Search

Background: The high prevalence of benign male breast tissue enlargement (gynecomastia) has resulted in a marked increase of gynecomastia cases. While about one third of male adults experience some form of gynecomastia, gynecomastia surgery (GS) outcome research is limited to small study populations and single-center/-surgeon databases. In this study, we aimed to access the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to identify preoperative risk factors for complications and investigate postoperative outcomes of GS., Methods: In this retrospective study, we queried the ACS-NSQIP database from 2008 to 2021 to identify male adult patients who underwent GS. Postoperative outcomes involved the occurrence of any, surgical and medical complications, as well as reoperation, readmission, and mortality within a 30-day postoperative time period. Univariable and multivariable assessment were performed to identify risk factors for complications while adjusting for possible confounders., Results: The study included 4,996 GS patients with a mean age of 33.7 ± 15 years and BMI of 28.2 ± 5.1 kg/m 2 . White patients constituted 54% (n = 2713) of the cohort, and 27% (n = 1346) were obese. Except for 2020, there was a steady increase in GS cases over the study period. Outpatient surgeries were most common at 95% (n = 4730), while general surgeons performed the majority of GS (n = 3580; 72%). Postoperatively, 91% (n = 4538) of patients were discharged home; 4.4% (n = 222) experienced any complications. Multivariable analysis identified inpatient setting (p < 0.001), BMI (p = 0.023), prior sepsis (p = 0.018), and bleeding disorders (p = 0.047) as independent risk factors for complications., Conclusion: In this study, we analyzed 4996 male adult GS patients from the ACS-NSQIP database, revealing an increased caseload and significant general surgeon involvement. Risk factors like bleeding disorders, inpatient status, and prior sepsis were linked to postoperative complications, while BMI was crucial for predicting adverse events. Overall, our findings may aid in enhancing patient care through advanced preoperative screening and closer perioperative management., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, presenting a persisting global health burden. Neutrophils have a double-edged role in tumor progression exhibiting both pro-tumor and anti-tumor functions. CD71, also known as transferrin receptor 1, performs a critical role in cellular iron uptake and is highly expressed on proliferating cells, and especially on activated immune cells. CD71 is known to be elevated in various types of solid cancers and is associated with poor prognosis, however, the expression of CD71 on neutrophils in PDAC and its potential clinical impact is still unknown. Therefore, we analyzed CD71 on circulating neutrophils in PDAC and clinical control patients and found a significant increased expression in PDAC patients. High expression of CD71 on neutrophils in PDAC patients was associated with reduced outcome compared to low expression. CD71 on neutrophils correlated positively with the levels of proinflammatory cytokines IL-6, IFN-γ, and growth factor ligands CD40-L, and BAFF in plasma of PDAC patients. Finally, we have demonstrated that high expression of CD71 on neutrophils was also associated with an increased expression of CD39 and CD25 on circulating T-cells. Based on our findings, we hypothesize that CD71 on neutrophils is associated with tumor progression in PDAC. Further studies are required to investigate the distinct functionality of CD71 expressing neutrophils and their potential clinical application., (© 2024. The Author(s).)

