[Correlation analysis of cervical spine dysfunction, pain and muscle strength in office workers].

Objective: To expore the correlation between neck disability, neck pain and muscle strength in cervical pondylosis of office worker, and to provide scientific basis for the prevention and treatment of cervical spondylosis. Methods: In April 2021 ,234 patients with cervical spondylotic myelopathy treated in the Subsidiary Rehabilitation Hospital of Fujian University of Traditional Chinese Medicine from April 2015 to April 2017 were selected, the correlation between Neck Disability Index (NDI) score, neck pain and muscle strength was analyzed using the Spearman rank correlation method. Mann-Whitney U test was used to compare the difference of maximum muscle strength of isometric contraction. Results: NDI score was negatively correlated with neck flexion, extension, and muscle strength in the left and right flexion directions (r(s)=-0.164, -0.169, -0.222, -0.176, P=0.012, 0.010, 0.001 , 0.007). In mild and moderate functional disorder patients, the muscle strength in flexion, extension and left and right flexion direction was greater, the difference was statistically significant (P <0.01). Conclusion: There is a negative correlation between cervical functional disorder and cervical muscle strength in office workers, suggesting that strengthening cervical muscle strength may be a way to improve cervical spine function.

Adjuvant chemotherapy for patients with gastric neuroendocrine carcinomas or mixed adenoneuroendocrine carcinomas.

BACKGROUND: The aim of this study was to evaluate whether adjuvant chemotherapy is associated with improved survival in patients with resectable gastric neuroendocrine carcinomas (G-NECs) or mixed adenoneuroendocrine carcinomas (G-MANECs). METHODS: The study included patients with G-NECs or G-MANECs who underwent surgery in one of 21 centres in China between 2004 and 2016. Propensity score matching analysis was used to reduce selection bias, and overall survival (OS) in different treatment groups was estimated by the Kaplan-Meier method. RESULTS: In total, 804 patients with resectable G-NECs or G-MANECs were included, of whom 490 (60·9 per cent) received adjuvant chemotherapy. After propensity score matching, OS in the chemotherapy group was similar to that in the no-chemotherapy group. Among patients with G-NECs, survival in the fluorouracil (5-FU)-based chemotherapy group and the non-5-FU-based chemotherapy group was similar to that in the no-chemotherapy group. Similarly, etoposide plus cisplatin or irinotecan plus cisplatin was not associated with better OS in patients with G-NECs. Among patients with G-MANECs, OS in the non-5-FU-based chemotherapy group was worse than that in the no-chemotherapy group. Patients with G-MANECs did not have better OS when platinum-based chemotherapy was used. CONCLUSION: There was no survival benefit in patients who received adjuvant chemotherapy for G-NECs or G-MANECs.

ANTECEDENTES: El objetivo de este estudio fue evaluar si la quimioterapia adyuvante mejoraba la supervivencia en pacientes con carcinomas gástricos resecables neuroendocrinos (gastric neuroendocrine carcinomas, G-NECs) y carcinomas adenoneuroendocrinos mixtos (mixed adenoneuroendocrine carcinomas, G-MANECs). MÉTODOS: Se incluyeron pacientes con G-NECs y G-MANECs tratados quirúrgicamente en 21 centros en China entre 2004 y 2016. Se utilizó un análisis de emparejamiento por puntaje de propensión para reducir el sesgo de selección y el método de Kaplan-Meier para estimar la supervivencia global (overall survival, OS) de los pacientes en los diferentes grupos de tratamiento. RESULTADOS: En total, se incluyeron en el estudio 804 pacientes con G-NECs y G-MANECs resecables y 490 pacientes (60,9%) recibieron quimioterapia adyuvante. Después del emparejamiento por puntaje de propensión, la OS del grupo con quimioterapia fue similar a la del grupo sin quimioterapia. En los pacientes con G-NECs, la supervivencia en los grupos con quimioterapia basada en 5-FU (fluorouracilo) y de quimioterapia sin 5-FU fue similar a la del grupo sin quimioterapia. Asimismo, la combinación de etopósido y cisplatino o de irinotecán y cisplatino no se asoció con una mejor OS en pacientes con G-NECs. En pacientes con G-MANECs, la OS del grupo con quimioterapia sin 5-FU fue peor que la del grupo sin quimioterapia. Los pacientes con G-MANECs no presentaron una mejor OS cuando se administró quimioterapia basada en platinos. CONCLUSIÓN: La administración de quimioterapia adyuvante en pacientes con G-NECs y G-MANECs no mejoró la supervivencia.

