwards, a retroperitoneal immunoblastic lymphoma was found associated with an immunoglobulin G-kappa-paraproteinemia, and gamma heavy and kappa-light chains in the urine; the intestinal biopsy specimen was normal. In the other patient, the alpha chain only appeared two years after the malabsorption syndrome. The fact that in the first, apparently cured patient, a tumor of different anatomic site and secretory capacity appeared, suggests the existence of a B-cell neoplasia of different clone from that which gave rise tothe original disease. In the second patient, it is probable that only the increase in the mass of neoplastic cells led to the detection of the protein abnormality, or alternatively the antigenic-oncogenic stimulus led to the abnormal secretion only after two years.

[Hereditary angioneurotic edema: study of serum complement and therapeutic trial with tranexamic acid (author's transl)]. / Edema angioneurótico hereditario: estudio del complemento y ensayo terapéutico con ácido tranexámico.

Three familial generations (five members with hereditary angioneurotic edema) have been evaluated under clinical and immunological standpoints. A therapeutic trial with tranexamic acid was carried out. The five members with hereditary angioneurotic edema showed: decreased values of total hemolytic activity (CH50), deficit of C4 (between 8 and 23 percent of the normal value), and normal levels of C3 and C9. C3PA was normal in four members and decreased in one. Asymptomatic familial members had normal serum complement levels; only three cases showed diminished values of CH50, C4, C-1-INH and C3PA. Therapeutic trial with tranexamic acid demonstrated the usefulness of this agent in the treatment of angioneurotic edema; it showed slighter adverse reactions than those derived from other therapeutic modalities. Screening of asymptomatic familial members is pointed out in order to detect low plasma values of C1-IHN.

[Absence of antiDNA antibodies in the cryoglobulins of a case with sicca syndrome (author's transl)]. / Ausencia de anticuerpos antiDNA en las crioglobulinas de un sicca syndrome.

Cryoglobulins are serum immunoglobulins (immunocomplexes) that precipitate in the cold and redissolve on warming. Cryoglobulins from patients with several diseases showed the presence of antiDNA antibodies when previously underwent incubation in acid buffer. The possibility that antiDNA antibodies might constitute the immunocomplexes found in patients with systemic lupus erythematosus and with other connective tissue diseases is suggested. Negative findings in relation to the presence of antiDNA antibodies in cryoglobulins of a case with sicca syndrome are reported.

[Mixed essential cryoglobulinemia. Report of five cases (author's transl)]. / Crioglobulinemia mixta esencial. Communicación de cinco casos.

Cryoglobulins are serum immunoglobulins which precipitate in the cold and redissolve on warming at 37 degrees C. According to its immunochemical composition three different types have been described. Cryoglobulins have been reported associated with hematologic disorders, systemic diseases, infectious conditions, and diseases of the liver and kidneys. There is also an idiopathic variant called essential cryoglobulinemia. Five patients (four males) with mixed essential cryoglobulinemia are reported. Common clinical manifestations included fever, articular symptoms, purpura, glomerulonephritis, Raynaud's phenomenon, erythematomacular cutaneous eruption, polyneuritis and abdominal pain. Serum activity of rheumatoid factor has been detected in three cases; in other three decreased levels of serum complement have been found. Serum HBsAg was negative in four cases (passive hemagglutination technique). It is possible that all cases of mixed essential cryoglobulinemia may correspond to bacterial, viral or fungal occult infections.

[Cryoglobulins and liver disease. Study of 34 cases (author's transl)]. / Crioglobulinemia en hepatopatías. Estudio en 34 pacientes.

Cryoglobulins are immunoglobulins characterized by precipitating when serum is cooled and redissolving when serum is heated. There is strong evidence to consider mixed cryoglobulins as circulating immunocomplexes, and various investigators have applied the precipitating physical property as a method to isolate immunocomplexes. In the recent years some authors have reported the presence of cryoglobulins in acute and chronic liver diseases of diverse etiology. This study investigates the presence of cryoglobulins in 34 patients with different liver diseases. Mixed cryoglobulins were detected in eight patients (23.5 percent), but only three of them had clinical symptoms attributable to the existence of cryoglobulins. In relation to the etiology of the liver disease, the highest frequency has been found among patients with hepatopathies of undetermined origin.

[Cryoglobulins in systemic and rheumatological diseases. Report of 70 cases (author's transl)]. / Crioglobulinas en enfermedades sistémicas y reumatológicas. Estudio en 70 casos.

