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BMP6 is a central cytokine in the induction of Sjögren's syndrome-associated (SS-associated) secretory hypofunction. However, the upstream initiation leading to the production of this cytokine in SS is unknown. In this study, RNA ISH on salivary gland sections taken from patients with SS indicated monocytic lineage cells as a cellular source of BMP6. RNA-Seq data on human salivary glands suggested that TLR4 signaling was an upstream regulator of BMP6, which was confirmed by in vitro cell assays and single-cell transcriptomics of human PBMCs. Further investigation showed that HSP70 was an endogenous natural TLR4 ligand that stimulated BMP6 expression in SS. Release of HSP70 from epithelial cells could be triggered by overexpression of lysosome-associated membrane protein 3 (LAMP3), a protein also associated with SS in several transcriptome studies. In vitro studies supported the idea that HSP70 was released as a result of lysosomal exocytosis initiated by LAMP3 expression, and reverse transcription PCR on RNA from minor salivary glands of patients with SS confirmed a positive correlation between BMP6 and LAMP3 expression. BMP6 expression could be experimentally induced in mice by overexpression of LAMP3, which developed an SS-like phenotype. The newly identified LAMP3/HSP70/BMP6 axis provided an etiological model for SS gland dysfunction and autoimmunity.

Purpose: To develop a novel method to quantify the amount of fibrosis in the salivary gland and to investigate the relationship between fibrosis and specific symptoms associated with Sjögren's syndrome (SS) using this method., Materials and Methods: Paraffin-embedded labial salivary gland (LSG) slides from 20 female SS patients and their clinical and LSG pathology data were obtained from the Sjögren's International Collaborative Clinical Alliance. Relative interstitial fibrosis area (RIFA) in Masson's trichrome-stained LSG sections was quantified from digitally scanned slides and used for correlation analysis. Gene expression levels were assessed by microarray analysis. Core promoter accessibility for RIFA-correlated genes was determined using DNase I hypersensitive sites sequencing analysis., Results: RIFA was significantly correlated with unstimulated whole saliva flow rate in SS patients. Sixteen genes were significantly and positively correlated with RIFA. In a separate analysis, a group of differentially expressed genes was identified by comparing severe and moderate fibrosis groups. This combined set of genes was distinct from differentially expressed genes identified in lung epithelium from idiopathic pulmonary fibrosis patients compared with controls. Single-cell RNA sequencing analysis of salivary glands suggested most of the RIFA-correlated genes are expressed by fibroblasts in the gland and are in a permissive chromatin state., Conclusion: RIFA quantification is a novel method for assessing interstitial fibrosis and the impact of fibrosis on SS symptoms. Loss of gland function may be associated with salivary gland fibrosis, which is likely to be driven by a unique set of genes that are mainly expressed by fibroblasts., 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 © 2021 Yin, Pranzatelli, French, Zhang, Warner, Chiorini and NIDCD/NIDCR Genomics and Computational Biology Core.)

Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.

Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals.

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

The increasing demand in the clinical genetics setting for information about teratogen exposures has created a need for genetic counselors to have the capabilities to appropriately address patient concerns. In order to assess how training in teratogen counseling is currently being conducted, the GLaRGG Teratogen Subcommittee surveyed all 17 genetic counseling training programs in North America in September 1993. Information was obtained from training programs about coursework, resources, and clinical training. In addition, each training program was asked to provide information about how their teratogen training needs could better be met. While all programs responded that some information in their coursework applicable to teratogen counseling was provided, there was wide variation in the amount of time devoted to this topic. The programs also greatly differed in the provision of clinical training in teratogen counseling. For both coursework and clinical work, genetic counselors were the main trainers in teratogen counseling. In spite of this, fewer than 25% of training programs have a defined teratogen clinical rotation. Data from the survey are discussed and recommendations presented.

We have studied seven patients who have chromosome 22q13.3 deletions as revealed by high-resolution cytogenetic analysis. Clinical evaluation of the patients revealed a common phenotype that includes generalized developmental delay, normal or accelerated growth, hypotonia, severe delays in expressive speech, and mild facial dysmorphic features. Dosage analysis using a series of genetically mapped probes showed that the proximal breakpoints of the deletions varied over approximately 13.8 cM, between loci D22S92 and D22S94. The most distally mapped locus, arylsulfatase A (ARSA), was deleted in all seven patients. Therefore, the smallest region of overlap (critical region) extends between locus D22S94 and a region distal to ARSA, a distance of > 25.5 cM.