[Effects of pneumoperitoneal pressure on air embolism duringlaparoscopic hepatectomy and degree of postoperative inflammation].

Objective: To investigate the incidence and severity of embolicevents, and degree of postoperative inflammation when pneumoperitoneal pressures 15 mmHg and 12 mmHg were used during laparoscopic hepatectomy. Methods: A computer-generated 1∶1 randomization protocol was used to assign fifty patients to either the 15 mmHg(P15, n=25) or 12 mmHg(P12, n=25) group. Throughout the surgery, air embolisms were detected by transesophageal echocardiography (TEE) and graded based on their size. Vital signs, arterial blood gases (ABG), P(ET)CO(2) levels, blood loss, operative time and postoperative hospital stays were monitored. 2 ml blood samples were taken before and after operation finished 0, 12 and 24 h by using EDTA anticoagulated tubes in order to detect the IL-6, TNF-α and IL-10 level in plasma. Results: CO(2) embolism occurred in 100% of the enrolled patients. The frequencies of severe air embolism were 76%(n=19) in P15 group and 52% (n=13) in P12 group, respectively. The duration of severe embolism episodes in P15 group was much longer than that in P12 group[(58.0±22.6) s vs(36.6±17.8)s, t=3.71, P<0.01]. The incidence of complications in group P15 was 24%, which was higher than that in group P12 of 4%(χ(2)=4.15, P<0.05). The postoperative pro-inflammatory cytokine IL-6 and TNF-α in group P15 at the point of 12 hour after operation[685.66(435.18-935.52)ng/L, 31.00(18.29-41.15)ng/L]were statistically higher than those in group P12 [480.50(255.28-685.34) ng/L, 21.00(14.87-31.64) ng/L, P<0.05], whereas the anti-inflammatory cytokine IL-10 in P15 group[18.00(5.75-30.55) ng/L]was statistically lower than the P12 group [26.89(15.03-38.00) ng/L, P<0.05]. There was no statistical difference in operative time, blood loss and postoperative hospital stay between the two groups. Conclusion: The higher pneumoperitoneal pressure during laparoscopic hepatectomy causes more serious gas embolism, prolongs embolic duration and lead to more sever inflammatory response.

Efficacy of pallidal stimulation in isolated dystonia: a systematic review and meta-analysis.

The aim of this review was to provide strong clinical evidence of the efficacy of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in isolated inherited or idiopathic dystonia. Eligible studies were identified after a systematic literature review of the effects of bilateral GPi-DBS in isolated dystonia. Absolute and percentage changes from baseline in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) motor and disability scores were pooled, and associations between treatment effect and patient characteristics were explored using meta-regression. In total, 24 studies were included in the meta-analysis, comprising 523 patients. The mean absolute and percentage improvements in BFMDRS motor score at the last follow-up (mean 32.5 months; 24 studies) were 26.6 points [95% confidence interval (CI), 22.4-30.8] and 65.2% (95% CI, 59.6-70.7), respectively. The corresponding changes in disability score at the last follow-up (mean 32.9 months; 14 studies) were 6.4 points (95% CI, 5.0-7.8) and 58.6% (95% CI, 50.3-66.9). Multivariate meta-regression of absolute scores indicated that higher BFMDRS motor and disability scores before surgery, together with younger age at time of surgery, were the main factors associated with significantly better DBS outcomes at the latest follow-up. Reporting of safety data was frequently inconsistent and could not be included in the meta-analysis. In conclusion, patients with isolated inherited or idiopathic dystonia significantly improved after GPi-DBS. Better outcomes were associated with greater dystonia severity at baseline. These findings should be taken into consideration for improving patient selection for DBS.

European consensus on the concepts and measurement of the pathophysiological neuromuscular responses to passive muscle stretch.