Cryoglobulins are immunoglobulins characterized by precipitating when serum is cooled and redissolving when serum is heated. There is strong evidence to consider mixed cryoglobulins as circulating immunocomplexes. Cryoglobulins have been demonstrated in association to hematologic, hepatic, lymphoproliferative, autoimmune and infectious conditions. There is also an essential or idiopathic variant. The present report studies a series of 70 patients with several rheumatic and systemic diseases, and a group of ten patients with cutaneous vasculitis. Significant levels of cryoglobulins have been detected in nine cases (overall incidence 12.8 percent). The diagnoses corresponding to these patients were as follows: systemic lupus erythematosus in three cases, dermatopolymyositis in three cases, Sjögren's syndrome in two cases, and Wegener's granulomatosis in one case. Cryoglobulins could not be demonstrated in patients with rheumatoid artritis, sclerodermia, periarteritis nodosa, cutaneous vasculitis, Reiter's syndrome, ankylosing spondilitis and acute articular rheumatism. Among patients with systemic lupus erythematosus a good correlation has been observed between the presence of serum cryoglobulins, the activity and severity of the diseases and the decrease of serum complement levels.

[Circulating immune complexes-like material and complement in rheumatoid arthritis and ankylosing spondylitis (author's transl)]. / Inmunocomplejos circulantes y complemento en la artritis reumatoidea y en la espondilartritis anquilosante.

Circulating immune complexes (IC) in 52 rheumatoid arthritis (RA) seropositive, 25 RA seronegative and 32 ankylosing spondylitis (AS) patients were assayed by two methods: 1) precipitation with a final 2% polyethylene glycol (PEG) concentration with immunoglobulins (Igs) quantitation in the precipitate and 2) the ability of IC to consume complement, evaluating conversion products from human C3 by bidimensional rocket immunoelectrophoresis. CH50, C3, C4, C3PA and circulating C3 conversion products were quantitated. IC precipitates with 2% PEG contained three classes of Igs: IgG, IgM and IgA, the latter being the most rare. In the control group Igs level precipitated with 2% PEG were: 2% PEG-IgG 2.5 mg/100 ml +/- 2; 2% PEG-IgM 0.72 mg/100 ml +/- 1.09; 2% PEG-IgA 0.04 mg/100 ml +/- 0.18. With 2% PEG IC-like material was detected in 58.5% of RA seropositive patients but none generated C3 conversion products. With neither methods was IC-like material detected in the RA seronegative group and none with 2% PEG in AS, either. However, in the latter, 21.8% generated C3 conversion products and 18.7% circulating C3 conversión products. In the RA seropositive patients no correlation was observed between the levels of 2% PEG-IgG and 2% PEG-IgM and the titre of antinuclear antibodies (ANA) nor between 2% PEG-IgG and that of IgG in serum. However, there was a low correlation between 2% PEG-IgM and that of IgM in serum and between 2% PEG-IgG and 2% PEG-IgM with rheumatoid factor (RF). It should be stressed that the value of the PEG method in the detection of IC-like material must be reconsidered, since using a 2% final concentration and a specific evaluation of Igs and complement components in the precipitate, it may be a method easy to perform and useful for clinical purposes.

[Familial study for the early diagnosis of insulin-dependent diabetes mellitus]. / Estudio familiar para el diagnóstico temprano de la diabetes mellitus insulinodependiente.

BACKGROUND: Diabetes is more frequently found than expected in families of first grade with children with diabetes type I. METHODS: With the aim of identifying the potential candidates prone to develop diabetes type I, genetic and metabolic analysis was carried out on the members of 11 families with a diabetic type I child. They were distributed into three groups: 11 diabetic patients (IDDM); 22 progenitors and 13 unaffected siblings. The HLA haplotype was determined, the spectrum of autoantibodies and the intravenous glucose tolerance test (IVTT) were performed. RESULTS: In two progenitors postprandial glycemia values corresponding to intolerance to carbon hydrates were obtained. Moreover, in one the IVTT was found to be low in the normal values. Of a total of 12 non diabetic descendents studied, 4 shared identical HLA haplotypes as the diabetic, 5 were haploidentical and 3 unidentical. The DR 3 antigen was detected in 90% of the diabetics; in 68% of the progenitor group and in 50% of the non diabetic descendents. Sixty-two percent of the children inherited the DR 4 antigen of the father (p less than 0.05), while 37% do so from the mother. Of the siblings with a haplotype identical to that of the diabetic, 2 were also ICA positive; asymptomatic at the moment of the study but in one the diabetes type I became manifest after 2 years of evolution. CONCLUSIONS: Subjects at high risk of becoming type I diabetics may be identified at a preclinical phase by means of HLA typing and the detection of immunologic and metabolic markers associated with the disease.

[Etiologic diagnosis of pneumoccocal pneumonia by counterimmunoelectrophoresis (author's transl)]. / Diagnóstico etiológico de la neumonía neumocócica por contrainmunoelectroforesis.

