Compound Heterozygous Frameshift Mutations in MESD Cause a Lethal Syndrome Suggestive of Osteogenesis Imperfecta Type XX.

Multiple genes are known to be associated with osteogenesis imperfecta (OI), a phenotypically and genetically heterogenous bone disorder, marked predominantly by low bone mineral density and increased risk of fractures. Recently, mutations affecting MESD, which encodes for a chaperone required for trafficking of the low-density lipoprotein receptors LRP5 and LRP6 in the endoplasmic reticulum, were described to cause autosomal-recessive OI XX in homozygous children. In the present study, whole-exome sequencing of three stillbirths in one family was performed to evaluate the presence of a hereditary disorder. To further characterize the skeletal phenotype, fetal autopsy, bone histology, and quantitative backscattered electron imaging (qBEI) were performed, and the results were compared with those from an age-matched control with regular skeletal phenotype. In each of the affected individuals, compound heterozygous mutations in MESD exon 2 and exon 3 were detected. Based on the skeletal phenotype, which was characterized by multiple intrauterine fractures and severe skeletal deformity, OI XX was diagnosed in these individuals. Histological evaluation of MESD specimens revealed an impaired osseous development with an altered osteocyte morphology and reduced canalicular connectivity. Moreover, analysis of bone mineral density distribution by qBEI indicated an impaired and more heterogeneous matrix mineralization in individuals with MESD mutations than in controls. In contrast to the previously reported phenotypes of individuals with OI XX, the more severe phenotype in the present study is likely explained by a mutation in exon 2, located within the chaperone domain of MESD, that leads to a complete loss of function, which indicates the relevance of MESD in early skeletal development. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..

Prevention of Decompression Sickness by Novel Artificial Oxygen Carriers.

For three decades, studies have demonstrated the therapeutic efficacy of perfluorocarbon (PFC) in reducing the onset of decompression trauma. However, none of these emulsion-based preparations are accepted for therapeutic use in the western world, mainly because of severe side effects and a long organ retention time. A new development to guarantee a stable dispersion without these disadvantages is the encapsulation of PFC in nanocapsules with an albumin shell. PURPOSE: Newly designed albumin-derived perfluorocarbon-based artificial oxygen carriers (A-AOC) are used in a rodent in vivo model as a preventive therapy for decompression sickness (DCS). METHODS: Thirty-seven rats were treated with A-AOC (n = 12), albumin nanocapsules filled with neutral oil (A-O-N, n = 12), or 5% human serum albumin solution (A-0-0, n = 13) before a simulated dive. Eleven rats, injected with A-AOC, stayed at normal pressure (A-AOC surface). Clinical, laboratory, and histological evaluations were performed. RESULTS: The occurrence of DCS depended on the treatment group. A-AOC significantly reduced DCS appearance and mortality. Furthermore, a significant improvement of survival time was found (A-AOC compared with A-0-0). Histological assessment of A-AOC-dive compared with A-0-0-dive animals revealed significantly higher accumulation of macrophages, but less blood congestion in the spleen and significantly less hepatic circulatory disturbance, vacuolization, and cell damage. Compared with nondiving controls, lactate and myoglobin showed a significant increase in the A-0-0- but not in the A-AOC-dive group. CONCLUSION: Intravenous application of A-AOC was well tolerated and effective in reducing the occurrence of DCS, and animals showed significantly higher survival rates and less symptoms compared with the albumin group (A-0-0). Analysis of histological results and fast reacting plasma parameters confirmed the preventive properties of A-AOC.

"Denervation" of autonomous nervous system in idiopathic pulmonary arterial hypertension by low-dose radiation: a case report with an unexpected outcome.

Vasointestinal peptide metabolism plays a key physiological role in multimodular levels of vasodilatory, smooth muscle cell proliferative, parenchymal, and inflammatory lung reactions. In animal studies, vasointestinal peptide relaxes isolated pulmonary arterial segments from several mammalian species in vitro and neutralizes the pulmonary vasoconstrictor effect of endothelin. In some animal models, it reduces pulmonary vascular resistance in vivo and in monocrotaline-induced pulmonary hypertension. A 58-year-old woman presented with dyspnea and mild edema of the lower extremities. A bronchoscopy was performed without any suspicious findings suggesting a central tumor or other infiltrative disease. Endobronchial ultrasound revealed enlarged pulmonary arteries containing thrombi, a few enlarged lymph nodes, and enlarged mediastinal tissue anatomy with suspicion for mediastinal infiltration of a malignant process. We estimated that less than 10% of the peripheral vascular bed of the lung was involved in direct consolidated fibrosis as demonstrated in the left upper lobe apex. Further, direct involvement of fibrosis around the main stems of the pulmonary arteries was assumed to be low from positron emission tomography and magnetic resonance imaging scans. Assuming a positive influence of low-dose radiation, it was not expected that this could have reduced pulmonary vascular resistance by over two thirds of the initial result. However; it was noted that this patient had idiopathic pulmonary arterial hypertension mixed with "acute" (mediastinal) fibrosis which could have contributed to the unexpected success of reduction of pulmonary vascular resistance. To the best of our knowledge, this is the first report of successful treatment of idiopathic pulmonary arterial hypertension, probably as a result of low-dose radiation to the pulmonary arterial main stems. The patient continues to have no specific complaints concerning her idiopathic pulmonary arterial hypertension.