BACKGROUND AND PURPOSE: To support clinical decision-making in central neurological disorders, a physical examination is used to assess responses to passive muscle stretch. However, what exactly is being assessed is expressed and interpreted in different ways. A clear diagnostic framework is lacking. Therefore, the aim was to arrive at unambiguous terminology about the concepts and measurement around pathophysiological neuromuscular response to passive muscle stretch. METHODS: During two consensus meetings, 37 experts from 12 European countries filled online questionnaires based on a Delphi approach, followed by plenary discussion after rounds. Consensus was reached for agreement ≥75%. RESULTS: The term hyper-resistance should be used to describe the phenomenon of impaired neuromuscular response during passive stretch, instead of for example 'spasticity' or 'hypertonia'. From there, it is essential to distinguish non-neural (tissue-related) from neural (central nervous system related) contributions to hyper-resistance. Tissue contributions are elasticity, viscosity and muscle shortening. Neural contributions are velocity dependent stretch hyperreflexia and non-velocity dependent involuntary background activation. The term 'spasticity' should only be used next to stretch hyperreflexia, and 'stiffness' next to passive tissue contributions. When joint angle, moment and electromyography are recorded, components of hyper-resistance within the framework can be quantitatively assessed. CONCLUSIONS: A conceptual framework of pathophysiological responses to passive muscle stretch is defined. This framework can be used in clinical assessment of hyper-resistance and will improve communication between clinicians. Components within the framework are defined by objective parameters from instrumented assessment. These parameters need experimental validation in order to develop treatment algorithms based on the aetiology of the clinical phenomena.

Differences in globus pallidus neuronal firing rates and patterns relate to different disease biology in children with dystonia.

BACKGROUND: The pathophysiology underlying different types of dystonia is not yet understood. We report microelectrode data from the globus pallidus interna (GPi) and globus pallidus externa (GPe) in children undergoing deep brain stimulation (DBS) for dystonia and investigate whether GPi and GPe firing rates differ between dystonia types. METHODS: Single pass microelectrode data were obtained to guide electrode position in 44 children (3.3-18.1 years, median 10.7) with the following dystonia types: 14 primary, 22 secondary Static and 8 progressive secondary to neuronal brain iron accumulation (NBIA). Preoperative stereotactic MRI determined coordinates for the GPi target. Digitised spike trains were analysed offline, blind to clinical data. Electrode placement was confirmed by a postoperative stereotactic CT scan. FINDINGS: We identified 263 GPi and 87 GPe cells. Both GPi and GPe firing frequencies differed significantly with dystonia aetiology. The median GPi firing frequency was higher in the primary group than in the secondary static group (13.5 Hz vs 9.6 Hz; p=0.002) and higher in the NBIA group than in either the primary (25 Hz vs 13.5 Hz; p=0.006) or the secondary static group (25 Hz vs 9.6 Hz; p=0.00004). The median GPe firing frequency was higher in the NBIA group than in the secondary static group (15.9 Hz vs 7 Hz; p=0.013). The NBIA group also showed a higher proportion of regularly firing GPi cells compared with the other groups (p<0.001). A higher proportion of regular GPi cells was also seen in patients with fixed/tonic dystonia compared with a phasic/dynamic dystonia phenotype (p<0.001). The GPi firing frequency showed a positive correlation with 1-year outcome from DBS measured by improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS-m) score (p=0.030). This association was stronger for the non-progressive patients (p=0.006). INTERPRETATION: Pallidal firing rates and patterns differ significantly with dystonia aetiology and phenotype. Identification of specific firing patterns may help determine targets and patient-specific protocols for neuromodulation therapy. FUNDING: National Institute of Health Research, Guy's and St. Thomas' Charity, Dystonia Society UK, Action Medical Research, German National Academic Foundation.

Good outcome following emergency decompressive craniectomy in a case of malignant middle cerebral artery infarction in a 14-month-old infant.

We report the case of a 14-month-old infant presenting with unresponsiveness and seizure following thoracic surgery. Imaging showed full territory left middle cerebral artery infarct and signs of raised intracranial pressure (ICP) that required emergency decompressive craniectomy (DC). The child made a good functional recovery. We discuss the case.

Expression of aberrant beta-catenin and impaired p63 in craniopharyngiomas.