Background: Capsular contracture (CC) is a common complication following implant-based breast surgery, often requiring surgical intervention. Yet, little is known about risk factors and outcomes following CC surgery., Methods: We reviewed the American College of Surgeons National Surgical Quality Improvement Program database (2008-2021) to identify female patients diagnosed with CC and treated surgically. Outcomes of interest included the incidence of surgical and medical complications at 30-days, reoperations, and readmissions. Confounder-adjusted multivariable analyses were performed to establish risk factors., Results: 5,057 patients with CC were identified (mean age: 55 ± 12 years and mean body mass index [BMI]: 26 ± 6 kg/m 2 ). While 2,841 (65%) women underwent capsulectomy, capsulotomy was performed in 742 patients (15%). Implant removal and replacement were recorded in 1,160 (23%) and 315 (6.2%) cases, respectively. 319 (6.3%) patients experienced postoperative complications, with 155 (3.1%) reoperations and 99 (2.0%) readmissions. While surgical adverse events were recorded in 139 (2.7%) cases, 86 (1.7%) medical complications occurred during the 30 day follow-up. In multivariate analyses, increased BMI (OR: 1.04; p = 0.009), preoperative diagnosis of hypertension (OR: 1.48; p = 0.004), and inpatient setting (OR: 4.15; p < 0.001) were identified as risk factors of complication occurrence., Conclusion: Based on 14 years of multi-institutional data, we calculated a net 30 day complication rate of 6.3% after the surgical treatment of CC. We identified higher BMI, hypertension, and inpatient setting as independent risk factors of postoperative complications. Plastic surgeons may wish to integrate these findings into their perioperative workflows, thus optimizing patient counseling and determining candidates' eligibility for CC surgery., Level of Evidence Iii: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Gastrointestinal (GI) tumors pose a significant global health burden, necessitating the exploration of novel therapeutic approaches. Plasmacytoid dendritic cells (pDCs) play a crucial role in tumor immunity, exhibiting both anti-tumor and pro-tumor effects. This review aims to summarize the role of pDCs in different types of GI tumors and assess their potential as therapeutic targets. In gastric cancer, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma, increased infiltration of pDCs was associated with a worse outcome, whereas in esophageal cancer, pancreatic cancer, and colorectal cancer, pDC infiltration improved the outcome. Initial animal studies of gastric cancer and hepatocellular carcinoma showed that pDCs could be a successful therapeutic target. In conclusion, pDCs play a multifaceted role in GI tumors, influencing both anti-tumor immunity and tumor progression. Further research is needed to optimize their clinical application and explore combinatorial approaches.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and peritoneal dissemination is one major cause for this poor prognosis. Exosomes have emerged as promising biomarkers for gastrointestinal cancers and can be found in all kinds of bodily fluids, also in peritoneal fluid (PF). This is a unique sample due to its closeness to gastrointestinal malignancies. The receptor tyrosine kinase-like orphan receptor 1 (ROR1) has been identified as a potential biomarker in human cancers and represents a promising target for an immunotherapy approach, which could be considered for future treatment strategies. Here we prospectively analyzed the exosomal surface protein ROR1 (exo-ROR1) in PF in localized PDAC patients (PER-) on the one hand and peritoneal disseminated tumor stages (PER+) on the other hand followed by the correlation of exo-ROR1 with clinical-pathological parameters., Methods: Exosomes were isolated from PF and plasma samples of non-cancerous (NC) (n = 15), chronic pancreatitis (CP) (n = 4), localized PDAC (PER-) (n = 18) and peritoneal disseminated PDAC (PER+) (n = 9) patients and the surface protein ROR1 was detected via FACS analysis. Additionally, soluble ROR1 in PF was analyzed. ROR1 expression in tissue was investigated using western blots (WB), qPCR, and immunohistochemistry (IHC). Exosome isolation was proven by Nano Tracking Analysis (NTA), WB, Transmission electron microscopy (TEM), and BCA protein assay. The results were correlated with clinical data and survival analysis was performed., Results: PDAC (PER+) patients have the highest exo-ROR1 values in PF and can be discriminated from NC (p <0.0001), PDAC (PER-) (p <0.0001), and CP (p = 0.0112). PDAC (PER-) can be discriminated from NC (p = 0.0003). In plasma, exo-ROR1 is not able to distinguish between the groups. While there is no expression of ROR1 in the exocrine pancreatic tissue, PDAC and peritoneal metastasis show expression of ROR1. High exo-ROR1 expression in PF is associated with lower overall survival (p = 0.0482)., Conclusion: With exo-ROR1 in PF we found a promising diagnostic and prognostic biomarker possibly discriminating between NC, PDAC (PER-) and PDAC (PER+) and might shed light on future diagnostic and therapeutic concepts in PDAC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mittelstädt, Anthuber, David, Podolska, Bénard, Brunner, Krautz, Jacobsen, Denz, Weber, Merkel, Hackner, Buniatov, Roßdeutsch, Klösch, Swierzy, Hansen, Strobel, Zopf, Baur, Van Deun, Immanuel Geppert, Gießl, Lettmaier, Semrau, Grützmann, Kouhestani and Weber.)