Refinement of the GINGF3 locus for hereditary gingival fibromatosis.

Hereditary gingival fibromatosis (HGF) is a rare, clinically variable disorder characterized by slowly progressive fibrous overgrowth of the gingiva. Four gene loci have been mapped for autosomal dominant non-syndromic HGF (adHGF). The molecular basis of adHGF remains largely unknown, with only a single SOS1 gene mutation identified so far at the gingival fibromatosis 1 (GINGF1) locus in one family. We identified an adHGF family with ten affected individuals in whom onset of gingival fibromatosis concurred with the eruption of the primary teeth. In order to identify the molecular basis in this family, we tested for linkage of the disease to known adHGF loci. A maximal multipoint logarithm of the odds score of 3.91 was obtained with marker D2S390 (theta = 0) at the GINGF3 locus on chromosome 2p23.3-p22.3, and linkage to other known loci was excluded. Sequencing two candidate genes, ALK and C2orf18, and a single nucleotide polymorphisms array analysis did not reveal a mutation or copy number variation in a patient from the family. We refined the GINGF3 locus to a 6.56-cM, 8.27-Mb region containing 112 known and hypothetical genes, and our data and a search of the literature suggest that GINGF3 is a major adHGF locus.

Neoadjuvant gonadotropin-releasing hormone therapy before surgery may improve the fertility index in undescended testes: a prospective randomized trial.

PURPOSE: Subfertility is considered the principal consequence of cryptorchidism even after timely orchiopexy. Gonadotropin-releasing hormone (GNRH) treatment appears to improve fertility later in life by inducing germ cell maturation. In a prospectively randomized trial we investigated whether preoperative GNRH therapy improves the fertility index in primary cryptorchidism. MATERIALS AND METHODS: A total of 42 boys 11 to 100 months old (median 33.5) with 63 undescended testes were prospectively assigned to 2 groups during a 6-month period. Patients were randomized to receive either orchiopexy alone (21 patients) or with neoadjuvant GNRH therapy (21) as a nasal spray for 4 weeks at 1.2 mg per day. In both groups testicular biopsies were performed at the time of orchiopexy and histopathological fertility index was determined. RESULTS: Mean fertility index in the group treated with GNRH before surgery was significantly higher (1.05, SD +/- 0.71) compared to the group without hormonal stimulation (0.52, SD +/- 0.39, p <0.05). The subgroup of neoadjuvant stimulated boys younger than 24 months achieved the best results compared to the age matched boys without hormonal treatment. CONCLUSIONS: Neoadjuvant GNRH treatment improves fertility index in prepubertal cryptorchidism. Consequently, preoperative hormone therapy should improve fertility in adulthood. Additionally, the nasal application is well tolerated, safe and already recommended in an adjuvant setting after orchiopexy. Maximum salvage of active germinal tissue is achieved by treating cryptorchidism before the end of the first year of life.

Steroid- and ATG-resistant rejection after double forearm transplantation responds to Campath-1H.

We herein report on immunological and histological observations in the first bilateral forearm transplant recipient. The last of three rejection episodes occurring on day 95 after transplantation was resistant to steroid and antithymocyte globulin (ATG) treatment. Histology demonstrated lymphocytic infiltrates, apoptotic and necrotic keratinocytes and focal desquamation of the epidermis. Therapy with Campath-1H, however, resulted in complete restitution of normal skin. This is the first report on a successful rescue therapy with Campath-1H in a severe, steroid- and ATG-resistant rejection. Hence, Campath-1H treatment might be a novel and powerful therapeutic option for multiresistant allograft rejection.

The rectogenital septum: morphology, function, and clinical relevance.

