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A 6-year-old girl presented with recurrent infections, seizures, regression of milestones, silvery hair and organomegaly. A diagnosis of Griscelli syndrome with unusual features of a Dandy Walker cyst and hypergammaglobulinemia, not previously described in literature, was made. The child was treated with supportive measures.
A new phosphoglycerate kinase variant (PGK New Jersey) has been purified from muscle and cultured fibroblasts of a patient with recurrent myoglobinuria. The mutant enzyme had higher than normal affinity for adenosine triphosphate (ATP) and 3-phosphoglycerate, and a shift of the pH optimum towards the acidic side. Antibodies raised against PGK purified from normal muscle were used to evaluate the presence of immunologically cross-reacting enzyme protein in tissues from the patient. Immunodiffusion and an antibody consumption test showed the presence of reduced amounts of cross-reacting material in the patient's muscle. Several PGK variants have been characterized in asymptomatic individuals or in patients with hemolytic anemia. The biochemical features of PGK New Jersey, the only known variant associated with recurrent myoglobinuria, distinguish this mutant enzyme from others.
PURPOSE: Since chronic inflammation contributes to tumorigenesis, we hypothesized that the risk and clinical outcome of bladder cancer (BC) might be modulated by genetic variations in inflammation genes. METHODS: Using the TaqMan method, we genotyped single nucleotide polymorphisms in interleukin (IL) -6 (-174 G-->C), IL-8 (-251 T-->A), tumor necrosis factor-alpha (TNF-alpha; -308 G-->A), and peroxisome proliferator-activated receptor gamma (PPARG; Pro12Ala), and determined their associations with BC initiation and clinical outcome. RESULTS: We found that the IL-6 variant genotype (C/C) was associated with an increased BC risk (OR, 1.77; 95% CI, 1.25 to 2.51). There were joint effects between the variant IL-6 genotypes and smoking status, and between the variant genotypes of IL-6 and other genes. To assess effect on recurrence, we grouped non-muscle-invasive BC patients according to intravesical Bacillus Calmette-Guerin (BCG) treatment status: no BCG, induction BCG (iBCG), and maintenance BCG (mBCG). In the Cox proportional hazards model, the variant IL-6 genotype was associated with an increased recurrence risk (hazard ratio [HR], 4.60; 95% CI, 1.24 to 17.09) in patients receiving mBCG. The variant PPARG genotype was associated with a reduced recurrence risk (HR, 0.41; 95% CI, 0.20 to 0.86) among untreated patients. In patients with non-muscle-invasive BC, the variant IL-6 genotype was associated with an increased progression risk (HR, 1.88; 95% CI, 0.80 to 4.11). In patients with invasive BC, variant IL-6 was associated with improved 5-year overall and disease-specific survival (HR, 0.43; 95% CI, 0.19 to 0.94 and HR, 0.39; 95% CI, 0.15 to 1.00, respectively). CONCLUSION: Inflammation gene polymorphisms are associated with modified BC risk, treatment response, and survival.
We studied a recurrent meningioma located in the right frontal lobe. The tumor showed high cellularity and the cells had plump, hyalinous cytoplasm. Immunohistochemically, almost all the tumor cells were positive for epithelial membrane antigen and vimentin, and unexpectedly, glial fibrillary acidic protein (GFAP). Ultrastructural investigation revealed abundant 8- to 10-nm filaments in the cytoplasm. Conspicuous interdigitations with numerous desmosomes were present. Frequently, intracellular and intercellular lumina lined by microvilli were also found. We considered the present case to be an unusual variant of meningioma with GFAP expression. A few cases of meningioma with triple expression of GFAP, vimentin and cytokeratin have been reported previously. However, the present case showed obvious pathological differences from these, and had no immunoreactivity for cytokeratin.