Background: Surgeons have historically used age as a preoperative predictor of postoperative outcomes. Sarcopenia, the loss of skeletal muscle mass due to disease or biological age, has been proposed as a more accurate risk predictor. The prognostic value of sarcopenia assessment in surgical patients remains poorly understood. Therefore, the authors aimed to synthesize the available literature and investigate the impact of sarcopenia on perioperative and postoperative outcomes across all surgical specialties., Methods: The authors systematically assessed the prognostic value of sarcopenia on postoperative outcomes by conducting a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching the PubMed/MEDLINE and EMBASE databases from inception to 1st October 2022. Their primary outcomes were complication occurrence, mortality, length of operation and hospital stay, discharge to home, and postdischarge survival rate at 1, 3, and 5 years. Subgroup analysis was performed by stratifying complications according to the Clavien-Dindo classification system. Sensitivity analysis was performed by focusing on studies with an oncological, cardiovascular, emergency, or transplant surgery population and on those of higher quality or prospective study design., Results: A total of 294 studies comprising 97 643 patients, of which 33 070 had sarcopenia, were included in our analysis. Sarcopenia was associated with significantly poorer postoperative outcomes, including greater mortality, complication occurrence, length of hospital stay, and lower rates of discharge to home (all P <0.00001). A significantly lower survival rate in patients with sarcopenia was noted at 1, 3, and 5 years (all P <0.00001) after surgery. Subgroup analysis confirmed higher rates of complications and mortality in oncological (both P <0.00001), cardiovascular (both P <0.00001), and emergency ( P =0.03 and P =0.04, respectively) patients with sarcopenia. In the transplant surgery cohort, mortality was significantly higher in patients with sarcopenia ( P <0.00001). Among all patients undergoing surgery for inflammatory bowel disease, the frequency of complications was significantly increased among sarcopenic patients ( P =0.007). Sensitivity analysis based on higher quality studies and prospective studies showed that sarcopenia remained a significant predictor of mortality and complication occurrence (all P <0.00001)., Conclusion: Sarcopenia is a significant predictor of poorer outcomes in surgical patients. Preoperative assessment of sarcopenia can help surgeons identify patients at risk, critically balance eligibility, and refine perioperative management. Large-scale studies are required to further validate the importance of sarcopenia as a prognostic indicator of perioperative risk, especially in surgical subspecialties., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Sepsis, a global health burden, is often complicated by viral infections leading to increased long-term morbidity and mortality. Interleukin-3 (IL-3) has been identified as an important mediator amplifying acute inflammation in sepsis; however, its function in the host response to viral infections during sepsis remains elusive., Objectives: To investigate the role of IL-3 during viral pneumonia in sepsis., Methods: We included septic patients from two different cohorts and used in vitro and in vivo assays. The obtained data were substantiated using a second model (SARS-CoV-2 infections)., Measurements and Main Results: Low plasma IL-3 levels were associated with increased herpes simplex virus (HSV) airway infections in septic patients, resulting in reduced overall survival. Likewise, Il-3 -deficient septic mice were more susceptible to pulmonary HSV-1 infection and exhibited higher pulmonary inflammation than control mice. Mechanistically, IL-3 increases innate antiviral immunity by promoting the recruitment of circulating plasmacytoid dendritic cells (pDCs) into the airways and by enhancing pDC-mediated T cell activation upon viral stimulation. Interestingly, the ability of IL-3 to improve adaptive immunity was confirmed in patients with SARS-CoV-2 infections., Conclusion: Our study identifies IL-3 as a predictive disease marker for viral reactivation in sepsis and reveals that IL-3 improves antiviral immunity by enhancing the recruitment and the function of pDCs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bénard, Hansen, Uhle, Klösch, Czubayko, Mittelstädt, Jacobsen, David, Podolska, Anthuber, Swierzy, Schaack, Mühl-Zürbes, Steinkasserer, Weyand, Weigand, Brenner, Krautz, Grützmann and Weber.)