The antigenic composition of the pneumoccocal capsule and its easy detection by counterimmunoelectrophoresis led us to carry out a comparative study of this method and the results obtained from cultures. A series of 159 patientes with suspected bacterial pneumonia were included in the study. Blood cultures were prepared for all of the patients; sputum cultures were practiced on 35 and cultures of pleural fluid on 32. Serum from all of the patients, urine from 104, sputum from 34, and pleural fluid from 16 were analyzed by counterimmunoelectrophoresis for pneumoccocal antigen. This method was particularly useful for detecting the germ in sputum and pleural fluid. Furthermore, a higher number of positive indexes in serum were obtained by counterimmunoelectrophoresis than by blood cultures (p less than 0.01). This was also true for tests with sputum and pleural fluid. Urine tests resulted in an even greater number of detections. Counterimmunoelectrophoresis is thus a simple, quick method for detecting pneumococcus and is especially useful when accompanied by cultures tests, since they are complementary. We were able to discover a positive indication of penumoccocus in bacterial pneumonia in 39.6 percent of cases with this technique, as opposed to 15 percent using cultures alone.

[The Royal Protomedicato Tribunal and the surgical profession in eighteenth century Spain]. / El Real Tribunal del Protomedicato y la profesión quirúgica española en el siglo XVIII.

Different approaches to the study of the Royal Protomedicato have not been entirely successful in defining its roles and connections with other organizations that controlled the practice of health professions during the Enlightenment. The loss of manuscript sources relating to the institution has been an almost insurmountable obstacle. In this study we examine the difficult relationships between the Protomedicato and the elite members of the Corps of Military Surgeons who made possible the implementation of a new model of training in surgery in Spain. The establishment of teaching imparted by the new colleges of surgery, together with the restrictions on access to the profession, drove a wedge into the traditional forms of control previously exerted by physicians through the Royal Protomedicato. These changes led to reforms in the tribunal.

[An unpublished letter by Ignacio María Ruiz de Luzuriaga (1763-1822) on the spread of vaccination in Spain (1801)]. / Una carta inédita de Ignacio María Ruiz de Luzuriaga (1763-1822) sobre la difusión de la vacuna en España (1801).

With this document we provide an initial study of the introduction of vaccination against smallpox in Spain. Despite the great number of studies on the topic, there is need for complementary research to examine in detail how, when, and with what means vaccination was introduced in and spread throughout the country. Doctor Ignacio María Ruiz Luzuriaga (1763-1822), a leading character in this process, was an ardent proponent of vaccination, and vaccinator to the court. Although he published nothing on the topic, he left behind several manuscripts, including reports and letters, that are held at the National Academy of Medicine in Madrid. We present one such letter, dated approximately in December, 1801, in which the writer gives an overview of the spread of vaccination and its proponents. Despite the inflated role Luzuriaga claims for himself, the text offers new information, and in particular, raises a number of questions (such as that regarding professional competition, the lack of a central vaccination committee, the role of enlightened bureaucrats, and communications with France during this period) which have yet to be examined in depth by Spanish medical historians.

[Internationalism and science. Social and scientific bases of the European information science movement]. / Internacionalismo y ciencia. Las bases sociocientíficas del movimiento documental europeo.

As part of a continuing line of research on scientific documentation we propose in this article a novel approach to the study of the European information science movement at the end of the nineteenth and beginning of the twentieth centuries. We suggest that this movement took place within the context of increasing internationalism of scientific endeavours, a process which was paralleled by the standardization of units, weight and measures for the different sciences. We investigate problems arising from scientific communication in connection with other aspects apparently unrelated to Information Science. Specifically, we refer to conflicts between nationalism and colonialism; concordance and discord between science policy and the corporate interests of nonscientific associations; higher educational policy; the professionalization of sciences; and the economic interests at stake as a consequence of the use of different information models.

Localized states in advanced dielectrics from the vantage of spin- and symmetry-polarized tunnelling across MgO.

Research on advanced materials such as multiferroic perovskites underscores promising applications, yet studies on these materials rarely address the impact of defects on the nominally expected materials property. Here, we revisit the comparatively simple oxide MgO as the model material system for spin-polarized solid-state tunnelling studies. We present a defect-mediated tunnelling potential landscape of localized states owing to explicitly identified defect species, against which we examine the bias and temperature dependence of magnetotransport. By mixing symmetry-resolved transport channels, a localized state may alter the effective barrier height for symmetry-resolved charge carriers, such that tunnelling magnetoresistance decreases most with increasing temperature when that state is addressed electrically. Thermal excitation promotes an occupancy switchover from the ground to the excited state of a defect, which impacts these magnetotransport characteristics. We thus resolve contradictions between experiment and theory in this otherwise canonical spintronics system, and propose a new perspective on defects in dielectrics.