BACKGROUND: Desmoplastic neurotropic melanoma (DNM) is an uncommon cutaneous melanoma variant with pronounced neurotropism. In contrast to ordinary melanomas, locoregional recurrences are common and distant metastasis are uncommon in patients with DNM. Local control with surgery and radiation therapy may assume a more important role in this variant of melanoma. We present a case of an unresectable skull base recurrence of DNM that was controlled using radiation therapy alone and review the literature. METHODS: Case report with 36-month follow-up. RESULTS: The patient is a 68-year-old with multiple recurrences of a DNM that originated on the forehead. After extensive surgery, including total parotidectomy and temporal bone resection, the patient had an unresectable recurrence of the skull base develop. This was treated with definitive radiation therapy, resulting in a complete response. The patient has had no evidence of recurrence at 3 years. CONCLUSIONS: DNM is a locally aggressive type of melanoma with a high risk of local recurrence that can be radioresponsive. The incidence of distant metastasis is low, so aggressive treatment to control local disease is warranted. This may include surgery plus adjuvant radiation therapy or definitive radiotherapy for unresectable recurrences.
A 40 year old man presented with recurrent episodes of dyspnoea whilst swallowing solid food. He had undergone right pneumonectomy and thoracoplasty for recurrent pneumonias and empyema 23 years previously. Solid food boluses appeared to cause bronchial obstruction by compressing the surgically distorted left main bronchus. This is a new variant of the post pneumonectomy syndrome.
The aim of the present work was to study the causes of post-operative recurrences of varicosity and to define approaches to their optimal correction. Duplex scanning (DS) with Color Doppler Imaging of the blood flow was used to examine 126 patients (136 extremities) with recurrences of varicosity. The patients were distributed according to the CEAP clinical classification. Altogether 76 patients (78) extremities with recurrences of varicosity were operated on. 27 persons received different variants of sclerotherapy including echoscleroobliteration. According to the DS data, the most frequently obtained finding in patients with recurrences of varicosity was identification of the perforating veins with valvular insufficiency, namely in 120 (or in 88.2%) extremities. The long stump of the greater saphenous vein (CSV) was discovered in 86 (63.2%) extremities, the long stump of the lesser saphenous vein (LSV) in 6 (4.4%), ectasia of LSV trunk was recognised in 20 (14.5%), incompetence of the valves of the sural veins in 12 (8.8%) extremities. Incompetence of the valves of the deep veins was present in 73 (53.6%) patients. No sources of pathological veno-venous runoff were identified in 12 (8.1%) cases. A good agreement was established between the incidence of valvular incompetence of the deep veins and the disease severity. The indications for surgical correction of valvular insufficiency were worked out. It has been demonstrated that sclero-obliteration is the method of choice in the treatment of the recurrences of varices. The long-term results of operations for recurrences of varicosity were followed up in 62 patients over the period of one to 15 years. Good and satisfactory results were obtained in 60 (96.8%) cases. The authors believe that the majority of varicosity recurrences arise from an inadequate assessment of the status of lower extremity venous bed as well as from technical and methodological faults of the operating surgeon. DS in an indispensable component of preoperative examination of patients with varicosity recurrences.
The high prevalence of nonrheumatic inflammatory diseases of the myocardium and their tendency to recur under the effect of exacerbation of a focal infection and respiratory diseases necessitate the organization of regular comprehensive medical examination of this category of patients and the prevention of recurrences. Preventive methods depending on the form and variant of the disease and on the presence or absence of foci of chronic infection are discussed. A follow-up of these patients showed that the conduction of preventive measures reduced considerably recurrences of the disease and the period during which the patients were incapable of working.