Pancreatic ductal adenocarcinoma (PDAC) ranks among the most fatal cancer diseases, widely accepted to have the most dismal prognoses. Although immunotherapy has broadly revolutionized cancer treatment, its value in PDAC appears to be relatively low. Exhibiting protumoral effects, monocytes have recently been proposed as potential targets of such immunotherapeutic regimens. However, to date, the body of evidence on monocytes’ role in PDAC is scarce. Therefore, we analyzed monocytes in the peripheral blood of 58 PDAC patients prior to surgery and compared them to healthy individuals. PDAC patients showed increased levels of monocytes when compared to healthy controls In addition, patients with perineural infiltration demonstrated a higher percentage of monocytes compared to non-infiltrating tumors and PDAC G3 was associated with higher monocyte levels than PDAC G2. Patients with monocyte levels > 5% were found to have an 8.9-fold increased risk for a G3 and perineural infiltrated PDAC resulting in poorer survival compared to patients with <5% monocyte levels. Furthermore, PDAC patients showed increased expressions of CD86 and CD11c and decreased expressions of PD-L1 on monocytes compared to healthy individuals. Finally, levels of monocytes correlated positively with concentrations of IL-6 and TNF-α in plasma of PDAC patients. Based on our findings, we propose monocytes as a novel prognostic biomarker. Large-scale studies are needed to further decipher the role of monocytes in PDAC and investigate their potential as therapeutic targets.

Electrochemiluminescence (ECL) has an inherently low background and enables precise chemical reactions through electrical control. Here, we report an advanced ECL system, termed ECLipse (ECL in paired signal electrode). We physically separated ECL generation from target detection: These two processes were carried out in isolated chambers and coupled through an electrode. The strategy allowed us to minimize cross-chemical reactions, design electrodes for high ECL signals, and integrate multiple sensors in a chip. As a proof of concept, we implemented an eight-plex ECLipse and applied it to detect host factors in human plasma. ECLipse achieved higher signal-to-noise ratio than conventional ECL assays and was >7000-fold more sensitive than enzyme-linked immunosorbent assay. In a pilot clinical study, we could detect septic conditions by measuring host factors [i.e., interleukin-3 (IL-3), IL-6, and procalcitonin (PCT)]. ECLipse assay further revealed distinct IL-3 and IL-6 patterns in patients with severe acute respiratory syndrome coronavirus 2 infection.

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5'-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73 + B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73 + B-cells. Finally, neoadjuvant therapy correlated with reduced CD73 + B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73 + B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.

Introduction : The cytokine storm is a form of excessive systemic inflammatory reaction triggered by a myriad of factors that may lead to multi-organ failure, and finally to death. The cytokine storm can occur in a number of infectious and noninfectious diseases including COVID-19, sepsis, ebola, avian influenza, and graft versus host disease, or during the severe inflammatory response syndrome. Area covered : This review mainly focuses on the most common and well-known methods of protein studies (PAGE, SDS-PAGE, and high- performance liquid chromatography). It also discusses other modern technologies in proteomics like mass spectrometry, soft ionization techniques, cytometric bead assays, and the next generation of microarrays that have been used to get an in-depth understanding of the pathomechanisms involved during the cytokine storm. Expert opinion : Overactivation of leukocytes drives the production and secretion of inflammatory cytokines fueling the cytokine storm. These events lead to a systemic hyper-inflammation, circulatory collapse and shock, and finally to multiorgan failure. Therefore, monitoring the patient's systemic cytokine levels with proteomic technologies that are redundant, economical, and require minimal sample volume for real-time assessment might help in a better clinical evaluation and management of critically ill patients.