Two siblings are reported with an autosomal recessive syndrome characterized by hair and skin abnormalities, hypoplastic nails, generalized hypotonia, absent reflexes, and progressive neurologic deterioration. Although this disorder shares clinical features with an ectodermal dysplasia syndrome with neurodegenerative changes, no specific neuropathologic findings were present. Instead, trichorrhexis invaginata was found in some hair shafts. Hair analysis may be helpful in classifying clinically confusing neurologic conditions.

The theories of abnormal embryogenesis suggested as explanations for the various forms of SBA and occult spinal dysraphism appear in some instances too all encompassing, as in Gardner's hydrodynamic theory or Padget's neuroschisis theory, or too limited, as in the theory of arrested development proposed by Daniel and Strich for the ACM, or just too speculative in many cases. The observation of a completed defect does not allow one to venture backwards in development to a specific time and cause with any accuracy. Perhaps several different causes striking different tissues at different times can set up a series of aberrations that lead to morphologically similar mature anomalies. The ability of developmental processes to heal themselves, as shown experimentally, may obscure the true mechanism and timing of occurrence although the final morphological expression may be dramatic. Since the study of human embryogenesis in the experimental laboratory is ethically unacceptable although technically feasible, the elucidation of the mechanisms of these neural defects will be long in coming.

Intracranial hemorrhage is a rare but life-threatening complication of childhood idiopathic thrombocytopenic purpura. We present three cases of this complication encountered at our institution, in addition to a tabulation of 15 previously reported cases. Prevention, diagnosis, and management of intracranial hemorrhage in idiopathic thrombocytopenic purpura are discussed. The importance of avoidance of antiplatelet drugs as well as the significance of the location of the intracranial hemorrhage are emphasized. Posterior fossa hemorrhages are especially dangerous because of the possibility of rapid cerebellar herniation and brainstem compression. Management of intracranial hemorrhage should be prompt and aggressive, and splenectomy should always be performed prior to any neurosurgical procedure. It is encouraging that 11 of 18 patients had a favorable outcome.

Two patients with previous brain stem infarction and current symptoms of vascular insufficiency in the basilar circulation had evidence of vertebral artery occlusive disease. Angiography demonstrated ostial stenosis of the dominant right vertebral artery and retrograde flow down the left vertebral artery to the level of the transverse process of C2 in the first case and to the level of a severely stenosed origin in the second case. Carotid circulation was patent in both cases. The blood flow in the posterior circulation was patent in both cases. The blood flow in the posterior circulation was augumented by extracranial anastomosis of the external carotid artery to the vertebral artery in the foramen transversarium at the level of C1-2 by a lateral approach in Case 1 and at the level of C4-5 by an anterior approach in Case 2. Postoperative improvement in neurologic status occurred in both cases.

One thousand consecutive head injuries were evaluated in a 14-month period. Computerized tomography (CT) was performed in 316 patients and 200 (63%) were scanned within 72 hours of injury. Fifty-one percent of patients had abnormal scans. The yield of abnormal scans varied with the neurological state at the time of the scan: alert and normal neurologically, 13%; alert and focal deficit, 50%; impaired consciousness and no lateralizing findings, 35%; impaired consciousness and lateralizing findings, 85%; deep coma or posturing, 56%. Thirty-eight percent of patients had multiple lesions. Repeat scans were done in 103 patients, 52% developed new lesions or deterioration in known lesions, and 31% required subsequent surgery. Ten patients developed delayed onset subdural hygromas noted six to 46 days after injury. Two of eight operated patients improved markedly. The CT scan appearance of subdural lesions may be independent of the time from injury depending upon initial composition and rebleeding episodes. Thus, subdural lesions should not be labeled "acute," "subacute," or "chronic" on the basis of CT morphology alone. Seven patients had subdural lesions with the same density as brain (isodense). Arteriography aided diagnosis in six patients. The CT scan readily shows what proportion of a parenchymal lesion is intracerebral hematoma, contusion, or edema, rather than nonspecific arteriographic mass effect, and allows precise surgical decisions. Eighteen of 40 patients (45%) with "brain stem contusion" harbored surgical lesions, including five cases of delayed subdural hygroma.

Five patients with hypoventilation and paresis of the diaphragm following trauma to the cervical spinal cord, brain stem, or both, were evaluated with phrenic nerve conduction studies while being considered for implantation of a phrenic nerve stimulator. Several distinct patterns of phrenic nerve function were elicited in the various cases, allowing accurate predictions and management decisions to be made. Phrenic nerve conduction studies are felt to be a valuable diagnostic tool in the management of the hypoventilating patient with cranio-cervical trauma. The procedure is safe, rapid, and easily performed at the bedside.