Developmental delay and seizures with or without movement abnormalities (OMIM 617836) caused by heterozygous pathogenic variants in the DHDDS gene (DHDDS-CDG) is a rare genetic disease that belongs to the progressive encephalopathy spectrum. It results in cognitive delay in affected children, accompanied by myoclonus, seizures, ataxia and tremor, which worsens over time. DHDDS encodes a subunit of a DHDDS/NUS1 cis-prenyltransferase (cis-PTase), a branch point enzyme of the mevalonate pathway essential for N-linked glycosylation. We describe the first mouse model of this disease, DhddsR37H+/- strain, heterozygous for the human recurrent de novo c.110G>A:p.R37H pathogenic variant. DhddsR37H+/- mice present with seizures, myoclonus and memory deficits associated with reduced density or/and maturity of inhibitory interneurons in the cortex. Multiomics analyses of mouse CNS tissues, together with the enzymatic/structural characterization of the R37H DHDDS mutant protein, reveal that the variant produces a catalytically inactive enzyme and results in a brain dolichol deficit, aberrant glycosylation of brain glycoproteins, including those involved in synaptic transmission and major perturbations in the CNS proteome and lipidome. Acetazolamide, a carbonic anhydrase inhibitor clinically approved for treatment of glaucoma, epilepsy, and intracranial hypertension, and successfully used "off-label" to treat genetic movement disorders, reduces seizure susceptibility to pentylenetetrazol in DhddsR37H+/- mice, suggesting potential therapeutic value of using this drug in human DHDDS-CDG patients. Together, our results define cis-PTase as a master regulator of CNS development and function and establish that its monoallelic debilitating variants cause a novel congenital disorder of glycosylation associated with aberrant levels of neuronal proteins and lipids.
We performed a retrospective evaluation of survival and patterns of failure in 317 consecutive endometrial cancer patients treated between 1974 and 1991 with surgery and adjuvant radiotherapy. Two hundred and forty seven patients (78%) had FIGO stage I disease, 30 (9%) - stage II, 35 (11%) - stage III and 5 (2%) - stage IV. Both low dose rate brachytherapy (BRT) and external beam radiation (EBRT) were applied in 247 patients (78%), only BRT in 49 (15%), and only EBRT in 21 (7%). Median follow-up was 7.3 years. Five-year overall survival was 75%, and five-year disease free survival was 81%. Both overall and disease free survival rates were correlated with stage (P = 0.001 and P = 0.000, respectively). Recurrence occurred in 70 patients (22%): 11 (3.5%) in the pelvis, 51 (16%) outside the pelvis and 6 (2%) both in- and outside the pelvis. Independent risk factors for local recurrence included older age (P = 0.03) and variant histologic subtypes (P = 0.039), whereas independent risk factors for distant spread were stage (P = 0.000) and older age (P = 0.011). Normalized Total Dose (the sum of EBRT and BRT doses, based on linear-quadratic equation), type of radiotherapy regimen, overall radiotherapy time and surgery-to-radiotherapy interval did not correlate with the risk of relapse. Severe early and late radiotherapy complications were observed in 21 (7%) and 35 patients (11%), respectively. In view of the relatively low risk of exclusive pelvic recurrences and the high rate of severe late radiotherapy complications, indications for postoperative radiotherapy and its scheme should be verified. A relatively high rate of extrapelvic recurrences calls for effective systemic adjuvants to surgery. Further definition of high risk patients is warranted in order to tailor postoperative therapy to the prognostic factors and to increase the therapeutic index of management of endometrial cancer.
A prospective study was performed to compare the diagnostic potential of color-coded duplex sonography (CCDS) and that of ascending pressure phlebography (APP) in 61 patients before venous stripping. Varicosis of the long saphenous vein was correctly diagnosed and graded by CCDS in 87% of cases, and varicosis of the short saphenous vein in 97%. CCDS was inaccurate in 3 of 4 cases of recurrent varicosis of the long saphenous vein. Anterior femoral cutaneous varicosis (n = 3), mild postthrombotic syndrome (n = 1) and variant venous anatomy (n = 1) were not diagnosed on CCDS. One Baker cyst was diagnosed by CCDS. In the assessment of venous reflux CCDS seems to be superior to APP. Our results suggest that CCDS is a valuable diagnostic tool for routine imaging before venous stripping. However, patients with ambiguous or inconclusive CCDS results (eg. recurrent varicosis, venous variants) should be examined by APP.