Defects in glycosylations of α-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of α-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal <150 IU/L). A homozygous, novel c.917A>G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Aim: The aim of the study was to identify the genetic background for Aicardi-Goutieres syndrome (AGS) in the Faroe Islands., Methods: Four patients with AGS were identified. The patients had a variable phenotype, from a severe prenatal form with intrauterine foetal death to a milder phenotype, albeit still with an early onset, within the first 2-3 months., Results: A genome-wide search for homozygosity revealed one single 15.6 Mb region of homozygosity on chromosome 13, which included RNASEH2B, where a splice site mutation c.322-3C>G was identified. Screening of 170 anonymous Faroese controls revealed a carrier frequency of approximately 1.8%, corresponding to an incidence of AGS in the Faroe Islands of around 1 in 12,300., Conclusion: The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harbouring at least one missense mutation. The severe phenotype of the Faroese patients compared with the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal, RNASEH2B proteins, and hence some residual activity of RNASEH2B, explaining their milder phenotype., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Array-CGH analysis using 244k Agilent oligoarray revealed a de novo 17q21.31 microduplication in a 10-year-old girl with severe psychomotor developmental delay, facial dysmorphism, microcephaly, abnormal digits and hirsutism. The duplication encompassed the MAPT and CRHR1 genes and was reciprocal to the recently described 17q21.31 microdeletion, associated with a recognizable clinical phenotype. Genotyping showed that the duplication was derived from non-allelic homologous recombination of paternal H1 and H2 haplotypes. To our knowledge this is the first report of a patient with a 17q21.31 microduplication.

We have identified 12 patients with autosomal recessive mitochondrial encephalomyopathy with elevated methylmalonic acid. The disorder has a high incidence of 1 in 1700 in the Faroe Islands due to a founder effect, and a carrier frequency of 1 in 33. The symptoms comprise hypotonia, muscle atrophy, hyperkinesia, severe hearing impairment and postnatal growth retardation. Neuroimaging showed demyelination and central and cortical atrophy, including atrophy of the basal ganglia, and some of the patients fulfilled the criteria for Leigh syndrome. Urine and plasma methylmalonic acid were elevated. Homozygosity mapping with the Affymetrix 10 K array revealed a homozygous region on chromosome 13q14 harbouring the SUCLA2 gene. Mutations in SUCLA2 were recently shown to cause a similar disorder in a small Israeli family. Mutation analysis identified a novel splice site mutation in SUCLA2, IVS4 + 1G --> A, leading to skipping of exon 4. The SUCLA2 gene encodes the ATP-forming beta subunit of the Krebs cycle enzyme succinyl-CoA ligase. The hallmark of the condition, elevated methylmalonic acid, can be explained by an accumulation of the substrate of the enzyme, succinyl-CoA, which in turn leads to elevated methylmalonic acid, because the conversion of methylmalonyl-CoA to succinyl-CoA is inhibited.

We present three patients with SURF1 mutations. In addition to Leigh syndrome all patients had hypertrichosis, a clinical sign that is not usually associated with Leigh syndrome. The hypertrichosis was not congenital and it was mainly distributed on the extremities and forehead. In addition to our three patients, we have identified five patients in the literature with hypertrichosis and Leigh syndrome due to SURF1 mutations. Since most patients had onset of hypertrichosis before the diagnosis of Leigh syndrome was made, we suggest that clinicians consider Leigh syndrome in patients with, for example, psychomotor retardation or other unspecific symptoms in combination with hypertrichosis., (Copyright 2005 Wiley-Liss, Inc)

Cerebral folate deficiency is characterized by low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate and a broad spectrum of clinical signs and symptoms. A patient with progressive spasticity, gait disturbance, speech difficulties, initially diagnosed as a recessive spastic paraplegia recovered on folinic acid (15-30 mg/day) and her 5-methyltetrahydrofolate in CSF normalized. This report demonstrates the importance of CSF investigation in the diagnosis of cerebral folate deficiency and efficiency of folinic acid (5-formyltetrahydrofolate) supplementation.