Craniopharyngiomas are rare, histologically benign, non-neuroepithelial epithelial tumors arising from the sellar region, the molecular pathogenesis of CPs is yet not understood. The aim of the present study was to assess expression of aberrant beta-catenin and impaired p63 in 66 craniopharyngiomas included 51 adamantinomatous craniopharyngiomas and 15 squamous papillary craniopharyngiomas. On immunohistochemistry, 47 out of 51 adamantinomatous craniopharyngiomas, but not squamous papillary craniopharyngiomas, showed strong nuclear/cytoplasmic expression for beta-catenin predominantly in compactly cohesive epithelial cells within the whorl-like arrays where ki-67 was almost absent and rarely in palisaded cells where ki-67 was mainly present. P63 overexpression was observed in 45 out of 51 adamantinomatous craniopharyngiomas and 14 out of 15 squamous papillary craniopharyngiomas. P63 stained not only in the nuclei of basal layer cells but also within the whorl-like arrays in adamantinomatous craniopharyngiomas and uniformly in squamous papillary craniopharyngiomas. Using quantitative real time polymerase chain reaction techniques to correlate p63 protein expression with p63 mRNA levels, TAp63 isoforms mRNA was reduced, whereas DeltaNp63 mRNA elevated at levels in 5 snap frozen tissue samples with multiple large p63 positive cell clusters compared with normal tissues. In conclusion, the present study confirmed that the two variants of CPs have genetically not only distinctive but also common feature. It demonstrated that cytoplasm/nuclear beta-catenin accumulation is an exclusively characteristic morphology of adaCPs. P63 immunohistochemical overexpression were found in both adaCPs and spCPs variant when analyzed in the same study. Taken together, the impaired p63 expression may be attributed to elevated DeltaNp63 mRNA and reduced TAp63mRNA in CPs.

Charcot-Marie-Tooth (CMT) disease 1A with superimposed inflammatory polyneuropathy in children.

Charcot-Marie-Tooth (CMT) disease is genetically heterogeneous and subdivided into demyelinating (CMT 1) and axonal (CMT 2) types based on neurophysiology findings. CMT1A, the commonest form associated with duplication of the PMP22 segment on chromosome 17p, often arises in childhood but is generally a slowly progressive disease. We report 2 children presenting with clinical features of an acute inflammatory demyelinating polyneuropathy (AIDP) who were subsequently diagnosed with underlying CMT1A. Both children had neurophysiology and histopathology features consistent with CMT1. Immunoglobulin treatment was initiated considering the evidence of superimposed inflammation and appeared to modify disease progression. Our findings indicate that CMT1A predisposes to a superimposed inflammatory neuropathy. Recognition of this association is difficult, particularly in children without clear family history, but of great importance as immunomodulatory treatment may improve outcome. In addition, we postulate that an underlying genetic polyneuropathy should be suspected if the recovery from AIDP is slower than expected, or incomplete.

Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31 and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at theta = 0.03 for the marker CA-2 (odds in favor of linkage 10(6):1. The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

Acetylcholine receptor delta subunit mutations underlie a fast-channel myasthenic syndrome and arthrogryposis multiplex congenita.

Limitation of movement during fetal development may lead to multiple joint contractures in the neonate, termed arthrogryposis multiplex congenita. Neuromuscular disorders are among the many different causes of reduced fetal movement. Many congenital myasthenic syndromes (CMSs) are due to mutations of the adult-specific epsilon subunit of the acetylcholine receptor (AChR), and, thus, functional deficits do not arise until late in gestation. However, an earlier effect on the fetus might be predicted with some defects of other AChR subunits. We studied a child who presented at birth with joint contractures and was subsequently found to have a CMS. Mutational screening revealed heteroallelic mutation within the AChR delta subunit gene, delta 756ins2 and delta E59K. Expression studies demonstrate that delta 756ins2 is a null mutation. By contrast, both fetal and adult AChR containing delta E59K have shorter than normal channel activations that predict fast decay of endplate currents. Thus, delta E59K causes dysfunction of fetal as well as the adult AChR and would explain the presence of joint contractures on the basis of reduced fetal movement. This is the first report of the association of AChR gene mutations with arthrogryposis multiplex congenita. It is probable that mutations that severely disrupt function of fetal AChR will underlie additional cases.

The effect of serial casting on gait in children with cerebral palsy: preliminary results from a crossover trial.

Serial casting aims to improve an equinus gait pattern in children with spastic cerebral palsy (SCP). We evaluated the effect of short-term stretch casting on gait in children with SCP, compared to the natural history. A crossover trial, consisting of a control phase and a casting phase, was conducted with children randomised into two groups. Both groups were assessed clinically, and using 3D gait analysis, at 0, 5 and 12 weeks. Subjects in one group had the 3 month casting phase first and in the other had the 3 month control period first. Casts were changed weekly and set at maximum available ankle dorsiflexion. The mean changes at 5 weeks and 12 weeks from baseline measurements in the casting phase were compared with the change within the same time interval in the control phase. Significant improvements in passive ankle dorsiflexion (knee flexed) were found at 5 and 12 weeks. Passive ankle dorsiflexion (knee extended), ankle dorsiflexion in single support, ankle dorsiflexion in swing and minimum hip flexion in stance improved significantly at 5 weeks but not at 12 weeks from baseline. Other kinematic parameters, the score on the Gillette Functional Assessment Questionnaire, and maximum reported walking distance were not changed by casting. Casting to improve range appears to improve passive and dynamic ankle dorsiflexion, but the changes are small, short lived and do not appear to affect function.