OBJECTIVE: To investigate clinical significance of non-recurrent laryngeal nerve. METHODS: Clinical data from 4 cases of non-recurrent laryngeal nerve and related literature review was made to acknowledge its incidence, variant types and matters concerned during thyroid surgery. RESULTS: Seven hundred and nineteen recurrent laryngeal nerves were exposed during 2156 thyroid operations in Xiangya Hospital, from which 4 were confirmed to hold non-recurrent laryngeal nerves (0.56%). Two cases were found on the right side and the other 2 on the left. Among the 4 cases, 3 (patients) were found to have non-recurrent laryngeal nerves during reoperation because of voice horse after the first operation. The other one was recognized during the first operation. CONCLUSIONS: Non-recurrent laryngeal nerve, a rare anomaly, is very vulnerable during thyroid surgery. Knowing the related knowledge of the non-recurrent laryngeal nerve and its types is helpful to avoid its damage during thyroid surgery.
The evolution of hepatitis C virus (HCV) envelope variation was studied using a liver-transplant model to evaluate the role of HCV quasispecies for hepatocyte infection. Twelve HCV polymerase chain reaction (PCR)-positive liver-transplant recipients (6 with posttransplantation biochemical hepatitis and 6 without hepatitis [controls]) were prospectively evaluated and underwent detailed quasispecies analysis of pre- and postoperative serum samples. HCV amino acid sequence diversity and complexity at the first hypervariable region (HVR1) of the second envelope protein (E2) was correlated with outcome. Recurrence of HCV-induced allograft injury was defined by persistently elevated serum alanine transaminase (ALT) levels. The major variant (sequences >10% of all clones) of recipients with hepatitis accounted for a significantly smaller percent of all preoperative clones compared with controls (41% +/- 6% vs. 69% +/- 8%; P <.015). Recipients with hepatitis had an increased number of pretransplantation major variants (2.5 +/- 0.3 vs. 1.1 +/- 0.2; P <.006). Eighty-three percent of controls had a predominant variant (accounting for >50% of clones) compared with 17% of those with recurrence (P <.05). These differences did not persist postoperatively. In addition, recipients without a pretransplantation predominant variant demonstrated an increased allograft fibrosis score (2.3 +/- 0.3 vs. 0.5 +/- 0.3; P <.015) at 181 to 360 days posttransplantation compared with those in whom a predominant variant was present. Increased HCV envelope complexity may act as a stronger antigenic stimulus or improve hepatocyte receptor binding and lead to allograft hepatitis and fibrosis. Although pretransplantation differences in HCV quasispecies did not persist postoperatively, pretransplantation quasispecies may be a predictor of HCV-induced hepatitis and graft fibrosis after liver transplantation.
Deficiencies of the early components of the classical complement pathway impair the actions of innate and humoral immunity and may lead to increased susceptibility to infections. We have studied the genetic basis of total C4B deficiency in a Finnish patient with recurrent meningitis, chronic fistulas and abscesses. The maternal chromosome carried a four-gene deletion including the C4B gene, and a conversion from C4B to C4A gene was found on the paternal chromosome resulting in complete deficiency of C4B. In the converted C4A gene, mutation screening did not reveal any amino acid changes or prominent mutations, yet a large number of nucleotide variations were found. Further, the patient was heterozygous for structural deficiency of mannan binding lectin (MBL) associating with medium levels of serum MBL. Our data provides new information on the genetic instability of the C4 gene region, and on the association of homozygous C4B deficiency and variant MBL genotype with increased susceptibility to recurrent and chronic infections. Importantly, plasma therapy induced a prompt clinical cure with long-term effects.
Idiopathic CD4+ T lymphocytopenia (ICL) has been defined as a cause of immunodeficiency with a variable clinical course and an unknown etiology. Here we describe a now 18-year-old boy with ICL, chronic mucocutaneous candidiasis (CMC), recurrent abscesses, and relapsing aphthous and ulcerous lesions. In addition to ICL the patient frequently showed a panlymphocytopenia. An increased percentage of gamma+delta+ T lymphocytes and IgD+ IgM+ B lymphocytes, and a decreased percentage of CD21+ B lymphocytes, were observed. In vitro assays showed normal T-cell responses to candidin and T-cell mitogens, but impaired B-cell responses to pokeweed mitogen (PWM). B-cell maturation after stimulation with Staphylococcus aureus Cowan I (SAC) and interleukin 2 (IL-2) was nearly normal. The clinical course of the patient improved substantially on administration of constant low-dose therapy with fluconazole.