Introduction: Continuous intrathecal baclofen has been used over the past years especially in adult patients with spasticity of spinal origin. Children and young adults with severe spasticity and dystonia of cerebral origin are difficult to treat in spite of optimal systemic antispasmotic therapy with baclofen, tizanidine, dantrolene and/or diazepam. Intrathecal baclofen has therefore been applied in a group of young patients., Material and Methods: Eight children and young adults from East Denmark with spasticity and 12 with dystonia aged 3-18 years (median 10.9 years) were tested, operated and treated with continuous intrathecal baclofen for a period of 2-64 months (median 22.2 months). Registration of efficacy, fillings, adjustments of baclofen and other therapies were performed in an out patient setting since 1995., Results: Spasticity in lower extremities was reduced from Ashworth score 3.5-4.5 (median 4.2) to Ashworth score 2.5-4.0 (median 2.9; p < 0.001) during infusion with baclofen 5-33 micrograms/kg/24 hours (median 19 micrograms/kg/24 hours). The infusion catheter tip was placed at levels Th1-Th12 (median Th7.5). Peroral baclofen was reduced from an average of 5.0 to 0.44 mg/kg/24 hours, tizanidine from 0.4 to 0.1 mg/kg/24 hours, and dantrolene from 4.0 to 0.4 mg/kg/24 hours. After initial adjustments successively increased dosages of average 0.46 microgram/kg/month were needed to maintain the same level of efficacy. In questionnaires parents or guardians rated less spasticity in lower extremities in 15 out of 19 patients, and less pain in 13 out of 19 patients., Conclusion: Continuous intrathecal baclofen was effective in treating severe spasticity and dystonia of cerebral origin with major effect on muscles of the lower extremities, pelvis, and back and in particular opisthotonus was relieved. Efficacy on upper extremities was far less pronounced.

We report a novel point mutation in the gene for the mitochondrially encoded ND6 subunit of the NADH:ubiquinone oxidoreductase (complex I of the respiratory chain) in a patient with MELAS syndrome. The mutation causes a change from alanine to valine in the most conserved region of the ND6 subunit. The patient was heteroplasmic for the mutation in both muscle and blood, but the mutation was not detected in the patient's mother. A marked reduction of complex I activity was found in the patient's muscular tissue. This is the first report of a mutation in the ND6 subunit causing MELAS. Our data confirm the genetic heterogeneity in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome, and confirms that MELAS can be caused by mutation in polypeptide-coding mtDNA genes.

Measles, mumps and rubella (MMR) vaccination was included in the Danish childhood vaccination programme in 1987. During the following 10-y period, 550 notification records of adverse events after MMR vaccination at 15 mo of age have been registered, and a total of 41 notifications have included "gait disturbance". This corresponds to a frequency of 8 per 100,000 doses of MMR vaccine used for 15-mo-old children. The symptoms and signs are characteristic of cerebellar ataxia. In 28 notifications, the descriptions by the doctors included only "gait disturbance", while in 13 an additional interpretation was included. Thirty-two parents (78%) filled in a questionnaire and 26 (63%) agreed to participate in a clinical follow-up study. The gait disturbance symptoms mainly occurred 7-14 d after the vaccination, and the duration was median 1-2 wk (range 1 d to more than 4 mo). One-third of the children had symptoms lasting more than 2 wk. Significantly more children with long duration of symptoms had some kind of complaint or clinical signs at the follow-up in 1997. Gait disturbance registered after MMR vaccination seems to be more frequent than hitherto reported. Most cases are mild and short-lasting and a longer duration of symptoms seems to be predictive of late sequelae. A clinical diagnosis of cerebellar ataxia after MMR and the exact frequency of this adverse event remains to be tested in prospective studies.

In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes. This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of cBCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and cBCD541 should help clarify the role of cBCD541 in the pathogenesis of SMA.