PURPOSE: The rectogenital septum (known in clinical literature as Denonvilliers' fascia) forms an incomplete partition between the rectum and the urogenital organs in both men and women. It is composed of collagenous and elastic fibers and smooth muscle cells intermingled with nerve fibers emerging from the autonomic inferior hypogastric plexus. The aim of this study was to investigate the fetal development of the rectogenital septum, and the origin and innervation of the longitudinal smooth muscle cells within the septum, as well as to consider possible effects on function of operations that compromise the integrity of these structures. METHODS: Macroscopic dissections on embalmed human pelves and plastination histology of 40 fetal and newborn pelvic specimens were performed. By means of conventional and immunohistochemical staining methods using monoclonal and polyclonal antibodies for tissue analysis and neuronal labeling, the motor and sensory innervation of the longitudinal muscle bundles within the septum was defined. RESULTS: The rectogenital septum is formed by a local condensation of mesenchymal connective tissue in the early fetal period. The longitudinal muscle bundles could be traced back to the longitudinal layer of the rectal wall, and, using the septum as a guiding structure, it was possible to identify autonomic nerve fibers and ganglion cells innervating the muscle cells and crossing the midline without detectable gender differences. CONCLUSIONS: Because of a coinnervation of the rectal muscle layers and the adjacent longitudinal muscle fibers of the septum, a functional correlation between the two structures during defecation is postulated. On the basis of these findings, a safer dissection of the anterior rectal wall during rectal resection is postulated, thus limiting functional disturbance and preventing neural damage.

Joubert-like syndrome unlinked to known candidate loci.

We observed the Joubert syndrome (JS) associated with bilateral morning glory disk anomaly and cystic dysplastic kidneys in three patients from a consanguineous kindred. Homozygosity mapping excluded three JS candidate loci as sites harboring the disease gene. We thus delineate an autosomal recessive disorder, distinct from JS and related conditions.

The superior rectal artery and its branching pattern with regard to its clinical influence on ligation techniques for internal hemorrhoids.

BACKGROUND: The hemorrhoidal artery ligation has been used for submucosal ligation of hemorrhoidal arteries by means of an ultrasonographic transducer since 1995. The success of this technique depends on the submucosal course of these arteries. Our investigation deals with branches of the superior rectal artery which pierce the rectal wall where they cannot be reached by this method. METHODS: The branching patterns were investigated by means of 5 macroscopic preparations of adult pelves, histological section series of 35 fetal and 3 adult pelves impregnated in epoxy-resin, and transperineal color Doppler ultrasound of 7 proctologic patients and 28 volunteers. RESULTS: Additional branches of the superior rectal artery coursing in outer layers of the rectal wall were shown entering the rectal wall just above the levator ani muscle to supply the internal hemorrhoidal plexus (corpus cavernosum recti). CONCLUSIONS: The terminal course of the branches of the superior rectal artery is not only applied to the rectal submucosa. We have shown that additional branches may be detected by ultrasonography and should be taken into account by the operating surgeon.

Lessons to be learned from a complicated case of rhino-cerebral mucormycosis in a renal allograft recipient.

Fungal infections still represent a serious complication after organ transplantation. Early diagnosis and aggressive treatment are crucial. Because of the many diagnostic problems involved, we present a case of mucormycosis--primarily affecting the paranasal sinuses with later intracranial extension--in a highly immunized recipient of a third renal transplant. Although fungal infection was suspected from various imaging techniques, only the detection of typical fungal hyphae in the infected tissue was diagnostic. Neither the blood tests and cerebrospinal fluid examinations performed nor cultures from maxillary sinus fluid were of any diagnostic help. Surgical debridement from a transnasal as well as an intracranial approach and systemic amphotericin B together with the discontinuation of immunosuppression after removal of the rejected graft were able to save the patient. This case stresses the importance of early diagnosis that can only be made from tissue biopsies and allows appropriate timely treatment.

High-dose-rate intraoperative brachytherapy (IOHDR) using flab technique in the treatment of soft tissue sarcomas.

BACKGROUND: Adjuvant radiotherapy has been shown to improve local control in patients with soft tissue sarcoma. Additional brachytherapy represents a means of enhancing the therapeutic ratio, as biological and dosimetric advantage over single external-beam irradiation (EBRT) can be expected. High-dose-rate intraoperative brachytherapy (IOHDR) as a boost therapy should therefore be able to further diminish the rate of local recurrence even when performing marginal resection. There are sparse data on IOHDR using flab applicators as adjuvant boost to EBRT in combination with marginal resection of soft tissue sarcomas. PATIENTS AND METHODS: Within a period of 8 years, we prospectively studied 39 adult patients treated by marginal resection, IOHDR using the flab technique and EBRT for soft tissue sarcomas. There were 32 high-grade and seven low-grade tumors, 35 were > 5 cm. Mean follow-up was 26 months (range 3-59 months). RESULTS: We could not detect any local recurrences. No treatment-related loss of limb or life occurred. There were no neurologic or vascular complications, all patients maintained functioning extremities as evidenced by a mean Musculoskeletal Tumor Society (MSTS) functional score of 88.5 (70-100). Treatment-related wound morbidity occurred in eleven patients necessitating revision surgery in eight. Metastatic disease developed in seven patients, six of them had died. The 2-year actuarial disease-free survival was 84%. CONCLUSIONS: IOHDR using the flab technique in combination with EBRT and marginal resection is an efficient treatment technique leading to optimal local control rates and limited functional impairment.