Polymorphic variants on chromosomes are considered 'normal', as heterochromatin has no coding potential and nucleolar organizing regions (NOR) contain genes coding for rRNA. Variants have been reported in infertility and recurrent abortions. With refined molecular techniques, genes for fertility and viability are now thought to reside in heterochromatin. DNA sequence analysis of human chromosome 9 has shown that it is highly structurally polymorphic, with many intrachromosomal and interchromosomal duplications, and contains the largest autosomal block of heterochromatin. Transcriptional activation of constitutive heterochromatic domains of the human genome in response to environmental stress was reported recently. Heat shock triggers the assembly of nuclear stress bodies on the pericentromeric heterochromatin of human chromosomes including chromosome 9. These are characterized by an epigenetic status typical of euchromatic regions. On acrocentric chromosomes, NOR-associated protein count and morphology was reported to separate benign and malignant melanocytic lesions. Hence all variants may not be 'normal'. The present study of karyotyping 842 individuals attending an IVF clinic with primary infertility or repeated miscarriages, showed polymorphic variants in 28.82% of males and 17.19% of females, which was quite high. It is suggested that variants should not be ignored by cytogeneticists. Screening prospective gamete donors for chromosome variants may help enhance the success of IVF.
Fortunately, posterior instability of the shoulder is a relatively uncommon occurrence in the athlete. Acute traumatic posterior dislocations can be readily managed by conservative measures. Recurrent posterior subluxation, however, represents a more challenging problem for the orthopedic surgeon. As has been discussed, most patients with this disorder respond to nonsurgical treatment including physical therapy and modification of the offending activities. Should these modalities fail, operative treatment may be necessary. Careful assessment of the patient to rule out the associated presence of excessive ligamentous laxity or a voluntary component to the instability is mandatory. Pain is clearly the principal indicator for surgical treatment. Painless subluxation, either voluntary or involuntary, should first be treated conservatively. The surgical options discussed in this article range from simple soft-tissue repair to more complex osteotomies with combined capsular plication. It is important that the procedure be appropriate to the pathology. We do not believe that one technique alone can address all variants of posterior instability. Most instances of recurrent posterior subluxation represent unidirectional instability in patients with otherwise normal bony morphology. In these patients, a posterior capsulorrhaphy combined with appropriate immobilization should be effective. In select instances, when either excessive glenoid retroversion or deficiency is encountered, a glenoid osteotomy and posterior capsulorrhaphy have proved successful. This technique, more than any other, carries a number of potential technical pitfalls and should be employed cautiously. Multidirectional posterior instability, now a well-recognized entity, requires a different surgical approach--the capsular shift. Designed to address the inferior redundancy, as well as posterior laxity, this procedure is applicable to the multidirectional posterior subluxator. In conclusion, posterior instability of the athlete's shoulder is an increasingly recognized entity. Most instances are amenable to nonsurgical care. Should surgical treatment be necessary, optimal results may be achieved by careful attention to patient assessment, instability categorization, determination of the presence of ligamentous laxity, and appropriate surgical technique.
Seven hundred twenty-one recurrent laryngeal nerves were visualized in 400 patients having thyroid or parathyroid surgery. Four hundred twenty-one nerves (58 percent) bifurcated or trifurcated more than 0.5 cm from the cricoid cartilage. Ninety-seven patients had bilateral bifurcations, and 10 patients had trifurcations. Six patients had direct laryngeal nerves, all on the right side. One patient had a direct laryngeal and a recurrent laryngeal nerve simultaneously, and one patient had a bifurcated recurrent laryngeal nerve with an accessory vagus nerve joining it 13.5 cm from the cricoid cartilage. Damage to any of the filaments of the recurrent laryngeal nerve to the cricothyroid musculature or to or from a variant direct laryngeal nerve or variant vagus nerve connection can cause vocal cord paralysis. Damage to any branches of the recurrent laryngeal nerve to the esophagus can cause dysphagia. Therefore, if possible, all branches of the recurrent laryngeal nerve, no matter how small, should be preserved.