A girl presented at age 8 months with generalized hypotonia and areflexia. The parents were unrelated and without symptoms. At the age of 2 years and 10 months she was able to stand and walk with support. Intellectual development was normal. The mean fibre size in the lateral vastus muscle was normal, the variability was slightly increased. Type I and II fibres tended to be aggregated, but there was no type grouping. Motor and sensory nerve conduction velocities were less than 6 m/s. The sural nerve lacked myelin sheaths, and large non-myelinated axons were surrounded by concentric layers ('onion bulbs') of basal lamina material. The disease was classified as 'autosomal recessive hereditary motor and sensory neuropathy type III(HMSN (III) with basal lamina onion bulbs'. The muscle biopsy findings suggest that congenital amyelination or hypomyelination does not necessarily result in neurogenic atrophy.

Clinical genetic evidence suggests the existence of an autosomal recessive form of congenital nemaline myopathy in addition to the autosomal dominant one(s). One mutation in an Australian kindred has been identified as causing an autosomal dominant form of the disease. This mutation in the alpha-tropomyosin gene TPM3 has previously been excluded as causing autosomal recessive nemaline myopathy. We searched systematically for genetic linkage to autosomal recessive nemaline myopathy (NEM2) by studying microsatellite marker alleles in seven multiplex families from Finland, Denmark, Wales, England and The Netherlands. Significant evidence of linkage was found to markers of chromosome 2q, the highest multipoint lod score value being 5.34 for the marker D2S151. Recombinant genotypes in affected individuals demarcate the the region in which the NEM2 gene is likely to reside as a 13 cM region between the markers D2S150 and D2S142. These results confirm the existence of at least one distinctive form of autosomal recessive nemaline myopathy and provide a basis for the identification of its gene.

A 6-year-old girl had progressive ataxia, and visual disturbances resulting in blindness. She died in her sleep at age 22 years. She shared with her sister and paternal relatives bilateral pes cavus deformities and impaired deep-tendon reflexes which suggested Charcot-Marie-Tooth disease. Her sister, who also had both polyneuropathy and a progressive central nervous system (CNS) disease, did not have pigmentary retinopathy. At autopsy, the patient was found to have neuronal ceroid-lipofuscinosis (NCL) marked by intraneuronal accumulation of autofluorescent granular lipopigments in ballooned perikarya and conspicuous extraneuronal pigmentation of subcortical grey matter, but without axonal spheroids. These findings indicate a pigment variant of NCL and represent one of very few patients recorded. The ultrastructure of the intraneuronal pigments was uniformly granular, while that of the extraneuronal pigments found within processes of the neuropil and glial perikarya was more variegated. In addition to those patients with the pigment variant of NCL, described earlier by Jakob and Kolkmann [1973: Acta Neuropathol (Berl) 26:225-236], and Jervis and Pullarkat [1978: Neurology 28:500-503], our patient shared clinical symptoms with those described in a family afflicted with polyneuropathy and NCL by Wisniewski et al. [1987: J Child Neurol 2:33-41]. Currently, it is unclear whether they have similar atypical forms of juvenile NCL (JNCL). We conclude that the spectrum of pigment variants in lysosomal diseases is heterogeneous: only few and recently described patients have had NCL, while others most likely had other forms of lipidosis.

We describe seven children with the carbohydrate-deficient glycoprotein syndrome, an autosomal recessive inborn error of protein glycosylation characterised by failure to thrive, neurological dysfunction and a unique pattern of physical abnormalities. Neuro-radiological investigations revealed cerebellar hypoplasia in all seven children. Two children also developed supratentorial atrophy following episodes of neurological deterioration.