Diffusion-weighted magnetic resonance imaging for monitoring diffusion changes in rectal carcinoma during combined, preoperative chemoradiation: preliminary results of a prospective study.

PURPOSE: To evaluate the clinical value of diffusion-weighted magnetic resonance imaging (DW-MRI) to monitor response of primary carcinoma of the rectum to preoperative chemoradiation by measuring tumor apparent diffusion coefficient (ADC). MATERIALS AND METHODS: Diffusion data of nine patients undergoing preoperative combined chemoradiation for clinical staged T3, N(0-2), M(0) carcinoma of the rectum were analyzed. Diffusion-weighted echo-planar MR images were obtained prior to and at specified intervals during chemoradiation and ADCs calculated from acquired tumor images. RESULTS: Comparison of mean ADC and cumulative radiation dose showed a significant decrease of mean ADC at the 2nd (P = 0.028), 3rd (P = 0.012), and 4th (P = 0.008) weeks of treatment. Cytotoxic edema and fibrosis were considered as reasons for ADC decrease. CONCLUSION: This study demonstrated tumor ADC changes via detection of therapy-induced alterations in tumor water mobility. Our results indicate that diffusion-weighted imaging may be a valuable clinical tool to diagnose the early stage of radiation-induced fibrosis.

Eosinophilic granuloma of the bone: ultrasonographic imaging.

Eosinophilic granuloma is a rare disease of unknown aetiology that affects the bones. Two cases of eosinophilic granuloma are presented. Ultrasonographic, CT and histopathological findings are described. Ultrasonographic-guided core-needle biopsy was performed. Treatment was initiated by installing steroid suspension into the lesions, which resulted in complete healing of the bone in both cases.

OCP2 immunoreactivity in the human fetal cochlea at weeks 11, 17, 20, and 28, and the human adult cochlea.

The two most abundant proteins of the organ of Corti, OCP1 and OCP2, are acidic, cytosolic, low molecular weight proteins diffusely distributed within the cytoplasm of supporting cells. A recent study by Henzl et al. (2001) found first, that these two proteins co-localize with connexin 26 along the epithelial gap junction system and second, that OCP2 could participate with OCP1 in an organ of Corti-specific SCF complex (Skp1, cul1in, and Fbp), a ubiquitin ligase complex. Previous study has also implicated OCP2 in the recycling and regulation of intracellular K(+) efflux as well as pH homeostatic mechanisms. In the present study, we document the emergence and distribution features of OCP2 through various stages (weeks 11-28) of gestation in human fetal cochleae. Four fetal cochleae, the cochleae of a normal hearing human adult and a mature rat for positive control were fixed in 4% formalin within 2 h post mortem. Immunohistochemical studies were performed using a rabbit polyclonal antibody raised against a synthetic peptide corresponding to amino acids 3-16. Specimens were mounted in paraffin sections. Results show that OCP2 immunoreactivity is evident at a prenatal age of 11 weeks, peaks in expression at the onset of cochlear function at 20 weeks and achieves adult-like patterns of distribution just prior to histological maturation at 28 weeks. Though this protein could be associated with the development, maturation, and electrochemical maintenance of the cochlear gap junction system, the nature of this protein's function in the developing and mature human cochlea remains unclear.

"Occupational backache" - surface electromyography demonstrates the advantage of an ergonomic versus a standard microscope workstation.

Musculoskeletal symptoms such as low back pain, neck pain, and tension headache are reported by up to 80% of professional personnel involved in daily microscope work. Yet, in striking contrast to the high prevalence of complaints, there is a general unawareness of this issue both in those suffering, and those ordering and designing microscopes. We intend to call attention to this underestimated work-related health hazard and to demonstrate a potential means of prevention. We obtained repeated surface electromyographic (EMG) recordings from the most strained neck, upper limb, and back muscles in 12 healthy volunteers while they were operating a near-to-ergonomic prototype workstation and a conventional microscope, respectively. Mean EMG activity was reduced in all recorded muscles when operating the ergonomic workstation compared to the standard microscope. This improvement became more distinct with sustained work, and was most pronounced in those muscles displaying the highest degree of activity while using the standard microscope. We demonstrate the usefulness of surface EMG recordings to show the advantage of an ergonomically tailored and individually adjustable microscope workstation over a standard microscope. The former allows the operator to maintain a more physiological posture, and may thus prevent the development of cumulative musculoskeletal disorders during prolonged microscope-related work.