Clonidine use in the outpatient management of severe secondary dystonia.

OBJECTIVE: To evaluate the safety, efficacy and effective dosage of clonidine in the outpatient (OP) management of secondary dystonia. METHODS: A retrospective analysis of children and young people (CAYP) prescribed clonidine in an OP clinic between January 2011 and November 2013 for dystonia management. Of 224 children receiving clonidine, 149/224 did not have a movement disorder and 12/224 had no data leaving 63 movement disorder cases, 15/63 managed as in-patients, 15/48 suffered from tics leaving 33/63 for OP evaluation. Clonidine effectiveness was assessed by 'yes/no' criteria in improving 5 areas: seating, sleep, pain, tone and involuntary movements. RESULTS: 2/33 motor cases had insufficient data; 7/33 had concurrent therapy leaving 24/33 for analysis. Improvement in at least one area was reported by 20/24 (83%) CAYP: Improved seating tolerance 14/24, and sleep 15/24; reduced pain 15/24; improved tone 16/24 and involuntary movements 17/24. Starting doses ranged from 1 mcg/kg OD to 2 mcg/kg TDS with optimum doses reached on average at 9.5 months follow-up. Maximum dose reached was 75 mcg/kg/day given in 8 divided doses. Average maximum daily dose was 20 mcg/kg/day. The commonest frequency of administration was 8 hourly. Side effects were reported in 11/24 CAYP and discontinued in 1/24 for lack of clinical effectiveness, 1/24 for side effects and 4/24 due to both lack of effectiveness and side effects. CONCLUSION: Clonidine was effective in secondary dystonia management in 83% of cases. A starting dose of 1 mcg/kg TDS was well tolerated and safely escalated. Prospective objective evaluation is now required to confirm the efficacy of clonidine.

Safety and efficacy of high-dose enteral, intravenous, and transdermal clonidine for the acute management of severe intractable childhood dystonia and status dystonicus: An illustrative case-series.

OBJECTIVE: Acute dystonia in children is distressing, painful and can progress to life-threatening status dystonicus. Typical management involves benzodiazepines which can result in respiratory depression requiring PICU admission. Clonidine is less respiratory-depressant, and by facilitating sleep, switches dystonia off. It can also be administered via enteral, continuous intravenous infusion, and transdermal slow release routes. We describe the dose range and safety profile of clonidine management in a case-series of children with severe acute exacerbation of dystonia in a tertiary hospital setting. METHODS: The management of 5 children (3 female, age range 8-14 years) suffering from an acute exacerbation of secondary dystonia requiring hospital admission at the Evelina London Children's Hospital was reviewed. The average and maximum dose of clonidine in mcg/kg/h and routes of administration were recorded for each day of hospital admission. Co-administration of any other medical treatments for dystonia and their route of administration were also recorded. Cardiovascular and respiratory clinical status were measured by recording the daily mean and maximum Paediatric Early Warning Scores (PEWS). RESULTS: Clonidine was administered via enteral, intravenous, and transdermal routes at a median dose of 2.5 mcg/kg/h (range 0.1-9 mcg/kg/h). Administration of high dose clonidine was associated with decreased use of benzodiazepines, morphine, and propofol: avoiding invasive respiratory support for ¾ cases during admission. Clonidine doses via all routes of administration did not correlate with poorer PEWS scores (p = 0.839). Both high dose intravenous and transdermal clonidine where found to be effective. CONCLUSIONS: High dose clonidine administered via different routes can be used in the acute management of severe exacerbations of dystonia. Its use in our cohort was not associated with significant cardio-respiratory depression even at doses as high as 9 mcg/kg/h.

A comparative historical and demographic study of the neuromodulation management techniques of deep brain stimulation for dystonia and cochlear implantation for sensorineural deafness in children.