Eight patients were found to have traumatic hematomas of the posterior fossa during a 6-year period. There were four patients with extradural hematomas, one patient with a subdural hematoma, and four patients with intracerebellar hematomas. In one patient, clinically significant hematomas were found both in the extradural space and in the cerebellum. Clinical or radiologic evidence of skull fracture was present in each case, and computed tomography scans were diagnostic of a posterior fossa hematoma in all cases. In six of the eight patients, there was clinical deterioration prior to surgical treatment, and in three cases, this was abrupt. All patients underwent suboccipital craniectomy. Six patients survived; four made a good recovery. Our experience indicates that early operation is usually indicated for these lesions.

Five patients studied by the authors and 28 mentioned in the literature indicate that recurrent stenosis occurs in no less than 0.6% of patients after carotid endarterectomy. The pathology of the recurrent stenosis was stated in only 10 cases indicating atherosclerotic disease in various stages of development in 7 and a fibrous intimal hyperplasia in 3. Correlation between risk factors for the development of atherosclerosis and the pathology of the recurrent disease was poor. Six patients developed recurrent disease despite postoperative prophylactic oral anticoagulation. Surgical technique appeared to have contributed to re-stenosis in 8 patients (1) by failure to remove the distal tongue of plaque or (2) narrowing of the lumen by the arteriotomy suture or (3) damage by a vascular clamp. In 18 symptomatic patients, 44% had symptoms by 3 years, 67% by 5 years, and 83% by 7 years after operation. The 8 patients with possible errors in surgical technique did not develop symptoms earlier than the other patients. Seventeen symptomatic patients had surgical correction of the re-stenosis (endarterectomy 9, vein patch 6, arterial homograft 1, not detailed 1). The incidence of recurrent stenosis after carotid endarterectomy is low and usually the operation provides a patent artery for life.

Ten patients underwent placement of a lumbar subarachnoid catheter attached to a subcutaneous reservoir allowing daily injection of intrathecal morphine sulfate by family members. Sacral and pelvic pain were fairly well controlled. Neck and leg pain and pain mediated by the celiac plexus were not as well controlled by the intrathecal injection of morphine. The only significant complication was collection of cerebrospinal fluid around three reservoirs. Using this technique, narcotic concentration and frequency of administration can be easily altered to provide a safe but effective dose. Lumbar administration appears to block pain from lumbar and sacral dermatomes without the sedating and mood-altering effects of systemic narcotics.

The deficiencies of cranial computed tomography in the evaluation of craniocerebral injury may be categorized as: problems with the patient (cervical spine injury, motion artifact, airway control, head tilt, metallic foreign bodies); the incomplete scan; failure to determine the attenuation coefficient; failure to perform contrast enhancement; and failure to perform cerebral angiography. Increased awareness of these shortcomings of computed tomography and the selected use of cerebral angiography will ensure more accurate detection of the various abnormalities encountered in traumatic pathology.

A 9-week-old infant manifested continuous vomiting for 1 week accompanied by a tense fontanel, "sun setting" of the eyes, frequent opisthotonos, and hypertonicity. The head circumference was at the 50th percentile. Computerized tomography (CT) revealed acute hydrocephalus and a posterior fossa subdural hematoma. The brain stem and cerebellum were of greater density (54 Hounsfield units) than normal cerebral white matter (42 Hounsfield units) whereas the subdural hematoma was the same density as normal cerebral white matter ("isodense"). The cerebellum and brain stem became enhanced by contrast (68 Hounsfield units), but no enhancement occurred in the cerebral white matter or subdural hematoma. A shunt followed by occipital craniectomy resolved both the hydrocephalus and subdural hematoma. Repeat CT scan 15 days postoperatively disclosed continuing higher density of the cerebellum and brain stem (60 Hounsfield units) relative to cerebral white matter. Increased density of the infantile cerebellum has been noted previously but not to the same extent as in this patient.

The radiographic evaluation of a spectrum of vascular cerebral damage is presented, ranging from simple porencephaly to the most severe form, classic hydranencephaly. With a combination of clinical materal and computed tomography, it is possible in most cases to arrive at a specific diagnosis of hydranencephaly or severe bilateral porencephaly. Pictorially similar entities, such as massive congenital subdural hematomas or hygromas, alobar holoprosencephaly, massive hydrocephalus, and massive postanoxic or infective encephalopathies, are discussed.