Recent studies show that patients presenting with cytochrome oxidase (COX) deficiency in infancy may have reduced mitochondrial DNA (mtDNA) in muscle. The human mitochondrial transcription factor A (h-mtTFA) may be an important regulator of both transcription and replication of mtDNA. h-mtTFA levels were investigated in cell lines which were either free of mtDNA (rho 0) or temporarily depleted by treatment with dideoxycytidine (ddC), and in tissue from three patients with mtDNA depletion and cytochrome oxidase deficiency. h-mtTFA was compared with other mitochondrial proteins such as pyruvate dehydrogenase and porin by Western blotting. The ratio of mtDNA and h-mtTFA mRNA to reference nuclear probes was measured by dual labelling of dot blots. The ratio of mtDNA to nuclear DNA in skeletal muscle was low in muscle in the three patients and in other tissues in one. h-mtTFA was low in cells depleted either permanently or transiently of mtDNA, and this reduction in h-mtTFA roughly paralleled mtDNA levels. Similarly, treatment of rho 0 cell lines with ddC induced a reduction in mtDNA as well as h-mtTFA protein. The relationship between h-mtTFA and mtDNA levels suggests that they may be causally linked. MtDNA depletion was accompanied by an increase in the level of h-mtTFA RNA in the cell lines but low levels in the patient. This suggests that either h-mtTFA regulates mtDNA levels, or that h-mtTFA expression may be regulated by a feedback mechanism initiated by MtDNA Depletion.

An elevated CSF glutamate level has recently been reported in Rett syndrome. Because the anticonvulsant effect of Lamotrigine is probably due to inhibition of glutamate release, this drug was given as an add-on drug to 4 girls with Rett syndrome. All patients responded with a seizure reduction of 50% or more and an improved well-being. A controlled study at the early stages of the syndrome could be interesting.

Among 2100 children with a diagnosis of cerebral palsy (CP) twenty carried the diagnosis: Previous CP, now normalized. Seventeen patients could be traced and were reevaluated. Cerebral palsy was diagnosed in these seventeen children (ten boys, seven girls) between the ages of three months and three years (average eleven months). They were found to be normal when reexamined between the ages of one year and five years (average two years two months). Two patients had tetraplegia, three diplegia, nine paraplegia ("paraplegia" were cases of diplegia with minimal affection of the upper limbs - now called "diplegia type I"), and one hemiplegia. One patient had atactic diplegia, and one was athetotic. The records of these seventeen patients were evaluated with respect to aetiology and symptomatology. Upon reexamination seven patients were found to be completely normal. Five patients had no motor symptoms but showed signs of specific neuropsychological difficulties. Two patients were intellectually retarded without motor symptoms. One showed signs of neuropathy, and one had fetal alcohol syndrome. Signs consistent with CP could be demonstrated in one patient only. This study shows that signs of CP may in rare cases disappear altogether.

Two cases of the Prader-Willi syndrome with 46,XY/47,XY,+mar are reported. The majority of Prader-Willi patients with chromosome abnormalities have either 15/15 translocations or mosaicism. Both of these aberrations presumably occur after fertilization. A possible relationship between high parental age and chromosome abnormalities in the Prader-Willi syndrome is discussed.

An unselected patient material of 182 children admitted consecutively with febrile convulsions during a period of two years was classified into five risk-groups. Continuous phenobarbital therapy for two years was recommended for 113 children (Groups I--IV). These children were followed-up as out-patients for at least one year after admission. In children receiving phenobarbital therapy, serum concentrations were controlled every third month. A total of 59 children completed the treatment according to the directives given and seven of these (12%) developed renewed febrile convulsions despite serum phenobarbital concentrations within the therapeutic range (70--120 mumol/l). No particular characteristics for these children could be established on the basis of the parameters registered. The therapeutic model established was found to be suitable for distinguishing between children with massive risk for renewed convulsions (Group I--IV) compared with children for whom treatment was not recommended (Group V).

Since the original description of cerebral gigantism, about 85 cases have been reported. Four papers comment on familial occurrence but never in parents and their children. This paper describes the syndrome in a mother and her child, which, together with facts pointing towards prenatal etiology, such as excessive birthweight, striking mutual resemblance and abnormal dermatoglyphics, points to a genetic defect. Previous endocrine studies are enlarged by the findings of normal serum somatomedin and serum prolactin.