Cochlear implants for sensorineural deafness in children is one of the most successful neuromodulation techniques known to relieve early chronic neurodisability, improving activity and participation. In 2012 there were 324,000 recipients of cochlear implants globally. AIM: To compare cochlear implant (CI) neuromodulation with deep brain stimulation (DBS) for dystonia in childhood and explore relations between age and duration of symptoms at implantation and outcome. METHODS: Comparison of published annual UK CI figures for 1985-2009 with a retrospective cohort of the first 9 years of DBS for dystonia in children at a single-site Functional Neurosurgery unit from 2006 to 14. RESULTS: From 2006 to 14, DBS neuromodulation of childhood dystonia increased by a factor of 3.8 to a total of 126 cases over the first 9 years, similar to the growth in cochlear implants which increased by a factor of 4.1 over a similar period in the 1980s rising to 527 children in 2009. The CI saw a dramatic shift in practice from implantation at >5 years of age at the start of the programme towards earlier implantation by the mid-1990s. Best language results were seen for implantation <5 years of age and duration of cochlear neuromodulation >4 years, hence implantation <1 year of age, indicating that severely deaf, pre-lingual children could benefit from cochlear neuromodulation if implanted early. Similar to initial CI use, the majority of children receiving DBS for dystonia in the first 9 years were 5-15 years of age, when the proportion of life lived with dystonia exceeds 90% thus limiting benefits. CONCLUSION: Early DBS neuromodulation for acquired motor disorders should be explored to maximise the benefits of dystonia reduction in a period of maximal developmental plasticity before the onset of disability. Learning from cochlear implantation, DBS can become an accepted management option in children under the age of 5 years who have a reduced proportion of life lived with dystonia, and not viewed as a last resort reserved for only the most severe cases where benefits may be at their most limited.

A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22).

Familial hyperaldosteronism type II (FH-II) is caused by adrenocortical hyperplasia or aldosteronoma or both and is frequently transmitted in an autosomal dominant fashion. Unlike FH type I (FH-I), which results from fusion of the CYP11B1 and CYP11B2 genes, hyperaldosteronism in FH-II is not glucocorticoid remediable. A large family with FH-II was used for a genome wide search and its members were evaluated by measuring the aldosterone:renin ratio. In those with an increased ratio, FH-II was confirmed by fludrocortisone suppression testing. After excluding most of the genome, genetic linkage was identified with a maximum two point lod score of 3.26 at theta=0, between FH-II in this family and the polymorphic markers D7S511, D7S517, and GATA24F03 on chromosome 7, a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II; its molecular elucidation may provide further insight into the aetiology of primary aldosteronism.

Evidence for genetic heterogeneity in monilethrix.

Monilethrix is a rare inherited defect of the hair shaft resulting in hair fragility and dystrophic alopecia. In contrast to recent reports mapping monilethrix to the type II epithelial and trichocyte keratin gene cluster on 12q13, we strongly excluded these candidate genes in another family with autosomal dominant monilethrix. Moreover, there was no evidence for linkage of the disease to the keratin gene cluster on chromosome 17q12-q21, thus excluding defects in all known trichocyte and epithelial keratins as the cause of monilethrix in this family. Likewise, several other genes known to play an important role in hair shaft formation (trichohyalin and involucrin, ultra-high sulfur matrix proteins, and transglutaminases 1, 2, and 3) did not provide any evidence for linkage. Our results indicate genetic heterogeneity in monilethrix and suggest that aberrations in at least one other gene result in a similar phenotype.

Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes.

Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized erythrokeratodermia variabilis, and one with erythrokeratodermia and ataxia. Another family had Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both erythrokeratodermia variabilis and erythrokeratodermia with ataxia map to a common region in 1p34-p35. Multipoint linkage and haplotype analyses place erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French-Canadian origin. In contrast, results excluded Greither's disease from the established erythrokeratodermia variabilis gene region indicating genetic heterogeneity of erythrokeratodermias. Based on recombinations, two genes assigned to 1p34-p35 were excluded: cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 (GJA4), a member of the connexin gene family, maps within the erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of erythrokeratodermia variabilis.

Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.

Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21-8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance (theta) of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21-8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21-8qtel most likely does not harbor the genetic defect in this kindred.

First position wobble in codon-anticodon pairing: amber suppression by a yeast glutamine tRNA.

A 2.4-kb fragment of DNA isolated from the Saccharomyces cerevisiae genome was found to suppress amber mutations when its carrier plasmid was present in high copy number. A 1.2-kb subclone of this fragment was sufficient to confer suppressor activity. Sequencing has established that this fragment carries a normal glutamine tRNA gene. Deletion of this tRNA gene from the subclone resulted in the loss of suppressor activity. The tRNAGln has the anticodon CUG that normally recognizes the glutamine codon CAG. We propose that suppression occurs via an inefficient readthrough of the UAG amber stop codons during translation. Such readthrough requires wobble in the first position of the codon.