Five patients who were involved in motor vehicle accidents sustained indirect, nonpenetrating carotid artery injuries leading to cerebral infarction. Four patients were conscious when a severe lateralized neurological deficit developed three to 12 hours after injury indicating the presence of a vascular injury and not a mass lesion. In 3 patients with occlusion of the main stem middle cerebral artery, computed tomographic (CT) scans performed between 1 and 7 hours after the onset of the ischemic signs were normal, but all scans performed after 11 or more hours revealed progressive edema in a vascular distribution leading to a midline shift. The fifth patient had a severe diffuse brain injury and no apparent clinical pattern of a posttraumatic vascular complication. Sequential changes on the CT scans similar to those of the other patients led to the proper diagnosis of vascular injury; this was later confirmed by arteriography. Indirect, nonpenetrating injury to the carotid artery should be suspected in the presence of the typical clinical pattern or when serial CT scans show the evolution of progressive edema in a distribution atypical for traumatic contusion.

Serial phrenic nerve conduction studies in 3 patients with high cervical cord injuries have demonstrated a pattern of function that changes with time. Nerves may be responsive initially and may then become unresponsive only to have responses reappear at a later date. Before a final decision is made about phrenic nerve viability prior to diaphragm pacing, serial studies should be carried out for at least 6 weeks postinjury on initially responsive nerves, and for at least 2 years postinjury on nonresponsive nerves or those with a changing functional pattern.

Here we report on a boy who died at 16 1/2 months with hemihypertrophy, eye abnormalities, macrodactyly, hamartomas, pigmented nevi, cerebral involvement, and other anomalies compatible with the Proteus syndrome. In addition, he also had abnormalities previously unreported in the Proteus syndrome including craniosynostosis and complex congenital heart defects. He seems to represent an extremely severe form of the Proteus syndrome and expands the already broad range of the phenotype.

Five hundred and forty-six patients in a consecutive series of 1,601 patients with craniocerebral trauma had computed tomography. One hundred and ninety-six patients had a follow-up CT scan. Thirteen patients (6.6%) developed apparently "silent" subdural hygromas of delayed evolution noted from six to 46 days after injury (average 22 days). Three of 10 patients (30%) improved after operation. No patient with a severe cerebral deficit (decortication or decerebration) improved. The three unoperated hygromas and the six that persisted after operation tended to resolve spontaneously. The infrequent and modest improvement following surgical treatment and the tendency to spontaneous resolution suggest that operation may be unnecessary in many patients with posttraumatic subdural hygroma of delayed evolution.

A child with 46,XY, 17q+ chromosome aberration and unusual skeletal abnormalities had the presenting symptom of respiratory arrest after a fall and minor head trauma. He exhibited proportionate short stature, peculiar facies with antimongoloid slant, simian creases, postaxial hexadactyly, metatarsus adductus deformity, and anomalous penoscrotal configuration. Delayed speech and mild mental retardation were also present. Atlantoaxial dislocation secondary to odontoid process hypoplasia was demonstrated. Additional skeletal abnormalities included dysplastic changes in the first and fourth metacarpals, the middle phalanx of the second finger, and hypoplasia of the first metatarsal, with medial insertion of the great toe. Treatment consisted of halo jacket cast and fusion of the occiput to C1, C2, and C3. Early detection and preventive surgery for atlantoaxial dislocation is necessary to prevent neurological deficit and possibly death by respiratory failure.

Rupture of a cerebral aneurysm during angiography, with confirmation by computed tomography (CT), is described. A review of 30 additional reported cases demonstrates no unusual profiles, with the exception of the predominance of female patients (71%), and the presence of pre-angiographic arterial hypertension. Experimental and clinical evidence increasingly suggests that intravascular pressures are transiently elevated during cerebral angiography. These changes may be enhanced by increased flow rates of contrast media, smaller diameters of the catheters, and the presence of intracranial arterial spasm, the latter presenting as a very prominent feature in intra-angiographic arterial rupture. However, direct evidence of elevation of the intra-aneurysmal pressure has not been documented, and may have occurred in only a portion of the cases.

Retrospective analysis of 200 cases of documented head trauma demonstrated an accuracy approaching 100% in the diagnosis of intra- and extracerebral collections of blood. Caution must be exercised in the evaluation of trauma 1 to 5 weeks old, since subdural hematomas have the same density as normal brain tissue, and angiography may be necessary. The clinical diagnosis of brainstem contusion is associated with a remarkably high level (54%) of surgically correctable lesions. The use of computed tomography in the evaluation of other traumatic intracranial lesions is discussed.